Two trials met the inclusion criteria. One compared 2% ketanserin ointment in polyethylene glycol (PEG) with PEG alone, used twice a day by 40 participants with arterial leg ulcers, for eight weeks or until healing, whichever was sooner. One compared topical application of blood-derived concentrated growth factor (CGF) with standard dressing (polyurethane film or foam); both applied weekly for six weeks by 61 participants with non-healing ulcers (venous, diabetic arterial, neuropathic, traumatic, or vasculitic). Both trials were small, reported results inadequately, and were of low methodological quality. Short follow-up times (six and eight weeks) meant it would be difficult to capture sufficient healing events to allow us to make comparisons between treatments. One trial demonstrated accelerated wound healing in the ketanserin group compared with the control group. In the trial that compared CGF with standard dressings, the number of participants with diabetic arterial ulcers were only reported in the CGF group (9/31), and the number of participants with diabetic arterial ulcers and their data were not reported separately for the standard dressing group. In the CGF group, 66.6% (6/9) of diabetic arterial ulcers showed more than a 50% decrease in ulcer size compared to 6.7% (2/30) of non-healing ulcers treated with standard dressing. We assessed this as very-low certainty evidence due to the small number of studies and arterial ulcer participants, inadequate reporting of methodology and data, and short follow-up period. Only one trial reported side effects (complications), stating that no participant experienced these during follow-up (six weeks, low-certainty evidence). It should also be noted that ketanserin is not licensed in all countries for use in humans. Neither study reported time to ulcer healing, patient satisfaction or quality of life. There is insufficient evidence to determine whether the choice of topical agent or dressing affects the healing of arterial leg ulcers.
We identified one RCT that involved 40 participants, and addressed the timing of surgery for people with recently symptomatic carotid artery stenosis. It compared very early surgery with surgery performed after 14 days of the last symptomatic event. The overall quality of the evidence was very low, due to the small number of participants from only one trial, and missing outcome data. We found no statistically significant difference between the effects of very early or delayed surgery in reducing the combined risk of stroke and death within 30 days of surgery (risk ratio (RR) 3.32; confidence interval (CI) 0.38 to 29.23; very low-quality evidence), or the combined risk of perioperative death and stroke (RR 0.47; CI 0.14 to 1.58; very low-quality evidence). To date, no results are available to confirm the optimal timing for surgery. There is currently no high-quality evidence available to support either very early or delayed cerebral revascularization after a recent ischemic stroke. Hence, further randomized trials to identify which patients should undergo very urgent revascularization are needed. Future studies should stratify participants by age group, sex, grade of ischemia, and degree of stenosis. Currently, there is one ongoing RCT that is examining the timing of cerebral revascularization.
We included 13 studies with a total of 721 participants in the review. The studies were observational, 12 studies had only one relevant treatment arm and no control and for the one study with a control arm, very few details were given. The risk of bias was high and the certainty of evidence was graded as very low for all outcomes. Due to heterogeneity of data, meta-analysis was not performed and therefore the data were synthesised via a narrative summary. The evidence for benefit derived from PN was very low for survival and quality of life. All the studies measured overall survival and 636 (88%) of participants were deceased at the end of the study. However there were varying definitions of overall survival that yielded median survival intervals between 15 to 155 days (range three to 1278 days). Three studies used validated measures of quality of life. The results from assessment of quality of life were equivocal; one study reported improvements up until three months and two studies reported approximately similar numbers of participants with improvements and deterioration. Different quality of life scales were used in each of the studies and quality of life was measured at different time points. Due to the very low certainty of the evidence, we are very uncertain about the adverse events related to PN use. Adverse events were measured by nine studies and data for individual participants could be extracted from eight studies. This revealed that 32 of 260 (12%) patients developed a central venous catheter infection or were hospitalised because of complications related to PN. We are very uncertain whether HPN improves survival or quality of life in people with MBO as the certainty of evidence was very low for both outcomes. As the evidence base is limited and at high risk of bias, further higher-quality prospective studies are required.
We included 25 RCTs involving 4788 participants. Six of twelve trials showed that written information significantly improved knowledge about a medicine, compared with no written information. The inability to combine results means we cannot conclude whether written information was effective for increasing knowledge. The results for attitudinal and behavioural outcomes were mixed. No studies showed an adverse effect of medicines information. The combined evidence was not strong enough to say whether written medicines information is effective in changing knowledge, attitudes and behaviours related to medicine taking. There is some evidence that written information can improve knowledge. The trials were generally of poor quality, which reduces confidence in the results. Trials examining the effects of written information need to be better designed and use consistent and validated outcome measures. Trials should evaluate internet-based medicines information. It is imperative that written medicines information be based on best practice for its information design and content, which could improve its effectiveness in helping people to use medicines appropriately.
We conducted this review in accordance with the published Cochrane protocol. Two randomised clinical trials with 104 participants fulfilled our inclusion criteria. Both trials were at high risk of bias (for outcomes other than overall survival), and we rated the evidence as moderate quality for overall survival and low quality for all other outcomes. One trial compared combined extrapleural pneumonectomy (EPP) plus neoadjuvant platinum-based chemotherapy plus postoperative high-dose hemithoracic radiotherapy with combined EPP plus platinum-based chemotherapy. The other trial compared EPP plus postoperative hemithoracic radiotherapy with standard (non-radical) therapy alone following platinum-based chemotherapy (patients in the standard therapy arm received continued oncological management according to local policy, which could include further chemotherapy or palliative radiotherapy). For the first trial, median overall survival calculated from registration was 20.8 months (95% confidence interval (CI) 14.4 to 27.8) in the no-radiotherapy group and 19.3 months (95% CI 11.5 to 21.8) in the radiotherapy group. For the second trial, median overall survival was 14.4 months (95% CI 5.3 to 18.7) for patients allocated to EPP and 19.5 months (95% CI 13.4 to time not yet reached) for patients randomised to standard non-radical therapy. In the second trial, 12 serious adverse events were reported during the study period: ten in the EPP group and two in the non-radical therapy group. Overall health-related quality of life scores were not different between the two arms in either study. We could not perform a meta-analysis of the two included trials due to clinical heterogeneity. We also identified three ongoing trials evaluating the topic of our review. The overall strength of the evidence gathered in this review is low and there is a lack of available evidence to support the use of radical multimodality therapy in routine clinical practice (particularly as one trial suggests greater harm). Given the added cost of multimodality treatment and the possible increase in risk of adverse effects, the lack of evidence of their effectiveness probably means that these interventions should currently be limited to clinical trials alone.
Two cluster-randomized controlled trials (RCTs) (involving a total of 5455 women) met the inclusion criteria. The two included trials measured the effectiveness of the intervention in different ways, which meant that meta-analysis of the results was not possible. The overall quality of the two studies, as assessed using the GRADE approach, was low, with high risk of detection and attrition bias in both included trials. One trial (432 women enrolled) conducted in Canada was judged of low methodological quality. This trial did not report on any of the review's pre-specified primary outcomes and the secondary outcomes reported results only as P values. Moreover, losses to follow-up were high (34%, 147 out of 432 women initially enrolled). The authors concluded that prenatal education can effectively change pregnant women's behavior as it increased pet, personal and food hygiene. The second trial conducted in France was also judged of low methodological quality. Losses to follow-up were also high (44.5%, 2233 out of 5023 women initially enrolled) and differential (40% in the intervention group and 52% in the control group). The authors concluded that prenatal education for congenital toxoplasmoses has a significant effect on improving women's knowledge, whereas it has no effect on changing women's behavior. In this trial 17/3949 pregnant women seroconverted for toxoplasmosis: 13/2591 (0.5%) in the intervention group and 4/1358 (0.3%) in the control group. The rate of seroconversion detected during the study did not differ between groups (risk ratio (RR) 1.70, 95% confidence interval (CI) 0.56 to 5.21; participants = 3949; studies = one, low quality evidence). The number of events was too small to reach conclusions about the effect of prenatal education on seroconversion rate during pregnancy. No other randomized trials on the effect of prenatal education on congenital toxoplasmosis rate, or toxoplasmosis seroconversion rate during pregnancy were detected. Even though primary prevention of congenital toxoplasmosis is considered a desirable intervention, given the lack of related risks compared to secondary and tertiary prevention, its effectiveness has not been adequately evaluated. There is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis even though evidence from observational studies suggests it is. Given the lack of good evidence supporting prenatal education for congenital toxoplasmosis prevention, further RCTs are needed to confirm any potential benefits and to further quantify the impact of different sets of educational intervention.
Of 1777 potential studies evaluated, only two Randomized Control Trials (123 patients) were included. ß-interferon treatment compared to placebo did not show differences regarding the proportion of patients with progression of the disease (RR 0.89, 95% CI 0.55 to1.43), and it was associated with a greater frequency of treatment-related adverse events (RR 1.90, 95% CI 1.45-2.48). One of the trials evaluated the MRI secondary outcome pre-specified in the protocol. This trial showed that at two years the numbers of active lesions on brain MRI scan in ß-interferon arm were significantly lower than in placebo arm (weighted mean difference -1.3, 95% CI -2.15 to -0.45, P = 0.003); also, the number of participants with active lesions was significantly higher in placebo arm vs. ß-interferon arm at two years (RR 0.43, 95% CI 0.22 to 0.86, P = 0.02). Limited data on the effect of ß-interferon treatment on PPMS exists. Only two single-centre placebo controlled trials of interferon beta have been done. Based on this review, the included studies showed that ß-interferon treatment was not associated with reduced disability progression in PPMS patients. However, the trial population was too small to allow definitive conclusions on the efficacy of ß-interferon therapy in PPMS patients. Larger research studies need to be done in patients with PPMS in order to clarify whether ß-interferon is effective in this population.
We included two randomised controlled trials (three reports) with 1674 participants, with mean age between 64.1 and 67.8 years. Follow-up ranged from 2 years to mean 4.3 years. For primary outcome measures, effect estimates from a single study showed uncertainty for the effect of NP-guided treatment on cardiovascular mortality in patients with cardiovascular risk factors and without heart failure (RR 0.33, 95% CI 0.04 to 3.17; 1 study; 300 participants; low-quality evidence). Pooled analysis demonstrated that in comparison to standard care, NP-guided treatment probably reduces the risk of cardiovascular hospitalisation (RR 0.52, 95% CI 0.40 to 0.68; 2 studies; 1674 participants; moderate-quality evidence). This corresponds to a risk of 163 per 1000 in the control group and 85 (95% CI 65 to 111) per 1000 in the NP-guided treatment group. When secondary outcome measures were evaluated, evidence from a pooled analysis showed uncertainty for the effect of NP-guided treatment on all-cause mortality (RR 0.90, 95% CI 0.60 to 1.35; 2 studies; 1354 participants; low-quality evidence). Pooled analysis indicates that NP-guided treatment probably reduces the risk of all-cause hospitalisation (RR 0.83, 95% CI 0.75 to 0.92; 2 studies; 1354 participants; moderate-quality evidence). This corresponds to a risk of 601 per 1000 in the control group and 499 (95% CI 457 to 553) per 1000 in the NP-guided treatment group. The effect estimate from a single study indicates that NP-guided treatment reduced the risk of ventricular dysfunction (RR 0.61, 95% CI 0.41 to 0.91; 1374 participants; high-quality evidence). The risk in this study's control group was 87 per 1000, compared with 53 (95% CI 36 to 79) per 1000 with NP-guided treatment. Results from the same study show that NP-guided treatment does not affect change in NP level at the end of follow-up, relative to standard care (MD -4.06 pg/mL, 95% CI -15.07 to 6.95; 1 study; 1374 participants; moderate-quality evidence). This review shows that NP-guided treatment is likely to reduce ventricular dysfunction and cardiovascular and all-cause hospitalisation for patients who have cardiovascular risk factors and who do not have heart failure. Effects on mortality and natriuretic peptide levels are less certain. Neither of the included studies were powered to evaluate mortality. Available evidence shows uncertainty regarding the effects of NP-guided treatment on both cardiovascular mortality and all-cause mortality; very low event numbers resulted in a high degree of imprecision in these effect estimates. Evidence also shows that NP-guided treatment may not affect NP level at the end of follow-up. As both trials included in our review were pragmatic studies, non-blinding of patients and practices may have biased results towards a finding of equivalence. Further studies with more adequately powered sample sizes and longer duration of follow-up are required to evaluate the effect of NP-guided treatment on mortality. As two trials are ongoing, one of which is a large multi-centre trial, it is hoped that future iterations of this review will benefit from larger sample sizes across a wider geographical area.
Three trials involving a total of 404, mainly female and older, people with displaced fractures of the distal radius were included. These failed to assess functional outcome, and only one trial reported on complications. One trial found no statistically significant differences between mechanical reduction using finger trap traction and manual reduction in anatomical outcomes. All participants of this trial were given intravenous regional anaesthesia. One trial compared a novel method of manual reduction where the non-anaesthetised patient actively provided counter-traction versus traditional manual reduction under intravenous regional anaesthesia. While participants of the novel method group suffered more, yet not intolerable, pain during the reduction procedure, the latter was shorter in duration. No differences in anatomical outcome were detected. The third study compared mechanical reduction involving a special device without anaesthesia versus manual reduction under haematoma block (local anaesthesia). Less pain during the reduction procedure was recorded for the mechanical traction group. Both methods yielded similar radiological results. Fewer participants of the mechanical traction group had signs of neurological impairment, mainly finger numbness, at five weeks but this difference was not statistically significant by one year. There was insufficient evidence from comparisons tested within randomised controlled trials to establish the relative effectiveness of different methods of closed reduction used in the treatment of displaced fractures of the distal radius in adults.
Twenty-two eligible randomised trials were identified, of which 11 were crossover trials. The trials included 1099 women with 673 receiving an adrenergic drug (phenylpropanolamine in 11 trials, midodrine in two, norepinephrine in three, clenbuterol in another three, terbutaline in one, eskornade in one and Ro 115-1240 in one). No trials included men. The limited evidence suggested that an adrenergic agonist drug is better than placebo in reducing the number of pad changes and incontinence episodes, as well as improving subjective symptoms. In two small trials, the drugs also appeared to be better than pelvic floor muscle training, possibly reflecting relative acceptability of the treatments to women but perhaps due to differential withdrawal of women from the trial groups. There was not enough evidence to evaluate the use of higher compared to lower doses of adrenergic agonists nor the relative merits of an adrenergic agonist drug compared with oestrogen, whether used alone or in combination. Over a quarter of women reported adverse effects. There were similar numbers of adverse effects with adrenergics, placebo or alternative drug treatment. However, when these were due to recognised adrenergic stimulation (insomnia, restlessness and vasomotor stimulation) they were only severe enough to stop treatment in 4% of women. There was weak evidence to suggest that use of an adrenergic agonist was better than placebo treatment. There was not enough evidence to assess the effects of adrenergic agonists when compared to or combined with other treatments. Further larger trials are needed to identify when adrenergics may be useful. Patients using adrenergic agonists may suffer from minor side effects, which sometimes cause them to stop treatment. Rare but serious side effects, such as cardiac arrhythmias and hypertension, have been reported.
Six studies met the inclusion criteria, including three RCTs, two cluster-RCTs and one ITS. All were conducted in the USA and comprised targeted mass media interventions for people of African descent (four studies), Spanish-language dominant Latino immigrants (one study), and Chinese immigrants (one study). The two latter studies offered the intervention in the participants’ first language (Spanish, Cantonese, or Mandarin). Three interventions targeted towards women only, one pregnant women specifically. We judged all studies as being at unclear risk of bias in at least one domain and three studies as being at high risk of bias in at least one domain. We categorised the findings into three comparisons. The first comparison examined mass media interventions targeted at ethnic minorities versus an equivalent mass media intervention intended for the general population. The one study in this category (255 participants of African decent) found little or no difference in effect on self-reported behavioural change for smoking and only small differences in attitudes to change between participants who were given a culturally specific smoking cessation booklet versus a booklet intended for the general population. We are uncertain about the effect estimates, as assessed by the GRADE methodology (very low quality evidence of effect). No study provided data for indicators of behavioural change or adverse effects. The second comparison assessed targeted mass media interventions versus no intervention. One study (154 participants of African decent) reported effects for our primary outcomes. Participants in the intervention group had access to 12 one-hour live programmes on cable TV and received print material over three months regarding nutrition and physical activity to improve health and weight control. Change in body mass index (BMI) was comparable between groups 12 months after the baseline (low quality evidence). Scores on a food habits (fat behaviours) and total leisure activity scores changed favourably for the intervention group (very low quality evidence). Two other studies exposed entire populations in geographical areas to radio advertisements targeted towards African American communities. Authors presented effects on two of our secondary outcomes, use of health promotion services and project costs. The campaign message was to call smoking quit lines. The outcome was the number of calls received. After one year, one study reported 18 calls per estimated 10,000 targeted smokers from the intervention communities (estimated target population 310,500 persons), compared to 0.2 calls per estimated 10,000 targeted smokers from the control communities (estimated target population 331,400 persons) (moderate quality evidence). The ITS study also reported an increase in the number of calls from the target population during campaigns (low quality evidence). The proportion of African American callers increased in both studies (low to very low quality evidence). No study provided data on knowledge and attitudes for change and adverse effects. Information on costs were sparse. The third comparison assessed targeted mass media interventions versus a mass media intervention plus personalised content. Findings are based on three studies (1361 participants). Participants in these comparison groups received personal feedback. Two of the studies recorded weight changes over time. Neither found significant differences between the groups (low quality evidence). Evidence on behavioural changes, and knowledge and attitudes typically found some effects in favour of receiving personalised content or no significant differences between groups (very low quality evidence). No study provided data on adverse effects. Information on costs were sparse. The available evidence is inadequate for understanding whether mass media interventions targeted toward ethnic minority populations are more effective in changing health behaviours than mass media interventions intended for the population at large. When compared to no intervention, a targeted mass media intervention may increase the number of calls to smoking quit line, but the effect on health behaviours is unclear. These studies could not distinguish the impact of different components, for instance the effect of hearing a message regarding behavioural change, the cultural adaptation to the ethnic minority group, or increase reach to the target group through more appropriate mass media channels. New studies should explore targeted interventions for ethnic minorities with a first language other than the dominant language in their resident country, as well as directly compare targeted versus general population mass media interventions.
We identified six new trials for this update. In total, the evidence for this review rests on 14 trials (805 participants). Music listening was the main intervention used, and 13 of the studies did not include a trained music therapist. Results indicated that music listening may be beneficial for anxiety reduction in mechanically ventilated patients. Specifically, music listening resulted, on average, in an anxiety reduction that was 1.11 standard deviation units greater (95% CI -1.75 to -0.47, P = 0.0006) than in the standard care group. This is considered a large and clinically significant effect. Findings indicated that listening to music consistently reduced respiratory rate and systolic blood pressure, suggesting a relaxation response. Furthermore, one large-scale study reported greater reductions in sedative and analgesic intake in the music listening group compared to the control group, and two other studies reported trends for reduction in sedative and analgesic intake for the music group. One study found significantly higher sedation scores in the music listening group compared to the control group. No strong evidence was found for reduction in diastolic blood pressure and mean arterial pressure. Furthermore, inconsistent results were found for reduction in heart rate with seven studies reporting greater heart rate reductions in the music listening group and one study a slightly greater reduction in the control group. Music listening did not improve oxygen saturation levels. Four studies examined the effects of music listening on hormone levels but the results were mixed and no conclusions could be drawn. No strong evidence was found for an effect of music listening on mortality rate but this evidence rested on only two trials. Most trials were assessed to be at high risk of bias because of lack of blinding. Blinding of outcome assessors is often impossible in music therapy and music medicine studies that use subjective outcomes, unless the music intervention is compared to another treatment intervention. Because of the high risk of bias, these results need to be interpreted with caution. No studies could be found that examined the effects of music interventions on quality of life, patient satisfaction, post-discharge outcomes, or cost-effectiveness. No adverse events were identified. This updated systematic review indicates that music listening may have a beneficial effect on anxiety in mechanically ventilated patients. These findings are consistent with the findings of three other Cochrane systematic reviews on the use of music interventions for anxiety reduction in medical patients. The review furthermore suggests that music listening consistently reduces respiratory rate and systolic blood pressure. Finally, results indicate a possible beneficial impact on the consumption of sedatives and analgesics. Therefore, we conclude that music interventions may provide a viable anxiety management option to mechanically ventilated patients.
We included in this updated review 33 RCTs with 3946 participants. Twenty new trials with 2780 participants had been completed since the previous review. Outcome data were available for up to 22 trials (2865 participants) that compared acupuncture with any control (open control or sham acupuncture) but for only six trials (668 participants) that compared acupuncture with sham acupuncture control. We downgraded the evidence to low or very low quality because of risk of bias in included studies, inconsistency in the acupuncture intervention and outcome measures, and imprecision in effect estimates. When compared with any control (11 trials with 1582 participants), findings of lower odds of death or dependency at the end of follow-up and over the long term (≥ three months) in the acupuncture group were uncertain (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.46 to 0.79; very low-quality evidence; and OR 0.67, 95% CI 0.53 to 0.85; eight trials with 1436 participants; very low-quality evidence, respectively) and were not confirmed by trials comparing acupuncture with sham acupuncture (OR 0.71, 95% CI 0.43 to 1.18; low-quality evidence; and OR 0.67, 95% CI 0.40 to 1.12; low-quality evidence, respectively). In trials comparing acupuncture with any control, findings that acupuncture was associated with increases in the global neurological deficit score and in the motor function score were uncertain (standardized mean difference [SMD] 0.84, 95% CI 0.36 to 1.32; 12 trials with 1086 participants; very low-quality evidence; and SMD 1.08, 95% CI 0.45 to 1.71; 11 trials with 895 participants; very low-quality evidence). These findings were not confirmed in trials comparing acupuncture with sham acupuncture (SMD 0.01, 95% CI -0.55 to 0.57; low-quality evidence; and SMD 0.10, 95% CI -0.38 to 0.17; low-quality evidence, respectively). Trials comparing acupuncture with any control have reported little or no difference in death or institutional care at the end of follow-up (OR 0.78, 95% CI 0.54 to 1.12; five trials with 1120 participants; low-quality evidence), death within the first two weeks (OR 0.91, 95% CI 0.33 to 2.55; 18 trials with 1612 participants; low-quality evidence), or death at the end of follow-up (OR 1.08, 95% CI 0.74 to 1.58; 22 trials with 2865 participants; low-quality evidence). The incidence of adverse events (eg, pain, dizziness, faint) in the acupuncture arms of open and sham control trials was 6.2% (64/1037 participants), and 1.4% of these (14/1037 participants) discontinued acupuncture. When acupuncture was compared with sham acupuncture, findings for adverse events were uncertain (OR 0.58, 95% CI 0.29 to 1.16; five trials with 576 participants; low-quality evidence). This updated review indicates that apparently improved outcomes with acupuncture in acute stroke are confounded by the risk of bias related to use of open controls. Adverse events related to acupuncture were reported to be minor and usually did not result in stopping treatment. Future studies are needed to confirm or refute any effects of acupuncture in acute stroke. Trials should clearly report the method of randomization, concealment of allocation, and whether blinding of participants, personnel, and outcome assessors was achieved, while paying close attention to the effects of acupuncture on long-term functional outcomes.
The search identified 14 new RCTs since the last published version of this review, resulting in 16 included RCTs involving 2091 high-risk women for this updated review. They evaluated three types of dopamine agonists: cabergoline, quinagolide and bromocriptine. When compared with placebo or no intervention, dopamine agonists seemed effective in the prevention of moderate or severe OHSS (OR 0.27, 95% CI 0.19 to 0.39; 1022 participants; 8 studies; I2 = 0%; moderate quality evidence). This suggests that if 29% of women undergoing ART experience moderate or severe OHSS, the use of dopamine agonists will lower this to 7% to 14% of women. There was no evidence of a difference in live birth rate, clinical pregnancy rate, multiple pregnancy rate or miscarriage rate (very low to moderate quality evidence). However, taking dopamine agonists (especially quinagolide) may increase the incidence of adverse events such as gastrointestinal adverse effects (OR 4.54, 95% CI 1.49 to 13.84; 264 participants; 2 studies; I2 = 49%, very low quality evidence). When we compared dopamine agonist plus co-intervention with co-intervention, there was no evidence of a difference in the outcomes of moderate or severe OHSS, live birth rate, clinical pregnancy rate, miscarriage rate or adverse events. The co-interventions were hydroxyethyl starch (two RCTs) and albumin (one RCT). Cabergoline was associated with a lower risk of moderate or severe OHSS compared with human albumin (OR 0.21, 95% CI 0.12 to 0.38; 296 participants; 3 studies; I2 = 72%). However, there was no evidence of a difference between cabergoline and hydroxyethyl starch, coasting (withholding any more ovarian stimulation for a few days) or prednisolone. There was an increased clinical pregnancy rate in the cabergoline group when cabergoline was compared with coasting (OR 2.65, 95% CI 1.13 to 6.21; 120 participants; 2 studies; I2 = 0%). In other respects, there was no evidence of a difference in clinical pregnancy rate, multiple pregnancy rate or miscarriage rate between cabergoline and other active interventions. The quality of the evidence between dopamine agonist and placebo or no intervention ranged from very low to moderate, mainly due to poor reporting of study methods (mostly a lack of details on randomisation or blinding) and serious imprecision for some comparisons. Dopamine agonists appear to reduce the incidence of moderate or severe OHSS in women at high risk of OHSS (moderate quality evidence). If a fresh embryo transfer is performed, the use of dopamine agonists does not affect the pregnancy outcome (live birth rate, clinical pregnancy rate and miscarriage rate) (very low to moderate quality evidence). However, dopamine agonists might increase the risk of adverse events, such as gastrointestinal symptoms. Further research should focus on dose-finding, comparisons with other effective treatments and consideration of combination treatments. Therefore, large, well-designed and well-executed RCTs that involve more clinical endpoints (e.g., live birth rate) are necessary to further evaluate the role of dopamine agonists in OHSS prevention.
Seven studies met our eligibility criteria. All were randomized controlled trials; six assigned clusters and one randomized individuals. Sample sizes for the cluster-randomized trials ranged from 2157 to 15,614; the number of clusters ranged from 18 to 70. Four trials took place in African countries, two in the USA, and one in England. Three were based mainly in schools, two were in community settings, one took place during military training, and one was clinic-based. Five studies provided data on pregnancy, either from pregnancy tests or national records of abortions and live births. Four trials assessed the incidence or prevalence of HIV and HSV-2. Three trials examined other STI. The trials showed or reported no significant difference between study groups for pregnancy or HIV, but favorable effects were evident for some STI. Two showed a lower incidence of HSV-2 for the behavioral-intervention group compared to the usual-care group, with reported adjusted rate ratios (ARR) of 0.65 (95% CI 0.43 to 0.97) and 0.67 (95% CI 0.47 to 0.97), while HIV did not differ significantly. One also reported lower syphilis incidence and gonorrhea prevalence for the behavioral intervention plus STI management compared to the usual-care group. The reported ARR were 0.58 (95% CI 0.35 to 0.96) and 0.28 (95% CI 0.11 to 0.70), respectively. Another study reported a negative effect on gonorrhea for young women in the intervention group versus the control group (ARR 1.93; 95% CI 1.01 to 3.71). The difference occurred among those with only one year of the intervention. We found few studies and little clinical evidence of effectiveness for interventions promoting condom use for dual protection. We did not find favorable results for pregnancy or HIV, and only found some for other STI. The overall quality of evidence was moderate to low; losses to follow up were high. Effective interventions for improving condom use are needed to prevent pregnancy and HIV/STI transmission. Interventions should be feasible for resource-limited settings and tested using valid and reliable outcome measures.
Of the 2077 references identified, 24 trials were included in this review. For electrostimulation compared with no treatment this review found that electrostimulation improved some aspects of functional motor ability and some aspects of motor impairment and normality of movement. In addition, there was a significant difference in favour of no treatment compared with electrostimulation for an aspect of functional motor ability. For electrostimulation compared with placebo this review found that electrostimulation improved an aspect of functional motor ability. For electrostimulation compared with conventional physical therapy this review found that electrostimulation improved an aspect of motor impairment. There were no statistically significant differences between electrostimulation and control treatment for all other outcomes. However, these results need to be interpreted with reference to the following: (1) the majority of analyses only contained one trial; (2) variation was found between included trials in time after stroke, level of functional deficit, and dose of electrostimulation; and (3) the possibility of selection and detection bias in the majority of included trials. At present, there are insufficient robust data to inform clinical use of electrostimulation for neuromuscular re-training. Research is needed to address specific questions about the type of electrostimulation that might be most effective, in what dose and at what time after stroke.
Two trials with a total of 529 patients met the inclusion criteria. Patients fulfilling the American Rheumatism Association 1987 RA diagnostic criteria were randomized to receive either infliximab 1mg/kg (with and without MTX), 3mg/kg(with and without MTX) , 10mg/kg of infliximab (with and without MTX) or placebo infusion plus MTX. Infusions were given every 4 or 8 weeks. After 6 months ACR 20, ACR 50 and ACR 70 response rates were significantly improved in all infliximab doses compared to control. The number needed to treat with infliximab to achieve an ACR 20, 50 or 70 response in patients with refractory RA under specialist care ranged from 2.94-3.33 for ACR 20, 3.57-4.76 for ACR 50 and 5.88 -12.5 for ACR 70 depending on the dose (3mg/kg or 10mg/kg given either every 4 or 8 weeks). Total withdrawals and withdrawals due to lack of efficacy were lower for all doses of infliximab versus controls. Withdrawals for adverse events and withdrawals for other reasons were not statistically significantly different for those receiving infliximab from control. Treatment with infliximab for 6 and 12 months significantly reduces RA disease activity and appeared to have an acceptable safety profile in these trials. Total radiographic scores improved, fewer patients showed radiographic progression, and more patients showed radiographic improvement with infliximab treatment at 12 months compared to controls. However, only 2 trials met the inclusion criteria, and these results are largely driven by the largest trial. The available efficacy and toxicity data is relatively short-term (6-12 months). In order to detect rare events that may be associated with infliximab, larger and longer term studies are required.
Fifteen trials met the inclusion criteria (2284 participants, 69% males, 16% children). They were conducted in disparate malaria endemic areas, with the earlier studies conducted in Thailand (five) and India (two), and the more recent studies (eight) spread across three continents (South America, Africa, Asia). The 15 studies involved 41 treatment arms, 12 different drugs, and 28 different treatment regimens. Two studies examined P. vivax. Three-day azithromycin (AZ) monotherapy did not perform well for P. vivax or P. falciparum (Thailand: P. vivax failure rate 0.5 g daily, 56%, 95% CI 31 to 78. India: P. vivax failure rate 1 g daily,12%, 95% CI 7 to 21; P. falciparum failure rate 1 g daily, 64%, 95% CI 36 to 86.) A 1 g azithromycin and 0.6 g chloroquine combination daily for three days for uncomplicated P. falciparum infections was associated with increased treatment failure in India and Indonesia compared with the combination of sulphadoxine-pyrimethamine and chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67), and compared with the combination atovaquone-proguanil in a multicentre trial in Columbia and Surinam (RR 24.72, 95% CI 6.16 to 99.20). No increased risk of treatment failure was seen in two studies in Africa with mefloquine as the comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.96, P = 0.3); the pooled RR for PCR-corrected data for the combination versus mefloquine was 1.01, 95% CI 0.18 to 5.84 (P = 1.0). An increased treatment failure risk was seen when comparing azithromycin in a dose of 1.2 to 1.5 mg in combination with artesunate (200 mg per day for three days) with artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; PCR-corrected pooled RR 3.63, 95% CI 2.02 to 6.52). Serious adverse events and treatment discontinuation were similar across treatment arms. More adverse events were reported when comparing the 1 g azithromycin/ 0.6 g chloroquine combination with mefloquine (pooled RR 1.20, 95% CI 1.06 to 1.36) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to1.83). Currently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations. The available evidence suggests that azithromycin is a weak antimalarial with some appealing safety characteristics. Unless the ongoing dose, formulation and product optimisation process results in a universally efficacious product, or a specific niche application is identified that is complementary to the current scala of more efficacious antimalarial combinations, azithromycin's future for the treatment of malaria does not look promising.
We included two separate German studies involving a total of 518 participants. One study was undertaken in the inpatient treatment of schizophrenia and the other in the treatment of people newly diagnosed with depression in primary care. Regarding the primary outcomes, one study reported statistically significant increases in patient satisfaction, the other study did not. There was no evidence of effect on clinical outcomes or hospital readmission rates in either study. Regarding secondary outcomes, there was an indication that interventions to increase shared decision making increased doctor facilitation of patient involvement in decision making, and did not increase consultation times. Nor did the interventions increase patient compliance with treatment plans. Neither study reported any harms of the intervention. Definite conclusions cannot be drawn, however, on the basis of these two studies. No firm conclusions can be drawn at present about the effects of shared decision making interventions for people with mental health conditions. There is no evidence of harm, but there is an urgent need for further research in this area.
As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs, but this did not appear to affect the acceptability of treatment, based on trials from 1980 to 1990. However, currently danazol is not a usual or recommended treatment for HMB. There was no clear evidence of difference between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system and the oral contraceptive pill (OCP), but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. The evidence quality ranged from low to moderate, the main limitations being risk of bias and imprecision. NSAIDs reduce HMB when compared with placebo, but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, there was no clear evidence of a difference in efficacy between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCP or the older progesterone-releasing intrauterine system.
We included 23 studies, all of which enrolled adults with frequent episodic TTH. Twelve studies used the IHS diagnostic criteria or similar, six used the older classification of the Ad Hoc Committee, and five did not describe specific diagnostic criteria but generally excluded participants with migraines. Participants had moderate or severe pain at the start of treatment. While 8079 people with TTH participated in these studies, the numbers available for any analysis were lower than this because outcomes were inconsistently reported and because many participants received active comparators. None of the included studies were at low risk of bias across all domains considered, although for most studies and domains this was likely to be due to inadequate reporting rather than poor methods. We judged five studies to be at high risk of bias for incomplete outcome reporting, and seven due to small size. For the IHS preferred outcome of being pain free at two hours the NNT for paracetamol 1000 mg compared with placebo was 22 (95% confidence interval (CI) 15 to 40) in eight studies (5890 participants; high quality evidence), with no significant difference from placebo at one hour. The NNT was 10 (7.9 to 14) for pain-free or mild pain at two hours in five studies (5238 participants; high quality evidence). The use of rescue medication was lower with paracetamol 1000 mg than with placebo, with an NNTp to prevent an event of 7.8 (6.0 to 11) in six studies (1856 participants; moderate quality evidence). On limited data, the efficacy of paracetamol 500 mg to 650 mg was not superior to placebo, and paracetamol 1000 mg was not different from either ketoprofen 25 mg or ibuprofen 400 mg (low quality evidence). Adverse events were not different between paracetamol 1000 mg and placebo (RR 1.1 (0.94 to 1.3); 5605 participants; 11 studies; high quality evidence). Studies reported no serious adverse events. The quality of the evidence using GRADE comparing paracetamol 1000 mg with placebo was moderate to high. Where evidence was downgraded it was because a minority of studies reported the outcome. For comparisons of paracetamol 500 mg to 650 mg with placebo, and of paracetamol 1000 mg with active comparators, we downgraded the evidence to low quality or very low quality because of the small number of studies and events. Paracetamol 1000 mg provided a small benefit in terms of being pain free at two hours for people with frequent episodic TTH who have an acute headache of moderate or severe intensity.
Ten relevant RCTs with 675 participants are included in this review. All trials were double blind except one single blind. All studies had a run-in phase to confirm they did not respond to their initial antipsychotic treatment. The trials were published between 1980 and 2016. In most studies the methods of randomisation, allocation and blinding were poorly reported. In addition sample sizes were often small, limiting the overall quality of the evidence. Overall, no clear difference was found between groups in terms of the number of participants who showed clinically relevant response (RR 1.09, 95% CI 0.86 to 1.40, 9 RCTs, N = 533, low-quality evidence), or left the study early due to adverse effects (RR 1.63, 95% CI 0.52 to 5.07, very low quality evidence), or due to any reason (RR 1.30, 95% CI 0.89 to 1.90, 5 RCTs, N = 353, low-quality evidence). Similarly, no clear difference was found in general mental state as measured by PANSS total score change (MD −1.44, 95% CI −6.85 to 3.97, 3 RCTs, N = 258, very low quality evidence). At least one adverse effect was equivocal between groups (RR 0.91, 95% CI 0.55 to 1.50, 2 RCTs, N = 191, very low quality evidence). Data were not reported for time in hospital or quality-of-life outcomes. Finally, subgroup and sensitivity analyses did not show any effect on the primary outcome but these analyses were clearly underpowered. Current data do not show any clear differences between increasing or maintaining the antipsychotic dose for people with schizophrenia who do not respond to their initial antipsychotic treatment. Adverse effect reporting was limited and poor. There is an urgent need for further trials in order to determine the optional treatment strategy in such cases.
One parallel trial and 12 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 512 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias. We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67; P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, mean difference -0.58 (95% confidence interval -0.85 to -0.30; P < 0.0001); proportion of days with abdominal pain, mean difference -7.96% (95% confidence interval -12.97 to -2.94; P = 0.002); and fecal fat excretion, mean difference -11.79 g (95% confidence interval -17.42 to -6.15; P < 0.0001). Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency, mean difference -0.70 (95% confidence interval -0.90 to -0.50; P < 0.00001). There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed study that can answer these questions.
We identified and included five eligible trials with a total of 167 patients. The investigators administered various G-CSF preparations, at different doses and for different durations of time. Adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, but it was associated with a significantly reduced likelihood of lower extremity surgical interventions (RR 0.38; 95 % CI 0.21 to 0.70), including amputation (RR 0.41; 95 % CI 0.18 to 0.95). Moreover, providing G-CSF reduced the duration of hospital stay (MD -1.40 days; 95% CI -2.27 to -0.53 days), but did not significantly affect the duration of systemic antibiotic therapy (MD -0.27 days; 95% CI -1.30 to 0.77 days). The available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalisation. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.
Out of 14 717 citations, only one study met the inclusion criteria; an RCT conducted on homeless and high-risk youth between September 1998 and October 1999 in Portland, United States. Participants (n=351) were offered counselling and oral HIV testing and were randomised into face-to-face (n=187 participants) and telephone (n=167) notification groups. The telephone notification group had the option of receiving HIV test results either by telephone or face-to-face. Overall, only 48% (n=168) of participants received their HIV test results and post-test counselling. Significantly more participants received their HIV test results in the telephone notification group compared to the face-to-face notification group; 58% (n=106) vs. 37% (n=62) (p < 0.001). In the telephone notification group, the majority of participants who received their HIV test results did so by telephone (88%, n=93). The study could not offer information about the effectiveness of telephone HIV test notification with HIV-positive participants because only two youth tested positive and both were assigned to the face-to-face notification group. The study had a high risk of bias. We found only one eligible study. Although this study showed the use of the telephone for HIV test results notification was more effective than face-to-face delivery, it had a high-risk of bias. The study was conducted about 13 years ago in a high-income country, on a high-risk population, with low HIV prevalence, and the applicability of its results to other settings and contexts is unclear. The study did not provide information about telephone HIV test results notification of HIV positive people since none of the intervention group participants were HIV positive. We found no information about the acceptability of the intervention to patients’ and providers’, its economic outcomes or potential adverse effects. There is a need for robust evidence from various settings on the effectiveness of telephone use for HIV test results notification.
We included three new trials in this update, which brings the total to 14 included studies that compared hypnotherapy with 22 different control interventions. The studies included a total of 1926 participants. Studies were diverse and a single meta-analysis was not possible. We judged only one study to be at low risk of bias overall; we judged 10 studies to be at high risk of bias and three at unclear risk. Studies did not provide reliable evidence of a greater benefit from hypnotherapy compared with other interventions or no treatment for smoking cessation. Most individual studies did not find statistically significant differences in quit rates after six months or longer, and studies that did detect differences typically had methodological limitations. Pooling small groups of relatively comparable studies did not provide reliable evidence for a specific effect of hypnotherapy relative to controls. There was low certainty evidence, limited by imprecision and risk of bias, that showed no statistically significant difference between hypnotherapy and attention-matched behavioural treatments (RR 1.21, 95% CI 0.91 to 1.61; I2 = 36%; 6 studies, 957 participants). Results were similarly imprecise, and also limited by risk of bias, when comparing hypnotherapy to intensive behavioural interventions (not matched for contact time) (RR 0.93, 95% CI 0.47 to 1.82; I2 = 0%; 2 studies, 211 participants; very low certainty evidence). Results from one small study (40 participants) detected a statistically significant benefit of hypnotherapy compared to no intervention (RR 19.00, 95% CI 1.18 to 305.88), but this evidence was judged to be of very low certainty due to high risk of bias and imprecision. No significant differences were detected in comparisons of hypnotherapy with brief behavioural interventions (RR 0.98, 95% CI 0.57 to 1.69; I² = 0%; 2 studies, 269 participants), rapid/focused smoking (RR 1.00, 95% CI 0.43 to 2.33; I2 = 65%; 2 studies, 54 participants), and pharmacotherapies (RR 1.68, 95% CI 0.88 to 3.20; I2 = 5%; 2 studies, 197 participants). When hypnotherapy was evaluated as an adjunct to other treatments, the pooled result from five studies showed a statistically significant benefit in favour of hypnotherapy (RR 2.10, 95% CI 1.31 to 3.35; I² = 62%; 224 participants); however, this result should be interpreted with caution due to the high risk of bias across studies (four had a high risk or bias, one had an unclear risk), and substantial statistical heterogeneity. Most studies did not provide information on whether data specifically relating to adverse events were collected, and whether or not any adverse events occurred. One study that did collect such data did not find a statistically significant difference in the adverse event ‘index’ between hypnotherapy and relaxation. There is insufficient evidence to determine whether hypnotherapy is more effective for smoking cessation than other forms of behavioural support or unassisted quitting. If a benefit is present, current evidence suggests the benefit is small at most. There is very little evidence on whether hypnotherapy causes adverse effects, but the existing data show no evidence that it does. Further large, high-quality randomized controlled trials, and more comprehensive assessments of safety, are needed on this topic.
We identified 12 RCTs comparing BCG versus MMC in participants with intermediate- and high-risk non-muscle invasive bladder tumours (published from 1995 to 2013). In total, 2932 participants were randomised. Time to death from any cause: BCG may make little or no difference on time to death from any cause compared to MMC (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.79 to 1.20; participants = 1132, studies = 5; 567 participants in the BCG arm and 565 in the MMC arm; low-certainty evidence). This corresponds to 6 fewer deaths (40 fewer to 36 more) per 1000 participants treated with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Serious adverse effects: 12/577 participants treated with BCG experienced serious non-fatal adverse effects compared to 4/447 participants in the MMC group. The pooled risk ratio (RR) is 2.31 (95% CI 0.82 to 6.52; participants = 1024, studies = 5; low-certainty evidence). Therefore, BCG may increase the risk for serious adverse effects compared to MMC. This corresponds to nine more serious adverse effects (one fewer to 37 more) with BCG. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Time to recurrence: BCG may reduce the time to recurrence compared to MMC (HR 0.88, 95% CI 0.71 to 1.09; participants = 2616, studies = 11, 1273 participants in the BCG arm and 1343 in the MMC arm; low-certainty evidence). This corresponds to 41 fewer recurrences (104 fewer to 29 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations, imprecision and inconsistency. Time to progression: BCG may make little or no difference on time to progression compared to MMC (HR 0.96, 95% CI 0.73 to 1.26; participants = 1622, studies = 6; 804 participants in the BCG arm and 818 in the MMC arm; low-certainty evidence). This corresponds to four fewer progressions (29 fewer to 27 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Quality of life: we found very limited data for this outcomes and were unable to estimate an effect size. Based on our findings, BCG may reduce the risk of recurrence over time although the Confidence Intervals include the possibility of no difference. It may have no effect on either the risk of progression or risk of death from any cause over time. BCG may cause more serious adverse events although the Confidence Intervals once again include the possibility of no difference. We were unable to determine the impact on quality of life. The certainty of the evidence was consistently low, due to concerns that include possible selection bias, performance bias, given the lack of blinding in these studies, and imprecision.
In this update, we identified eight new studies, thereby including a total of 22 trials (2503 participants), 10 of which had a low risk of bias. Most rehabilitation programmes were assessed in only one study. Both men and women were included, and overall mean age was 41.4 years. All participants had received standard discectomy, microdiscectomy and in one study standard laminectomy and (micro)discectomy. Mean duration of the rehabilitation intervention was 12 weeks; eight studies assessed six to eight-week exercise programmes, and eight studies assessed 12 to 13-week exercise programmes. Programmes were provided in primary and secondary care facilities and were started immediately after surgery (n = 4) or four to six weeks (n = 16) or one year after surgery (n = 2). In general, the overall quality of the evidence is low to very low. Rehabilitation programmes that started immediately after surgery were not more effective than their control interventions, which included exercise. Low- to very low-quality evidence suggests that there were no differences between specific rehabilitation programmes (multidisciplinary care, behavioural graded activity, strength and stretching) that started four to six weeks postsurgery and their comparators, which included some form of exercise. Low-quality evidence shows that physiotherapy from four to six weeks postsurgery onward led to better function than no treatment or education only, and that multidisciplinary rehabilitation co-ordinated by medical advisors led to faster return to work than usual care. Statistical pooling was performed only for three comparisons in which the rehabilitation programmes started four to six weeks postsurgery: exercise programmes versus no treatment, high- versus low-intensity exercise programmes and supervised versus home exercise programmes. Very low-quality evidence (five RCTs, N = 272) shows that exercises are more effective than no treatment for pain at short-term follow-up (standard mean difference (SMD) -0.90; 95% confidence interval (CI) -1.55 to -0.24), and low-quality evidence (four RCTs, N = 252) suggests that exercises are more effective for functional status on short-term follow-up (SMD -0.67; 95% CI -1.22 to -0.12) and that no difference in functional status was noted on long-term follow-up (three RCTs, N = 226; SMD -0.22; 95% CI -0.49 to 0.04). None of these studies reported that exercise increased the reoperation rate. Very low-quality evidence (two RCTs, N = 103) shows that high-intensity exercise programmes are more effective than low-intensity exercise programmes for pain in the short term (weighted mean difference (WMD) -10.67; 95% CI -17.04 to -4.30), and low-quality evidence (two RCTs, N = 103) shows that they are more effective for functional status in the short term (SMD -0.77; 95% CI -1.17 to -0.36). Very low-quality evidence (four RCTs, N = 154) suggests no significant differences between supervised and home exercise programmes for short-term pain relief (SMD -0.76;  95% CI -2.04 to 0.53) or functional status (four RCTs, N = 154; SMD -0.36; 95% CI -0.88 to 0.15). Considerable variation was noted in the content, duration and intensity of the rehabilitation programmes included in this review, and for none of them was high- or moderate-quality evidence identified. Exercise programmes starting four to six weeks postsurgery seem to lead to a faster decrease in pain and disability than no treatment, with small to medium effect sizes, and high-intensity exercise programmes seem to lead to a slightly faster decrease in pain and disability than is seen with low-intensity programmes, but the overall quality of the evidence is only low to very low. No significant differences were noted between supervised and home exercise programmes for pain relief, disability or global perceived effect. None of the trials reported an increase in reoperation rate after first-time lumbar surgery. High-quality randomised controlled trials are strongly needed.
We included 23 RCTs that were published between 1968 and 2015 and included 39,195 participants in total. The mean age ranged from 33 to 71 years. The median duration of treatment was 11.5 months, and the median dose of niacin was 2 g/day. The proportion of participants with prior myocardial infarction ranged from 0% (4 trials) to 100% (2 trials, median proportion 48%); the proportion of participants taking statin ranged from 0% (4 trials) to 100% (12 trials, median proportion 100%). Using available cases, niacin did not reduce overall mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.97 to 1.12; participants = 35,543; studies = 12; I2 = 0%; high-quality evidence), cardiovascular mortality (RR 1.02, 95% CI 0.93 to 1.12; participants = 32,966; studies = 5; I2 = 0%; moderate-quality evidence), non-cardiovascular mortality (RR 1.12, 95% CI 0.98 to 1.28; participants = 32,966; studies = 5; I2 = 0%; high-quality evidence), the number of fatal or non-fatal myocardial infarctions (RR 0.93, 95% CI 0.87 to 1.00; participants = 34,829; studies = 9; I2 = 0%; moderate-quality evidence), nor the number of fatal or non-fatal strokes (RR 0.95, 95% CI 0.74 to 1.22; participants = 33,661; studies = 7; I2 = 42%; low-quality evidence). Participants randomised to niacin were more likely to discontinue treatment due to side effects than participants randomised to control group (RR 2.17, 95% CI 1.70 to 2.77; participants = 33,539; studies = 17; I2 = 77%; moderate-quality evidence). The results were robust to sensitivity analyses using different assumptions for missing data. Moderate- to high-quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non-cardiovascular mortality, the number of fatal or non-fatal myocardial infarctions, nor the number of fatal or non-fatal strokes but is associated with side effects. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely.
Seven RCTs (1154 patients) of low or moderate quality were identified. The incidence of MUCs was significantly reduced (RR 0.24, 95% CI 0.07 to 0.77, P = 0.02, NNT 13) by universal prophylactic stenting. This was dependent on whether the same surgeon performed, or was in attendance, during the operations. Two patients lost their grafts to infective urinary tract complications in the stented group. UTIs, in general, were more common in stented patients (RR 1.49, 95% CI 1.04 to 2.15) unless the patients were prescribed cotrimoxazole 480 mg/d: in which case the incidence was equivalent (RR 0.97, 95% CI 0.71 to 1.33). Stents appeared generally well tolerated, although studies using longer stents (≥ 20 cm) for longer periods (> 6 weeks) had more problems with encrustation and migration. Routine prophylactic stenting reduces the incidence of MUCs. Studies comparing selective stenting and universal prophylactic stenting, whilst difficult to design and analyse, would address the unresolved quality of life and economic issues.
One trial was eligible for inclusion.  All participants were age 60 years or over and had received a repeat prescription from their general practitioner of quinine for nighttime cramps in the preceding three months. This review includes data from only those participants who were advised to continue taking quinine. Forty-nine participants were advised to complete lean-to-wall calf muscle stretching held for 10 s three times per day. Forty-eight participants were allocated to a placebo stretching group. After 12 weeks, there was no statistically significant difference in recalled cramp frequency between groups. No "significant" adverse effect was reported. Limitations in the study's design impede interpretation of the results and clinical applicability. There is limited evidence on which to base clinical decisions regarding the use of non-drug therapies for the treatment of lower limb muscle cramp. Serious methodological limitations in the existing evidence hinder clinical application. There is an urgent need to carefully evaluate many of the commonly recommended and emerging non-drug therapies in well designed randomised controlled trials.
We included 12 studies (2351 participants: range 27 to 841). Characteristics: The 12 included studies compared hypertonic (colloids) with isotonic fluids (crystalloids); of these, five studies (1420 participants) also compared 0.9% saline with another fluid. No data were available to make other comparisons. Delay from stroke to recruitment varied from less than 24 hours to 72 hours. Duration of fluid delivery was between two hours and 10 days. Bias assessment: Investigators and participants in eight of the 12 included studies were blind to treatment allocation, seven of the 12 included studies gave details of randomisation, and eight of the 12 included studies reported all outcomes measured. Results: There were no relevant completed trials that addressed the effect of volume, duration, or mode of fluid delivery on death or dependence in people with stroke. The odds of death or dependence were similar in participants allocated to colloids or crystalloid fluid regimens (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.79 to 1.21, five studies, I² = 58%, low-quality evidence), and between 0.9% saline or other fluid regimens (OR 1.04, 95% CI 0.82 to 1.32, three studies, I² = 71%, low-quality evidence). There was substantial heterogeneity in these estimates. The odds of death were similar between colloids and crystalloids (OR 1.02, 95% CI 0.82 to 1.27, 12 studies, I² = 24%, moderate-quality evidence), and 0.9% saline and other fluids (OR 0.87, 95% CI 0.67 to 1.12, five studies, I² = 53%, low-quality evidence). The odds of pulmonary oedema were higher in participants allocated to colloids (OR 2.34, 95% CI 1.28 to 4.29, I² = 0%). Although the studies observed a higher risk of cerebral oedema (OR 0.20, 95% CI 0.02 to 1.74) and pneumonia (OR 0.58, 95% CI 0.17 to 2.01) with crystalloids, we could not exclude clinically important benefits or harms. We found no evidence that colloids were associated with lower odds of death or dependence in the medium term after stroke compared with crystalloids, though colloids were associated with greater odds of pulmonary oedema. We found no evidence to guide the best volume, duration, or mode of parenteral fluid delivery for people with acute stroke.
Three trials involving 5905 participants were included. In patients with mild asthma who do not need maintenance treatment, no clinically important advantages of budesonide/formoterol as reliever were found in comparison to formoterol as reliever. Two studies enrolled patients with more severe asthma who were not controlled on high doses of inhaled corticosteroids (around 700 mcg/day in adults), and had suffered a clinically important asthma exacerbation in the past year. Hospitalisations related to asthma in the two studies comparing budesonide/formoterol for maintenance and relief with the same dose of budesonide/formoterol for maintenance with terbutaline for relief yielded an odds ratio of 0.68 (95% CI 0.40 to 1.16), which was not a statistically significant reduction. In adults there was a reduction in exacerbations requiring oral corticosteroids compared to terbutaline, odds ratio 0.54 (95% CI 0.44 to 0.65), which translates into a number needed to treat over 12 months of 15 (95% CI 13 to 21). The study in children found less serious adverse events with budesonide/formoterol used for maintenance and relief. There was no significant difference in annual growth in children using budesonide/formoterol reliever in comparison to terbutaline. In mild asthma it is not yet known whether patients who use a budesonide/formoterol inhaler for relief of asthma symptoms derive any clinically important benefits. In more severe asthma, two studies enrolled patients who were not controlled on inhaled corticosteroids, and had suffered an exacerbation in the previous year, and then had their maintenance inhaled corticosteroids reduced in both arms of the study. Under these conditions the studies demonstrated a reduction in the risk of exacerbations that require oral corticosteroids with budesonide/formoterol for maintenance and relief in comparison with budesonide/formoterol for maintenance and terbutaline or formoterol for relief. The incidence of serious adverse events in children was also less using budesonide/formoterol for maintenance and relief in one study, which similarly enrolled children who were not controlled on inhaled corticosteroids, and who had their maintenance inhaled corticosteroids reduced at the start of the study. This study also compared an explorative maintenance dose of budesonide/formoterol that is not approved for treatment.
In this updated review four studies met the inclusion criteria. In total 366 participants were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 212 with placebo. Active comparators were naproxen 500 mg, rofecoxib 50 mg, celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 400 mg. With lumiracoxib 400 mg 50% of participants had at least 50% pain relief over six hours, compared with 8% given placebo; RB 6.9 (95% CI 4.1 to 12), NNT 2.4 (2.1 to 2.8). Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than placebo (>12 hours). Fewer participants needed rescue medication with lumiracoxib (64%) than with placebo (91%) over 12 to 24 hours; NNT to prevent remedication 3.7 (2.9 to 5.0). The weighted median time to use of rescue medication was 9.4 hours for lumiracoxib 400 mg and 1.7 hours for placebo. Adverse events were generally mild to moderate in severity, with one serious event reported in a placebo patient. Lumiracoxib 400 mg given as a single oral dose is an effective analgesic for acute postoperative pain, and has a relatively long duration of action. Adverse events with lumiracoxib did not differ from placebo.
We found no evidence comparing slow-release fluoride devices against other types of fluoride therapy. We found only one double-blind RCT involving 174 children comparing a slow-release fluoride device (glass beads with fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth) against control (glass beads without fluoride were attached to buccal surfaces of right maxillary first permanent molar teeth). This study was assessed to be at high risk of bias. The study recruited children from seven schools in an area of deprivation that had low levels of fluoride in the water. The mean age at the beginning of the study was 8.8 years and at the termination was 10.9 years. DMFT in permanent teeth or dmft in primary teeth was greater than one at the start of the study and greater than one million colony-forming units of Streptococcus mutans per millilitre of saliva. Although 132 children were still included in the trial at the two-year completion point, examination and statistical analysis was performed on only the 63 children (31 in intervention group, 32 in control group) who had retained the beads (retention rate was 47.7% at 2 years). Among these 63 children, caries increment was reported to be statistically significantly lower in the intervention group than in the control group (DMFT: mean difference -0.72, 95% confidence interval (CI) -1.23 to -0.21; DMFS: mean difference -1.52, 95% CI -2.68 to -0.36 (very low-quality evidence)). Although this difference was clinically significant, it only holds true for those children who maintain the fluoride beads; over 50% of children did not retain the beads. Harms were not reported within the trial report. Evidence for other outcomes sought in this review (progression to of caries lesion, dental pain, healthcare utilisation data) were also not reported. There is insufficient evidence to determine the caries-inhibiting effect of slow-release fluoride glass beads. The body of evidence available is of very low quality and there is a potential overestimation of benefit to the average child. The applicability of the findings to the wider population is unclear; the study had included children from a deprived area that had low levels of fluoride in drinking water, and were considered at high risk of caries. In addition, the evidence was only obtained from children who still had the bead attached at 2 years (48% of all available children); children who had lost their slow-release fluoride devices earlier might not have benefited as much from the devices.
The review included six trials with a total of 361 participants. Two studies were conducted in America and one each in Germany, Greece, India, and Saudi Arabia. The participants of four trials had open-angle glaucoma; one study included participants with primary open-angle or primary closed-angle glaucoma, and one study did not specify the type of glaucoma. Three studies used a combined procedure (phacotrabeculectomy). Trabeculectomy with mitomycin C (MMC) was performed in four studies, and trabeculectomy with 5-fluorouracil (5-FU) was performed in only one study. None of the included trials reported trabeculectomy failure at 24 months. Only one trial reported the failure rate of trabeculectomy as a late complication. Failure was higher among participants randomised to the limbal-based surgery: 1/50 eyes failed trabeculectomy in the fornix group compared with 3/50 in the limbal group (risk ratio (RR) 0.33, 95% confidence interval (95% CI) 0.04 to 3.10); therefore we are very uncertain as to the relative effect of the two procedures on failure rate. Four studies including 252 participants provided measures of mean IOP at 12 months. In the fornix-based surgeries, mean IOP ranged from 12.5 to 15.5 mmHg and similar results were noted in limbal-based surgeries with mean IOP ranging from 11.7 to 15.1 mmHg without significant difference. Mean difference was 0.44 mmHg (95% CI −0.45 to 1.33) and 0.86 mmHg, (95% CI −0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Neither of these pooled analyses showed a statistically significant difference in IOP between groups (moderate quality of evidence). One trial reported number of anti-glaucoma medications at 24 months of follow-up with no difference noted between surgical groups. However, three trials reported the mean number of anti-glaucoma medications at 12 months of follow-up without significant difference in the mean number of postoperative IOP-lowering medications between the two surgical techniques. Mean difference was 0.02, (95% CI −0.15 to 0.19) at 12 months of follow-up (high quality of evidence). Because of the small numbers of events and total participants, the risk of many reported adverse events were uncertain and those that were found to be statistically significant may have been due to chance. For risk of bias assessment: although all six trials were randomised selection bias was mostly unclear, with unclear random sequence generation in four of the six studies and unclear allocation concealment in five of the six studies. Attrition bias was encountered in only one trial which also suffered from reporting bias. All other trials had an unclear risk of reporting bias as there was no access to study protocols. All included trials were judged to have high risk of detection bias due to lack of masking of the outcomes. Trabeculectomy is quite a standard procedure and unlikely to induce bias due to surgeon 'performance', hence performance bias was not evaluated. The main result of this review was that there was uncertainty as to the difference between fornix- and limbal-based trabeculectomy surgeries due to the small number of events and confidence intervals that cross the null. This also applied to postoperative complications, but without any impact on long-term failure rate between the two surgical techniques.
For this 2015 update, we did not identify any new RCTs for inclusion. The previous version of the review included seven trials with a total of 362 participants. Four trials compared the effectiveness of a steroid to placebo for short-term symptom control in glandular fever, one to aspirin, and two trials explored the effects of steroids in conjunction with an antiviral. Heterogeneity between trials prevented a combined analysis. Trials under-reported methodological design features. Three trials did not adequately describe sequence generation for randomisation. Four trials provided adequate details of allocation concealment. All trials were double-blind but four were not specific as to who was blinded. Loss to follow-up was under-reported in four trials, making it difficult to exclude attrition bias. The risk of selective reporting in the included trials was unclear. Across the trials, no benefit was found in 8/10 assessments of health improvement. Two trials found benefit of steroid therapy over placebo in reducing sore throat at 12 hours (eight-day course odds ratio (OR) 21.00, 95% confidence interval (CI) 1.94 to 227.20; one-dose OR 4.20, 95% CI 1.08 to 16.32), but the benefit was not maintained. In combination with an antiviral drug, participants in the steroid group had less pharyngeal discomfort between days two to four (OR 0.31, 95% CI 0.09 to 1.08) compared to placebo. Across the trials the effects on other common symptoms were less clear. Two trials set out to measure safety; they documented no major adverse effects. In two other trials adverse events were reported, including respiratory distress and acute onset of diabetes. However, the association of the events with the steroid is not definite. There is insufficient evidence to the efficacy of steroids for symptom control in infectious mononucleosis. There is a lack of research on the side effects and long-term complications.
We considered twenty-four studies for inclusion in the final analysis. Twenty of these studies (enrolling a total of 2344 participants) evaluated the use of phlebotonics versus a control intervention. One of these twenty studies evaluated the use of phlebotonics with a medical intervention and another study with rubber band ligation. The remaining four studies included two which compared different forms of phlebotonics with each other, one study which evaluated phlebotonics with a medical intervention and one study which compared the use of phlebotonics with infrared photocoagulation. Eight studies were excluded for various reasons including poor methodological quality. Phlebotonics demonstrated a statistically significant beneficial effect for the outcomes of  pruritus (OR 0.23; 95% CI 0.07 to 0.79) (P=0.02), bleeding (OR 0.12; 95% CI 0.04 to 0.37) (P=0.0002), bleeding post-haemorrhoidectomy (OR 0.18; 95% 0.06 to 0.58)(P=0.004), discharge and leakage (OR 0.12; 95% CI 0.04 to 0.42) (P=0.0008) and overall symptom improvement (OR 15.99 95% CI 5.97 to 42.84) (P< 0.00001), in comparison with a control intervention. Although beneficial they did not show a statistically significant effect compared with a control intervention for pain (OR 0.11; 95% CI 0.01 to 1.11) (P=0.06), pain scores post-haemorrhoidectomy (SMD -1.04; 95% CI -3.21 to 1.12 ) (P= 0.35) or post-operative analgesic consumption (OR 0.54; 95% CI 0.30 to 0.99)(P=0.05). The evidence suggests that there is a potential benefit in using phlebotonics in treating haemorrhoidal disease as well as a benefit in alleviating post-haemorrhoidectomy symptoms. Outcomes such as bleeding and overall symptom improvement show a statistically significant beneficial effect and there were few concerns regarding their overall safety from the evidence presented in the clinical trials. However methodological limitations were encountered. In order to enhance our conclusion further, more robust clinical trials which take into account these limitations will need to be performed in the future.
We included seven trials with a total of 239 participants. Two trials were of cross-over design, and outcome data were not available from the first phase (precross-over) in an appropriate format for inclusion as a parallel randomised controlled trial (RCT). Thus, the results of the review are based on five trials with 213 participants. Treatment effects were observed on the following primary endpoints of emotionalism: There is very low quality of evidence from one small RCT that antidepressants increased the number of people who had 50% reduction in emotionalism (RR 16.50, 95% CI 1.07 to 253.40; 19 participants) and low quality evidence from one RCT of improved scores on Center for Neurologic Study - Lability Scale (CNS-LS) and Clinician Interview-Based Impression of Change (CIBIC) with antidepressants (RR 1.44, 95% CI 0.95 to 2.19; 28 participants). There was moderate quality evidence from three RCTS that they increased the number of people who had a reduction in tearfulness (RR 2.18, 95% CI 1.29 to 3.71; 164 participants); and low quality evidence from one RCT of improved scores on the Pathological Laughter and Crying Scale (PLCS) (MD 8.40, 95% CI 11.56 to 5.24; 28 participants). Six trials reported adverse events (death) and found no difference between the groups in death (RR 0.59, 95% CI 0.08 to 4.50; 6 RCTs, 172 participants, moderate-quality evidence). Antidepressants may reduce the frequency and severity of crying or laughing episodes based on very low quality evidence. Our conclusions must be qualified by several methodological deficiencies in the studies and interpreted with caution despite the effect being very large. The effect does not seem specific to one drug or class of drugs. More reliable data are required before appropriate conclusions can be made about the treatment of post-stroke emotionalism. Future trialists investigating the effect of antidepressants in people with emotionalism after stroke should consider developing and using a standardised method to diagnose emotionalism, determine severity and assess change over time; provide treatment for a sufficient duration and follow-up to better assess rates of relapse or maintenance and include careful assessment and complete reporting of adverse events.
Eleven trials, involving a total of 698 participants, were included. The trials enrolled three types of participants (high risk of failure, trabeculectomy combined with cataract surgery, no previous surgical intervention). Mitomycin C appears to reduce the relative risk of failure of trabeculectomy both in eyes at high risk of failure (relative risk 0.32, 95% confidence interval: 0.20 to 0.53) and those undergoing surgery for the first time (relative risk 0.29, 95% confidence interval 0.16 to 0.53). No significant effect on failure was noted in the group undergoing trabeculectomy combined with cataract extraction. Mean IOP was significantly reduced at 12 months in all three participant groups receiving MMC compared to placebo. No significant increase in permanent sight-threatening complications was detected. However, none of the trials were large enough or of sufficient duration to address the long-term risk of bleb infection and endophthalmitis which has been reported in observational studies. Some evidence exists that MMC increases the risk of cataract. Intraoperative MMC reduces the risk of surgical failure in eyes that have undergone no previous surgery and in eyes at high risk of failure. Compared to placebo it reduces mean IOP at 12 months in all groups of participants in this review. Apart from an increase in cataract formation following MMC, there was insufficient power to detect any increase in other serious side effects such as endophthalmitis.
We included only one trial in the review. Keszler 1991 randomly assigned 166 preterm infants; reported data on 144 infants; and permitted cross-over to the alternate treatment if initial treatment failed. Investigators found no statistically significant differences in overall mortality (including survival after cross-over) between the two groups (RR 1.07, 95% confidence interval (CI) 0.67 to 1.72). In a secondary analysis of infants up to the time of cross-over, rescue treatment with HFJV was associated with lower mortality (RR 0.66, 95% CI 0.45 to 0.97). Researchers reported no significant differences in the incidence of CLD among survivors at 28 days of age, nor in the incidence of intraventricular haemorrhage, new air leaks, airway obstruction and necrotising tracheobronchitis. Study authors reported no significant differences in overall mortality between rescue high-frequency jet ventilation and conventional ventilation and presented highly imprecise results for important adverse effects such as intraventricular haemorrhage, new air leaks, airway obstruction and necrotising tracheobronchitis. The overall quality of evidence is affected by limitations in trial design and by imprecision due to the small number of infants in the included study. Existing evidence does not support the use of high-frequency jet ventilation as rescue therapy in preterm infants. Studies that target populations at greatest risk and that have sufficient power to assess important outcomes are needed. These trials should incorporate long-term pulmonary and neurodevelopmental outcomes.
We included five trials in this review, all were conducted in high-income countries. Three additional trials are ongoing. One trial compared fresh frozen plasma (FFP) transfusion with no transfusion given. One trial compared FFP or platelet transfusion or both with neither FFP nor platelet transfusion given. One trial compared FFP transfusion with administration of alternative pro-haemostatic agents (factors II, IX, and X followed by VII). One trial compared the use of different transfusion triggers using the international normalised ratio measurement. One trial compared the use of a thromboelastographic-guided transfusion trigger using standard laboratory measurements of coagulation. Four trials enrolled only adults, whereas the fifth trial did not specify participant age. Four trials included only minor procedures that could be performed by the bedside. Only one trial included some participants undergoing major surgical operations. Two trials included only participants in intensive care. Two trials included only participants with liver disease. Three trials did not recruit sufficient participants to meet their pre-calculated sample size. Overall, the quality of evidence was low to very low across different outcomes according to GRADE methodology, due to risk of bias, indirectness, and imprecision. One trial was stopped after recruiting two participants, therefore this review's findings are based on the remaining four trials (234 participants). When plasma transfusion was compared with no transfusion given, we are very uncertain whether there was a difference in 30-day mortality (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; risk ratio (RR) 0.38, 95% confidence interval (CI) 0.13 to 1.10; very low-quality evidence). We are very uncertain whether there was a difference in major bleeding within 24 hours (1 trial comparing FFP transfusion vs no transfusion, 76 participants; RR 0.33, 95% CI 0.01 to 7.93; very low-quality evidence; 1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; RR 1.59, 95% CI 0.28 to 8.93; very low-quality evidence). We are very uncertain whether there was a difference in the number of blood product transfusions per person (1 trial, 76 participants; study authors reported no difference; very low-quality evidence) or in the number of people requiring transfusion (1 trial comparing FFP or platelet transfusion or both with neither FFP nor platelet transfusion, 72 participants; study authors reported no blood transfusion given; very low-quality evidence) or in the risk of transfusion-related adverse events (acute lung injury) (1 trial, 76 participants; study authors reported no difference; very low-quality evidence). When plasma transfusion was compared with other pro-haemostatic agents, we are very uncertain whether there was a difference in major bleeding (1 trial; 21 participants; no events; very low-quality evidence) or in transfusion-related adverse events (febrile or allergic reactions) (1 trial, 21 participants; RR 9.82, 95% CI 0.59 to 162.24; very low-quality evidence). When different triggers for FFP transfusion were compared, the number of people requiring transfusion may have been reduced (for overall blood products) when a thromboelastographic-guided transfusion trigger was compared with standard laboratory tests (1 trial, 60 participants; RR 0.18, 95% CI 0.08 to 0.39; low-quality evidence). We are very uncertain whether there was a difference in major bleeding (1 trial, 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence) or in transfusion-related adverse events (allergic reactions) (1 trial; 60 participants; RR 0.33, 95% CI 0.01 to 7.87; very low-quality evidence). Only one trial reported 30-day mortality. No trials reported procedure-related harmful events (excluding bleeding) or quality of life. Review findings show uncertainty for the utility and safety of prophylactic FFP use. This is due to predominantly very low-quality evidence that is available for its use over a range of clinically important outcomes, together with lack of confidence in the wider applicability of study findings, given the paucity or absence of study data in settings such as major body cavity surgery, extensive soft tissue surgery, orthopaedic surgery, or neurosurgery. Therefore, from the limited RCT evidence, we can neither support nor oppose the use of prophylactic FFP in clinical practice.
We included 18 studies involving 1266 participants. We were not able to pool due to the heterogeneity of many of the studies. Our primary outcomes were 'Global improvement of nail psoriasis as rated by a clinician', 'Improvement of nail psoriasis scores (NAS, NAPSI)', 'Improvement of nail psoriasis in the participant's opinion'. Our secondary outcomes were 'Adverse effects (and serious adverse effects)'; 'Effects on quality of life'; and 'Improvement in nail features, pain score, nail thickness, thickness of subungual hyperkeratosis, number of affected nails, and nail growth'. We assessed short-term (3 to 6 months), medium-term (6 to 12 months), and long-term (> 12 months) treatments separately if possible. Two systemic biologic studies and three radiotherapy studies reported significant results for our first two primary outcomes. Infliximab 5 mg/kg showed 57.2% nail score improvement versus -4.1% for placebo (P < 0.001); golimumab 50 mg and 100 mg showed 33% and 54% improvement, respectively, versus 0% for placebo (P < 0.001), both after medium-term treatment. Infliximab and golimumab also showed significant results after short-term treatment. From the 3 radiotherapy studies, only the superficial radiotherapy (SRT) study showed 20% versus 0% nail score improvement (P = 0.03) after short-term treatment. Studies with ciclosporin, methotrexate, and ustekinumab were not significantly better than their respective comparators: etretinate, ciclosporin, and placebo. Nor were studies with topical interventions (5-fluorouracil 1% in Belanyx® lotion, tazarotene 0.1% cream, calcipotriol 50 ug/g, calcipotriol 0.005%) better than their respective comparators: Belanyx® lotion, clobetasol propionate, betamethasone dipropionate with salicylic acid, or betamethasone dipropionate. Of our secondary outcomes, not all included studies reported adverse events; those that did only reported mild adverse effects, and there were more in studies with systemic interventions. Only one study reported the effect on quality of life, and two studies reported nail improvement only per feature. Infliximab, golimumab, SRT, grenz rays, and electron beam caused significant nail improvement compared to the comparative treatment. Although the quality of trials was generally poor, this review may have some implications for clinical practice. Although powerful systemic treatments have been shown to be beneficial, they may have serious adverse effects. So they are not a realistic option for people troubled with nail psoriasis, unless the patient is prescribed these systemic treatments because of cutaneous psoriasis or psoriatic arthritis or the nail psoriasis is severe, refractory to other treatments, or has a major impact on the person's quality of life. Because of their design and timescale, RCTs generally do not pick up serious side-effects. This review reported only mild adverse effects, recorded mainly for systemic treatments. Radiotherapy for psoriasis is not used in common practice. The evidence for the use of topical treatments is inconclusive and of poor quality; however, this does not imply that they do not work. Future trials need to be rigorous in design, with adequate reporting. Trials should correctly describe the participants' characteristics and diagnostic features, use standard validated nail scores and participant-reported outcomes, be long enough to report efficacy and safety, and include details of effects on nail features.
Four studies with a total of 233 participants, comparing BTXA with placebo, met the inclusion criteria. In one study with 145 participants, significant improvement rates of pain intensity scores and duration of daily pain were demonstrated when comparing BTXA with placebo. The three other studies showed that there was no statistically significant difference between BTXA and placebo in pain intensity. Since the first publication of this review, no new studies were found. There is inconclusive evidence to support the use of botulinum toxin in the treatment of MPS based on data from four studies with a total of 233 participants, which we considered were of sufficient quality to be included in this review. Meta-analyses were not possible due to the heterogeneity between studies. We suggest that in future studies the same methodology to assess pain, a standardised dose of treatment, follow-up of at least four months (to observe the maximum and minimum curve of the drug effect) and appropriate data presentation should be used. More high-quality RCTs of botulinum toxin for treating MPS need to be conducted before firm conclusions on its effectiveness and safety can be drawn.
We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of −0.43 (95% confidence interval (CI) −0.38 to −0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at −0.42 (95% CI −0.35 to −0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was −0.46 (95% CI −0.39 to −0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue. Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.
The search resulted in 2693 articles that we screened on title and abstract for eligibility.Thirteen studies were selected for full text assessment. We included three randomised trials involving 1150 women. Two trials compared the administration of prostaglandins in the morning versus the evening in women with an unfavourable cervix, and one trial compared induction of labour in the morning versus the evening in women with a favourable cervix and/or ruptured membranes with intravenous oxytocin. Because of the different mechanism, we have reported results for these two comparisons separately. In the two trials comparing prostaglandins in the morning versus the evening there were few clinically significant differences between study groups for maternal or neonatal outcomes. One study reported a statistically significant preference by women to start induction of labour with prostaglandins in the morning. In the trial examining induction of labour with intravenous oxytocin, the number of neonatal admissions was statistically significantly increased in the group of women that started induction in the morning. This finding was unexpected, and while the trial authors offered some possible explanations for this, it is important that any future trials examine neonatal outcomes. Taking into account women's preferences that favoured administration of prostaglandins in the morning, we conclude that caregivers should preferably consider administering prostaglandins in the morning. There is no strong evidence that induction of labour with intravenous oxytocin in the evening is more or less effective than induction in the morning. Consideration may be given to start induction of labour with oxytocin in the evening when indicated.
We included 14 studies with a total of 698 participants undergoing thoracotomy. There are two studies awaiting classification. The studies demonstrated high heterogeneity in insertion and use of both regional techniques, reflecting real-world differences in the anaesthesia techniques. Overall, the included studies have a moderate to high potential for bias, lacking details of randomization, group allocation concealment or arrangements to blind participants or outcome assessors. There was low to very low-quality evidence that showed no significant difference in 30-day mortality (2 studies, 125 participants. risk ratio (RR) 1.28, 95% confidence interval (CI) 0.39 to 4.23, P value = 0.68) and major complications (cardiovascular: 2 studies, 114 participants. Hypotension RR 0.30, 95% CI 0.01 to 6.62, P value = 0.45; arrhythmias RR 0.36, 95% CI 0.04 to 3.29, P value = 0.36, myocardial infarction RR 3.19, 95% CI 0.13, 76.42, P value = 0.47); respiratory: 5 studies, 280 participants. RR 0.62, 95% CI 0.26 to 1.52, P value = 0.30). There was moderate-quality evidence that showed comparable analgesic efficacy across all time points both at rest and after coughing or physiotherapy (14 studies, 698 participants). There was moderate-quality evidence that showed PVB had a better minor complication profile than TEB including hypotension (8 studies, 445 participants. RR 0.16, 95% CI 0.07 to 0.38, P value < 0.0001), nausea and vomiting (6 studies, 345 participants. RR 0.48, 95% CI 0.30 to 0.75, P value = 0.001), pruritis (5 studies, 249 participants. RR 0.29, 95% CI 0.14 to 0.59, P value = 0.0005) and urinary retention (5 studies, 258 participants. RR 0.22, 95% CI 0.11 to 0.46, P value < 0.0001). There was insufficient data in chronic pain (six or 12 months). There was no difference found in and length of hospital stay (3 studies, 124 participants). We found no studies that reported costs. Paravertebral blockade reduced the risks of developing minor complications compared to thoracic epidural blockade. Paravertebral blockade was as effective as thoracic epidural blockade in controlling acute pain. There was a lack of evidence in other outcomes. There was no difference in 30-day mortality, major complications, or length of hospital stay. There was insufficient data on chronic pain and costs. Results from this review should be interpreted with caution due to the heterogeneity of the included studies and the lack of reliable evidence. Future studies in this area need well-conducted, adequately-powered RCTs that focus not only on acute pain but also on major complications, chronic pain, length of stay and costs.
We included eight trials in this review with a total of 1708 participants. Trials were conducted in India, Nepal and South Africa. Follow-up ranged from one day to six months, but most trials reported at six to eight weeks after surgery. Overall the trials were judged to be at risk of bias due to unclear reporting of masking and follow-up. No studies reported presenting visual acuity so data were collected on both best-corrected (BCVA) and uncorrected (UCVA) visual acuity. Most studies reported visual acuity of 6/18 or better (rather than 6/12 or better) so this was used as an indicator of good functional vision. Seven studies (1223 participants) reported BCVA of 6/18 or better at six to eight weeks (pooled risk ratio (RR) 0.99 95% confidence interval (CI) 0.98 to 1.01) indicating no difference between the MSICS and phacoemulsification groups. Three studies (767 participants) reported UCVA of 6/18 or better at six to eight weeks, with a pooled RR indicating a more favourable outcome with phacoemulsification (0.90, 95% CI 0.84 to 0.96). One trial (96 participants) reported UCVA at six months with a RR of 1.07 (95% CI 0.91 to 1.26). Regarding BCVA of less than 6/60: there were only 11/1223 events reported. The pooled Peto odds ratio was 2.48 indicating a more favourable outcome using phacoemulsification but with wide confidence intervals (0.74 to 8.28) which means that we are uncertain as to the true effect. The number of complications reported were also low for both techniques. Again this means the review is underpowered to detect a difference between the two techniques with respect to these complications. One study reported on cost which was more than four times higher using phacoemulsification than MSICS. On the basis of this review, removing cataract by phacoemulsification may result in better UCVA in the short term (up to three months after surgery) compared to MSICS, but similar BCVA. There is a lack of data on long-term visual outcome. The review is currently underpowered to detect differences for rarer outcomes, including poor visual outcome. In view of the lower cost of MSICS, this may be a favourable technique in the patient populations examined in these studies, where high volume surgery is a priority. Further studies are required with longer-term follow-up to better assess visual outcomes and complications which may develop over time such as posterior capsule opacification.
Of the 908 participants enrolled (three RCTs), 454 were allocated for drainage and 454 for no drainage. We found no new RCTs for this review update. Two trials reported the primary outcome measure of anastomotic dehiscence. There was no statistically significant difference in anastomotic dehiscence in participants treated with intra-abdominal drainage routinely compared to no treatment (risk ratio (RR) 1.40, 95% confidence intervals (CI) 0.45 to 4.40; I2 = 0%; 2 RCTs; 809 participants). There was no statistically significant difference in mortality (RR 0.77, 95% CI 0.41 to 1.45; I2 = 0%; 3 RCTs; 908 participants); surgical re-intervention (RR 1.11, 95% CI 0.67 to 1.82; I2 = 29%; 3 RCTs; 908 participants); radiological dehiscence (RR 0.85, 95% CI 0.39 to 1.83; I2 = 0%; 2 RCTs; 809 participants) and wound infection (RR 0.82, 95% CI 0.45 to 1.51; I2 = 0%; 3 RCTs; 908 participants) in participants treated with routine prophylactic drainage compared to no treatment undergoing elective colorectal surgery. The quality of evidence was low according to GRADE method assessment. There was insufficient evidence for the use of prophylactic drains after elective colorectal anastomoses. The conclusions of this review were limited due to the nature of the available clinical data; The three included RCTs performed different interventions with relatively small sample sizes of eligible participants.
The search identified one new RCT, making a total of 10 included RCTs (442 participants, 42% women). The median number of participants per RCT was 29 (range 10 to 117). Four RCTs recruited people with a range of chronic wounds; three RCTs recruited people with venous leg ulcers, and three RCTs considered foot ulcers in people with diabetes. The median length of treatment was 12 weeks (range 8 to 40 weeks). It is unclear whether autologous PRP improves the healing of chronic wounds generally compared with standard treatment (with or without placebo) (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.95 to 1.50; I2 = 27%, low quality evidence, 8 RCTs, 391 participants). Autologous PRP may increase the healing of foot ulcers in people with diabetes compared with standard care (with or without placebo) (RR 1.22, 95% CI 1.01 to 1.49; I2 = 0%, low quality evidence, 2 RCTs, 189 participants). It is unclear if autologous PRP affects the healing of venous leg ulcers (RR 1.02, 95% CI 0.81 to 1.27; I2 = 0% ). It is unclear if there is a difference in the risk of adverse events in people treated with PRP or standard care (RR 1.05, 95% CI 0.29 to 3.88; I2 = 0%, low quality evidence from 3 trials, 102 participants). PRP may improve the healing of foot ulcers associated with diabetes, but this conclusion is based on low quality evidence from two small RCTs. It is unclear whether PRP influences the healing of other chronic wounds. The overall quality of evidence of autologous PRP for treating chronic wounds is low. There are very few RCTs evaluating PRP, they are underpowered to detect treatment effects, if they exist, and are generally at high or unclear risk of bias. Well designed and adequately powered clinical trials are needed.
Two cluster-randomised control trials were included: one randomised at hospital level (23 hospitals in Australia) and one at ward level (16 wards in the UK). The primary outcome in the Australian trial (a composite score comprising incidence of unexpected cardiac arrests, unexpected deaths and unplanned ICU admissions) showed no statistical significant difference between control and medical emergency team (MET) hospitals (adjusted P value 0.640; adjusted odds ratio (OR) 0.98; 95% confidence interval (CI) 0.83 to 1.16). The UK-based trial found that outreach reduced in-hospital mortality (adjusted OR 0.52; 95% CI 0.32 to 0.85) compared with the control group. The evidence from this review highlights the diversity and poor methodological quality of most studies investigating outreach. The results of the two included studies showed either no evidence of the effectiveness of outreach or a reduction in overall mortality in patients receiving outreach. The lack of evidence on outreach requires further multi-site RCT's to determine potential effectiveness.
We included six new studies (624 participants) for this update, which now includes a total of 23 trials that randomised a total of 2890 participants undergoing cardiac rehabilitation. Participants had an acute myocardial infarction, revascularisation or heart failure. A number of studies provided insufficient detail to enable assessment of potential risk of bias, in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in clinical primary outcomes up to 12 months of follow up: total mortality (relative risk (RR) = 1.19, 95% CI 0.65 to 2.16; participants = 1505; studies = 11/comparisons = 13; very low quality evidence), exercise capacity (standardised mean difference (SMD) = -0.13, 95% CI -0.28 to 0.02; participants = 2255; studies = 22/comparisons = 26; low quality evidence), or health-related quality of life up to 24 months (not estimable). Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate quality evidence). However, there was evidence of marginally higher levels of programme completion (RR 1.04, 95% CI 1.00 to 1.08; participants = 2615; studies = 22/comparisons = 26; low quality evidence) by home-based participants. This update supports previous conclusions that home- and centre-based forms of cardiac rehabilitation seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction or revascularisation, or with heart failure. This finding supports the continued expansion of evidence-based, home-based cardiac rehabilitation programmes. The choice of participating in a more traditional and supervised centre-based programme or a home-based programme may reflect local availability and consider the preference of the individual patient. Further data are needed to determine whether the effects of home- and centre-based cardiac rehabilitation reported in the included short-term trials can be confirmed in the longer term and need to consider adequately powered non-inferiority or equivalence study designs.
We included eight RCTs involving 2156 participants with different stages of breast cancer and chemotherapy regimens. The trials were carried out between 1995 and 2008 and judged as being at least at moderate risk of bias. The strength of the evidence was weak for the majority of outcomes, which was mostly because of the small numbers of evaluable patients, varying definitions, as well as unclear measurements of the trials' outcomes and uncertain influences of supportive treatments on them. In most trials, the chemotherapy regimens had a risk of FN that was below the threshold at which current guidelines recommend routine primary prophylaxis with CSFs. Using CSFs significantly reduced the proportion of patients with FN (RR 0.27; 95% CI 0.11 to 0.70; number needed to treat for an additional beneficial outcome (NNTB) 12) but there was substantial heterogeneity which can be explained by possible differential effects of G-CSFs and GM-CSFs and different definitions of FN. A significant reduction in early mortality was observed in CSF-treated patients compared to placebo or no treatment (RR 0.32; 95% CI 0.13 to 0.77; NNTB 79). This finding was based on 23 fatal events in 2143 patients; wherein 19 of these 23 events occurred in one study and 17 events were attributed to progression of the disease by the study authors. For infection-related mortality, there were no significant differences between CSF and control groups (RR 0.14; 95% CI 0.02 to 1.29). In CSF-treated patients, the risk for hospitalization was significantly reduced (RR 0.14; 95% CI 0.06 to 0.30; NNTB 13), as well as the use of intravenous antibiotics (RR 0.35; 95% CI 0.22 to 0.55; NNTB 18). The risks of severe neutropenia, infection or not maintaining the scheduled dose of chemotherapy did not differ between CSF-treated and control groups. CSFs frequently led to bone pain (RR 5.88; 95% CI 2.54 to 13.60; number needed to treat for an additional harmful outcome (NNTH) 3) and injection-site reactions (RR 3.59; 95% CI 2.33 to 5.53; NNTH 3). In patients with breast cancer receiving chemotherapy, CSFs have shown evidence of benefit in the prevention of FN. There is evidence, though less reliable, of a decrease of all-cause mortality during chemotherapy and a reduced need for hospital care. No reliable evidence was found for a reduction of infection-related mortality, a higher dose intensity of chemotherapy with CSFs or diminished rates of severe neutropenia and infections. The majority of adverse events reported from CSF use were bone pain and injection-site reactions but no conclusions could be drawn regarding late-term side effects.
We identified one trial comparing early versus delayed laparoscopic cholecystectomy for people with mild acute pancreatitis. Fifty participants with mild acute gallstone pancreatitis were randomised either to early laparoscopic cholecystectomy (within 48 hours of admission irrespective of whether the abdominal symptoms were resolved or the laboratory values had returned to normal) (n = 25), or to delayed laparoscopic cholecystectomy (surgery after resolution of abdominal pain and after the laboratory values had returned to normal) (n = 25). This trial is at high risk of bias. There was no short-term mortality in either group. There was no significant difference between the groups in the proportion of participants who developed serious adverse events (RR 0.33; 95% CI 0.01 to 7.81). Health-related quality of life was not reported in this trial. There were no conversions to open cholecystectomy in either group. The total hospital stay was significantly shorter in the early laparoscopic cholecystectomy group than in the delayed laparoscopic cholecystectomy group (MD -2.30 days; 95% CI -4.40 to -0.20). This trial reported neither the number of work-days lost nor the costs. We did not identify any trials comparing early versus delayed laparoscopic cholecystectomy after severe acute pancreatitis. There is no evidence of increased risk of complications after early laparoscopic cholecystectomy. Early laparoscopic cholecystectomy may shorten the total hospital stay in people with mild acute pancreatitis. If appropriate facilities and expertise are available, early laparoscopic cholecystectomy appears preferable to delayed laparoscopic cholecystectomy in those with mild acute pancreatitis. There is currently no evidence to support or refute early laparoscopic cholecystectomy for people with severe acute pancreatitis. Further randomised controlled trials at low risk of bias are necessary in people with mild acute pancreatitis and severe acute pancreatitis.
We included 24 studies that involved a total of 1787 participants. Studies reported on various types of acupuncture and related interventions including manual acupuncture and acupressure, ear acupressure, transcutaneous electrical acupuncture point stimulation, far-infrared radiation on acupuncture points and indirect moxibustion. CKD stages included pre-dialysis stage 3 or 4 and end-stage kidney disease on either haemodialysis or peritoneal dialysis. None of the included studies assessed pain outcomes, nor formally addressed occurrence of serious adverse events, although three studies reported three participant deaths and three hospitalisations as reasons for attrition. Three studies reported minor acupuncture-related harms; the remainder did not report if those events occurred. All studies were assessed at high or unclear risk of bias in terms of allocation concealment. Seventeen studies reported outcomes measured for only two months. There was very low quality of evidence that compared with routine care, manual acupressure reduced scores of the Beck Depression Inventory score (scale from 0 to 63) (3 studies, 128 participants: MD -4.29, 95% CI -7.48 to -1.11, I2 = 0%), the revised Piper Fatigue Scale (scale from 0 to 10) (3 studies, 128 participants: MD -1.19, 95% CI -1.77 to -0.60, I2 = 0%), and the Pittsburgh Sleep Quality Index (scale from 0 to 21) (4 studies, 180 participants: MD -2.46, 95% CI -4.23 to -0.69, I2 = 50%). We were unable to perform further meta-analyses because of the paucity of data and problems with clinical heterogeneity, such as different interventions, comparisons and timing of outcome measurements. There was very low quality of evidence of the short-term effects of manual acupressure as an adjuvant intervention for fatigue, depression, sleep disturbance and uraemic pruritus in patients undergoing regular haemodialysis. The paucity of evidence indicates that there is little evidence of the effects of other types of acupuncture for other outcomes, including pain, in patients with other stages of CKD. Overall high or unclear risk of bias distorts the validity of the reported benefit of acupuncture and makes the estimated effects uncertain. The incomplete reporting of acupuncture-related harm does not permit us to assess the safety of acupuncture and related interventions. Future studies should investigate the effects and safety of acupuncture for pain and other common symptoms in patients with CKD and those undergoing dialysis.
The search identified 16 eligible studies, in which only adults with cirrhosis were included. In one study, people with portal thrombosis were also included. We classified most of the studies at high risk of bias for the 'Participants selection' and the 'Flow and timing' domains. One study assessed the accuracy of capsule endoscopy for the diagnosis of large (high-risk) oesophageal varices. In the remaining15 studies that assessed the accuracy of capsule endoscopy for the diagnosis of oesophageal varices of any size in people with cirrhosis, 936 participants were included; the pooled estimate of sensitivity was 84.8% (95% confidence interval (CI) 77.3% to 90.2%) and of specificity 84.3% (95% CI 73.1% to 91.4%). Eight of these studies included people with suspected varices or people with already diagnosed or even treated varices, or both, introducing a selection bias. Seven studies including only people with suspected but unknown varices were at low risk of bias; the pooled estimate of sensitivity was 79.7% (95% CI 73.1% to 85.0%) and of specificity 86.1% (95% CI 64.5% to 95.5%). Six studies assessed the diagnostic accuracy of capsule endoscopy for the diagnosis of large oesophageal varices, associated with a higher risk of bleeding; the pooled sensitivity was 73.7% (95% CI 52.4% to 87.7%) and of specificity 90.5% (95% CI 84.1% to 94.4%). Two studies also evaluated the presence of red marks, which are another marker of high risk of bleeding; the estimates of sensitivity and specificity varied widely. Two studies obtained similar results with the use of a modified device as index test (string capsule). Due to the absence of data, we could not perform all planned subgroup analyses. Interobserver agreement in the interpretation of capsule endoscopy results and any adverse event attributable to capsule endoscopy were poorly assessed and reported. Only four studies evaluated the interobserver agreement in the interpretation of capsule endoscopy results: the concordance was moderate. The participants' preferences for capsule endoscopy or oesophago-gastro-duodenoscopy were reported differently but seemed in favour of capsule endoscopy in nine of 10 studies. In 10 studies, participants reported some minor discomfort on swallowing the capsule. Only one study identified other significant adverse events, including impaction of the capsule due to previously unidentified oesophageal strictures in two participants. No adverse events were reported as a consequence of the reference standard. We cannot support the use of capsule endoscopy as a triage test in adults with cirrhosis, administered before oesophago-gastro-duodenoscopy, despite the low incidence of adverse events and participant reports of being better tolerated. Thus, we cannot conclude that oesophago-gastro-duodenoscopy can be replaced by capsule endoscopy for the detection of oesophageal varices in adults with cirrhosis. We found no data assessing capsule endoscopy in children and in people with portal thrombosis.
We included six trials that enrolled 794 women and their babies and all assessed nifedipine as calcium channel blocker maintenance therapy. The six trials were judged to be at a moderate risk of bias overall. No differences in the incidence of preterm birth (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.87 to 1.09; five trials, 681 women), birth within 48 hours of treatment (RR 0.46; 95% CI 0.07 to 3.00; two trials, 128 women) or neonatal mortality (average RR 0.75; 95% CI 0.05 to 11.76; two trials, 133 infants) were seen when nifedipine maintenance therapy was compared with placebo or no treatment. No stillbirths were reported in the one trial that provided data for this outcome. No trials reported on longer-term follow-up of infants. Women receiving nifedipine maintenance therapy were significantly more likely to have their pregnancy prolonged (mean difference (MD) 5.35 days; 95% CI 0.49 to 10.21; four trials, 275 women); however, no differences between groups were shown for birth at less than 34 weeks' gestation, birth at less than 28 weeks' gestation, birth within seven days of treatment, or gestational age at birth. No significant differences were shown between the nifedipine and control groups for any of the secondary neonatal morbidities reported. Similarly, no significant differences were seen for the outcomes relating to the use of health services, except for in one trial, where infants whose mothers received nifedipine were significantly more likely to have a longer length of hospital stay as compared with infants born to mothers who received a placebo (MD 14.00 days; 95% CI 4.21 to 23.79; 60 infants). Based on the current available evidence, maintenance treatment with a calcium channel blocker after threatened preterm labour does not prevent preterm birth or improve maternal or infant outcomes.
We identified eight studies with a total of 204 participants and a mean sample size of 25. All trials were single-centre trials, and participants seen on an outpatient basis. Seven studies compared medication and placebo (n = 184); one study compared medication and another active agent (n = 13). Duration of the studies was six to twelve weeks. Meta-analysis was not undertaken because of the methodological heterogeneity of the trials. The studies did not employ intention-to-treat analyses and were at a high risk of attrition bias. Adverse events were not well-documented in the studies. None of the three studies of selective serotonin reuptake inhibitors (SSRIs) demonstrated strong evidence of a treatment effect on any of the outcomes of interest. The unpublished naltrexone study did not provide strong evidence of a treatment effect. Two studies, an olanzapine study and a N-acetylcysteine (NAC) study, reported statistically significant treatment effects. One study of clomipramine demonstrated a treatment effect on two out of three measures of response to treatment. No particular medication class definitively demonstrates efficacy in the treatment of trichotillomania. Preliminary evidence suggests treatment effects of clomipramine, NAC and olanzapine based on three individual trials, albeit with very small sample sizes.
Nine studies (1265 participants) met the inclusion criteria of the review. Two studies were conducted in children. Study reporting quality was fair, but all studies were of short duration (three to twelve weeks). Lung function was not significantly different between extrafine BDP and FP when compared at the same dose in parallel studies, change in FEV1: 0.04 litres (95% CI -0.03 to 0.11 litres; three studies, 659 adults); change in FEV1 predicted: -2.18% (95% CI -4.62 to 0.26; three studies, 334 adults); change in am PEF: -0.69 litres (95% CI -11.21 to 9.83 litres; two studies, 364 adults). Individual studies reported non-significant findings in symptom scores and quality of life questionnaires. There was no significant difference between FP and extrafine HFA-BDP in the risk of study withdrawal, dysphonia or when data were reported as any adverse event. There was no significant difference between FP and extrafine HFA-BDP on FEV1 or peak flow at a dose ratio of 1:1. However, the number of studies and width of the confidence intervals in the analyses do not exclude a clinically meaningful difference between these two drugs. Difficulty in the successful manipulation of the devices studied may be a barrier to the widespread use of MDIs. Only two small paediatric studies were included in the review, so extrapolation of the findings of this review to children is limited. Further longer term studies in adults and children with moderate and severe asthma are required.
We included 17 RCTs comprising a total of 2264 participants; 13 RCTs included 1954 adult participants, and four RCTs included 310 children. This update included 12 new studies, excluded one previously included study, and excluded five new trials. One trial awaits classification. All trials limited inclusion to inpatients with community-acquired pneumonia (CAP), with or without healthcare-associated pneumonia (HCAP). We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials. Corticosteroids significantly reduced mortality in adults with severe pneumonia (RR 0.58, 95% CI 0.40 to 0.84; moderate-quality evidence), but not in adults with non-severe pneumonia (RR 0.95, 95% CI 0.45 to 2.00). Early clinical failure rates (defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8) were significantly reduced with corticosteroids in people with severe and non-severe pneumonia (RR 0.32, 95% CI 0.15 to 0.7; and RR 0.68, 95% CI 0.56 to 0.83, respectively; high-quality evidence). Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications. Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates (defined as for adults, RR 0.41, 95% CI 0.24 to 0.70; high-quality evidence) based on two small, clinically heterogeneous trials, and reduced time to clinical cure. Hyperglycaemia was significantly more common in adults treated with corticosteroids (RR 1.72, 95% CI 1.38 to 2.14). There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections (RR 1.19, 95% CI 0.73 to 1.93). Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.
Twelve randomized controlled trials met our inclusion criteria. Study findings were similar between 28-day and extended or continuous regimens in regard to contraceptive efficacy (i.e., pregnancy rates) and safety profiles. When compliance was reported, no difference between 28-day and extended or continuous cycles was found. Participants reported high satisfaction with both dosing regimens, but this was not an outcome universally studied. Overall discontinuation and discontinuation for bleeding problems were not uniformly higher in either group. The studies that reported menstrual symptoms found that the extended or continuous group fared better in terms of headaches, genital irritation, tiredness, bloating, and menstrual pain. Eleven out of the twelve studies found that bleeding patterns were either equivalent between groups or improved with extended or continuous cycles over time. Endometrial lining assessments by ultrasound and/or endometrial biopsy were done in some participants and were all normal after cyclic or extended CHC use. The 2014 update yielded four additional trials but unchanged conclusions. Evidence from existing randomized control trials comparing continuous or extended-cycle CHCs (greater than 28 days of active combined hormones) to traditional cyclic dosing (21 days of active hormone and 7 days of placebo, or 24 days of active hormone and 4 days of placebo) is of good quality. However, the variations in type of hormones and time length for extended-cycle dosing make a formal meta-analysis impossible. Future studies should choose a previously described type of CHC and dosing regimen. More attention needs to be directed towards participant satisfaction, continuation, and menstruation-associated symptoms.
A total of 798 studies were identified following the initial search. No published or unpublished randomised controlled trials comparing primary tumour resection versus no resection in asymptomatic patients with unresectable stage IV colorectal cancer who were treated with chemo/radiotherapy were identified. Seven non-randomised studies, potentially eligible for inclusion, were identified: 2 case-matched studies, 2 CCTs and 3 retrospective cohort studies. Overall, these trials included 1.086 patients (722 patients treated with primary tumour resection, and 364 patients managed first with chemotherapy and/or radiotherapy). Resection of the primary tumour in asymptomatic patients with unresectable stage IV colorectal cancer who are managed with chemo/radiotherapy is not associated with a consistent improvement in overall survival. In addition, resection does not significantly reduce the risk of complications from the primary tumour (i.e.  obstruction, perforation or bleeding). Yet there is enough doubt with regard to the published literature to justify further clinical trials in this area. The results from an ongoing high quality randomised controlled trial will help to answer this question.
A total of 14 relevant trials were identified, consisting of a total of 3157 patients. There was a statistically significant overall survival advantage in favor of the donor versus no donor group (HR 0.86; 95% CI 0.77 to 0.97; P = 0.01), as well as significant improvement in disease-free survival in the donor group(HR 0.82; 95% CI 0.72 to 0.94; P = 0.004). Those in the donor group had significant reduction in primary disease relapse(RR 0.53; 95% CI 0.37 to 0.76; P = 0.0004) and significant increase in non-relapse mortality(RR 2.8; 95% CI 1.66 to 4.73; P = 0.001). Significant heterogeneity was detected in analysis of relapse (Chi2 40.51, df = 6, P < 0.00001; I2 = 85%). In regard to methodologic quality, the majority of included studies were free of selective reporting, and performed analyses according to intention to treat. Conversely, few reported sample size calculation that informed the study design. While blinding was considered as an important domain of methodological quality, none of the studies reported on whether any of the study personnel were blinded (e.g. subjects, personnel, outcome assessors, data analysts etc). Therefore, we did not consider blinding further in the analysis of methodological quality in this review. The results of this systematic review and meta-analysis support matched sibling donor allogeneic hematopoietic cell transplantation as the optimal post-remission therapy in ALL patients aged 15 years or over. This therapy offers superior overall survival and disease-free survival, and significantly reduces the risk of disease relapse, but does impose an increased risk of non-relapse mortality. Importantly these data are based on adult ALL treated with largely total body irradiation-based myeloablative conditioning and sibling donor transplantation and, therefore, cannot be generalized to pediatric ALL, alternative donors including HLA (human leukocyte antigen) mismatched or unrelated donors, or reduced toxicity or non-myeloablative conditioning regimens.
Thirty eight randomised controlled comparisons (made within 22 trials) were identified. Most were based on 'healthy' adult participants who were not considered to be at increased risk of regurgitation or aspiration during anaesthesia. Few trials reported the incidence of aspiration/regurgitation or related morbidity but relied on indirect measures of patient safety i.e. intra-operative gastric volume and pH. There was no evidence that the volume or pH of participants' gastric contents differed significantly depending on whether the groups were permitted a shortened preoperative fluid fast or continued a standard fast. Fluids evaluated included water, coffee, fruit juice, clear fluids and other drinks (e.g. isotonic drink, carbohydrate drink). Participants given a drink of water preoperatively were found to have a significantly lower volume of gastric contents than the groups that followed a standard fasting regimen. This difference was modest and clinically insignificant. There was no indication that the volume of fluid permitted during the preoperative period (i.e. low or high) resulted in a difference in outcomes from those participants that followed a standard fast. Few trials specifically investigated the preoperative fasting regimen for patient populations considered to be at increased risk during anaesthesia of regurgitation/aspiration and related morbidity. There was no evidence to suggest a shortened fluid fast results in an increased risk of aspiration, regurgitation or related morbidity compared with the standard 'nil by mouth from midnight' fasting policy. Permitting patients to drink water preoperatively resulted in significantly lower gastric volumes. Clinicians should be encouraged to appraise this evidence for themselves and when necessary adjust any remaining standard fasting policies (nil-by-mouth from midnight) for patients that are not considered 'at-risk' during anaesthesia.
We included two RCTs (involving 154 women) with a low risk of bias. It was not possible to pool the available studies. The two studies do not consistently report outcomes defined in the review. However, no significant differences were observed between the two groups (surgical versus non-surgical repair) in incidence of pain and wound complications, self-evaluated measures of pain at hospital discharge and postpartum and re-initiation of sexual activity. Differences in the use of analgesia varied between the studies, being high in the sutured group in one study. The other trial showed differences in wound closure and poor wound approximation in the non-suturing group, but noted incidentally also that more women were breastfeeding in this group. There is limited evidence available from RCTs to guide the choice between surgical or non-surgical repair of first- or second-degree perineal tears sustained during childbirth. Two studies find no difference between the two types of management with regard to clinical outcomes up to eight weeks postpartum. Therefore, at present there is insufficient evidence to suggest that one method is superior to the other with regard to healing and recovery in the early or late postnatal periods. Until further evidence becomes available, clinicians' decisions whether to suture or not can be based on their clinical judgement and the women's preference after informing them about the lack of long-term outcomes and the possible chance of a slower wound healing process, but possible better overall feeling of well being if left un-sutured.
Eleven studies (1117 participants) met our inclusion criteria. These consisted of six case-control studies, two retrospective cohort studies and three prospective cohort studies. Three studies used single-headed camera SPECT while the remaining eight used multiple-headed camera SPECT. Study design and methods varied widely. Overall, participant selection was not well described and the studies were judged as having either high or unclear risk of bias. Often the threshold used to define a positive SPECT result was not predefined and the results were reported with knowledge of the reference standard. Concerns regarding applicability of the studies to the review question were generally low across all three domains (participant selection, index test and reference standard). Sensitivities and specificities for differentiating FTD from non-FTD ranged from 0.73 to 1.00 and from 0.80 to 1.00, respectively, for the three multiple-headed camera studies. Sensitivities were lower for the two single-headed camera studies; one reported a sensitivity and specificity of 0.40 (95% confidence interval (CI) 0.05 to 0.85) and 0.95 (95% CI 0.90 to 0.98), respectively, and the other a sensitivity and specificity of 0.36 (95% CI 0.24 to 0.50) and 0.92 (95% CI 0.88 to 0.95), respectively. Eight of the 11 studies which used SPECT to differentiate FTD from Alzheimer's disease used multiple-headed camera SPECT. Of these studies, five used a case-control design and reported sensitivities of between 0.52 and 1.00, and specificities of between 0.41 and 0.86. The remaining three studies used a cohort design and reported sensitivities of between 0.73 and 1.00, and specificities of between 0.94 and 1.00. The three studies that used single-headed camera SPECT reported sensitivities of between 0.40 and 0.80, and specificities of between 0.61 and 0.97. At present, we would not recommend the routine use of rCBF SPECT in clinical practice because there is insufficient evidence from the available literature to support this. Further research into the use of rCBF SPECT for differentiating FTD from other dementias is required. In particular, protocols should be standardised, study populations should be well described, the threshold for 'abnormal' scans predefined and clear details given on how scans are analysed. More prospective cohort studies that verify the presence or absence of FTD during a period of follow up should be undertaken.
The 19 included trials (involving 1589 older adults) were small, often with methodological flaws. Just two pairs of trials tested similar interventions. Twelve trials evaluated mobilisation strategies started soon after hip fracture surgery. Single trials found improved mobility from, respectively, a two-week weight-bearing programme, a quadriceps muscle strengthening exercise programme and electrical stimulation aimed at alleviating pain. Single trials found no significant improvement in mobility from, respectively, a treadmill gait retraining programme, 12 weeks of resistance training, and 16 weeks of weight-bearing exercise. One trial testing ambulation started within 48 hours of surgery found contradictory results. One historic trial found no significant difference in unfavourable outcomes for weight bearing started at two versus 12 weeks. Of two trials evaluating more intensive physiotherapy regimens, one found no difference in recovery, the other reported a higher level of drop-out in the more intensive group. Two trials tested electrical stimulation of the quadriceps: one found no benefit and poor tolerance of the intervention; the other found improved mobility and good tolerance. Seven trials evaluated strategies started after hospital discharge. Started soon after discharge, two trials found improved outcome after 12 weeks of intensive physical training and a home-based physical therapy programme respectively. Begun after completion of standard physical therapy, one trial found improved outcome after six months of intensive physical training, one trial found increased activity levels from a one year exercise programme, and one trial found no significant effects of home-based resistance or aerobic training. One trial found improved outcome after home-based exercises started around 22 weeks from injury. One trial found home-based weight-bearing exercises starting at seven months produced no significant improvement in mobility. There is insufficient evidence from randomised trials to establish the best strategies for enhancing mobility after hip fracture surgery.
We included two randomized controlled trials (218 eyes of 216 participants) comparing the effectiveness of pneumatic retinopexy versus scleral buckle for eyes with RRD. We identified no studies investigating the comparison of pneumatic retinopexy versus a combination treatment of scleral buckle and vitrectomy. Of the two included studies, one was a small study with 20 participants enrolled in Ireland and followed for an average of 16 months. The second study was larger with 196 participants (198 eyes) enrolled in the United States and followed for at least 6 months. Cautious interpretation of the results is warranted, since we graded the evidence as low to moderate quality due to insufficient reporting of study methods and imprecision and inconsistency among study results. Both studies showed fewer eyes achieving retinal reattachment in the pneumatic retinopexy group compared with the scleral buckle group by six-months follow-up (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.77 to 1.02, 218 eyes); however, we are uncertain as to whether the intervention has an important effect on reattachment because the results are imprecise. Eyes in the pneumatic retinopexy group also were more likely to have had a recurrence of retinal detachment by six-months follow-up (RR 1.80, 95% CI 1.00 to 3.24, 218 eyes); however, we are uncertain as to whether the intervention has an important effect on recurrence because the lower CI equals no difference. Neither study reported mean change in visual acuity, quality of life data, or economic measures. Differences between the pneumatic retinopexy group and scleral buckle group were uncertain due to small numbers of events with respect to operative ocular adverse events (RR 0.67, 95% CI 0.32 to 1.42, 218 eyes), development of cataract (RR 0.92, 95% CI 0.06 to 14.54, 198 eyes), glaucoma (RR 0.31, 95% CI 0.03 to 2.91, 198 eyes), macular pucker (RR 0.74, 95% CI 0.20 to 2.67, 198 eyes), and proliferative vitreoretinopathy (RR 0.94, 95% CI 0.30 to 2.96, 218 eyes). Fewer eyes in the pneumatic retinopexy group compared with the scleral buckle group experienced choroidal detachment (RR 0.17, 95% CI 0.05 to 0.57, 198 eyes) or myopic shift equal to or greater than 1 diopter spherical equivalent (RR 0.04, 95% CI 0.01 to 0.13, 198 eyes). The evidence suggests that pneumatic retinopexy may result in lower rates of reattachment and higher rates of recurrence than scleral buckle for eyes with RRD, but does not rule out no difference between procedures. The relative safety of the procedures is uncertain and the relative effects of these procedures in terms of other patient-important outcomes, such as visual acuity and quality of life, is unknown. Due to the limited information available between pneumatic retinopexy and scleral buckle procedures, future research addressing these evidence gaps are warranted.
We included 58 trials, involving 2797 participants, which comprised cardiorespiratory interventions (28 trials, 1408 participants), resistance interventions (13 trials, 432 participants), and mixed training interventions (17 trials, 957 participants). Thirteen deaths occurred before the end of the intervention and a further nine before the end of follow-up. No dependence data were reported. Diverse outcome measures restricted pooling of data. Global indices of disability show moderate improvement after cardiorespiratory training (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) 0.19 to 0.84; P value = 0.002) and by a small amount after mixed training (SMD 0.26, 95% CI 0.04 to 0.49; P value = 0.02); benefits at follow-up (i.e. after training had stopped) were unclear. There were too few data to assess the effects of resistance training. Cardiorespiratory training involving walking improved maximum walking speed (mean difference (MD) 6.71 metres per minute, 95% CI 2.73 to 10.69), preferred gait speed (MD 4.28 metres per minute, 95% CI 1.71 to 6.84), and walking capacity (MD 30.29 metres in six minutes, 95% CI 16.19 to 44.39) at the end of the intervention. Mixed training, involving walking, increased preferred walking speed (MD 4.54 metres per minute, 95% CI 0.95 to 8.14), and walking capacity (MD 41.60 metres per six minutes, 95% CI 25.25 to 57.95). Balance scores improved slightly after mixed training (SMD 0.27, 95% CI 0.07 to 0.47). Some mobility benefits also persisted at the end of follow-up. The variability, quality of the included trials, and lack of data prevents conclusions about other outcomes and limits generalisability of the observed results. Cardiorespiratory training and, to a lesser extent, mixed training reduce disability during or after usual stroke care; this could be mediated by improved mobility and balance. There is sufficient evidence to incorporate cardiorespiratory and mixed training, involving walking, within post-stroke rehabilitation programmes to improve the speed and tolerance of walking; some improvement in balance could also occur. There is insufficient evidence to support the use of resistance training. The effects of training on death and dependence after stroke are still unclear but these outcomes are rarely observed in physical fitness training trials. Cognitive function is under-investigated despite being a key outcome of interest for patients. Further well-designed randomised trials are needed to determine the optimal exercise prescription and identify long-term benefits.
Sixteen studies (894 patients) were included. No formulation, route, or schedule of vitamin D compound was found to alter the mortality risk or need for dialysis. Vitamin D compounds significantly lowered serum PTH (4 studies, 153 patients: MD -49.34 pg/mL, 95% CI -85.70 to -12.97 (-5.6 pmol/L, 95% CI -9.77 to -1.48)) and were more likely to reduce serum PTH > 30% from baseline value (264 patients: RR 7.87, 95% CI 4.87 to 12.73). Vitamin D treatment was associated with increased end of treatment serum phosphorus (3 studies, 140 patients: MD 0.37 mg/dL, 95% CI 0.09, 0.66 (0.12 mmol/L, 95% CI 0.03, 0.21)) and serum calcium (5 studies, 184 patients: MD 0.20 mg/dL, 95% CI 0.17 to 0.23 (0.05 mmol/L, 95% CI 0.04 to 0.06)). Few data were available comparing intermittent with daily vitamin D administration, or other schedules of dosing. There are not sufficient data to determine the effect of vitamin D compounds on mortality and cardiovascular outcomes in people with CKD not requiring dialysis. While vitamin D compounds reduce serum PTH (49.3 pg/mL (5.6 pmol/L)) compared with placebo, the relative clinical benefits of PTH lowering versus treatment-related increases in serum phosphorus and calcium remain to be understood.
Sixteen trials, involving over one million adults, children and infants, fulfilled the inclusion criteria. Twenty-four comparisons reported on vaccine efficacy (cholera cases and/or deaths) and 11 comparisons considered adverse effects (nine reported on both). Compared to placebo, vaccinees had a reduced risk of death from cholera (RR 0.49, 95% CI 0.25 to 0.93; 837,442 participants) and a reduced risk of contracting cholera at 12 months (RR 0.52, 95% CI 0.42 to 0.65, random-effects model; 1,512,573 participants). This translates to an efficacy of 48%, 95% confidence interval 35% to 58%. Significant protection lasted for two years, even after only a single dose, and for three years with an annual booster. Children over five years and adults were protected for up to three years, while children under five years were protected for up to a year. Injected cholera vaccines were associated with more systemic and local adverse effects compared to placebo, but these were not severe or life-threatening. Injected cholera vaccines appear to be safe and relatively more effective than usually realized. Protection against cholera persists for up to two years following a single dose of vaccine, and for three years with an annual booster. However, they have been superseded by oral vaccines.
We included two trials with 215 participants. One trial was published in 2011 and included 193 children aged 9 months to 18 months, and compared treatment with hydroxyurea to placebo. The second trial was published in 1998 and included 22 adults with normal blood pressure and microalbuminuria and compared ACEI to placebo. We rated the quality of evidence as low to very low across different outcomes according to GRADE methodology. This was due to trials having: a high or unclear risk of bias including attrition and detection bias; indirectness (the available evidence was for children aged 9 months to 18 months in one trial and a small and select adult sample size in a second trial); and imprecise outcome effect estimates of significant benefit or harm. Hydroxyurea versus placebo We are very uncertain if hydroxyurea reduces or prevents progression of kidney disease (assessed by change in glomerular filtration rate), or reduces hyperfiltration in children aged 9 to 18 months, mean difference (MD) 0.58 (95% confidence interval (CI) -14.60 to 15.76 (mL/min per 1.73 m²)) (one study; 142 participants; very low-quality evidence). In children aged 9 to 18 months, hydroxyurea may improve the ability to concentrate urine, MD 42.23 (95% CI 12.14 to 72.32 (mOsm/kg)) (one study; 178 participants; low-quality evidence). Hydroxyurea may make little or no difference to SCD-related serious adverse events including: incidence of acute chest syndrome, risk ratio (RR) 0.39 (99% CI 0.13 to 1.16); painful crisis, RR 0.68 (99% CI 0.45 to 1.02); and hospitalisations, RR 0.83 (99% CI 0.68 to 1.01) (one study, 193 participants; low-quality evidence). No deaths occurred in the trial. Quality of life was not reported. ACEI versus placebo We are very uncertain if ACEI reduces proteinuria in adults with SCD who have normal blood pressure and microalbuminuria, MD -49.00 (95% CI -124.10 to 26.10 (mg per day)) (one study; 22 participants; very low-quality evidence). We are very uncertain if ACEI reduce or prevent kidney disease as measured by creatinine clearance. The authors state that creatinine clearance remained constant over six months in both groups, but no comparative data were provided (very low-quality evidence). All-cause mortality, serious adverse events and quality of life were not reported. In young children aged 9 months to 18 months, we are very uncertain if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration, but it may improve young children's ability to concentrate urine and may make little or no difference on the incidence of acute chest syndrome, painful crises and hospitalisations. We are very uncertain if giving ACEI to adults with normal blood pressure and microalbuminuria has any effect on preventing or reducing kidney complications. This review identified no trials that looked at red cell transfusions nor any combinations of interventions to prevent or reduce kidney complications. Due to lack of evidence this review cannot comment on the management of either children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately-designed and powered studies, and no ongoing trials which address this critical question. Trials of hydroxyurea, ACEI or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction kidney complications in people with SCD.
Five trials with 196 people were included. One three-arm trial (47 participants) compared arthrographic distension using steroid and air to distension using air alone and to steroid injection alone. One trial (46 participants) compared arthrographic distension using steroid and saline to placebo. Two trials (45 and 22 participants) compared arthrographic distension using steroid to steroid injection alone. One trial (36 participants) compared arthrographic distension using steroid and saline plus physical therapy to physical therapy alone. Trials included similar study participants, but quality and reporting of data were variable. Only one trial was at low risk of bias. No meta-analysis was performed. The trial with low risk of bias demonstrated that distension with saline and steroid was better than placebo for pain (number needed to treat to benefit (NNTB) = 2), function (NNTB = 3) and range of movement at three weeks. This benefit was maintained at six and 12 weeks only for one of two scores measuring function (NNT = 3). A second trial with high risk of bias also reported that distension combined with physical therapy improved range of movement and median percent improvement in pain (but not pain score) at eight weeks compared to physical therapy alone. Three further trials, all at high risk of bias, reported conflicting, variable effects of arthrographic distension with steroid compared to distension alone, and arthrographic distension with steroid compared to intra-articular steroid injection. The trials reported a small number of minor adverse effects, mainly pain during and after the procedure. There is "silver" level evidence that arthrographic distension with saline and steroid provides short-term benefits in pain, range of movement and function in adhesive capsulitis. It is uncertain whether this is better than alternative interventions.
We included six trials (483 adult ICU participants). Exercise-based interventions were delivered on the ward in two studies; both on the ward and in the community in one study; and in the community in three studies. The duration of the intervention varied according to length of hospital stay following ICU discharge (up to a fixed duration of 12 weeks). Risk of bias was variable for all domains across all trials. High risk of bias was evident in all studies for performance bias, although blinding of participants and personnel in therapeutic rehabilitation trials can be pragmatically challenging. For other domains, at least half of the studies were at low risk of bias. One study was at high risk of selection bias, attrition bias and other sources of bias. Risk of bias was unclear for the remaining studies across domains. We decided not to undertake a meta-analysis because of variation in study design, types of interventions and outcome measurements. We present a narrative description of individual studies for each outcome. All six studies assessed functional exercise capacity, although we noted wide variability in the nature of interventions, outcome measures and associated metrics and data reporting. Overall quality of the evidence was very low. Individually, three studies reported positive results in favour of the intervention. One study found a small short-term benefit in anaerobic threshold (mean difference (MD) 1.8 mL O2/kg/min, 95% confidence interval (CI) 0.4 to 3.2; P value = 0.02). In a second study, both incremental (MD 4.7, 95% CI 1.69 to 7.75 watts; P value = 0.003) and endurance (MD 4.12, 95% CI 0.68 to 7.56 minutes; P value = 0.021) exercise testing results were improved with intervention. Finally self reported physical function increased significantly following use of a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention. Similar variability was evident with regard to findings for the primary outcome of health-related quality of life. Only two studies evaluated this outcome. Individually, neither study reported differences between intervention and control groups for health-related quality of life due to the intervention. Overall quality of the evidence was very low. Four studies reported rates of withdrawal, which ranged from 0% to 26.5% in control groups, and from 8.2% to 27.6% in intervention groups. The quality of evidence for the effect of the intervention on withdrawal was low. Very low-quality evidence showed rates of adherence with the intervention. Mortality ranging from 0% to 18.8% was reported by all studies. The quality of evidence for the effect of the intervention on mortality was low. Loss to follow-up, as reported in all studies, ranged from 0% to 14% in control groups, and from 0% to 12.5% in intervention groups, with low quality of evidence. Only one non-mortality adverse event was reported across all participants in all studies (a minor musculoskeletal injury), and the quality of the evidence was low. At this time, we are unable to determine an overall effect on functional exercise capacity, or on health-related quality of life, of an exercise-based intervention initiated after ICU discharge for survivors of critical illness. Meta-analysis of findings was not appropriate because the number of studies and the quantity of data were insufficient. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others did not. No effect on health-related quality of life was reported. Methodological rigour was lacking across several domains, influencing the quality of the evidence. Wide variability was noted in the characteristics of interventions, outcome measures and associated metrics and data reporting. If further trials are identified, we may be able to determine the effects of exercise-based intervention following ICU discharge on functional exercise capacity and health-related quality of life among survivors of critical illness.
We included 12 trials with 734 patients randomised to miniport laparoscopic cholecystectomy (380 patients) versus standard laparoscopic cholecystectomy (351 patients). Only one trial which included 70 patients was of low risk of bias. Miniport laparoscopic cholecystectomy could be completed successfully in more than 80% of patients in most trials. The remaining patients were mostly converted to standard port laparoscopic cholecystectomy but some were also converted to open cholecystectomy. These patients were included for the outcome conversion to open cholecystectomy but excluded from other outcomes. Accordingly, the results of the other outcomes are on 343 patients in the miniport laparoscopic cholecystectomy group and 351 patients in the standard port laparoscopic cholecystectomy group, and therefore the results have to be interpreted with extreme caution. There was no mortality in the seven trials that reported mortality (0/194 patients in miniport laparoscopic cholecystectomy versus 0/203 patients in standard port laparoscopic cholecystectomy). There were no significant differences between miniport laparoscopic cholecystectomy and standard laparoscopic cholecystectomy in the proportion of patients who developed serious adverse events (eight trials; 460 patients; RR 0.33; 95% CI 0.04 to 3.08) (miniport laparoscopic cholecystectomy: 1/226 (adjusted proportion 0.4%) versus standard laparoscopic cholecystectomy: 3/234 (1.3%); quality of life at 10 days after surgery (one trial; 70 patients; SMD -0.20; 95% CI -0.68 to 0.27); or in whom the laparoscopic operation had to be converted to open cholecystectomy (11 trials; 670 patients; RR 1.23; 95% CI 0.44 to 3.45) (miniport laparoscopic cholecystectomy: 8/351 (adjusted proportion 2.3%) versus standard laparoscopic cholecystectomy 6/319 (1.9%)). Miniport laparoscopic cholecystectomy took five minutes longer to complete than standard laparoscopic cholecystectomy (12 trials; 695 patients; MD 4.91 minutes; 95% CI 2.38 to 7.44). There were no significant differences between miniport laparoscopic cholecystectomy and standard laparoscopic cholecystectomy in the length of hospital stay (six trials; 351 patients; MD -0.00 days; 95% CI -0.12 to 0.11); the time taken to return to activity (one trial; 52 patients; MD 0.00 days; 95% CI -0.31 to 0.31); or in the time taken for the patient to return to work (two trials; 187 patients; MD 0.28 days; 95% CI -0.44 to 0.99) between the groups. There was no significant difference in the cosmesis scores at six months to 12 months after surgery between the two groups (two trials; 152 patients; SMD 0.13; 95% CI -0.19 to 0.46). Miniport laparoscopic cholecystectomy can be completed successfully in more than 80% of patients. There appears to be no advantage of miniport laparoscopic cholecystectomy in terms of decreasing mortality, morbidity, hospital stay, return to activity, return to work, or improving cosmesis. On the other hand, there is a modest increase in operating time after miniport laparoscopic cholecystectomy compared with standard port laparoscopic cholecystectomy and the safety of miniport laparoscopic cholecystectomy is yet to be established. Miniport laparoscopic cholecystectomy cannot be recommended routinely outside well-designed randomised clinical trials. Further trials of low risks of bias and low risks of random errors are necessary.
We identified two RCTs and one CCT (total number of participants 149) evaluating the use of amifostine versus no additional treatment in the original version of the review; the updates identified no additional studies. Two studies included children with osteosarcoma, and the other study included children with hepatoblastoma. Children received cisplatin only or a combination of cisplatin and carboplatin, either intra-arterially or intravenously. Pooling of results of the included studies was not possible. From individual studies the effect of amifostine on symptomatic ototoxicity only (i.e. National Cancer Institute Common Toxicity Criteria version 2 (NCICTCv2) or modified Brock grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (i.e. NCICTCv2 or modified Brock grade 1 or higher) were uncertain (low-certainty evidence). Only one study including children with osteosarcoma treated with intra-arterial cisplatin provided information on tumour response, defined as the number of participants with a good or partial remission. The available-data analysis (data were missing for one participant), best-case scenario analysis and worst-case scenario analysis showed a difference in favour of amifostine, although the certainty of evidence for this effect was low. There was no information on survival for any of the included studies. Only one study, including children with osteosarcoma treated with intra-arterial cisplatin, provided data on the number of participants with adverse effects other than ototoxicity grade 3 or higher (on NCICTCv2 scale). There was low-certainty evidence that grade 3 or 4 vomiting was higher with amifostine (risk ratio (RR) 9.04, 95% confidence interval (CI) 1.99 to 41.12). The effects on cardiotoxicity and renal toxicity grade 3 or 4 were uncertain (low-certainty evidence). None of the studies evaluated quality of life. In the recent update, we also identified one RCT including 109 children with localized hepatoblastoma evaluating the use of sodium thiosulfate versus no additional treatment. Children received intravenous cisplatin only (one child also received carboplatin). There was moderate-certainty evidence that both symptomatic ototoxicity only (i.e. Brock criteria grade 2 or higher) and combined asymptomatic and symptomatic ototoxicity (i.e. Brock criteria grade 1 or higher) was lower with sodium thiosulfate (combined asymptomatic and symptomatic ototoxicity: RR 0.52, 95% CI 0.33 to 0.81; symptomatic ototoxicity only: RR 0.39, 95% CI 0.19 to 0.83). The effect of sodium thiosulfate on tumour response (defined as number of participants with a complete or partial response at the end of treatment), overall survival (calculated from time of randomization to death or last follow-up), event-free survival (calculated from time of randomization until disease progression, disease relapse, second primary cancer, death, or last follow-up, whichever came first) and adverse effects other than hearing loss and tinnitus grade 3 or higher (according to National Cancer Institute Common Toxicity Criteria Adverse Effects version 3 (NCICTCAEv3) criteria) was uncertain (low-certainty evidence for all these outcomes). Quality of life was not assessed. We found no eligible studies for possible otoprotective medical interventions other than amifostine and sodium thiosulfate and for other types of malignancies. At the moment there is no evidence from individual studies in children with osteosarcoma or hepatoblastoma treated with different platinum analogues and dosage schedules that underscores the use of amifostine as an otoprotective intervention as compared to no additional treatment. Since pooling of results was not possible and the evidence was of low certainty, no definitive conclusions can be made. Since we found only one RCT evaluating the use of sodium thiosulfate in children with localized hepatoblastoma treated with cisplatin, no definitive conclusions on benefits and harms can be drawn. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. We identified no eligible studies for other possible otoprotective medical interventions and other types of malignancies, so no conclusions can be made about their efficacy in preventing ototoxicity in children treated with platinum-based therapy. More high-quality research is needed.
Six trials involving 988 patients (645 women and 343 men) and reporting eight comparisons were found. Two studies reported withdrawals and dropouts, but none mentioned analysis by intention to treat (ITT). 5-FU presented better results for cure than placebo or no treatment (relative risk (RR) 0.39, 95% confidence interval (CI) 0.23 to 0.67), meta-cresol-sulfonic acid (MCSA) (RR 2.11, 95% CI 0.83 to 5.37), Podophylin 2%, 4% or 25% (RR 1.26, 95% CI 0.86 to 1.82). There were no statistical differences for treatment failure for 5-FU versus CO2 Laser (RR 0.69, 95% CI 0.43 to 1.11) versus 5-FU + INFα-2a (low dose) (RR 1.02, 95% CI 0.87 to 1.119). Worse results were found for 5-FU versus 5-FU + INFα-2a (high dose) (RR 10.78, 95% CI 1.50 to 77.36), and 5-FU + CO2 Laser INFα-2a (high dose) (RR 7.97, 95% CI 2.87 to 22.13). The reviewed trials were highly variable in methods and quality, and the evidence provided by these studies was weak. Cure rates with several treatments were variable, and although 5-FU presents therapeutic results that are inferior to those seen with 5-FU + Inf α-2a (high dose) and 5-FU + CO2 Laser + Inf α-2a (high dose), the treatment should not be abandoned. Topical treatment with 5-FU has a therapeutic effect; however, the benefits and risks have not been determined clearly and further studies are needed.
Eleven eligible studies included 1339 participants. All the studies were of poor methodological quality. Seven studies evaluated pelvic endometriosis, one study considered DIE and/or ovarian endometrioma, two studies differentiated endometrioma from other ovarian cysts and one study addressed mapping DIE at specific anatomical sites. Fifteen different diagnostic combinations were assessed, including blood, urinary or endometrial biomarkers, transvaginal ultrasound (TVUS) and clinical history or examination. We did not pool estimates of sensitivity and specificity, as each study analysed independent combinations of the non-invasive tests. Tests that met the criteria for a replacement test were: a combination of serum IL-6 (cut-off >15.4 pg/ml) and endometrial PGP 9.5 for pelvic endometriosis (sensitivity 1.00 (95% confidence interval (CI) 0.91 to 1.00), specificity 0.93 (95% CI, 0.80, 0.98) and the combination of vaginal examination and transvaginal ultrasound (TVUS) for rectal endometriosis (sensitivity 0.96 (95% CI 0.86 to 0.99), specificity 0.98 (95% CI 0.94 to 1.00)). Tests that met the criteria for SpIN triage tests for pelvic endometriosis were: 1. a multiplication of urine vitamin-D-binding protein (VDBP) and serum CA-125 (cut-off >2755) (sensitivity 0.74 (95% CI 0.60 to 0.84), specificity 0.97 (95% CI 0.86 to 1.00)) and 2. a combination of history (length of menses), serum CA-125 (cut-off >35 U/ml) and endometrial leukocytes (sensitivity 0.61 (95% CI 0.54 to 0.69), specificity 0.95 (95% CI 0.91 to 0.98)). For endometrioma, the following combinations qualified as SpIN test: 1. TVUS and either serum CA-125 (cut-off ≥25 U/ml) or CA 19.9 (cut-off ≥12 U/ml) (sensitivity 0.79 (95% CI 0.64 to 0.91), specificity 0.97 (95% CI 0.91 to 1.00)); 2. TVUS and serum CA 19.9 (cut-off ≥12 U/ml) (sensitivity 0.54 (95% CI 0.37 to 0.70), specificity 0.97 (95% CI 0.91 to 1.0)); 3-4. TVUS and serum CA-125 (cut-off ≥20 U/ml or cut-off ≥25 U/ml) (sensitivity 0.69 (95% CI 0.49 to 0.85), specificity 0.96 (95% CI 0.88 to 0.99)); 5. TVUS and serum CA-125 (cut-off ≥35 U/ml) (sensitivity 0.52 (95% CI 0.33 to 0.71), specificity 0.97 (95% CI 0.90 to 1.00)). A combination of vaginal examination and TVUS reached the threshold for a SpIN test for obliterated pouch of Douglas (sensitivity 0.87 (95% CI 0.69 to 0.96), specificity 0.98 (95% CI 0.95 to 1.00)), vaginal wall endometriosis (sensitivity 0.82 (95% CI 0.60 to 0.95), specificity 0.99 (95% CI 0.97 to 1.0)) and rectovaginal septum endometriosis (sensitivity 0.88 (95% CI 0.47 to 1.00), specificity 0.99 (95% CI 0.96 to 1.00)). All the tests were evaluated in individual studies and displayed wide CIs. Due to the heterogeneity and high risk of bias of the included studies, the clinical utility of the studied combination diagnostic tests for endometriosis remains unclear. None of the biomarkers evaluated in this review could be evaluated in a meaningful way and there was insufficient or poor-quality evidence. Laparoscopy remains the gold standard for the diagnosis of endometriosis and using any non-invasive tests should only be undertaken in a research setting.
Only three trials, involving 189 participants, satisfied the inclusion criteria and these were of low methodological quality. One study showed a significant difference in hearing recovery in the vasodilator group (carbogen combined with a course of several other drugs) compared to the control group (a course of several other drugs alone). Another study only showed a significant improvement in higher frequencies in the vasodilator group (prostaglandin E1 + steroid) compared with the control group (placebo and steroid), no difference having been shown in overall hearing gain. In the third study the vasodilator group (naftidrofuryl and low-molecular weight dextran) showed an improvement only in lower frequencies over the control group (placebo and low-molecular weight dextran). Two of the studies reported adverse effects from vasodilator treatment, whereas there was no mention of any side effects in the third. Five patients in one study developed a sensation of heaviness in the head which settled spontaneously and did not interfere with treatment. In the other study one patient developed an allergic reaction and had to be excluded from the study. The effectiveness of vasodilators in the treatment of ISSHL remains unproven. The included studies were of relatively poor quality and the number of patients included was small. Moreover, there were differences in the type, dosage and duration of vasodilator used in each study. Due to the degree of heterogeneity the results could not be combined to reach a conclusion.
One trial involving 104 adult RRMS patients with an entry score ≤ 5.0 on the Expanded Disability Status Scale (EDSS) and at least one relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0%). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91%) and in annualised rate of relapse at week 24 (0.37 versus 0.84) but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3% versus 40.0%), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngolaryngeal pain, and most were mild-to-moderate events (92.6%). The most common infection-associated adverse events (> 10% in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5% versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group. One ongoing trial was identified. There is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only one RCT was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. The potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.
We included three RCTs (351 participants) that had moderate to high risk of bias. The quality of the evidence was very low for all outcomes. We downgraded the studies because of limitations in study design or execution (risk of bias), imprecision and inconsistency of results. We included a new trial presented only as a conference abstract in this update. In one study of acute laryngitis in adults, 100 participants were randomised to receive penicillin V (800 mg twice daily for five days) or an identical placebo. A recording of each patient reading a standardised text was made at the first visit, during re-examination after one and two weeks, and at follow-up after two to six months. No significant differences were found between the groups. The trial also measured symptoms reported by participants and found no significant differences. One study investigated erythromycin for acute laryngitis in 106 adults. The mean objective voice scores measured at the first visit, at re-examination after one and two weeks, and at follow-up after two to six months did not significantly differ between the groups. At one week there were significant beneficial differences in the severity of reported vocal symptoms (slight, moderate and severe) as judged by participants (P value = 0.042). However, the rates of participants having improved voice disturbance (subjective symptoms) at one and two weeks were not significantly different among groups. Comparing erythromycin and placebo groups on the rate of persistence of cough at two weeks, the risk ratio (RR) was 0.38 (95% confidence interval (CI) 0.15 to 0.97, P value = 0.04) and the number needed to treat for an additional beneficial outcome (NNTB) was 5.87 (95% CI 3.09 to 65.55). We calculated a RR of 0.64 (95% CI 0.46 to 0.90, P value = 0.034) and a NNTB of 3.76 (95% CI 2.27 to 13.52; P value = 0.01) for the subjective voice scores at one week. A third trial from Russia included 145 patients with acute laryngitis symptoms. Participants were randomised to three treatment groups: Group 1: seven-day course of fusafungine (six times a day by inhalation); Group 2: seven-day course of fusafungine (six times a day by inhalation) plus clarithromycin (250 mg twice daily for seven days); Group 3: no treatment. Clinical cure rates were measured at days 5 ± 1, 8 ± 1 and 28 ± 2. The authors reported significant differences in the rates of clinical cure at day 5 ± 1 favouring fusafungine (one trial; 93 participants; RR 1.50, 95% CI 1.02 to 2.20; P value = 0.04) and fusafungine plus clarithromycin (one trial 97 participants; RR 1.47, 95% CI 1.00 to 2.16; P value = 0.05) when compared to no treatment. However, no significant differences were found at days 8 ± 1 and 28 ± 2. Also, no significant differences were found when comparing fusafungine to fusafungine plus clarithromycin at days 5 ± 1, 8 ± 1 and 28 ± 2. Antibiotics do not appear to be effective in treating acute laryngitis when assessing objective outcomes. They appear to be beneficial for some subjective outcomes. Erythromycin could reduce voice disturbance at one week and cough at two weeks when measured subjectively. Fusafungine could increase the cure rate at day five. The included RCTs had important methodological problems and these modest benefits from antibiotics may not outweigh their cost, adverse effects or negative consequences for antibiotic resistance patterns.
Thirty-five randomised controlled trials, one ongoing, involving 5796 participants met the criteria for inclusion in this review. Included studies assessed the efficacy of tobacco cessation interventions, including counselling, and pharmacotherapy consisting of nicotine replacement therapy (NRT) or non-NRT, or the two combined, in both inpatient and outpatient settings for participants in treatment and in recovery. Most studies did not report information to assess the risk of allocation, selection, and attrition bias, and were classified as unclear. Analyses considered the nature of the intervention, whether participants were in treatment or recovery and the type of dependency. Of the 34 studies included in the meta-analysis, 11 assessed counselling, 11 assessed pharmacotherapy, and 12 assessed counselling in combination with pharmacotherapy, compared to usual care or no intervention. Tobacco cessation interventions were significantly associated with tobacco abstinence for two types of interventions. Pharmacotherapy appeared to increase tobacco abstinence (RR 1.88, 95% CI 1.35 to 2.57, 11 studies, 1808 participants, low quality evidence), as did combined counselling and pharmacotherapy (RR 1.74, 95% CI 1.39 to 2.18, 12 studies, 2229 participants, low quality evidence) at the period of longest follow-up, which ranged from six weeks to 18 months. There was moderate evidence of heterogeneity (I2 = 56% with pharmacotherapy and 43% with counselling plus pharmacotherapy). Counselling interventions did not significantly increase tobacco abstinence (RR 1.33, 95% CI 0.90 to 1.95). Interventions were significantly associated with tobacco abstinence for both people in treatment (RR 1.99, 95% CI 1.59 to 2.50) and people in recovery (RR 1.33, 95% CI 1.06 to 1.67), and for people with alcohol dependence (RR 1.47, 95% CI 1.20 to 1.81) and people with other drug dependencies (RR 1.85, 95% CI 1.43 to 2.40). Offering tobacco cessation therapy to people in treatment or recovery for other drug dependence was not associated with a difference in abstinence rates from alcohol and other drugs (RR 0.97, 95% CI 0.91 to 1.03, 11 studies, 2231 participants, moderate evidence of heterogeneity (I2 = 66%)). Data on adverse effect of the interventions were limited. The studies included in this review suggest that providing tobacco cessation interventions targeted to smokers in treatment and recovery for alcohol and other drug dependencies increases tobacco abstinence. There was no evidence that providing interventions for tobacco cessation affected abstinence from alcohol and other drugs. The association between tobacco cessation interventions and tobacco abstinence was consistent for both pharmacotherapy and combined counselling and pharmacotherapy, for participants both in treatment and in recovery, and for people with alcohol dependency or other drug dependency. The evidence for the interventions was low quality due primarily to incomplete reporting of the risks of bias and clinical heterogeneity in the nature of treatment. Certain results were sensitive to the length of follow-up or the type of pharmacotherapy, suggesting that further research is warranted regarding whether tobacco cessation interventions are associated with tobacco abstinence for people in recovery, and the outcomes associated with NRT versus non-NRT or combined pharmacotherapy. Overall, the results suggest that tobacco cessation interventions incorporating pharmacotherapy should be incorporated into clinical practice to reduce tobacco addiction among people in treatment for or recovery from alcohol and other drug dependence.
Four randomised controlled trials with up to three months duration and investigating 479 participants met the inclusion criteria. Risk of bias of these trials (only two studies were published as a full peer-reviewed publication) was generally high. Two RCTs compared the effects of preparations from different parts of the momordica charantia plant with placebo on glycaemic control in type 2 diabetes mellitus. There was no statistically significant difference in the glycaemic control with momordica charantia preparations compared to placebo. When momordica charantia was compared to metformin or glibenclamide, there was also no significant change in reliable parameters of glycaemic control. No serious adverse effects were reported in any trial. No trial investigated death from any cause, morbidity, health-related quality of life or costs. There is insufficient evidence on the effects of momordica charantia for type 2 diabetes mellitus. Further studies are therefore required to address the issues of standardization and the quality control of preparations. For medical nutritional therapy, further observational trials evaluating the effects of momordica charantia are needed before RCTs are established to guide any recommendations in clinical practice.
We included five RCTs with 666 randomized adults. We identified three ongoing studies. All study participants were scheduled for elective general surgery (including abdominal, urological, orthopaedic and gynaecological surgery) under general, spinal or regional anaesthesia. Studies compared continuation of single or dual antiplatelet therapy (aspirin or clopidogrel) with discontinuation of therapy for at least five days before surgery. Three studies reported adequate methods of randomization, and two reported methods to conceal allocation. Three studies were placebo-controlled trials and were at low risk of performance bias, and three studies reported adequate methods to blind outcome assessors to group allocation. Attrition was limited in four studies and two studies had reported prospective registration with clinical trial registers and were at low risk of selective outcome reporting bias. We reported mortality at two time points: the longest follow-up reported by study authors up to six months, and time point reported by study authors up to 30 days. Five studies reported mortality up to six months (of which four studies had a longest follow-up at 30 days, and one study at 90 days) and we found that either continuation or discontinuation of antiplatelet therapy may make little or no difference to mortality up to six months (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.34 to 4.27; 659 participants; low-certainty evidence); the absolute effect is three more deaths per 1000 with continuation of antiplatelets (ranging from eight fewer to 40 more). Combining the four studies with a longest follow-up at 30 days alone showed the same effect estimate, and we found that either continuation or discontinuation of antiplatelet therapy may make little or no difference to mortality at 30 days after surgery (RR 1.21, 95% CI 0.34 to 4.27; 616 participants; low-certainty evidence); the absolute effect is three more deaths per 1000 with continuation of antiplatelets (ranging from nine fewer to 42 more). We found that either continuation or discontinuation of antiplatelet therapy probably makes little or no difference in incidences of blood loss requiring transfusion (RR 1.37, 95% CI 0.83 to 2.26; 368 participants; absolute effect of 42 more participants per 1000 requiring transfusion in the continuation group, ranging from 19 fewer to 119 more; four studies; moderate-certainty evidence); and may make little or no difference in incidences of blood loss requiring additional surgery (RR 1.54, 95% CI 0.31 to 7.58; 368 participants; absolute effect of six more participants per 1000 requiring additional surgery in the continuation group, ranging from seven fewer to 71 more; four studies; low-certainty evidence). We found that either continuation or discontinuation of antiplatelet therapy may make little or no difference to incidences of ischaemic events (to include peripheral ischaemia, cerebral infarction, and myocardial infarction) within 30 days of surgery (RR 0.67, 95% CI 0.25 to 1.77; 616 participants; absolute effect of 17 fewer participants per 1000 with an ischaemic event in the continuation group, ranging from 39 fewer to 40 more; four studies; low-certainty evidence). We used the GRADE approach to downgrade evidence for all outcomes owing to limited evidence from few studies. We noted a wide confidence in effect estimates for mortality at the end of follow-up and at 30 days, and for blood loss requiring transfusion which suggested imprecision. We noted visual differences in study results for ischaemic events which suggested inconsistency. We found low-certainty evidence that either continuation or discontinuation of antiplatelet therapy before non-cardiac surgery may make little or no difference to mortality, bleeding requiring surgical intervention, or ischaemic events. We found moderate-certainty evidence that either continuation or discontinuation of antiplatelet therapy before non-cardiac surgery probably makes little or no difference to bleeding requiring transfusion. Evidence was limited to few studies with few participants, and with few events. The three ongoing studies may alter the conclusions of the review once published and assessed.
We included 29 studies (33,147 children) conducted in low- and middle-income countries in Asia, Africa, Latin America, and the Caribbean, where anaemia is a public health problem. Twenty-six studies with 27,051 children contributed data. The interventions lasted between 2 and 44 months, and the powder formulations contained between 5 and 22 nutrients. Among the 26 studies contributing data, 24 studies (26,486 children) compared the use of MNP versus no intervention or placebo; the two remaining studies compared the use of MNP versus an iron-only supplement (iron drops) given daily. The main outcomes of interest were related to anaemia and iron status. We assessed most of the included studies at low risk of selection and attrition bias. We considered some studies to be at high risk of performance and detection bias due to lack of blinding. Most studies were funded by government programmes or foundations; only two were funded by industry. Home fortification with MNP, compared with no intervention or placebo, reduced the risk of anaemia in infants and young children by 18% (RR 0.82, 95% CI 0.76 to 0.90; 16 studies; 9927 children; moderate-certainty evidence) and iron deficiency by 53% (RR 0.47, 95% CI 0.39 to 0.56; 7 studies; 1634 children; high-certainty evidence). Children receiving MNP had higher haemoglobin concentrations (MD 2.74 g/L, 95% CI 1.95 to 3.53; 20 studies; 10,509 children; low-certainty evidence) and higher iron status (MD 12.93 μg/L, 95% CI 7.41 to 18.45; 7 studies; 2612 children; moderate-certainty evidence) at follow-up compared with children receiving the control intervention. We did not find an effect on weight-for-age (MD 0.02, 95% CI −0.03 to 0.07; 10 studies; 9287 children; moderate-certainty evidence). Few studies reported morbidity outcomes (three to five studies each outcome) and definitions varied, but MNP did not increase diarrhoea, upper respiratory infection, malaria, or all-cause morbidity. In comparison with daily iron supplementation, the use of MNP produced similar results for anaemia (RR 0.89, 95% CI 0.58 to 1.39; 1 study; 145 children; low-certainty evidence) and haemoglobin concentrations (MD −2.81 g/L, 95% CI −10.84 to 5.22; 2 studies; 278 children; very low-certainty evidence) but less diarrhoea (RR 0.52, 95% CI 0.38 to 0.72; 1 study; 262 children; low-certainty of evidence). However, given the limited quantity of data, these results should be interpreted cautiously. Reporting of death was infrequent, although no trials reported deaths attributable to the intervention. Information on side effects and morbidity, including malaria and diarrhoea, was scarce. It appears that use of MNP is efficacious among infants and young children aged 6 to 23 months who are living in settings with different prevalences of anaemia and malaria endemicity, regardless of intervention duration. MNP intake adherence was variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups. Home fortification of foods with MNP is an effective intervention for reducing anaemia and iron deficiency in children younger than two years of age. Providing MNP is better than providing no intervention or placebo and may be comparable to using daily iron supplementation. The benefits of this intervention as a child survival strategy or for developmental outcomes are unclear. Further investigation of morbidity outcomes, including malaria and diarrhoea, is needed. MNP intake adherence was variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups.
Nine trials including more than 25,000 participants were included in this review. No effect was observed on child health, measures of child mental health or emotional state. Non-significant effects favouring the intervention group were seen for child cognitive development and educational achievement, and a non-significant effect favouring controls in rates of teenage pregnancy. The review set out to examine the potential of financial support to poor families to improve circumstances for children. However, on the basis of current evidence we cannot state unequivocally whether financial benefits delivered as an intervention are effective at improving child health or well-being in the short term. Our conclusions are limited by the fact that most of the studies had small effects on total household income and that, while no conditions were attached to how money was spent, all studies included strict conditions for receipt of payments. We note particular concerns by some authors that sanctions and conditions (such as working hours) placed on families may increase family stress.
Overall, 10 RCTs with 565 participants which investigated different non-pharmacological interventions for the management of chronic pain in MS fulfilled the review inclusion criteria. The non-pharmacological interventions evaluated included: transcutaneous electrical nerve stimulation (TENS), psychotherapy (telephone self-management, hypnosis and electroencephalogram (EEG) biofeedback), transcranial random noise stimulation (tRNS), transcranial direct stimulation (tDCS), hydrotherapy (Ai Chi) and reflexology. There is very low-level evidence for the use of non-pharmacological interventions for chronic pain such as TENS, Ai Chi, tDCS, tRNS, telephone-delivered self-management program, EEG biofeedback and reflexology in pain intensity in pwMS. Although there were improved changes in pain scores and secondary outcomes (such as fatigue, psychological symptoms, spasm in some interventions), these were limited by methodological biases within the studies. Despite the use of a wide range of non-pharmacological interventions for the treatment of chronic pain in pwMS, the evidence for these interventions is still limited or insufficient, or both. More studies with robust methodology and greater numbers of participants are needed to justify the effect of these interventions for the management of chronic pain in pwMS.
We included 21 reviews with 381 included studies and 37,143 participants. Of these, 264 studies (19,642 participants) examined exercise versus no exercise/minimal intervention in adults with chronic pain and were used in the qualitative analysis. Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia, low back pain, intermittent claudication, dysmenorrhoea, mechanical neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral pain. None of the reviews assessed 'chronic pain' or 'chronic widespread pain' as a general term or specific condition. Interventions included aerobic, strength, flexibility, range of motion, and core or balance training programmes, as well as yoga, Pilates, and tai chi. Reviews were well performed and reported (based on AMSTAR), and included studies had acceptable risk of bias (with inadequate reporting of attrition and reporting biases). However the quality of evidence was low due to participant numbers (most included studies had fewer than 50 participants in total), length of intervention and follow-up (rarely assessed beyond three to six months). We pooled the results from relevant reviews where appropriate, though results should be interpreted with caution due to the low quality evidence. Pain severity: several reviews noted favourable results from exercise: only three reviews that reported pain severity found no statistically significant changes in usual or mean pain from any intervention. However, results were inconsistent across interventions and follow-up, as exercise did not consistently bring about a change (positive or negative) in self-reported pain scores at any single point. Physical function: was the most commonly reported outcome measure. Physical function was significantly improved as a result of the intervention in 14 reviews, though even these statistically significant results had only small-to-moderate effect sizes (only one review reported large effect sizes). Psychological function and quality of life: had variable results: results were either favourable to exercise (generally small and moderate effect size, with two reviews reporting significant, large effect sizes for quality of life), or showed no difference between groups. There were no negative effects. Adherence to the prescribed intervention: could not be assessed in any review. However, risk of withdrawal/dropout was slightly higher in the exercising group (82.8/1000 participants versus 81/1000 participants), though the group difference was non-significant. Healthcare use/attendance: was not reported in any review. Adverse events, potential harm, and death: only 25% of included studies (across 18 reviews) actively reported adverse events. Based on the available evidence, most adverse events were increased soreness or muscle pain, which reportedly subsided after a few weeks of the intervention. Only one review reported death separately to other adverse events: the intervention was protective against death (based on the available evidence), though did not reach statistical significance. The quality of the evidence examining physical activity and exercise for chronic pain is low. This is largely due to small sample sizes and potentially underpowered studies. A number of studies had adequately long interventions, but planned follow-up was limited to less than one year in all but six reviews. There were some favourable effects in reduction in pain severity and improved physical function, though these were mostly of small-to-moderate effect, and were not consistent across the reviews. There were variable effects for psychological function and quality of life. The available evidence suggests physical activity and exercise is an intervention with few adverse events that may improve pain severity and physical function, and consequent quality of life. However, further research is required and should focus on increasing participant numbers, including participants with a broader spectrum of pain severity, and lengthening both the intervention itself, and the follow-up period.
We included 12 studies involving 2887 participants with LBP. Three studies had low risk of bias. Included studies evaluated a range of chiropractic procedures in a variety of sub-populations of people with LBP. No trials were located of combined chiropractic interventions compared to no treatment. For acute and subacute LBP, chiropractic interventions improved short- and medium-term pain (SMD -0.25 (95% CI -0.46 to -0.04) and MD -0.89 (95%CI -1.60 to -0.18)) compared to other treatments, but there was no significant difference in long-term pain (MD -0.46 (95% CI -1.18 to 0.26)). Short-term improvement in disability was greater in the chiropractic group compared to other therapies (SMD -0.36 (95% CI -0.70 to -0.02)). However, the effect was small and all studies contributing to these results had high risk of bias. There was no difference in medium- and long-term disability. No difference was demonstrated for combined chiropractic interventions for chronic LBP and for studies that had a mixed population of LBP. Combined chiropractic interventions slightly improved pain and disability in the short-term and pain in the medium-term for acute and subacute LBP. However, there is currently no evidence that supports or refutes that these interventions provide a clinically meaningful difference for pain or disability in people with LBP when compared to other interventions. Future research is very likely to change the estimate of effect and our confidence in the results.
We included three trials involving 254 adolescent girls with type 1 or type 2 diabetes, with an overall unclear to high risk of bias. The three trials were conducted at diabetes clinics in the USA, and assessed the READY-Girls (Reproductive-health Education and Awareness of Diabetes in Youth for Girls) programme versus standard care. Considering primary outcomes, one trial reported no pregnancies in the trial period (12 months) (very low-quality evidence, with downgrading based on study limitations (risk of bias) and imprecision); in the other two trials, pregnancy was an exclusion criterion, or was not clearly reported on. None of the trials reported on the other primary maternal outcomes, hypertensive disorders of pregnancy and caesarean section; or primary infant outcomes, large-for-gestational age, perinatal mortality, death or morbidity composite, or congenital malformations. Similarly, none of the trials reported on the secondary outcomes, for which we had planned to assess the quality of the evidence using the GRADE approach (maternal: induction of labour; perineal trauma; gestational weight gain; long-term cardiovascular health; infant: adiposity; type 1 or 2 diabetes; neurosensory disability). The majority of secondary maternal and infant outcomes, and outcomes relating to the use and costs of health services were not reported by the three included trials. Regarding behaviour changes associated with the intervention, in one trial, participants in the preconception care group had a slightly higher score for the actual initiation of discussion regarding preconception care with healthcare providers at follow-up (nine months), compared with those in the standard care group (mean difference 0.40, 95% confidence interval -0.02 to 0.82 (on a scale of 0 to 4 points); participants = 87) (a summation of four dichotomous items; possible range 0 to 4, with 0 being no discussion). There are insufficient RCT data available to assess the effects of preconception care for diabetic women on health outcomes for mothers and their infants. More high-quality evidence is needed to determine the effects of different protocols of preconception care for diabetic women. Future trials should be powered to evaluate effects on short- and long-term maternal and infant outcomes, and outcomes relating to the use and costs of health services. We have identified three ongoing studies that we will consider in the next review update.
We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate. Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95% CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the meta-analysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69). Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment (RR 0.24, 95% CI 0.13 to 0.44). Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies suggested the vaccine was more effective than gamma globulin. No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Non-serious adverse events included transient fever, rash, muscle stiffness, local redness and induration. Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83% less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit (NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the ARR of gamma globulin compared to no treatment is 629 and the NNTB is two. It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies could not be identified. Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined. Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative effectiveness. The included studies were not specifically designed to detect adverse events. Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.
We included 37 RCTs (3872 women), one ongoing trial, and one trial awaiting classification. These trials made nine different comparisons between protocols. Twenty of the RCTs compared long protocols and short protocols. Only 19/37 RCTs reported live birth or ongoing pregnancy. There was no conclusive evidence of a difference between a long protocol and a short protocol in live birth and ongoing pregnancy rates (OR 1.30, 95% CI 0.94 to 1.81; 12 RCTs, n = 976 women, I² = 15%, low quality evidence). Our findings suggest that in a population in which 14% of women achieve live birth or ongoing pregnancy using a short protocol, between 13% and 23% will achieve live birth or ongoing pregnancy using a long protocol. There was evidence of an increase in clinical pregnancy rates (OR 1.50, 95% CI 1.18 to 1.92; 20 RCTs, n = 1643 women, I² = 27%, moderate quality evidence) associated with the use of a long protocol. There was no evidence of a difference between the groups in terms of live birth and ongoing pregnancy rates when the following GnRHa protocols were compared: long versus ultrashort protocol (OR 1.78, 95% CI 0.72 to 4.36; one RCT, n = 150 women, low quality evidence), long luteal versus long follicular phase protocol (OR 1.89, 95% CI 0.87 to 4.10; one RCT, n = 223 women, low quality evidence), when GnRHa was stopped versus when it was continued (OR 0.75, 95% CI 0.42 to 1.33; three RCTs, n = 290 women, I² = 0%, low quality evidence), when the dose of GnRHa was reduced versus when the same dose was continued (OR 1.02, 95% CI 0.68 to 1.52; four RCTs, n = 407 women, I² = 0%, low quality evidence), when GnRHa was discontinued versus continued after human chorionic gonadotrophin (HCG) administration in the long protocol (OR 0.89, 95% CI 0.49 to 1.64; one RCT, n = 181 women, low quality evidence), and when administration of GnRHa lasted for two versus three weeks before stimulation (OR 1.14, 95% CI 0.49 to 2.68; one RCT, n = 85 women, low quality evidence). Our primary outcomes were not reported for any other comparisons. Regarding adverse events, there were insufficient data to enable us to reach any conclusions except about the cycle cancellation rate. There was no conclusive evidence of a difference in cycle cancellation rate (OR 0.95, 95% CI 0.59 to 1.55; 11 RCTs, n = 1026 women, I² = 42%, low quality evidence) when a long protocol was compared with a short protocol. This suggests that in a population in which 9% of women would have their cycles cancelled using a short protocol, between 5.5% and 14% will have cancelled cycles when using a long protocol. The quality of the evidence ranged from moderate to low. The main limitations in the evidence were failure to report live birth or ongoing pregnancy, poor reporting of methods in the primary studies, and imprecise findings due to lack of data. Only 10 of the 37 included studies were conducted within the last 10 years. When long GnRHa protocols and short GnRHa protocols were compared, we found no conclusive evidence of a difference in live birth and ongoing pregnancy rates, but there was moderate quality evidence of higher clinical pregnancy rates in the long protocol group. None of the other analyses showed any evidence of a difference in birth or pregnancy outcomes between the protocols compared. There was insufficient evidence to make any conclusions regarding adverse effects.
Twelve trials including 754 participants met our inclusion criteria. Trials were from eight to 26 weeks in duration. We judged all trials to be at moderate or high risk of bias in at least some domains. Reporting of some risk of bias domains was poor. Our analyses comparing aerobic exercise to any active intervention showed no evidence of benefit from aerobic exercise in any cognitive domain. This was also true of our analyses comparing aerobic exercise to no intervention. Analysing only the subgroup of trials in which cardiorespiratory fitness improved in the aerobic exercise group showed that this improvement did not coincide with improvements in any cognitive domains assessed. Our subgroup analyses of aerobic exercise versus flexibility or balance interventions also showed no benefit of aerobic exercise in any cognitive domain. Dropout rates did not differ between aerobic exercise and control groups. No trial reported on adverse effects. Overall none of our analyses showed a cognitive benefit from aerobic exercise even when the intervention was shown to lead to improved cardiorespiratory fitness. We found no evidence in the available data from RCTs that aerobic physical activities, including those which successfully improve cardiorespiratory fitness, have any cognitive benefit in cognitively healthy older adults. Larger studies examining possible moderators are needed to confirm whether or not aerobic training improves cognition.
In this review, we included 37 trials involving 15,813 children and adolescents. All trials tested supervised use of fluoride mouthrinse in schools, with two studies also including home use. Almost all children received a fluoride rinse formulated with sodium fluoride (NaF), mostly on either a daily or weekly/fortnightly basis and at two main strengths, 230 or 900 ppm F, respectively. Most studies (28) were at high risk of bias, and nine were at unclear risk of bias. From the 35 trials (15,305 participants) that contributed data on permanent tooth surface for meta-analysis, the D(M)FS pooled PF was 27% (95% confidence interval (CI), 23% to 30%; I2 = 42%) (moderate quality evidence). We found no significant association between estimates of D(M)FS prevented fractions and baseline caries severity, background exposure to fluorides, rinsing frequency or fluoride concentration in metaregression analyses. A funnel plot of the 35 studies in the D(M)FS PF meta-analysis indicated no relationship between prevented fraction and study precision (no evidence of reporting bias). The pooled estimate of D(M)FT PF was 23% (95% CI, 18% to 29%; I² = 54%), from the 13 trials that contributed data for the permanent teeth meta-analysis (moderate quality evidence). We found limited information concerning possible adverse effects or acceptability of the treatment regimen in the included trials. Three trials incompletely reported data on tooth staining, and one trial incompletely reported information on mucosal irritation/allergic reaction. None of the trials reported on acute adverse symptoms during treatment. This review found that supervised regular use of fluoride mouthrinse by children and adolescents is associated with a large reduction in caries increment in permanent teeth. We are moderately certain of the size of the effect. Most of the evidence evaluated use of fluoride mouthrinse supervised in a school setting, but the findings may be applicable to children in other settings with supervised or unsupervised rinsing, although the size of the caries-preventive effect is less clear. Any future research on fluoride mouthrinses should focus on head-to-head comparisons between different fluoride rinse features or fluoride rinses against other preventive strategies, and should evaluate adverse effects and acceptability.
Six studies were eligible for inclusion (517 patients). Five studies compared type I IFNs to placebo injections (485 patients) and a single study compared IFNs to prednisolone enemas in patients with left-sided colitis (32 patients). The active comparator study was rated as high risk of bias due to an open-label design. Three studies were rated as unclear risk of bias for random sequence generation and allocation concealment. Two studies described as double blind were rated as unclear risk of bias for blinding. There was no significant benefit of type I IFNs over placebo for inducing clinical remission or improvement in patients with active ulcerative colitis. Thirty-six per cent (87/242) of patients in the type I IFNs group achieved clinical remission by 8 to 12 weeks compared to 30% (36/120) of placebo patients (RR 1.16, 95% CI 0.84 to 1.58; 4 studies, 362 patients). A GRADE analysis indicated that the overall quality of the evidence supporting the outcome clinical remission was moderate due to sparse data (123 events). Fifty-six per cent (149/264) of patients in the type I IFNs group improved clinically by 8 to 12 weeks compared to 48% (77/161) of placebo patients (RR 1.16, 95% CI 0.96 to 1.40; 4 studies, 425 patients). A GRADE analysis indicated that the overall quality of the evidence supporting the outcome clinical improvement was moderate due to sparse data (226 events). Patients who received type I IFNs were significantly more likely to withdraw from the studies due to adverse events than those who received placebo. Seven per cent (18/42) of type I IFNs patients withdrew due to adverse events compared to 2% (3/152) of placebo patients (RR 3.16, 95% CI 1.06 to 9.40). A GRADE analysis indicated that the overall quality of the evidence supporting the outcome withdrawal due to adverse events was low due to very sparse data (21 events). The study comparing type I IFNs to prednisolone enemas found no difference between the treatment groups in quality of life or disease activity scores. Common adverse events included headaches, arthralgias, myalgias, fatigue, back pain, nausea, application site reactions, rigors, and fevers. There were no statistically significant differences in the other secondary outcomes. Moderate quality evidence suggests that type I IFNs are not effective for the induction of remission in UC. In addition, there are concerns regarding the tolerability of this class of treatment.
For the first publication of this review, two RCTs involving 260 children with measles which compared vitamin A with placebo met the inclusion criteria. Neither study reported blindness or other ocular morbidities as end points. One trial of moderate quality suggested evidence of a significant increase in serum retinol levels in the vitamin A group one week after two doses of vitamin A (MD 9.45 µg/dL, 95% CI 2.19 to 16.71; 17 participants, moderate-quality evidence), but not six weeks after three doses of vitamin A (MD 2.56 µg/dL, 95% CI -5.28 to 10.40; 39 participants, moderate-quality evidence). There was no significant difference in weight gain six weeks (MD 0.39 kg, -0.04 to 0.82; 48 participants, moderate-quality evidence) and six months (MD 0.52 kg, 95% CI -0.08 to 1.12; 36 participants, moderate-quality evidence) after three doses of vitamin A. The second trial found no significant difference in serum retinol levels two weeks after a single dose of vitamin A (MD 2.67 µg/dL, 95% CI -0.29 to 5.63; 155 participants, moderate-quality evidence). Percentage of undernutrition between the two groups did not differ significantly at one week (RR 0.93, 95% CI 0.56 to 1.54, 145 participants) and two weeks (RR 0.82, 95% CI 0.52 to 1.29, 147 participants) after a single dose of vitamin A. No adverse event was reported in either study. We did not find any new RCTS for this second update. We did not find any trials assessing whether or not vitamin A supplementation in children with measles prevents blindness, as neither study reported blindness or other ocular morbidities as end points.
We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks. Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency. We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy. Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d. Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.
Twenty randomized trials were identified of which thirteen were included in the quantitative analysis with data from 1022 subjects. Although all agents were better than placebo, parenteral high dose methotrexate (not included), sulfasalazine, azathioprine and etretinate were the agents that achieved statistical significance in a global index of disease activity (although it should be noted that only one component variable was available for azathioprine and only one trial was available for etretinate suggesting some caution is necessary in interpreting these results). Analysis of response in individual disease activity markers was more variable with considerable differences between different medications and responses. In all trials the placebo group improved over baseline (pooled improvement 0.39 DI units, 95% CI 0.26-0.54). There was insufficient data to examine toxicity. Parenteral high dose methotrexate and sulfasalazine are the only two agents with well demonstrated published efficacy in psoriatic arthritis. The magnitude of the effect seen with azathioprine, etretinate, oral low dose methotrexate and perhaps colchicine suggests that they may be effective but that further multicentre clinical trials are required to establish their efficacy. Furthermore, the magnitude of the improvement observed in the placebo group strongly suggests that uncontrolled trials should not be used to guide management decisions in this condition.
Five trials with a total of 1159 women were included. All used X-ray pelvimetry to assess the pelvis. X-ray pelvimetry versus no pelvimetry or clinical pelvimetry is the only comparison included in this review due to the lack of trials identified that examined other types of radiological pelvimetry or that compared clinical pelvimetry versus no pelvimetry. The included trials were generally at high risk of bias. There is an overall high risk of performance bias due to lack of blinding of women and staff. Two studies were also at high risk of selection bias. We used GRADEpro software to grade evidence for our selected outcomes; for caesarean section we rated the evidence low quality and all the other outcomes (perinatal mortality, wound sepsis, blood transfusion, scar dehiscence and admission to special care baby unit) as very low quality. Downgrading was due to risk of bias relating to lack of allocation concealment and blinding, and imprecision of effect estimates. Women undergoing X-ray pelvimetry were more likely to have a caesarean section (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.19 to 1.52; 1159 women; 5 studies; low-quality evidence). There were no clear differences between groups for perinatal outcomes: perinatal mortality (RR 0.53, 95% CI 0.19 to 1.45; 1159 infants; 5 studies; very low-quality evidence), perinatal asphyxia (RR 0.66, 95% CI 0.39 to 1.10; 305 infants; 1 study), and admission to special care baby unit (RR 0.20, 95% CI 0.01 to 4.13; 288 infants; 1 study; very low-quality evidence). Other outcomes assessed were wound sepsis (RR 0.83, 95% CI 0.26 to 2.67; 288 women; 1 study; very low-quality evidence), blood transfusion (RR 1.00, 95% CI 0.39 to 2.59; 288 women; 1 study; very low-quality evidence), and scar dehiscence (RR 0.59, 95% CI 0.14 to 2.46; 390 women; 2 studies; very low-quality evidence). Again, no clear differences were found for these outcomes between the women who received X-ray pelvimetry and those who did not. Apgar score less than seven at five minutes was not reported in any study. X-ray pelvimetry versus no pelvimetry or clinical pelvimetry is the only comparison included in this review due to the lack of trials identified that used other types or pelvimetry (other radiological examination or clinical pelvimetry versus no pelvimetry). There is not enough evidence to support the use of X-ray pelvimetry for deciding on mode of delivery in women whose fetuses have a cephalic presentation. Women who undergo an X-ray pelvimetry may be more likely to have a caesarean section. Further research should be directed towards defining whether there are specific clinical situations in which pelvimetry can be shown to be of value. Newer methods of pelvimetry (CT, MRI) should be subjected to randomised trials to assess their value. Further trials of X-ray pelvimetry in cephalic presentations would be of value if large enough to assess the effect on perinatal mortality.
We included one study with 211 participants (median age 13 years), in which etanercept (dosage ranged from 0.8 to 50 mg per kilogram of body weight) was compared to placebo. Follow-up was over a 48-week period. At week 12, 57% versus 11% who received etanercept or placebo, respectively, achieved the PASI 75 (risk ratio 4.95, 95% confidence interval (CI) 2.83 to 8.65; high-quality evidence). Absolute risk reduction and the number needed to treat to obtain a benefit with etanercept was 45% (95% CI 33.95 to 56.40) and 2 (95% CI 1.77 to 2.95), respectively. The percentage improvement from baseline of the CDLQI scores at week 12 was better in the etanercept group than the placebo group (52.3% versus 17.5%, respectively (P = 0.0001)). Analysis between the groups showed an effect size that was clinically important (mean difference 2.30, 95% CI 0.85 to 3.75; high-quality evidence). However, means, medians, and minimal important difference results and results of the Pediatric Quality of Life Inventory, Stein Impact on Family Scale, and Harter Self-Perception Profile for Children scores must be interpreted with caution, as they were not prespecified outcomes. Three serious adverse events were reported, but they were resolved without sequelae. Deaths or other events such as malignant tumours, opportunistic infections, tuberculosis, or demyelination were not reported in the included study. Also, 13% of participants in the placebo group and 53% in the etanercept group had a PGA of clear or almost clear (risk ratio 3.96, 95% CI 2.36 to 6.66; high-quality evidence) at week 12. This review found only one RCT evaluating the use of this type of biological therapy. Although the risk of publication bias was high, as we included only one industry-sponsored RCT, the risk of allocation, selection, performance, attrition, and selective reporting biases for all outcomes (except for CDLQI) was low, and no short-term serious adverse events were found. We can conclude, based on this single included study, that etanercept seems to be efficacious and safe (at least in the short term) for the treatment of paediatric psoriasis. However, as the GRADE approach refers not to individual studies but to a body of evidence, we shall wait for the results of the ongoing studies in a future update of this review. In addition, future studies should evaluate quality-of-life endpoints established a priori and standardise primary outcome measures such as PASI 75, and should include the PGA as a secondary endpoint. Also, collating and reporting adverse events uniformly is required to better evaluate safety.
The search retrieved 126 trials; 10 fulfilled the inclusion criteria and we included them in the review (a total sample of 510 participants). Seven studies were considered to have low risk of bias, and three were considered as high risk of bias. A total of six trials compared Pilates to minimal intervention. There is low quality evidence that Pilates reduces pain compared with minimal intervention, with a medium effect size at short-term follow-up (less than three months after randomisation) (MD -14.05, 95% confidence interval (CI) -18.91 to -9.19). For intermediate-term follow-up (at least three months but less than 12 months after randomisation), two trials provided moderate quality evidence that Pilates reduces pain compared to minimal intervention, with a medium effect size (MD -10.54, 95% CI -18.46 to -2.62). Based on five trials, there is low quality evidence that Pilates improves disability compared with minimal intervention, with a small effect size at short-term follow-up (MD -7.95, 95% CI -13.23 to -2.67), and moderate quality evidence for an intermediate-term effect with a medium effect size (MD -11.17, 95% CI -18.41 to -3.92). Based on one trial and low quality evidence, a significant short-term effect with a small effect size was reported for function (MD 1.10, 95% CI 0.23 to 1.97) and global impression of recovery (MD 1.50, 95% CI 0.70 to 2.30), but not at intermediate-term follow-up for either outcome. Four trials compared Pilates to other exercises. For the outcome pain, we presented the results as a narrative synthesis due to the high level of heterogeneity. At short-term follow-up, based on low quality evidence, two trials demonstrated a significant effect in favour of Pilates and one trial did not find a significant difference. At intermediate-term follow-up, based on low quality evidence, one trial reported a significant effect in favour of Pilates, and one trial reported a non-significant difference for this comparison. For disability, there is moderate quality evidence that there is no significant difference between Pilates and other exercise either in the short term (MD -3.29, 95% CI -6.82 to 0.24) or in the intermediate term (MD -0.91, 95% CI -5.02 to 3.20) based on two studies for each comparison. Based on low quality evidence and one trial, there was no significant difference in function between Pilates and other exercises at short-term follow-up (MD 0.10, 95% CI -2.44 to 2.64), but there was a significant effect in favour of other exercises for intermediate-term function, with a small effect size (MD -3.60, 95% CI -7.00 to -0.20). Global impression of recovery was not assessed in this comparison and none of the trials included quality of life outcomes. Two trials assessed adverse events in this review, one did not find any adverse events, and another reported minor events. We did not find any high quality evidence for any of the treatment comparisons, outcomes or follow-up periods investigated. However, there is low to moderate quality evidence that Pilates is more effective than minimal intervention for pain and disability. When Pilates was compared with other exercises we found a small effect for function at intermediate-term follow-up. Thus, while there is some evidence for the effectiveness of Pilates for low back pain, there is no conclusive evidence that it is superior to other forms of exercises. The decision to use Pilates for low back pain may be based on the patient's or care provider's preferences, and costs.
We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes. Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm. There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo. All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.
This update of the systematic review includes a total of 91 trials with 20,102 participants. Use of ESAs significantly reduced the relative risk of red blood cell transfusions (risk ratio (RR) 0.65; 95% confidence interval (CI) 0.62 to 0.68, 70 trials, N = 16,093). On average, participants in the ESAs group received one unit of blood less than the control group (mean difference (MD) -0.98; 95% CI -1.17 to -0.78, 19 trials, N = 4,715). Haematological response was observed more often in participants receiving ESAs (RR 3.93; 95% CI 3.10 to 3.71, 31 trials, N = 6,413). There was suggestive evidence that ESAs may improve Quality of Life (QoL). There was strong evidence that ESAs increase mortality during active study period (hazard ratio (HR) 1.17; 95% CI 1.06 to 1.29, 70 trials, N = 15,935) and some evidence that ESAs decrease overall survival (HR 1.05; 95% CI 1.00 to 1.11, 78 trials, N = 19,003). The risk ratio for thromboembolic complications was increased in patients receiving ESAs compared to controls (RR 1.52, 95% CI 1.34 to 1.74; 57 trials, N = 15,498). ESAs may also increase the risk for hypertension (fixed-effect model: RR 1.30; 95% CI 1.08 to 1.56; random-effects model: RR 1.12; 95% CI 0.94 to 1.33, 31 trials, N = 7,228) and thrombocytopenia/haemorrhage (RR 1.21; 95% CI 1.04 to 1.42; 21 trials, N = 4,507). There was insufficient evidence to support an effect of ESA on tumour response (fixed-effect RR 1.02; 95% CI 0.98 to 1.06, 15 trials, N = 5,012). ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. There is suggestive evidence that ESAs may improve QoL. Whether and how ESAs affects tumour control remains uncertain. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient’s clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression. Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth.
We included seven randomised and cluster-randomised controlled trials that together recruited 1614 participants. Four studies evaluated interventions delivered by specialised palliative care teams, and the remaining studies assessed models of co-ordinated care. Overall, risk of bias at the study level was mostly low, apart from possible selection bias in three studies and attrition bias in one study, along with insufficient information on blinding of participants and outcome assessment in six studies. Compared with usual/standard cancer care alone, early palliative care significantly improved health-related quality of life at a small effect size (SMD 0.27, 95% confidence interval (CI) 0.15 to 0.38; participants analysed at post treatment = 1028; evidence of low certainty). As re-expressed in natural units (absolute change in Functional Assessment of Cancer Therapy-General (FACT-G) score), health-related quality of life scores increased on average by 4.59 (95% CI 2.55 to 6.46) points more among participants given early palliative care than among control participants. Data on survival, available from four studies enrolling a total of 800 participants, did not indicate differences in efficacy (death hazard ratio 0.85, 95% CI 0.56 to 1.28; evidence of very low certainty). Levels of depressive symptoms among those receiving early palliative care did not differ significantly from levels among those receiving usual/standard cancer care (five studies; SMD -0.11, 95% CI -0.26 to 0.03; participants analysed at post treatment = 762; evidence of very low certainty). Results from seven studies that analysed 1054 participants post treatment suggest a small effect for significantly lower symptom intensity in early palliative care compared with the control condition (SMD -0.23, 95% CI -0.35 to -0.10; evidence of low certainty). The type of model used to provide early palliative care did not affect study results. One RCT reported potential adverse events of early palliative care, such as a higher percentage of participants with severe scores for pain and poor appetite; the remaining six studies did not report adverse events in study publications. For these six studies, principal investigators stated upon request that they had not observed any adverse events. This systematic review of a small number of trials indicates that early palliative care interventions may have more beneficial effects on quality of life and symptom intensity among patients with advanced cancer than among those given usual/standard cancer care alone. Although we found only small effect sizes, these may be clinically relevant at an advanced disease stage with limited prognosis, at which time further decline in quality of life is very common. At this point, effects on mortality and depression are uncertain. We have to interpret current results with caution owing to very low to low certainty of current evidence and between-study differences regarding participant populations, interventions, and methods. Additional research now under way will present a clearer picture of the effect and specific indication of early palliative care. Upcoming results from several ongoing studies (N = 20) and studies awaiting assessment (N = 10) may increase the certainty of study results and may lead to improved decision making. In perspective, early palliative care is a newly emerging field, and well-conducted studies are needed to explicitly describe the components of early palliative care and control treatments, after blinding of participants and outcome assessors, and to report on possible adverse events.
Seven studies were found to be suitable for inclusion from 33 identified as relevant. None of the trials provided adequate evidence to support the use of hydroxyurea owing to small sample size, large numbers of post-randomisation exclusions and questionable rules for censoring, particularly a failure to include treatment-related deaths in the survival analysis. Details of statistical analysis were limited and often confusing, and we felt meta-analysis would lead to unreliable and invalid conclusions. Most studies appeared to be double blind placebo-controlled studies but none give details of power calculations or reasons for stopping recruitment. Only two studies had more than 50 patients. Patients were excluded from analysis in most trials for treatment-related reasons; in one, less than half those recruited were used in the analysis, the remainder having been excluded because of tumour progression or treatment-related conditions e.g. septicaemia, worsening renal/hepatic function. In another trial five out of 20 in the hydroxyurea group died of treatment-related complications but the five-year survival group was presented as 94%. We found no evidence to support the use of hydroxyurea in addition to radiotherapy in the routine treatment of cervix cancer.
A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted. The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.64, 95% CI 1.46 to 1.845. Compared with twice-daily beta2-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta2-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. For patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily long-acting beta2-agonists, but the comparative effect on quality of life remains uncertain, as important differences cannot be excluded.
Nine RCTs of mixed duration (3 days-52 weeks), recruiting 1175 participants were included (NYHA functional classes II-IV). Intravenous prostacyclin versus usual care (four studies) : There were significant improvements in exercise capacity of around 90 metres, cardiopulmonary haemodynamics and NYHA functional class over 3 days-12 weeks. Effects were consistent in primary and secondary pulmonary hypertension. Oral prostacyclin versus placebo (two studies) : Short-term data (3-6 months) indicated that there was a significant improvement in exercise capacity, but data from one study of 52 weeks reported no significant difference at 12 months. No significant differences were observed for any other outcome. Subcutaneous treprostinil versus placebo (two studies, 8-12 weeks):  One large study reported a significant median improvement in exercise capacity of around 16 metres. Cardiopulmonary haemodynamics and symptom scores favoured treprostinil. Infusion site pain and withdrawals due to adverse events were more frequent with treprostinil. Inhaled prostacyclin versus placebo (one study, 12 weeks):  There was a significant increase in exercise capacity of approximately 36 metres. Treatment led to better symptom scores and functional class status than with placebo. Subgroup analyses reported by individual studies showed a better exercise capacity in participants with PPH, than those participants with PH secondary to other diseases. Side effects and adverse events were common in the studies. There is evidence that intravenous prostacyclin in addition to conventional therapy at tolerable doses optimised by titration, can confer some short-term benefits (up to 12 weeks of treatment) in exercise capacity, NYHA functional class and cardiopulmonary haemodynamics. There is also some evidence that patients with more severe disease based upon NYHA functional class showed a greater response to treatment.
The review now includes four trials (total 75 people, one additional trial since 2006, 21 people) randomising inpatients and outpatients in China and the USA. Risk of bias was mostly unclear as reporting was poor. We are uncertain about all the effects as all evidence was graded at very low quality. We found no significant difference between benzodiazepines and placebo for the outcome of 'no clinically important improvement in TD' (2 RCTs, 32 people, RR 1.12, 95% CI 0.60 to 2.09, very low quality evidence). Significantly fewer participants allocated to clonazepam compared with phenobarbital (as active placebo) experienced no clinically important improvement (RR 0.44, 95% CI 0.20 to 0.96, 1 RCT, 21 people, very low quality evidence). For the outcome 'deterioration of TD symptoms,' we found no clear difference between benzodiazepines and placebo (2 RCTs, 30 people, RR 1.48, 95% CI 0.22 to 9.82, very low quality evidence). All 10 participants allocated to benzodiazepines experienced any adverse event compared with 7/11 allocated to phenobarbital (RR 1.53, 95% CI 0.97 to 2.41, 1 RCT, 21 people, very low quality evidence). There was no clear difference in the incidence of participants leaving the study early for benzodiazepines compared with placebo (3 RCTs, 56 people, RR 2.73, 95% CI 0.15 to 48.04, very low quality evidence) or compared with phenobarbital (as active placebo) (no events, 1 RCT, 21 people, very low quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, which are outcomes designated important by patients. No trials comparing benzodiazepines with placebo or treatment as usual reported on adverse effects. There is only evidence of very low quality from a few small and poorly reported trials on the effect of benzodiazepines as an adjunctive treatment for antipsychotic-induced TD. These inconclusive results mean routine clinical use is not indicated and these treatments remain experimental. New and better trials are indicated in this under-researched area; however, as benzodiazepines are addictive, we feel that other techniques or medications should be adequately evaluated before benzodiazepines are chosen.
Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages). Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12). Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies. Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study. Overall survival Twelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Four studies were assessed as low risk, and eight studies as high risk of bias for the domain other prognostic factors (covariates). Nine studies were assessed as low risk, and three studies as high risk of bias for the domain 'statistical analysis and reporting'. We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result. Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence). Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as low risk, and ten studies as high risk of bias for the domain other prognostic factors (covariates). Eight studies were assessed as high risk, thirteen as low risk of bias for statistical analysis and reporting. We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result. Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence). PET-associated adverse events No study measured PET-associated AEs. This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.
Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin, however, between studies, all used different protocols for the standard and experimental arms with different concentrations of heparin and different frequency of flushes reported. In addition, not all studies reported on all outcomes. The quality of the evidence ranged from low to very low because there was no blinding, heterogeneity and inconsistency between studies was high and the confidence intervals were wide. CVC occlusion was assessed in all three trials (243 participants). We were able to pool the results of two trials for the outcomes of CVC occlusion and CVC-associated blood stream infection. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). The duration of catheter placement was reported to be similar between the two study arms, in one study (203 participants). The review found that there was not enough evidence to determine the effects of intermittent flushing of heparin versus normal saline to prevent occlusion in long term central venous catheters in infants and children. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.
We included six studies with a total of 438 participants. Five studies were conducted in the USA, and one in Iran. All studies evaluated a long-acting version of bupropion, with the dosage ranging from 150 mg up to 450 mg daily. Study intervention length varied from six to 10 weeks. Four studies explicitly excluded participants with psychiatric comorbidity and one study included only participants with opioid dependency. Four studies were funded by industry, but the impact of this on study results is unknown. Two studies were publicly funded and in one of these studies, the lead author was a consultant for several pharmaceutical companies and also received investigator-driven funding from two companies, however none of these companies manufacture bupropion. We judged none of the studies to be free of bias because for most risk of bias domains the study reports failed to provide sufficient details. Using the GRADE approach, we rated the overall quality of evidence as low. We downgraded the quality of the evidence because of serious risk of bias and serious imprecision due to small sample sizes. We found low-quality evidence that bupropion decreased the severity of ADHD symptoms (standardised mean difference -0.50, 95% confidence interval (CI) -0.86 to -0.15, 3 studies, 129 participants), and increased the proportion of participants achieving clinical improvement (risk ratio (RR) 1.50, 95% CI 1.13 to 1.99, 4 studies, 315 participants), and reporting an improvement on the Clinical Global Impression - Improvement scale (RR 1.78, 95% CI 1.27 to 2.50, 5 studies, 337 participants). There was low-quality evidence that the proportion of participants who withdrew due to any adverse effect was similar in the bupropion and placebo groups (RR 1.20, 95% CI 0.35 to 4.10, 3 studies, 253 participants). The results were very similar when using a random-effects model and when we analysed only studies that excluded participants with a psychiatric comorbidity. The findings of this review, which compared bupropion to placebo for adult ADHD, indicate a possible benefit of bupropion. We found low-quality evidence that bupropion decreased the severity of ADHD symptoms and moderately increased the proportion of participants achieving a significant clinical improvement in ADHD symptoms. Furthermore, we found low-quality evidence that the tolerability of bupropion is similar to that of placebo. In the pharmacological treatment of adults with ADHD, extended- or sustained-release bupropion may be an alternative to stimulants. The low-quality evidence indicates uncertainty with respect to the pooled effect estimates. Further research is very likely to change these estimates. More research is needed to reach more definite conclusions as well as clarifying the optimal target population for this medicine. Treatment response remains to be reported in a DSM5-diagnosed population. There is also a lack of knowledge on long-term outcomes.
In total, we identified 1298 publications through the search strategy. We included 28 publications reporting on 24 studies. COC users were at increased risk of myocardial infarction or ischemic stroke compared with non-users: relative risk (RR) 1.6 (95% CI 1.3-1.9).These RRs were similar for myocardial infarction (1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9). The risks did not vary clearly according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen. This meta-analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6-fold increased in women using COCs . The risk was highest for pills with > 50 microgram estrogen. When combined with the results of studies on the risk of venous thrombosis in COC users, it seems that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of combined oral hormonal contraception.
Nine trials were identified and seven (with a total of 237 adult participants) were included. Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates. In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.
We included seventeen studies with a total of 1655 randomised participants in this review. Risk of bias was variable among studies. Blinding of participants, personnel and outcome assessment was not possible in most trials because of obvious differences between the treatments. The lack of a blinded outcome assessor may have caused detection bias when ulcer healing was assessed. However, possible detection bias is hard to prevent due to the nature of the skin replacement products we assessed, and the fact that they are easily recognisable. Strikingly, nearly all studies (15/17) reported industry involvement; at least one of the authors was connected to a commercial organisation or the study was funded by a commercial organisation. In addition, the funnel plot for assessing risk of bias appeared to be asymmetrical; suggesting that small studies with 'negative' results are less likely to be published. Thirteen of the studies included in this review compared a skin graft or tissue replacement with standard care. Four studies compared two grafts or tissue replacements with each other. When we pooled the results of all the individual studies, the skin grafts and tissue replacement products that were used in the trials increased the healing rate of foot ulcers in patients with diabetes compared to standard care (risk ratio (RR) 1.55, 95% confidence interval (CI) 1.30 to 1.85, low quality of evidence). However, the strength of effect was variable depending on the specific product that was used (e.g. EpiFix® RR 11.08, 95% CI 1.69 to 72.82 and OrCel® RR 1.75, 95% CI 0.61 to 5.05). Based on the four included studies that directly compared two products, no specific type of skin graft or tissue replacement showed a superior effect on ulcer healing over another type of skin graft or tissue replacement. Sixteen of the included studies reported on adverse events in various ways. No study reported a statistically significant difference in the occurrence of adverse events between the intervention and the control group. Only two of the included studies reported on total incidence of lower limb amputations. We found fewer amputations in the experimental group compared with the standard care group when we pooled the results of these two studies, although the absolute risk reduction for amputation was small (RR 0.43, 95% CI 0.23 to 0.81; risk difference (RD) -0.06, 95% CI -0.10 to -0.01, very low quality of evidence). Based on the studies included in this review, the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers and slightly fewer amputations in people with diabetes compared with standard care alone. However, the data available to us was insufficient for us to draw conclusions on the effectiveness of different types of skin grafts or tissue replacement therapies. In addition, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain.
Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates. Inhaled magnesium sulfate in addition to inhaled β₂-agonist and ipratropium We included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD −0.3 % predicted peak expiratory flow rate (PEFR), 95% CI −2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI −0.03 to 0.05; participants = 1197; studies = 2). Inhaled magnesium sulfate in addition to inhaled β₂-agonist We included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO₄ and β₂-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD −0.01, 95% CI −0.05 to 0.03; participants = 694; studies = 5). Inhaled magnesium sulfate versus inhaled β₂-agonist We included four studies in this comparison. The evidence for the efficacy of β₂-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of β₂-agonist over MgSO₄ alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise. Treatment with nebulised MgSO₄ may result in modest additional benefits for lung function and hospital admission when added to inhaled β₂-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO₄ does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted. Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled β₂-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO₄ has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely.
Authors identified 19 studies, of which nine studies with 202 participants met the review's inclusion criteria. There was wide variation in the methodological and written quality of the included studies. Four of the nine included studies were published as abstracts only and lacking concise details, thus limiting the information available. Seven studies were parallel studies and two of a cross-over design. Respiratory muscle training interventions varied dramatically, with frequency, intensity and duration ranging from thrice weekly to twice daily, 20% to 80% of maximal effort, and 10 to 30 minutes, respectively. Participant numbers ranged from 11 to 39 participants in the included studies; five studies were in adults only and four in a combination of children and adults. No significant improvement was reported in the primary outcome of pulmonary function (forced expiratory volume in one second and forced vital capacity) (very low-quality evidence). Although no change was reported in exercise capacity as assessed by the maximum rate of oxygen use, a 10% improvement in exercise duration was found when working at 60% of maximal effort in one study (n = 20) (very low-quality evidence). In a further study (n = 18), when working at 80% of maximal effort, health-related quality of life improved in the mastery and emotion domains (very low-quality evidence). With regards to the review's secondary outcomes, one study (n = 11) found a significant change in intramural pressure, functional residual capacity and maximal inspiratory pressure following training (low-quality evidence). A further study (n = 22) reported that respiratory muscle endurance was significantly longer in the training group (P < 0.01). No studies reported on any other secondary outcomes. Meta-analyses could not be performed due to a lack of consistency and insufficient detail in reported outcome measures. There is insufficient evidence to suggest whether this intervention is beneficial or not. Healthcare practitioners should consider the use of respiratory muscle training on a case-by-case basis. Further research of reputable methodological quality is needed to determine the effectiveness of respiratory muscle training in people with cystic fibrosis. Researchers should consider the following clinical outcomes in future studies; respiratory muscle function, pulmonary function, exercise capacity, hospital admissions, and health-related quality of life. Sensory-perceptual changes, such as respiratory effort sensation (e.g. rating of perceived breathlessness) and peripheral effort sensation (e.g. rating of perceived exertion) may also help to elucidate mechanisms underpinning the effectiveness of respiratory muscle training.
We found two studies involving 162 adults that met our inclusion criteria. Neither of the two studies included children. The duration of treatment and length of sessions varied between studies from four sessions delivered weekly, to four sessions over two months. Similarly, length of sessions varied slightly from one 60-minute session and three 45-minute sessions to four 30-minute sessions. The control interventions were healthy lifestyle advice in both studies. One study contributed HRQoL data, using the Leicester Cough Questionnaire (LCQ), and we judged the quality of the evidence to be low using the GRADE approach. Data were reported as between-group difference from baseline to four weeks (MD 1.53, 95% confidence interval (CI) 0.21 to 2.85; participants = 71), revealing a statistically significant benefit for people receiving a physiotherapy and speech and language therapy intervention (PSALTI) versus control. However, the difference between PSALTI and control was not observed between week four and three months. The same study provided information on SAEs, and there were no SAEs in either the PSALTI or control arms. Using the GRADE approach we judged the quality of evidence for this outcome to be low. Data were also available for our prespecified secondary outcomes. In each case data were provided by only one study, therefore there were no opportunities for aggregation; we judged the quality of this evidence to be low for each outcome. A significant difference favouring therapy was demonstrated for: objective cough counts (ratio for mean coughs per hour on treatment was 59% (95% CI 37% to 95%) relative to control; participants = 71); symptom score (MD 9.80, 95% CI 4.50 to 15.10; participants = 87); and clinical improvement as defined by trialists (OR 48.13, 95% CI 13.53 to 171.25; participants = 87). There was no significant difference between therapy and control regarding subjective measures of cough (MD on visual analogue scale of cough severity: −9.72, 95% CI −20.80 to 1.36; participants = 71) and cough reflex sensitivity (capsaicin concentration to induce five coughs: 1.11 (95% CI 0.80 to 1.54; participants = 49) times higher on treatment than on control). One study reported data on adverse events, and there were no adverse events reported in either the therapy or control arms of the study. The paucity of data in this review highlights the need for more controlled trial data examining the efficacy of SLT interventions in the management of UCC. Although a large number of studies were found in the initial search as per protocol, we could include only two studies in the review. In addition, this review highlights that endpoints vary between published studies.  The improvements in HRQoL (LCQ) and reduction in 24-hour cough frequency seen with the PSALTI intervention were statistically significant but short-lived, with the between-group difference lasting up to four weeks only. Further studies are required to replicate these findings and to investigate the effects of SLT interventions over time. It is clear that SLT interventions vary between studies. Further research is needed to understand which aspects of SLT interventions are most effective in reducing cough (both objective cough frequency and subjective measures of cough) and improving HRQoL. We consider these endpoints to be clinically important. It is also important for future studies to report information on adverse events. Because of the paucity of data, we can draw no robust conclusions regarding the efficacy of SLT interventions for improving outcomes in unexplained chronic cough. Our review identifies the need for further high-quality research, with comparable endpoints to inform robust conclusions.
Six RCTs (434 participants) appraised four types of chest physiotherapy (conventional chest physiotherapy; osteopathic manipulative treatment (which includes paraspinal inhibition, rib raising and myofascial release); active cycle of breathing techniques (which include active breathing control, thoracic expansion exercises and forced expiration techniques); and positive expiratory pressure). None of the physiotherapies (versus no physiotherapy or placebo) improved mortality rates of adults with pneumonia. Conventional chest physiotherapy (versus no physiotherapy), active cycle of breathing techniques (versus no physiotherapy) and osteopathic manipulative treatment (versus placebo) did not increase the cure rate or chest X-ray improvement rate. Osteopathic manipulative treatment (versus placebo) and positive expiratory pressure (versus no physiotherapy) reduced the mean duration of hospital stay by 2.0 days (mean difference (MD) -2.0 days, 95% CI -3.5 to -0.6) and 1.4 days (MD -1.4 days, 95% CI -2.8 to -0.0), respectively. Conventional chest physiotherapy and active cycle of breathing techniques did not. Positive expiratory pressure (versus no physiotherapy) reduced fever duration (MD -0.7 day, 95% CI -1.4 to -0.0). Osteopathic manipulative treatment did not. Osteopathic manipulative treatment (versus placebo) reduced the duration of intravenous (MD -2.1 days, 95% CI -3.4 to -0.9) and total antibiotic treatment (MD -1.9 days, 95% CI -3.1 to -0.7). Limitations of this review are that the studies addressing osteopathic manipulative treatment were small, and that six published studies which appear to meet the inclusion criteria are awaiting classification. Based on current limited evidence, chest physiotherapy might not be recommended as routine additional treatment for pneumonia in adults.
This review included four RCTs with 442 participants. The evidence was very low-quality with the main limitations being due to serious imprecision, inconsistency and indirectness. Myomectomy versus no intervention One study examined the effect of myomectomy compared to no intervention on reproductive outcomes. We are uncertain whether myomectomy improves clinical pregnancy rate for intramural (odds ratio (OR) 1.88, 95% confidence interval (CI) 0.57 to 6.14; 45 participants; one study; very low-quality evidence), submucous (OR 2.04, 95% CI 0.62 to 6.66; 52 participants; one study; very low-quality evidence), intramural/subserous (OR 2.00, 95% CI 0.40 to 10.09; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 3.24, 95% CI 0.72 to 14.57; 42 participants; one study; very low-quality evidence). Similarly, we are uncertain whether myomectomy reduces miscarriage rate for intramural fibroids (OR 1.33, 95% CI 0.26 to 6.78; 45 participants; one study; very low-quality evidence), submucous fibroids (OR 1.27, 95% CI 0.27 to 5.97; 52 participants; one study; very low-quality evidence), intramural/subserous fibroids (OR 0.80, 95% CI 0.10 to 6.54; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 2.00, 95% CI 0.32 to 12.33; 42 participants; one study; very low-quality evidence). This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Laparoscopic myomectomy versus myomectomy by laparotomy or mini-laparotomy Two studies compared laparoscopic myomectomy to myomectomy at laparotomy or mini-laparotomy. We are uncertain whether laparoscopic myomectomy compared to laparotomy or mini-laparotomy improves live birth rate (OR 0.80, 95% CI 0.42 to 1.50; 177 participants; two studies; I2 = 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I2 = 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I2 = 0%, very low-quality evidence), ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04; 115 participants; one study; very low-quality evidence), miscarriage rate (OR 1.25, 95% CI 0.40 to 3.89; participants = 177; two studies; I2 = 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I2 = 21%, very low-quality evidence). Monopolar resectoscope versus bipolar resectoscope One study evaluated the use of two electrosurgical systems during hysteroscopic myomectomy. We are uncertain whether bipolar resectoscope use compared to monopolar resectoscope use improves live birth/ongoing pregnancy rate (OR 0.86, 95% CI 0.30 to 2.50; 68 participants; one study, very low-quality evidence), clinical pregnancy rate (OR 0.88, 95% CI 0.33 to 2.36; 68 participants; one study; very low-quality evidence), or miscarriage rate (OR 1.00, 95% CI 0.19 to 5.34; participants = 68; one study; very low-quality evidence). This study did not report on preterm delivery or caesarean section rate. There is limited evidence to determine the role of myomectomy for infertility in women with fibroids as only one trial compared myomectomy with no myomectomy. If the decision is made to have a myomectomy, the current evidence does not indicate a superior method (laparoscopy, laparotomy or different electrosurgical systems) to improve rates of live birth, preterm delivery, clinical pregnancy, ongoing pregnancy, miscarriage, or caesarean section. Furthermore, the existing evidence needs to be viewed with caution due to the small number of events, minimal number of studies and very low-quality evidence.
We included 10 studies (1354 women). The risk of bias was unclear or high in most of the included studies. All of the included trials involved women undergoing caesarean section whether elective or non-elective. Intravenous antibiotics versus antibiotic irrigation (nine studies, 1274 women) Nine studies (1274 women) compared the administration of intravenous antibiotics with antibiotic irrigation. There were no clear differences between groups in terms of this review's maternal primary outcomes: endometritis (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.29; eight studies (966 women) (low-quality evidence)); wound infection (RR 0.49, 95% CI 0.17 to 1.43; seven studies (859 women) (very low-quality evidence)). The outcome of infant sepsis was not reported in the included studies. In terms of this review's maternal secondary outcomes, there were no clear differences between intravenous antibiotic or irrigation antibiotic groups in terms of postpartum febrile morbidity (RR 0.87, 95% CI 0.48 to 1.60; three studies (264 women) (very low-quality evidence)); or urinary tract infection (RR 0.74, 95% CI 0.25 to 2.15; five studies (660 women) (very low-quality evidence)). In terms of adverse effects of the treatment on the women, no drug allergic reactions were reported in three studies (284 women) (very low-quality evidence), and there were no cases of serious infectious complications reported (very low-quality evidence). There was no clear difference between groups in terms of maternal length of hospital stay (mean difference (MD) 0.28 days, 95% CI -0.22 to 0.79 days, (random-effects analysis), four studies (512 women). No data were reported for the number of women readmitted to hospital. For the baby, there were no data reported in relation to oral thrush, infant length of hospital stay or immediate adverse effects of the antibiotics on the infant. Intravenous antibiotic prophylaxis versus oral antibiotic prophylaxis (one study, 80 women) One study (80 women) compared an intravenous versus an oral route of administration of prophylactic antibiotics, but did not report any of this review's primary or secondary outcomes. There was no clear difference between irrigation and intravenous antibiotic prophylaxis in reducing the risk of post-caesarean endometritis. For other outcomes, there is insufficient evidence regarding which route of administration of prophylactic antibiotics is most effective at preventing post-caesarean infections. The quality of evidence was very low to low, mainly due to limitations in study design and imprecision. Furthermore, most of the included studies were underpowered (small sample sizes with few events). Therefore, we advise caution in the interpretation and generalisability of the results. For future research, there is a need for well-designed, properly-conducted, and clearly-reported RCTs. Such studies should evaluate the more recently available antibiotics, elaborating on the various available routes of administration, and exploring potential neonatal side effects of such interventions.
We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons. The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 μg. Another indicated less bone resorption in the group with gestodene plus EE 30 μg versus EE 20 μg. Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.
The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry. Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence). There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence). However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence). Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively. The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence).
Twenty-eight study comparisons drawn from 27 trials (22 adult; five paediatric) met the review entry criteria (8050 participants). Baseline data from the studies indicated that trial populations had moderate or mild airway obstruction (FEV1≥65% predicted), and that they were symptomatic prior to randomisation. In comparison 1, the combination of ICS and LABA was not associated with a significantly lower risk of patients with exacerbations requiring oral corticosteroids (RR 1.04; 95% confidence interval (CI) 0.73 to 1.47) or requiring hospital admissions (RR 0.38; 95% CI 0.09 to 1.65) compared to a similar dose of ICS alone. The combination of LABA and ICS led to a significantly greater improvement from baseline in FEV1 (0.12 L/sec; 95% CI 0.07 to 0.17), in symptoms (SMD -0.26; 95% CI -0.37 to -0.14) and in rescue ß2-agonist use (-0.41 puffs/day; 95% CI -0.73 to -0.09) compared with a similar dose of ICS alone. There was no significant group difference in the risk of serious adverse events (RR 1.15; 95% CI 0.64 to 2.09), any adverse events (RR 1.02; 95% CI 0.96 to 1.09), study withdrawals (RR 0.95; 95% CI 0.82 to 1.11), or withdrawals due to poor asthma control (RR 0.94; 95% CI 0.63 to 1.41). In comparison 2, the combination of LABA and ICS was associated with a higher risk of patients requiring oral corticosteroids (RR 1.24; 95% CI 1 to 1.53) and study withdrawal (RR 1.31; 95% CI 1.07 to 1.59) than a higher dose of ICS alone. For every 100 patients treated over 43 weeks, nine patients using a higher dose ICS compared to 11 (95% CI 9 to 14) on LABA and ICS suffered one or more exacerbations requiring rescue oral corticosteroids. There was a high level of statistical heterogeneity for FEV1 and morning peak flow. There was no statistically significant group difference in the risk of serious adverse events. Due to insufficient data we could not aggregate results for hospital admission, symptoms and other outcomes. In steroid-naive patients with mild to moderate airway obstruction, the combination of ICS and LABA does not significantly reduce the risk of patients with exacerbations requiring rescue oral corticosteroids over that achieved with a similar dose of ICS alone. However, it significantly improves lung function, reduces symptoms and marginally decreases rescue ß2-agonist use. Initiation of a higher dose of ICS is more effective at reducing the risk of exacerbations requiring rescue systemic corticosteroids, and of withdrawals, than combination therapy. Although children appeared to respond similarly to adults, no firm conclusions can be drawn regarding combination therapy in steroid-naive children, given the small number of children contributing data.
We found three relevant small, short trials (total n=126). Clinical Global Impression data were equivocal (n=27, 1 RCT, WMD -0.43 CI -0.9 to 0.1). Average total PANSS scores were not significantly different between the DHEA plus antipsychotic group and those given antipsychotic drugs and placebo (n=82, 2 RCTs, WMD -4.16 CI -13.8 to 5.5). PANSS positive scores were equivocal (n=55, 1 RCT, WMD -1.00 CI -3.8 to 1.8). For negative symptoms binary SANS scale data favoured the DHEA plus antipsychotic group (n=30, 1 RCT, RR 0.23 CI 0.1 to 0.6, NNT 2 CI 2 to 3) but PANSS negative scores were not significantly different between comparison groups (n=55, 1 RCT, WMD -2.30 CI -6.4 to 1.8). About 17% of people left both groups early (n=64, 2 RCTs, RR 0.80 CI 0.3 to 2.4). St Hans Rating Scale data for extrapyramidal symptoms favoured the DHEA plus antipsychotic group (n=30, 1 RCT, WMD -5.00 CI -8.8 to -1.2) but akathisia ratings were equivocal (n=34, 1 RCT, RR 2.67 CI 0.3 to 23.1). Ratings of parkinsonian movement disorder differed within the same trial depending of the outcome scale used. Quality of life seemed unaffected by use of DHEA (n=55, 1 RCT, WMD 6.20 CI -1.4 to 13.8). Results are inconclusive with most outcomes being either non-significant or producing contradictory findings. Currently, adjunctive DHEA should remain an experimental treatment for people with schizophrenia.
Six studies met the inclusion criteria; two were randomised studies and four were observational comparative studies evaluating different methods for obtaining missing data. Methods to obtain missing data Five studies, two randomised studies and three observational comparative studies, assessed methods for obtaining missing data (i.e. data available to the original researchers but not reported in the published study). Two studies found that correspondence with study authors by e-mail resulted in the greatest response rate with the fewest attempts and shortest time to respond. The difference between the effect of a single request for missing information (by e-mail or surface mail) versus a multistage approach (pre-notification, request for missing information and active follow-up) was not significant for response rate and completeness of information retrieved (one study). Requests for clarification of methods (one study) resulted in a greater response than requests for missing data. A well-known signatory had no significant effect on the likelihood of authors responding to a request for unpublished information (one study). One study assessed the number of attempts made to obtain missing data and found that the number of items requested did not influence the probability of response. In addition, multiple attempts using the same methods did not increase the likelihood of response. Methods to obtain unpublished studies One observational comparative study assessed methods to obtain unpublished studies (i.e. data for studies that have never been published). Identifying unpublished studies ahead of time and then asking the drug industry to provide further specific detail proved to be more fruitful than sending of a non-specific request. Those carrying out systematic reviews should continue to contact authors for missing data, recognising that this might not always be successful, particularly for older studies. Contacting authors by e-mail results in the greatest response rate with the fewest number of attempts and the shortest time to respond.
Two randomized controlled trials enrolling a total of 268 patients satisfied the inclusion criteria. The risk of bias for Drewry 1994 was unclear as this study was presented as an abstract, while Bennett 2003 was rated as at low risk. Pooling of data was not possible. In one study there was no evidence of improved effectiveness with the addition of a non-steroidal anti-inflammatory drug (tenoxicam) to routine recompression therapy (at six weeks: relative risk (RR) 1.04, 95% confidence interval (CI) 0.90 to 1.20, P = 0.58) but there was a reduction in the number of compressions required when tenoxicam was added from three to two (P = 0.01, 95% CI 0 to 1). In the other study, the odds of multiple recompressions were lower with a helium and oxygen (heliox) table compared to an oxygen treatment table (RR 0.56, 95% CI 0.31 to 1.00, P = 0.05). Recompression therapy is standard for the treatment of DCI, but there is no randomized controlled trial evidence for its use. Both the addition of a non-steroidal anti-inflammatory drug (NSAID) and the use of heliox may reduce the number of recompressions required, but neither improve the odds of recovery. The application of either of these strategies may be justified. The modest number of patients studied demands a cautious interpretation. Benefits may be largely economic and an economic analysis should be undertaken. There is a case for large randomized trials of high methodological rigour in order to define any benefit from the use of different breathing gases and pressure profiles during recompression therapy.
We included one trial with 226 participants: A Randomized trial of Unruptured Brain Arteriovenous Malformations (ARUBA), comparing intervention versus conservative management for unruptured brain AVMs (that had never bled). The quality of evidence was moderate because we found just one trial that was at low risk of bias other than a high risk of performance bias due to participants and treating physicians not being blinded to allocated treatment. Data on functional outcome and death at a follow-up of 12 months were provided for 218 (96%) of the participants in ARUBA. In this randomized controlled trial (RCT), intervention compared to conservative management increased death or dependency (modified Rankin Scale score ≥ 2, risk ratio (RR) 2.53, 95% confidence interval (CI) 1.28 to 4.98; 1 trial, 226 participants; moderate-quality evidence) and the proportion of participants with symptomatic intracranial haemorrhage (RR 6.75, 95% CI 2.07 to 21.96; 1 trial, 226 participants; moderate-quality evidence), but there was no difference in the frequency of epileptic seizures (RR 1.14, 95% CI 0.63 to 2.06; 1 trial, 226 participants; moderate-quality evidence). Three RCTs are ongoing. We found moderate-quality evidence from one RCT including adults with unruptured brain AVMs that conservative management was superior to intervention with respect to functional outcome and symptomatic intracranial haemorrhage over one year after randomization. More RCTs will help to confirm or refute these findings.
Ten trials, with a total of 2345 participants, met the inclusion criteria. The trials were conducted in four geographical regions and were often small, but they included comparisons across eight drugs. Nine trials were funded by a pharmaceutical company, only three carried out an intention-to-treat analysis, and allocation concealment was unclear in seven. Atovaquone-proguanil had fewer treatment failures by day 28 than chloroquine (RR 0.04, 95% CI 0.00 to 0.57; 27 participants, 1 trial), amodiaquine (RR 0.22, 95% CI 0.13 to 0.36; 342 participants, 2 trials), and mefloquine (RR 0.04, 95% CI 0.00 to 0.73; 158 participants, 1 trial). There were insufficient data to draw a conclusion for this outcome from comparisons with sulfadoxine-pyrimethamine (172 participants, 2 trials), halofantrine (205 participants, 1 trial), artesunate plus mefloquine (1063 participants, 1 trial), quinine plus tetracycline (154 participants, 1 trial), and dihydroartemisinin-piperaquine-trimethoprim-primaquine (161 participants, 1 trial). Adverse events were mainly common symptoms of malaria and did not differ in frequency between groups. Data are limited but appear to suggest that atovaquone-proguanil is more effective than chloroquine, amodiaquine, and mefloquine. There are insufficient data for comparisons against sulfadoxine-pyrimethamine, halofantrine, artesunate plus mefloquine, quinine plus tetracycline, and dihydroartemisinin-piperaquine-trimethoprim-primaquine in treating malaria. There are not enough data to assess safety, but a number of adverse events were identified with all drugs. Large trials comparing atovaquone-proguanil with other new combination therapies are needed.
We included seven RCTs and studied 7586 women of the 8955 enrolled. Local recurrence-free survival appeared worse for women receiving PBI/APBI compared to WBRT (hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.11 to 2.35; six studies, 6820 participants, low-quality evidence). Cosmesis (physician-reported) appeared worse with PBI/APBI (odds ratio (OR) 1.51, 95% CI 1.17 to 1.95, five studies, 1720 participants, low-quality evidence). Overall survival did not differ with PBI/APBI (HR 0.90, 95% CI 0.74 to 1.09, five studies, 6718 participants, high-quality evidence). Late radiation toxicity (subcutaneous fibrosis) appeared worse with PBI/APBI (OR 6.58, 95% CI 3.08 to 14.06, one study, 766 participants, moderate-quality evidence). Acute skin toxicity appeared reduced with PBI/APBI (OR 0.04, 95% CI 0.02 to 0.09, two studies, 608 participants). Telangiectasia (OR 26.56, 95% CI 3.59 to 196.51, 1 study, 766 participants) and radiological fat necrosis (OR 1.58, 95% CI 1.02 to 2.43, three studies, 1319 participants) appeared worse with PBI/APBI. Late skin toxicity (OR 0.21, 95% CI 0.01 to 4.39, two studies, 608 participants) and breast pain (OR 2.17, 95% CI 0.56 to 8.44, one study, 766 participants) appeared not to differ with PBI/APBI. 'Elsewhere primaries' (new primaries in the ipsilateral breast) appeared more frequent with PBI/APBI (OR 3.97, 95% CI 1.51 to 10.41, three studies, 3009 participants). We found no clear evidence of a difference for the comparison of PBI/APBI with WBRT for the outcomes of: cause-specific survival (HR 1.08, 95% CI 0.73 to 1.58, five studies, 6718 participants, moderate-quality evidence), distant metastasis-free survival (HR 0.94, 95% CI 0.65 to 1.37, four studies, 3267 participants, moderate-quality evidence), relapse-free survival (HR 1.36, 95% CI 0.88 to 2.09, three studies, 3811 participants), loco-regional recurrence-free survival (HR 1.80, 95% CI 1.00 to 3.25, two studies, 3553 participants) or mastectomy rates (OR 1.20, 95% CI 0.77 to 1.87, three studies, 4817 participants, low-quality evidence). Compliance was met: more than 90% of the women in all studies received the RT they were assigned to receive. We found no data for the outcomes of costs, quality of life or consumer preference. It appeared that local recurrence and 'elsewhere primaries' (new primaries in the ipsilateral breast) are increased with PBI/APBI (the difference was small), but we found no evidence of detriment to other oncological outcomes. It appeared that cosmetic outcomes and some late effects were worse with PBI/APBI but its use was associated with less acute skin toxicity. The limitations of the data currently available mean that we cannot make definitive conclusions about the efficacy and safety or ways to deliver of PBI/APBI. We await completion of ongoing trials.
Four studies with a total of 141 participants were included in the review, two of these were in children (aged six months to 14.5 years), and the other two did not specify participants’ age. All studies used different formulations and doses of vitamin E for various durations of treatment (10 days to six months). Two studies compared the supplementation of fat-soluble as well as water-soluble formulations to no supplementation in different arms of the same study. A third study compared a water-soluble formulation to a placebo; and in the fourth study a fat-soluble formulation of vitamin E was assessed against placebo. At one month, three months and six months, water-soluble vitamin E significantly improved serum vitamin E levels compared with control: at one month, two studies, mean difference 17.66 (95% confidence interval 10.59 to 24.74); at three months, one study, mean difference 11.61 (95% confidence interval 4.77 to 18.45); and at six months, one study, mean difference 19.74 (95% confidence interval 13.48 to 26.00). At one month fat-soluble vitamin E significantly improved serum vitamin E levels compared with control: one month, two studies, mean difference 13.59 (95% CI 9.52 to 17.66). The findings at three months were imprecise; one study; mean difference 6.40 (95% confidence interval -1.45 to 14.25). None of the studies report the review's primary outcomes of vitamin E total lipid ratio or the incidence of vitamin E-specific deficiency disorders, or the secondary outcomes lung function or quality of life. Only one study, comparing water-soluble vitamin E with placebo, reported the secondary outcome of growth and nutritional status (weight), but the results are uncertain due to imprecision around the effect estimate. There was limited detail about randomisation and blinding in the included studies which compromises the quality of the evidence base for the review. The heterogeneous mix of the formulations with differing biovailabilities among these studies also limits the generalisability of the data to the wider cystic fibrosis population. Vitamin E supplementation led to an improvement in vitamin E levels in people with cystic fibrosis, although the studies may have been at risk of bias. No data on other outcomes of interest were available to allow conclusions about any other benefits of this therapy. In future, larger studies are needed, especially in people already being treated with enteric-coated pancreatic enzymes and supplemented with vitamin E, to look at more specific outcome measures such as vitamin E status, lung function and nutritional status. Future studies could also look at the optimal dose of vitamin E required to achieve maximal clinical effectiveness.
Two RCTs from Kenya were included in the review. One trial compared short weekly text messages against standard care. The other trial compared short daily, long daily, short weekly and long weekly messages against standard care. Both trials were with adult patients. In the trial comparing only short weekly messages to standard care, text messaging was associated with a lower risk of non-adherence at 12 months (RR 0.77, 95% CI 0.63 to 0.93) and with the non-occurrence of virologic failure at 12 months (RR 0.83, 95% CI 0.69 to 0.99). In the trial that compared different intervals and lengths for text-messaging to standard care, long weekly text-messaging was not significantly associated with a lower risk of non-adherence compared to standard care (RR 0.79, 95% CI 0.60 to 1.04). Patients receiving weekly text-messages of any length were at lower risk of non-adherence at 48 weeks than were patients receiving daily messages of any length (RR 0.79, 95% CI 0.64 to 0.99). There were no significant differences between weekly text-messaging of any length (RR 1.01, 95% CI 0.75 to 1.37) and between short or long messaging at either interval (RR 0.99, 95% CI 0.78 to 1.27). Compared to standard care, any daily text-messaging, whether short or long, did not reduce the risk for non-adherence (RR 0.99, 95% CI 0.82 to 1.20). In meta-analysis of both trials, any weekly text-messaging (i.e. whether short or long messages) was associated with a lower risk of non-adherence at 48-52 weeks (RR 0.78, 95% CI 0.68 to 0.89). The effect of short weekly text-messaging was also significant (RR 0.77, 95% CI 0.67 to 0.89). There is high-quality evidence from the two RCTs that mobile phone text-messaging at weekly intervals is efficacious in enhancing adherence to ART, compared to standard care. There is high quality evidence from one trial that weekly mobile phone text-messaging is efficacious in improving HIV viral load suppression. Policy-makers should consider funding programs proposing to provide weekly mobile phone text-messaging as a means for promoting adherence to antiretroviral therapy. Clinics and hospitals should consider implementing such programs. There is a need for large RCTs of this intervention in adolescent populations, as well as in high-income countries.
When the described search method was used and the eligibility criteria of the search results were applied, 653 records were found. Only two of these were randomised clinical trials that were considered eligible for inclusion. We assessed both trials as trials with high risk of bias. One of the trials was a pilot trial in which 16 participants with biopsy-proven NASH were randomised to receive simvastatin 40 mg (n = 10) or placebo (n = 6) once daily for 12 months. No statistically significant improvement in the aminotransferase level was seen in the simvastatin group compared with the placebo group. Liver histology was not significantly affected by simvastatin. The other trial had three arms. The trial compared atorvastatin 20 mg daily (n = 63) versus fenofibrate 200 mg daily (n = 62) versus a group treated with a combination of the two interventions (n = 61). There were no statistically significant differences between any of the three intervention groups regarding the week 54 mean activity levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. The triglyceride levels seemed higher in the fenofibrate group compared with the atorvastatin group. Liver histology was not assessed in this trial. The presence of biochemical and ultrasonographic evidence of NAFLD seemed to be higher in the fenofibrate group compared with the atorvastatin group (58% versus 33%). Three patients discontinued treatment due to myalgia and elevated serum creatine kinase activity; one from the atorvastatin group and two from the combination group. Another patient from the atorvastatin group discontinued treatment due to alanine aminotransferase activity that was over three times the upper normal limit. No data for all-cause mortality and hepatic-related mortality were reported in the included trials. Based on the findings of this review, which included two trials with high risk of bias and a small numbers of participants, it seems possible that statins may improve serum aminotransferase levels as well as ultrasound findings. Neither of the trials reported on possible histological changes, liver-related morbidity or mortality. Trials with larger sample sizes and low risk of bias are necessary before we may suggest statins as an effective treatment for patients with NASH. However, as statins can improve the adverse outcomes of other conditions commonly associated with NASH (for example, hyperlipidaemia, diabetes mellitus, metabolic syndrome), their use in patients with non-alcoholic steatohepatitis may be justified.
We included one RCT with 184 participants comparing Aquablation to TURP. The mean age and International Prostate Symptom Score were 65.9 years and 22.6, respectively. The mean prostate volume was 53.2 mL. We only found short-term data for all outcomes based on a single randomised trial. Primary outcomes Up to 12 months, Aquablation likely results in a similar improvement in urologic symptom scores to TURP (mean difference (MD) −0.06, 95% confidence interval (CI) −2.51 to 2.39; participants = 174; moderate-certainty evidence). We downgraded the evidence certainty by one level due to study limitations. Aquablation may also result in similar quality of life when compared to TURP (MD 0.27, 95% CI −0.24 to 0.78; participants = 174, low-certainty evidence). We downgraded the evidence certainty by two levels due to study limitations and imprecision. Aquablation may result in little to no difference in major adverse events (risk ratio (RR) 0.84, 95% CI 0.31 to 2.26; participants = 181, very low-certainty evidence) but we are very uncertain of this finding. This would correspond to 15 fewer major adverse events per 1000 participants (95% CI 64 fewer to 116 more). We downgraded the evidence certainty by one level for study limitations and two levels for imprecision. Secondary outcomes Up to 12 months, Aquablation may result in little to no difference in retreatments (RR 1.68, 95% CI 0.18 to 15.83; participants = 181, very low-certainty evidence) but we are very uncertain of this finding. This would correspond to 10 more retreatments per 1000 participants (95% CI 13 fewer to 228 more). We downgraded the evidence certainty by one level due to study limitations and two levels for imprecision. Aquablation may result in little to no difference in erectile function as measured by International Index of Erectile Function questionnaire Erectile Function domain compared to TURP (MD 2.31, 95% CI −0.63 to 5.25; participants = 64, very low-certainty evidence), and may cause slightly less ejaculatory dysfunction than TURP, as measured by Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MD 2.57, 95% CI 0.60 to 4.53; participants = 121, very low-certainty evidence). However, we are very uncertain of both findings. We downgraded the evidence certainty by two levels due to study limitations and one level for imprecision for both outcomes. We did not find other prospective, comparative studies comparing Aquablation to TURP or other procedures such as laser ablation, enucleation, or other minimally invasive therapies. Based on short-term (up to 12 months) follow-up, the effect of Aquablation on urological symptoms is probably similar to that of TURP (moderate-certainty evidence). The effect on quality of life may also be similar (low-certainty evidence). We are very uncertain whether patients undergoing Aquablation are at higher or lower risk for major adverse events (very low-certainty evidence). We are very uncertain whether Aquablation may result in little to no difference in erectile function but offer a small improvement in preservation of ejaculatory function (both very low-certainty evidence). These conclusions are based on a single study of men with a prostate volume up to 80 mL in size. Longer-term data and comparisons with other modalities appear critical to a more thorough assessment of the role of Aquablation for the treatment of LUTS in men with BPH.
Two new trials were included in this update. Baker 2003 was an expanded study of Baker 2001 reported in the previous version. Both Baker 2003 and van Weert 2005 examined the short-term and longer-term effects of snoezelen on behaviour, mood, and communication of people with moderate to severe dementia. The format of implementation was different in the two trials: one was session-based snoezelen programme (Baker 2003), whilst the other was a 24-hour integrated snoezelen care (van Weert 2005). Owing to the differences in study methodology, the results of the two trials were not pooled for analysis. The session-based snoezelen programme (Baker 2003) did not show any effects on behaviour, mood, cognition and communication / interaction in the short term (during or immediately after sessions) or longer term (at post-intervention or 1-month post-intervention follow-up). Likewise, the 24-hour integrated snoezelen care (van Weert 2005) failed to demonstrate any significant short-term and longer term effects on behaviour, mood and interaction. A more vigorous review methodology was adopted in this update. The study of Kragt 1997, reported in the previous version, was excluded because the snoezelen programme only consisted of three sessions, which was considered too brief for a therapeutic intervention. Two new trials were reviewed. Meta-analyses could not be performed because of the limited number of trials and different study methods of the available trials. Overall, there is no evidence showing the efficacy of snoezelen for dementia. There is a need for more reliable and sound research-based evidence to inform and justify the use of snoezelen in dementia care.
Twenty-one trials with 2570 participants met the inclusion criteria; 18 trials with 2376 participants for the prevention of dry socket and three studies with 194 participants for the treatment of dry socket. The risk of bias assessment identified six studies at high risk of bias, 14 studies at unclear risk of bias and one studies at low risk of bias. When compared to placebo, rinsing with chlorhexidine mouthrinses (0.12% and 0.2% concentrations) both before and after extraction(s) prevented approximately 42% of dry socket(s) with a RR of 0.58 (95% CI 0.43 to 0.78; P < 0.001) (four trials, 750 participants, moderate quality of evidence). The prevalence of dry socket varied from 1% to 5% in routine dental extractions to upwards of 30% in surgically extracted third molars. The number of patients needed to be treated with (0.12% and 0.2%) chlorhexidine rinse to prevent one patient having dry socket (NNT) was 232 (95% CI 176 to 417), 47 (95% CI 35 to 84) and 8 (95% CI 6 to 14) for control prevalences of dry socket of 1%, 5% and 30% respectively. Compared to placebo, placing chlorhexidine gel (0.2%) after extractions prevented approximately 58% of dry socket(s) with a RR of 0.42 (95% CI 0.21 to 0.87; P = 0.02) (two trials, in 133 participants, moderate quality of evidence). The number of patients needed to be treated with chlorhexidine gel to prevent one patient having dry socket (NNT) was 173 (95% CI 127 to 770), 35 (95% CI 25 to 154) and 6 (95% CI 5 to 26) for control prevalences of dry socket of 1%, 5% and 30% respectively. A further 10 intrasocket interventions to prevent dry socket were each evaluated in single studies, and therefore there is insufficient evidence to determine their effects. Five interventions for the treatment of dry socket were evaluated in a total of three studies providing insufficient evidence to determine their effects. Most tooth extractions are undertaken by dentists for a variety of reasons, however, all but three studies included in the present review included participants undergoing extraction of third molars, most of which were undertaken by oral surgeons. There is some evidence that rinsing with chlorhexidine (0.12% and 0.2%) or placing chlorhexidine gel (0.2%) in the sockets of extracted teeth, provides a benefit in preventing dry socket. There was insufficient evidence to determine the effects of the other 10 preventative interventions each evaluated in single studies. There was insufficient evidence to determine the effects of any of the interventions to treat dry socket. The present review found some evidence for the association of minor adverse reactions with use of 0.12%, 0.2% and 2% chlorhexidine mouthrinses, though most studies were not designed to detect the presence of hypersensitivity reactions to mouthwash as part of the study protocol. No adverse events were reported in relation to the use of 0.2% chlorhexidine gel placed directly into a socket (though previous allergy to chlorhexidine was an exclusion criterion in these trials). In view of recent reports in the UK of two cases of serious adverse events associated with irrigation of dry socket with chlorhexidine mouthrinse, it is recommended that all members of the dental team prescribing chlorhexidine products are aware of the potential for both minor and serious adverse side effects.
A total of 43 trials (35 RCTs and eight qRCTs) with 7465 participants were identified. Twenty-two trials with 5546 participants were involved in prevention of Aloe vera for phlebitis, and a further 21 trials with 1919 participants were involved in the treatment of phlebitis. The included studies compared external application of Aloe vera alone or plus non-Aloe vera interventions with no treatment or the same non-Aloe vera interventions. The duration of the intervention lasted from one day to 15 days. Most of the included studies were of low methodological quality with concerns for selection bias, attrition bias, reporting bias and publication bias. The effects of external application of fresh Aloe vera on preventing total incidence of phlebitis varied across the studies and we did not combine the data. Aloe vera reduced the occurrence of third degree phlebitis (RR 0.06, 95% CI 0.03 to 0.11, P < 0.00001) and second degree phlebitis (RR 0.18, 95% CI 0.10 to 0.31, P < 0.00001) compared with no treatment. Compared with external application of 75% alcohol, or 33% MgSO4 alone, Aloe vera reduced the total incidence of phlebitis (RR 0.02, 95% CI 0.00 to 0.28, P = 0.004 and RR 0.43, 95% CI 0.24 to 0.78, P = 0.005 respectively) but there was no clear evidence of an effect when compared with 50% or 75% MgSO4 (total incidence of phlebitis RR 0.41, 95% CI 0.16 to 1.07, P = 0.07 and RR 1.10 95% CI 0.54 to 2.25, P = 0.79 respectively; third degree phlebitis (RR 0.28, 95% CI 0.07 to 1.02, P = 0.051 and RR 1.19, 95% CI 0.08 to 18.73, P = 0.9 respectively; second degree phlebitis RR 0.68, 95% CI 0.21 to 2.23, P = 0.53 compared to 75% MgSO4) except for a reduction in second degree phlebitis when Aloe vera was compared with 50% MgSO4 (RR 0.26, 95% CI 0.14 to 0.50, P < 0.0001). For the treatment of phlebitis, Aloe vera was more effective than 33% or 50% MgSO4 in terms of both any improvement (RR 1.16, 95% CI 1.09 to 1.24, P < 0.0001 and RR 1.22, 95% CI 1.16 to 1.28, P < 0.0001 respectively) and marked improvement of phlebitis (RR 1.97, 95% CI 1.44 to 2.70, P < 0.001 and RR 1.56, 95% CI 1.29 to 1.87, P = 0.0002 respectively). Compared with 50% MgSO4, Aloe vera also improved recovery rates from phlebitis (RR 1.42, 95% CI 1.24 to 1.61, P < 0.0001). Compared with routine treatments such as external application of hirudoid, sulphonic acid mucopolysaccharide and dexamethasone used alone, addition of Aloe vera improved recovery from phlebitis (RR 1.75, 95% CI 1.24 to 2.46, P = 0.001) and had a positive effect on overall improvement (marked improvement RR 1.26, 95% CI 1.09 to 1.47, P = 0.0003; any improvement RR 1.23, 95% CI 1.13 to 1.35, P < 0.0001). Aloe vera, either alone or in combination with routine treatment, was more effective than routine treatment alone for improving the symptoms of phlebitis including shortening the time of elimination of red swelling symptoms, time of pain relief at the location of the infusion vein and time of resolution of phlebitis. Other secondary outcomes including health-related quality of life and adverse effects were not reported in the included studies. There is no strong evidence for preventing or treating infusion phlebitis with external application of Aloe vera. The current available evidence is limited by the poor methodological quality and risk of selective outcome reporting of the included studies, and by variation in the size of effect across the studies. The positive effects observed with external application of Aloe vera in preventing or treating infusion phlebitis compared with no intervention or external application of 33% or 50% MgSO4 should therefore be viewed with caution.
We included 14 studies that evaluated the effect of training and education on RPE use, which involved 2052 participants. The included studies had been conducted with farm, healthcare, production line, office and coke oven workers as well as nursing students and people with mixed occupations. All included studies reported the effects of interventions as use of RPE, as correct use of RPE or as indirect measures of RPE use. We did not find any studies where the intervention was delivered and assessed at the whole organization level or in which the main focus was on positive or negative incentives. We rated the quality of the evidence for all comparisons as low to very low. Training versus no training One CBA study in healthcare workers compared training with and without a fit test to no intervention. The study found that the rate of properly fitting respirators was not considerably different in the workers who had received training with a fit test (RR 1.17, 95% Confidence Interval (CI) 0.97 to 1.10) or training without a fit test (RR 1.16, 95% CI 0.95 to 1.42) compared to those who had no training. Two RCTs that evaluated training did not contribute to the analyses because of lack of data. Conventional training plus additions versus conventional training alone One cluster-randomised trial compared conventional training plus RPE demonstration versus training alone and reported no significant difference in appropriate use of RPE between the two groups (RR 1.41, 95% CI 0.96 to 2.07). One RCT compared interactive training with passive training, with an information screen, and an information book. The mean RPE performance score for the active group was not different from that of the passive group (MD 2.10, 95% CI -0.76 to 4.96). However, the active group scored significantly higher than the book group (MD 4.20, 95% CI 0.89 to 7.51) and the screen group (MD 7.00, 95% CI 4.06 to 9.94). One RCT compared computer-simulation training with conventional personal protective equipment (PPE) training but reported only results for donning and doffing full-body PPE. Education versus no education One RCT found that a multifaceted educational intervention increased the use of RPE (risk ratio (RR) 1.69, 95% CI 1.10 to 2.58) at three years' follow-up when compared to no intervention. However, there was no difference between intervention and control at one year's, two years' or four years' follow-up. Two RCTs did not report enough data to be included in the analysis. Four CBA studies evaluated the effectiveness of education interventions and found no effect on the frequency or correctness of RPE use, except in one study for the use of an N95 mask (RR 4.56, 95% CI 1.84 to 11.33, 1 CBA) in workers. Motivational interviewing versus traditional lectures One CBA study found that participants given motivational group interviewing-based safety education scored higher on a checklist measuring PPE use (MD 2.95, 95% CI 1.93 to 3.97) than control workers given traditional educational sessions. There is very low quality evidence that behavioural interventions, namely education and training, do not have a considerable effect on the frequency or correctness of RPE use in workers. There were no studies on incentives or organisation level interventions. The included studies had methodological limitations and we therefore need further large RCTs with clearer methodology in terms of randomised sequence generation, allocation concealment and assessor blinding, in order to evaluate the effectiveness of behavioural interventions for improving the use of RPE at both organisational and individual levels. In addition, further studies should consider some of the barriers to the successful use of RPE, such as experience of health risk, types of RPE and the employer's attitude to RPE use.
We included three trials (four interventions) involving 196 participants with stroke and co-morbid anxiety. One trial (described as a 'pilot study') randomised 21 community-dwelling stroke survivors to four-week use of a relaxation CD or to wait list control. This trial assessed anxiety using the Hospital Anxiety and Depression Scale and reported a reduction in anxiety at three months among participants who had used the relaxation CD (mean (standard deviation (SD) 6.9 (± 4.9) and 11.0 (± 3.9)), Cohen's d = 0.926, P value = 0.001; 19 participants analysed). The second trial randomised 81 participants with co-morbid anxiety and depression to paroxetine, paroxetine plus psychotherapy, or standard care. Mean levels of anxiety severity scores based on the Hamilton Anxiety Scale (HAM-A) at follow-up were 5.4 (SD ± 1.7), 3.8 (SD ± 1.8), and 12.8 (SD ± 1.9), respectively (P value < 0.01). The third trial randomised 94 stroke patients, also with co-morbid anxiety and depression, to receive buspirone hydrochloride or standard care. At follow-up, the mean levels of anxiety based on the HAM-A were 6.5 (SD ± 3.1) and 12.6 (SD ± 3.4) in the two groups, respectively, which represents a significant difference (P value < 0.01). Half of the participants receiving paroxetine experienced adverse events that included nausea, vomiting, or dizziness; however, only 14% of those receiving buspirone experienced nausea or palpitations. Trial authors provided no information about the duration of symptoms associated with adverse events. The trial of relaxation therapy reported no adverse events. The quality of the evidence was very low. Each study included a small number of participants, particularly the study of relaxation therapy. Studies of pharmacological agents presented details too limited to allow judgement of selection, performance, and detection bias and lack of placebo treatment in control groups. Although the study of relaxation therapy had allocated participants to treatment using an adequate method of randomisation, study recruitment methods might have introduced bias, and drop-outs in the intervention group may have influenced results. Evidence is insufficient to guide the treatment of anxiety after stroke. Further well-conducted randomised controlled trials (using placebo or attention controls) are required to assess pharmacological agents and psychological therapies.
We identified five RCTs involving 167 participants (mean age ranged from 54 to 72.5 years; sample size ranged from 19 to 60 participants). Overall, we found that the risk of bias in the included studies was high, and the quality of evidence for all outcomes was low. Pooled data from four studies demonstrated that preoperative exercise training reduced the risk of developing a postoperative pulmonary complication by 67% (risk ratio (RR) 0.33, 95% CI 0.17 to 0.61). The number of days patients in the exercise group needed an intercostal catheter was lower than in the non-exercise group (mean difference (MD) -3.33 days, 95% CI -5.35 to -1.30 days; two studies); postoperative length of hospital stay was also lower in the exercise group (MD -4.24 days, 95% CI -5.43 to -3.06 days; four studies). Pooled data from two studies demonstrated that compared to the non-exercise group, post-intervention 6-minute walk distance (MD 18.23 m, 95% CI 8.50 to 27.96 m), and post-intervention FVC (MD 2.97% predicted, 95% CI 1.78 to 4.16% predicted) were higher in the exercise group. Preoperative exercise training may reduce the risk of developing a postoperative pulmonary complication, the duration of intercostal catheter use, postoperative length of hospital stay, and improve both exercise capacity and FVC in people undergoing lung resection for NSCLC. The findings of this review should be interpreted with caution due to disparities between the studies, risk of bias, and small sample sizes. This review emphasises the need for larger RCTs.
We identified 1036 records, scrutinized 52 full-text articles and included 19 completed RCTs (one trial is awaiting assessment). A total of 2216 participants entered the trials, 1280 participants were randomly assigned to fluoxetine (60 mg/d, 40 mg/d, 20 mg/d and 10 mg/d) and 936 participants were randomly assigned to various comparison groups (placebo; the anti-obesity agents diethylpropion, fenproporex, mazindol, sibutramine, metformin, fenfluramine, dexfenfluramine, fluvoxamine, 5-hydroxy-tryptophan; no treatment; and omega-3 gel). Within the 19 RCTs there were 56 trial arms. Fifteen trials were parallel RCTs and four were cross-over RCTs. The participants in the included trials were followed up for periods between three weeks and one year. The certainty of the evidence was low or very low: the majority of trials had a high risk of bias in one or more of the risk of bias domains. For our main comparison group — fluoxetine versus placebo — and across all fluoxetine dosages and durations of treatment, the MD was −2.7 kg (95% CI −4 to −1.4; P < 0.001; 10 trials, 956 participants; low-certainty evidence). The 95% prediction interval ranged between −7.1 kg and 1.7 kg. The MD in body mass index (BMI) reduction across all fluoxetine dosages compared with placebo was −1.1 kg/m² (95% CI −3.7 to 1.4; 3 trials, 97 participants; very low certainty evidence). Only nine placebo-controlled trials reported adverse events. A total of 399 out of 627 participants (63.6%) receiving fluoxetine compared with 352 out of 626 participants (56.2%) receiving placebo experienced an adverse event. Random-effects meta-analysis showed an increase in the risk of having at least one adverse event of any type in the fluoxetine groups compared with placebo (RR 1.18, 95% CI 0.99 to 1.42; P = 0.07; 9 trials, 1253 participants; low-certainty evidence). The 95% prediction interval ranged between 0.74 and 1.88. Following fluoxetine treatment the adverse events of dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often compared to placebo. A total of 15 out of 197 participants (7.6%) receiving fluoxetine compared with 12 out of 196 participants (6.1%) receiving placebo experienced depression. The RR across all fluoxetine doses compared with placebo was 1.20 (95% CI 0.57 to 2.52; P = 0.62; 3 trials, 393 participants; very low certainty evidence). All-cause mortality, health-related quality of life and socioeconomic effects were not reported. The comparisons of fluoxetine with other anti-obesity agents (3 trials, 234 participants), omega-3 gel (1 trial, 48 participants) and no treatment (1 trial, 60 participants) showed inconclusive results (very low certainty evidence). Low-certainty evidence suggests that off-label fluoxetine may decrease weight compared with placebo. However, low-certainty evidence suggests an increase in the risk for dizziness, drowsiness, fatigue, insomnia and nausea following fluoxetine treatment.
We included 20 RCTs and two quasi-RCTs with 7711 participants, all of which compared antibiotic prophylaxis with placebo or no treatment control. We found no studies comparing antibiotic prophylaxis with non-antibiotic prophylaxis. Primary outcomes Systemic UTI: antibiotic prophylaxis may have little or no effect on the risk of systemic UTI compared with placebo or no treatment (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.38 to 3.32; 5 RCTs; 504 participants; low-quality evidence); this corresponds to two more people (95% CI 12 fewer to 46 more) per 1000 people developing a systemic UTI. We downgraded the quality of the evidence for study limitations and imprecision. Symptomatic UTI: antibiotic prophylaxis may reduce the risk of symptomatic UTI (RR 0.49, 95% CI 0.28 to 0.86; 11 RCTs; 5441 participants; low-quality evidence); this corresponds to 30 fewer people (95% CI 42 fewer to 8 fewer) per 1000 people developing a symptomatic UTI when provided with antibiotic prophylaxis. We downgraded the quality of the evidence for study limitations and potential publication bias. Serious adverse events: the studies reported no serious adverse events in either the intervention group or control group and no effect size could be calculated. Antibiotic prophylaxis may have little or no effect on serious adverse events (4 RCTs, 630 participants; very low-quality evidence), but we are very uncertain of this finding. We downgraded the quality of the evidence for study limitations and very serious imprecision. Secondary outcomes Minor adverse events: prophylactic antibiotics may have little or no effect on minor adverse events when compared with placebo or no treatment (RR 2.82, 95% CI 0.54 to 14.80; 4 RCTs; 630 participants; low-quality evidence). We downgraded the quality of the evidence for study limitations and imprecision. Localized UTI: prophylactic antibiotics may have little or no effect on the risk of localized UTI (RR 1.0, 95% CI 0.06 to 15.77; 1 RCT; 200 participants; very low-quality evidence), but we were very uncertain of this finding. We downgraded the quality of the evidence for study limitations and very serious imprecision. Bacterial resistance: prophylactic antibiotics may increase bacterial resistance (RR 1.73, 95% CI 1.04 to 2.87; 38 participants; 2 RCTs; very low-quality evidence), but we were uncertain of this finding. We downgraded the quality of the evidence for study limitations, indirectness, and imprecision. We were able to perform few secondary analyses; these did not suggest any subgroup effects. Antibiotic prophylaxis may reduce the risk of symptomatic UTI but not systemic UTIs. Serious and minor adverse events may not be increased with the use of antibiotic prophylaxis. The findings are informed by low- and very low-quality evidence ratings for all outcomes.
Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between-genotype comparisons within treatment arms. For those meta-analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants. Comparisons of relative treatment effects by genotype For six-month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six-month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3). Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation arms For those receiving active NRT, treatment was more effective in achieving six-month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo. We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta-analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies.
Three completed randomised-controlled studies examined the role of alendronate in patients with HIV and osteopenia or osteoporosis. When all three studies were combined, much heterogeneity was seen (p<0.0001), most likely due to different populations and interventions. A sensitivity analysis showed that in two studies without heterogeneity (p=0.11), alendronate, calcium and vitamin D improved lumbar BMD after one year when compared with calcium and vitamin D (weighted mean difference +2.65 95% confidence interval (CI) 0.80, 4.51 percent). However the alendronate group did not have less fragility fractures, relative risk (RR) 1.28 (95% CI 0.20, 8.21), or osteoporosis, RR 0.50 (95% CI 0.24, 1.01). Adverse events were not significantly different between groups, RR 1.28 (95% 0.20, 8.21). One randomised-controlled study done in patients with AIDS wasting found that after three months, testosterone enanthane improved lumbar BMD compared to placebo by +3.70 (95% CI 0.48, 6.92) percent, but progressive resistance training did not improve lumbar BMD (+0.40 95% CI -2.81, 3.61 percent). No group in this study had any adverse effects. The very limited data reviewed showed that bisphosphonate therapy andin those with AIDS wasting syndrome, testosteronemay be safe and possibly effective methods to improve bone mineral density in HIV patients. The available studies are small, of short duration, and not powered to detect changes in WHO categories and fracture rates. Larger studies using bisphosphonates are currently underway. The role of colecalciferol, androgen replacement in women, and growth hormone are also under investigation.
We included three trials involving 538 participants. We found low quality of evidence indicating uncertainty whether pre-hopsital thrombolysis reduces all-cause mortality in individuals with STEMI compared to in-hospital thrombolysis (risk ratio 0.73, 95% confidence interval 0.37 to 1.41). We found high-quality evidence (two trials, 438 participants) that pre-hospital thrombolysis reduced the time to receipt of thrombolytic treatment compared with in-hospital thrombolysis. For adverse events, we found moderate-quality evidence that the occurrence of bleeding events was similar between participants receiving in-hospital or pre-hospital thrombolysis (two trials, 438 participants), and low-quality evidence that the occurrence of ventricular fibrillation (two trials, 178 participants), stroke (one trial, 78 participants) and allergic reactions (one trial, 100 participants) was also similar between participants receiving in-hospital or pre-hospital thrombolysis. We considered the included studies to have an overall unclear/high risk of bias. Pre-hospital thrombolysis reduces time to treatment, based on studies conducted in higher income countries. In settings where it can be safely and correctly administered by trained staff, pre-hospital thrombolysis may be an appropriate intervention. Pre-hospital thrombolysis has the potential to reduce the burden of STEMI in lower- and middle-income countries, especially in individuals who have limited access to in-hospital thrombolysis or percutaneous coronary interventions. We found no randomised controlled trials evaluating the efficacy of pre-hospital thrombolysis for STEMI in lower- and middle-income countries. Large high-quality multicentre randomised controlled trials implemented in resource-constrained countries will provide additional evidence for the efficacy and safety of this intervention. Local policy makers should consider their local health infrastructure and population distribution needs. These considerations should be taken into account when developing clinical guidelines for pre-hospital thrombolysis.
A total of 1912 children were enrolled from seven studies. Data interpretation was limited by the inability to extract data that referred to children with M. pneumoniae. In most studies, clinical response did not differ between children randomised to a macrolide antibiotic and children randomised to a non-macrolide antibiotic. In one controlled study (of children with recurrent respiratory infections, whose acute LRTI was associated with Mycoplasma, Chlamydia or both, by polymerase chain reaction and/or paired sera) 100% of children treated with azithromycin had clinical resolution of their illness compared to 77% not treated with azithromycin at one month. There is insufficient evidence to draw any specific conclusions about the efficacy of antibiotics for this condition in children (although one trial suggests macrolides may be efficacious in some children with LRTI secondary to Mycoplasma). The use of antibiotics has to be balanced with possible adverse events. There is still a need for high quality, double-blinded RCTs to assess the efficacy and safety of antibiotics for LRTI secondary to M. pneumoniae in children.
Six heterogeneous trials were identified with 442 participants. Methodological flaws of the included trials included incomplete follow-up and inadequate reporting of outcomes. Three trials compared ACI versus mosaicplasty. One reported statistically significant results in favour of ACI at one year in the numbers of people with 'good' or 'excellent' functional results. Conversely, another trial found significant improvement for the mosaicplasty group when assessed using one functional scoring system at two years, but no statistically significant differences based on two other scoring systems. A third trial found no difference between ACI and mosaicplasty, 10 months on average after the surgery. There was no statistically significant difference in functional outcomes at two years in a single trial comparing ACI with microfracture nor in the functional results at 18 months of a single trial comparing characterised chondrocyte implantation versus microfracture. However, the results at 36 months for this trial seemed to indicate better functional results for characterised chondrocyte implantation compared with those for microfracture. The sixth trial comparing matrix-guided ACI versus microfracture found significantly better results for functional outcomes at two year follow-up in the MACI group. There is insufficient evidence to draw conclusions on the use of ACI for treating full thickness articular cartilage defects in the knee. Further good quality randomised controlled trials with long-term functional outcomes are required.
We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months. There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons. Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.
We identified three randomised controlled trials with 84 participants. Forty-one participants underwent surgical palliation and 43 participants underwent duodenal stent placement. There may have been little or no difference in the technical success of the procedure (RR 0.98, 95% CI 0.88 to 1.09; low-quality evidence), or whether the time to resumption of oral intake was quicker for participants who had undergone duodenal stent placement (MD -3.07 days, 95% CI -4.76 to -1.39; low-quality evidence). Due to very low-quality evidence, we were uncertain whether surgical palliation improved all-cause mortality and median survival postintervention. The time to recurrence of obstructive symptoms may have increased slightly following duodenal stenting (RR 5.08, 95% CI 0.96 to 26.74; moderate-quality evidence). Due to very low-quality evidence, we were uncertain whether surgical palliation improved serious and minor adverse events. The heterogeneity for adverse events was moderately high (serious adverse events: Chi² = 1.71; minor adverse events: Chi² = 3.08), reflecting the differences in definitions used and therefore, may have impacted the outcomes. The need for reintervention may have increased following duodenal stenting (RR 4.71, 95% CI 1.36 to 16.30; very low-quality evidence). The length of hospital stay may have been shorter (by approximately 4 to 10 days) following stenting (MD -6.70 days, 95% CI -9.41 to -3.98; moderate-quality evidence). The use of duodenal stent placement in malignant gastric outlet obstruction has the benefits of a quicker resumption of oral intake and a reduced inpatient hospital stay; however, this is balanced by an increase in the recurrence of symptoms and the need for further intervention. It is impossible to draw further conclusions on these and the other measured outcomes, primarily due to the low number of eligible studies and small number of participants which resulted in low-quality evidence. It was not possible to analyse the impact on quality of life each intervention had for these participants.
Fifty-eight studies met the inclusion criteria, nine of which are new for this update. Pooling 44 studies (over 20,000 participants) comparing a nursing intervention to a control or to usual care, we found the intervention increased the likelihood of quitting (RR 1.29, 95% CI 1.21 to 1.38); however, statistical heterogeneity was moderate (I2 = 50%) and not explained by subgroup analysis. Because of this, we judged the quality of evidence to be moderate. Despite most studies being at unclear risk of bias in at least one domain, we did not downgrade the quality of evidence further, as restricting the main analysis to only those studies at low risk of bias did not significantly alter the effect estimate. Subgroup analyses found no evidence that high-intensity interventions, interventions with additional follow-up or interventions including aids that demonstrate the pathophysiological effect of smoking are more effective than lower intensity interventions, or interventions without additional follow-up or aids. There was no evidence that the effect of support differed by patient group or across healthcare settings. There is moderate quality evidence that behavioural support to motivate and sustain smoking cessation delivered by nurses can lead to a modest increase in the number of people who achieve prolonged abstinence. There is insufficient evidence to assess whether more intensive interventions, those incorporating additional follow-up, or those incorporating pathophysiological feedback are more effective than one-off support. There was no evidence that the effect of support differed by patient group or across healthcare settings.
We included 15 trials (5540 participants). Tramadol was examined in five trials (1378 participants); it was found to be better than placebo for pain (SMD -0.55, 95% CI -0.66 to -0.44; low quality evidence) and function (SMD -0.18, 95% CI -0.29 to -0.07; moderate quality evidence). Transdermal buprenorphine (two trials, 653 participants) may make little difference for pain (SMD -2.47, 95%CI -2.69 to -2.25; very low quality evidence), but no difference compared to placebo for function (SMD -0.14, 95%CI -0.53 to 0.25; very low quality evidence). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol), examined in six trials (1887 participants), were better than placebo for pain (SMD -0.43, 95%CI -0.52 to -0.33; moderate quality evidence) and function (SMD -0.26, 95% CI -0.37 to -0.15; moderate quality evidence). One trial (1583 participants) demonstrated that tramadol may make little difference compared to celecoxib (RR 0.82, 95% CI 0.76 to 0.90; very low quality evidence) for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for either pain (SMD 0.21, 95% CI -0.03 to 0.45; very low quality evidence), or function (SMD -0.11, 95% -0.63 to 0.42; very low quality evidence). The included trials in this review had high drop-out rates, were of short duration, and had limited interpretability of functional improvement. They did not report any serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism). In general, the effect sizes were medium for pain and small for function. There is some evidence (very low to moderate quality) for short-term efficacy (for both pain and function) of opioids to treat CLBP compared to placebo. The very few trials that compared opioids to non-steroidal anti-inflammatory drugs (NSAIDs) or antidepressants did not show any differences regarding pain and function. The initiation of a trial of opioids for long-term management should be done with extreme caution, especially after a comprehensive assessment of potential risks. There are no placebo-RCTs supporting the effectiveness and safety of long-term opioid therapy for treatment of CLBP.
We identified 1332 records as a result of the search (excluding duplicates). Of the 26 studies that potentially met the review criteria, we included four studies involving 205 women; most of the trials had unclear risks of bias. We identified one ongoing trial. The analysis of overall survival was not feasible, as there were no deaths reported among women allocated to standard radical hysterectomy. However, there were two deaths in among women allocated to the nerve-sparing technique. None of the included studies reported rates of intermittent self-catheterisation over one month following surgery. We could not analyse the relative effect of the two surgical techniques on quality of life due to inconsistent data reported. Nerve-sparing radical hysterectomy reduced postoperative bladder dysfunctions in terms of a shorter time to postvoid residual volume of urine ≤ 50 mL (mean difference (MD) -13.21 days; 95% confidence interval (CI) -24.02 to -2.41; 111 women; 2 studies; low-certainty evidence) and lower volume of postvoid residual urine measured one month following operation (MD -9.59 days; 95% CI -16.28 to -2.90; 58 women; 2 study; low-certainty evidence). There were no clear differences in terms of perioperative complications (RR 0.55; 95% CI 0.24 to 1.26; 180 women; 3 studies; low-certainty evidence) and disease-free survival (HR 0.63; 95% CI 0.00 to 106.95; 86 women; one study; very low-certainty evidence) between the comparison groups. Nerve-sparing radical hysterectomy may lessen the risk of postoperative bladder dysfunction compared to the standard technique, but the certainty of this evidence is low. The very low-certainty evidence for disease-free survival and lack of information for overall survival indicate that the oncological safety of nerve-sparing radical hysterectomy for women with early stage cervical cancer remains unclear. Further large, high-quality RCTs are required to determine, if clinically meaningful differences of survival exist between these two surgical treatments.
We included five trials (1799 participants) rated at low risk of bias apart from a high risk of attrition bias; all studies were funded by BIAL. The overall risk ratio (RR) with 95% confidence interval (CI) for 50% or greater reduction in seizure frequency was 1.71 (95% CI 1.42 to 2.05). Dose regression analysis showed evidence that ESL reduced seizure frequency with an increase in efficacy with increasing doses of ESL. ESL was significantly associated with seizure freedom (RR 2.90, 95% CI 1.49 to 5.68). Participants were more likely to have ESL withdrawn for adverse effects (RR 2.66, 95% CI 1.42 to 4.96) but not for any reason (RR 1.19, 95% CI 0.86 to 1.64). The following adverse effects were significantly associated with ESL: dizziness (RR 2.81, 99% CI 1.86 to 4.27); nausea (RR 2.61, 99% CI 1.36 to 5.01); diplopia (RR 4.14, 99% CI 1.74 to 9.84); somnolence (RR 1.71, 99% CI 1.11 to 2.63) and vomiting (RR 3.30, 99% CI 1.34 to 8.13). Overall the quality of the evidence was rated as moderate due to a high discontinuation rate. ESL reduces seizure frequency when used as an add-on treatment for people with drug-resistant focal epilepsy. The trials included in this review were of short-term duration and focused on adults. One new trial has been included in this update, but the conclusions are unchanged.
Four RCTs were identified, each using a different image guided technique: 1. iMRI (58 patients), 2. 5-aminolevulinic acid (5-ALA) fluorescence guided surgery (322 patients), 3. neuronavigation (45 patients) and 4. DTI-neuronavigation (238 patients). Meta-analysis was not appropriate due to differences in the tumours included (eloquent versus non-eloquent locations) and variations in the image guidance tools used in the control arms (usually selective utilisation of neuronavigation). There were significant concerns regarding risk of bias in all the included studies, especially for the study using DTI-neuronavigation. All studies included patients with high grade glioma, with one study also including patients with low grade glioma. The extent of resection was increased with iMRI (risk ratio (RR) (incomplete resection) 0.13, 95% CI 0.02 to 0.96, low quality evidence), 5-ALA (RR 0.55, 95% CI 0.42 to 0.71) and DTI-neuronavigation (RR 0.35, 95% CI 0.20 to 0.63, very low quality evidence). Insufficient data were available to evaluate the effects of neuronavigation on extent of resection. Reporting of adverse events was incomplete, with a suggestion of significant reporting bias. Overall, reported events were low in most studies, but there was concern that surgical resection using 5-ALA may lead to more frequent early neurological deficits. There was no clear evidence of improvement in overall survival (OS) with 5-ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07) or DTI-neuronavigation (HR 0.57, 95% CI 0.32 to 1.00) in patients with high grade glioma. Progression-free survival (PFS) data were not available in the appropriate format for analysis. Data for quality of life (QoL) were only available for one study and suffered from significant attrition bias. There is low to very low quality evidence (according to GRADE criteria) that image guided surgery using iMRI, 5-ALA or DTI-neuronavigation increases the proportion of patients with high grade glioma that have a complete tumour resection on post-operative MRI. There is a theoretical concern that maximising the extent of resection may lead to more frequent adverse events but this was poorly reported in the included studies. Effects of image guided surgery on survival and QoL are unclear. Further research, including studies of ultrasound guided surgery, is needed.
This review included two randomised controlled trials involving 38 children (20 boys, 18 girls), aged 15 to 96 months, and their mothers. All children had developmental disabilities; 10 had motor disorders, but it was unclear if these motor disorders affected their gestural, vocal or verbal communication. Mothers attended eight group training sessions over 11 to 12 weeks and received two or three home visits. Outcomes were assessed immediately after training. We found no report of longer-term follow-up. One study took place at an intervention centre in Canada and the other in South Korea. Both studies recruited small numbers of participants from single centres. Since it is not possible to blind participants attending or therapists providing training to group allocation, we considered both studies to be at high risk of performance bias. We also rated one study at high risk of attrition bias, and both studies at low risk of reporting bias. There was very low-quality evidence for all outcomes assessed. There was no evidence of an effect of training for children's initiation of conversation or engagement in joint attention during interaction with their mothers. Mothers who received training became more responsive to their children's communication, but there were no differences in the extent to which they controlled conversation by directing their children. Missing data meant that we were unable to evaluate the effects of training on children's frequency of communication, frequency of spoken language in conversation, speech production, or receptive or expressive language development. There were no effects on maternal stress. We found no reports of the effects of parent training on children's use of individual communication skills, such as asking questions or providing information, on their generic participation or adverse outcomes. Neither did we find reports of mothers' satisfaction with treatment, its acceptability or their compliance with it. There is only limited, very low quality evidence that parent-mediated communication interventions may be associated with improvements in interaction between mothers and their preschool children who have motor disorders. The indirectness of the study samples and high risk of bias in the included the studies significantly limits our confidence in the evidence, as do issues with study design and lack of detail in results. It is not clear if training has been tested with children whose motor disorders limit the consistency and accuracy of movements underpinning spoken or gestural communication. Some speech and language therapists currently provide communication training for parents. Further research, with larger numbers of children whose movement disorders affect their speech and gestures, coupled with detailed reporting of children's baseline skills, is needed to test whether communication training for parents can help them to promote the communication development of their young children with movement disorders.
Two small studies involving 116 children, mainly boys between 10 and 18 years of age, met the inclusion criteria. One study was conducted in a school setting, the other at a specialised clinic. Both studies used three months of a combination of omega-3 and omega-6 supplements as the intervention compared with placebo. Although both studies had generally low risk of bias, we judged the risk of reporting bias as unclear in one study, and as high in the other study. In addition, one of the studies was funded by industry and reported active company involvement in the study. None of the studies reported data on the primary outcomes of reading, writing, spelling and mathematics scores, as assessed by standardised tests. Evidence of low quality indicates that supplementation of PUFAs did not increase the risk of gastrointestinal disturbances (risk ratio 1.43, 95% confidence interval 0.25 to 8.15; two studies, 116 children). Investigators reported no other adverse effects. Both studies reported attention deficit hyperactivity disorder (ADHD)-related behaviour outcomes. We were unable to combine the results in a meta-analysis because one study reported findings as a continuous outcome, and the other as a dichotomous outcome. No other secondary outcomes were reported. We excluded one study because it used a cointervention (carnosine), and five other studies because they did not provide a robust diagnosis of a specific learning disorder. We identified one ongoing study and found three studies awaiting classification. Evidence is insufficient to permit any conclusions about the effect of PUFAs on the learning abilities of children with specific learning disorders. Well-designed RCTs with clearly defined populations of children with specific learning disorders who have been diagnosed by standardised diagnostic criteria are needed.
From 16,144 citations, 71 papers described IQCODE test accuracy. We included 10 papers (11 independent datasets) representing data from 2644 individuals (n = 379 (14%) with dementia). Using IQCODE cut-offs commonly employed in clinical practice (3.3, 3.4, 3.5, 3.6) the sensitivity and specificity of IQCODE for diagnosis of dementia across the studies were generally above 75%. Taking an IQCODE threshold of 3.3 (or closest available) the sensitivity was 0.80 (95% CI 0.75 to 0.85); specificity was 0.84 (95% CI 0.78 to 0.90); positive likelihood ratio was 5.2 (95% CI 3.7 to 7.5) and the negative likelihood ratio was 0.23 (95% CI 0.19 to 0.29). Comparative analysis suggested no significant difference in the test accuracy of the 16 and 26-item IQCODE tests and no significant difference in test accuracy by language of administration. There was little difference in sensitivity across our predefined diagnostic cut-points. There was substantial heterogeneity in the included studies. Sensitivity analyses removing potentially unrepresentative populations in these studies made little difference to the pooled data estimates. The majority of included papers had potential for bias, particularly around participant selection and sampling. The quality of reporting was suboptimal particularly regarding timing of assessments and descriptors of reproducibility and inter-observer variability. Published data suggest that if using the IQCODE for community dwelling older adults, the 16 item IQCODE may be preferable to the traditional scale due to lesser test burden and no obvious difference in accuracy. Although IQCODE test accuracy is in a range that many would consider 'reasonable', in the context of community or population settings the use of the IQCODE alone would result in substantial misdiagnosis and false reassurance. Across the included studies there were issues with heterogeneity, several potential biases and suboptimal reporting quality.
From the 9330 reports found by our searches, 39 studies were eligible for this review with effect estimate and measure of precision extracted for 190 comparisons of IPD-MA and AD-MA. We classified the quality of studies as ‘no important flaws’ (29 (74%) studies) or ‘possibly important flaws’ (10 (26%) studies). A median of 4 (interquartile range (IQR): 2 to 6) comparisons were made per study, with 6 (IQR 4 to 11) trials and 1225 (542 to 2641) participants in IPD-MAs and 7 (4 to 11) and 1225 (705 to 2541) for the AD-MAs. One hundred and forty-four (76%) comparisons were made on the main treatment effect meta-analysis and 46 (24%) made using results from analyses to explore treatment effect modifiers. There is agreement in statistical significance between the IPD-MA and AD-MA for 152 (80%) comparisons, 23 of which disagreed in direction of effect. There is disagreement in statistical significance for 38 (20%) comparisons with an excess proportion of IPD-MA detecting a statistically significant result that was not confirmed with AD-MA (28 (15%)), compared with 10 (5%) comparisons with a statistically significant AD-MA that was not confirmed by IPD-MA. This pattern of disagreement is consistent for the 144 main effect analyses but not for the 46 comparisons of treatment effect modifier analyses. Conclusions from some IPD-MA and AD-MA differed even when based on identical trials, participants (but not necessarily identical follow-up) and treatment effect measures. The average difference between IPD-MA and AD-MA in z scores, ratio effect estimates and standard errors is small but limits of agreement are wide and include important differences in both directions. Discrepancies between IPD-MA and AD-MA do not appear to increase as the differences between trials and participants increase. IPD offers the potential to explore additional, more thorough, and potentially more appropriate analyses compared to those possible with AD. But in many cases, similar results and conclusions can be drawn from IPD-MA and AD-MA. Therefore, before embarking on a resource-intensive IPD-MA, an AD-MA should initially be explored and researchers should carefully consider the potential added benefits of IPD.
Twelve studies (2215 participants) met the inclusion criteria and compared pharmacy-based management with treatment as usual. Two studies (291 participants) also included an active control (both used patient information leaflets providing information about the prescribed antidepressant). Neither of these studies reported depression symptom change. A narrative synthesis of results on acceptability of the intervention was inconclusive, with one study reporting better acceptability of pharmacy-based management and the other better acceptability of the active control. One study reported that participants in the pharmacy-based management group had better medication adherence than the control participants. One study reported adverse events with no difference between groups. The studies reported no other outcomes. Meta-analyses comparing pharmacy-based management with treatment as usual showed no evidence of a difference in the effect of the intervention on depression symptom change (dichotomous data; improvement in symptoms yes/no: risk ratio (RR), 0.95, 95% confidence interval (CI) 0.86 to 1.05; 4 RCTs, 475 participants; moderate-quality evidence; continuous data: standard mean difference (SMD) -0.04, 95% CI -0.19 to 0.10; 5 RCTs, 718 participants; high-certainty evidence), or acceptability of the intervention (RR 1.09, 95% CI 0.81 to 1.45; 12 RCTs, 2072 participants; moderate-certainty evidence). The risk of non-adherence was reduced in participants receiving pharmacy-based management (RR 0.73, 95% CI 0.61 to 0.87; 6 RCTs, 911 participants; high-certainty evidence). We were unable to meta-analyse data on diagnosis of depression, frequency of primary care appointments, quality of life, or social functioning. We found no evidence of a difference between pharmacy-based management for depression in adults compared with treatment as usual in facilitating depression symptom change. Based on numbers of participants leaving the trials early, there may be no difference in acceptability between pharmacy-based management and controls. However, there was uncertainty due to the low-certainty evidence.
Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality. The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15). Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.
Four randomised controlled trials have compared pramipexole with placebo in 669 patients with later Parkinson's disease. Two phase III studies were medium term (24 weeks maintenance period) and 2 phase II studies were short term (4 weeks maintenance period). The reduction in off time was significantly greater with pramipexole compared with placebo (weighted mean difference 1.8 hours; 1.2, 2.3 95% CI). No significant changes were noted in a dyskinesia rating scale in any of the 4 studies, but dyskinesia as an adverse event was reported more frequently with pramipexole. A significant improvement occurred in UPDRS complication score (part IV) in 2 studies but not in the remaining trials. Statistically significant improvements in UPDRS ADL score occurred with pramipexole in all studies. Significant improvements in UPDRS motor scores in the on state were reported in 3 of the 4 studies. Levodopa dose reduction was allowed in 3 studies and meta-analysis shows a significant difference in favour of pramipexole (weighted mean difference 115 mg; 87, 143 95% CI). Trends toward a higher incidence of dopaminergic adverse events with pramipexole only reached statistical significance regarding hallucinations. There were significantly fewer withdrawals from pramipexole. Pramipexole can be used to reduce off time, improve motor impairments and disability and reduce levodopa dose at the expense of increased dyskinetic adverse events. This conclusion is based on short and medium term trials (up to 24 weeks). Further trials are required to directly compare the newer with the older dopamine agonists.
We included eight trials, which randomised 365 participants. The trials all used a split-mouth design, some with more than one pair of lesions treated within the same participant. Studies took place in university or dental public health clinics in Brazil, Colombia, Denmark, Germany, Thailand, Greenland and Chile. Six studies evaluated the effects of micro-invasive treatments in the permanent dentition and two studies on the primary dentition, with caries risk ranging from low to high. Investigators measured caries risk in different studies either by caries experience alone or by using the Cariogram programme, which combines eight contributing factors, including caries experience, diet, saliva and other factors related to caries. The follow-up period in the trials ranged from one to three years. All studies used lesion progression as the primary outcome, evaluating it by different methods of reading radiographs. Four studies received industry support to carry out the research, with one of them being carried out by inventors of the intervention. We judged seven studies to be at high overall risk of bias, primarily due to lack of blinding of participants and personnel. We evaluated intervention effects for all micro-invasive therapies and analysed subgroups according to the different treatment methods reported in the included studies. Our meta-analysis, which pooled the most sensitive set of data (in terms of measurement method) from studies presenting data in a format suitable for meta-analysis, showed that micro-invasive treatment significantly reduced the odds of lesion progression compared with non-invasive treatment (e.g fluoride varnish) or oral hygiene advice (e.g to floss) (OR 0.24, 95% CI 0.14 to 0.41; 602 lesions; seven studies; I2 = 32%). There was no evidence of subgroup differences (P = 0.36). The four studies that measured adverse events reported no adverse events after micro-invasive treatment. Most studies did not report on any further outcomes. We assessed the quality of evidence for micro-invasive treatments as moderate. It remains unclear which micro-invasive treatment is more advantageous, or if certain clinical conditions or patient characteristics are better suited for micro-invasive treatments than others. The available evidence shows that micro-invasive treatment of proximal caries lesions arrests non-cavitated enamel and initial dentinal lesions (limited to outer third of dentine, based on radiograph) and is significantly more effective than non-invasive professional treatment (e.g. fluoride varnish) or advice (e.g. to floss). We can be moderately confident that further research is unlikely to substantially change the estimate of effect. Due to the small number of studies, it does remain unclear which micro-invasive technique offers the greatest benefit, or whether the effects of micro-invasive treatment confer greater or lesser benefit according to different clinical or patient considerations.
Seventy-one studies (14,602 participants) representing 74 randomised comparisons met the inclusion criteria. Methodological quality was fair. Dose ratio 1:2:  FP produced a significantly greater end of treatment FEV1 (0.04 litres (95% CI 0 to 0.07 litres), end of treatment and change in morning PEF, but not change in FEV1 or evening PEF. This applied to all drug doses, age groups, and delivery devices. No difference between FP and BDP/BUD were seen for trial withdrawals. FP led to fewer symptoms and less rescue medication use. When given at half the dose of BDP/BUD, FP led to a greater likelihood of pharyngitis. There was no difference in the likelihood of oral candidiasis. Plasma cortisol and 24 hour urinary cortisol was measured frequently but data presentation was limited. Dose ratio 1:1:  FP produced a statistically significant difference in morning PEF, evening PEF, and FEV1 over BDP or BUD. The effects on exacerbations were mixed. There were no significant differences incidence of hoarseness, pharyngitis, candidiasis, or cough. Fluticasone given at half the daily dose of beclomethasone or budesonide leads to small improvements in measures of airway calibre, but it appears to have a higher risk of causing sore throat and when given at the same daily dose leads to increased hoarseness. There are concerns about adrenal suppression with Fluticasone given to children at doses greater than 400 mcg/day, but the randomised trials included in this review did not provide sufficient data to address this issue.
We included five RCTs with a total of 227 participants (age range 23 to 76 years; 65% men) with acute pancreatitis pain. The opioids assessed were intravenous and intramuscular buprenorphine, intramuscular pethidine, intravenous pentazocine, transdermal fentanyl and subcutaneous morphine. One RCT, comparing subcutaneous morphine with intravenous metamizole reported non-significant reduction in the number of participants with improvements in pain intensity (primary outcome) (RR 0.50, 95% CI 0.19 to 1.33). Three studies compared analgesia using opioids with non-opioid treatments. After excluding one study that used opioids through continuous intravenous infusion, there was a decrease in the number of patients requiring supplementary analgesia (RR 0.53, 95% CI 0.30 to 0.93). In a single study, there were no differences in the number of patients requiring supplementary analgesia between buprenorphine and pethidine (RR 0.82, 95% CI 0.61 to 1.10). Pancreatitis complications were not associated with a significant difference between the drugs tested. No clinically serious or life-threatening adverse events occurred related to treatment. No differences for this outcome were found between opioid and non-opioid treatments, or for type of adverse event (nausea-vomiting and somnolence-sedation). One death in the procaine group was reported across all the trials. One RCT comparing pethidine with intramuscular buprenorphine reported non-significant differences of supplementary analgesic, adverse events or deaths. One RCT comparing fentanyl with placebo found no difference in adverse events. The findings of this review are limited by the lack of information to allow full appraisal of the risk of bias, the measurement of relevant outcomes and the small numbers of participants and events covered by the trials. Opioids may be an appropriate choice in the treatment of acute pancreatitis pain. Compared with other analgesic options, opioids may decrease the need for supplementary analgesia. There is currently no difference in the risk of pancreatitis complications or clinically serious adverse events between opioids and other analgesia options. Future research should focus on the design of trials with larger samples and the measurement of relevant outcomes for decision-making, such as the number of participants showing reductions in pain intensity. The reporting of these RCTs should also be improved to allow users of the medical literature to appraise their results accurately. Large longitudinal studies are also needed to establish the risk of pancreatitis complications and adverse events related to drugs.
The effect of interventions on self-reported physical activity (19 studies; 7598 participants) was positive and moderate (pooled SMD random effects model 0.28 95% CI 0.15 to 0.41) as was the effect of interventions (11 studies; 2195 participants) on cardio-respiratory fitness (pooled SMD random effects model 0.52 95% CI 0.14 to 0.90). There was significant heterogeneity in the reported effects as well as heterogeneity in characteristics of the interventions. The heterogeneity in reported effects was reduced in higher quality studies, when physical activity was self-directed with some professional guidance and when there was on-going professional support. Our review suggests that physical activity interventions have a moderate effect on self-reported physical activity, on achieving a predetermined level of physical activity and cardio-respiratory fitness. Due to the clinical and statistical heterogeneity of the studies, only limited conclusions can be drawn about the effectiveness of individual components of the interventions. Future studies should provide greater detail of the components of interventions.
Fourteen studies appeared potentially relevant but only three studies (61 patients) met the entry criteria. Two studies compared a dry powder device (Turbuhaler or Rotahaler) with a pMDI for beta2-agonist delivery, and one (36 patients cross-over design) the Respimat (soft mist device for ipratropium) vs a pMDI. For the Turbuhaler and Rotahaler, none of the reported outcome measures were significantly different. The Rotahaler study used a high and low dose of medication with or without large volume spacer. The study using the Respimat showed significant increases in FEV1 when compared to a pMDI (difference in change from base line 70 ml, 95% CI 10, 130 ml). The effect on change in FVC was of similar size. There were no differences between these two devices for any other reported outcomes. Although none of the included studies required prior patient ability to use any of the inhalers (and no study mentioned device training), it was assumed that all patients randomised into the study would have undergone training in use of the study inhalers and were capable of using those devices. In patients with stable COPD, pMDI produced similar outcomes to a dry powder device for delivering beta2-agonists, but the very small number of studies and included patients does not permit firm conclusions to be drawn. The soft mist device for ipratropium was more effective than a pMDI, but the data come from one small study. There need to be further well designed randomised controlled trials to define the role of inhaler devices using bronchodilators in stable COPD.
Of 157 records reviewed, 16 were included, representing five trials. In general, the studies were small and had inconsistent methodological rigor. Overall, the quality of evidence was rated as low. Each study used a different MOIT protocol. A total of 196 patients were studied (106 MOIT, 90 control) and all were children. Three studies were blinded and two used an avoidance diet control.  Sixty-six patients (62%) in the MOIT group were able to tolerate a full serving of milk (about 200 mL) compared to seven (8%) of the control group (RR 6.61, 95% CI 3.51 to 12.44). In addition, 27 (25%) in the MOIT group could ingest a partial serving of milk (10 to 184 mL) while none could in the control group (RR 9.34, 95% CI 2.72 to 32.09). None of the studies assessed the patients following a period off immunotherapy. Adverse reactions were common (97 of 106 MOIT patients had at least one symptom), although most were local and mild. Because of variability in reporting methods, adverse effects could not be combined quantitatively. For every 11 patients receiving MOIT, one required intramuscular epinephrine. One patient required it on two occasions. Studies to date have involved small numbers of patients and the quality of evidence is generally low. The current evidence shows that MOIT can lead to desensitization in the majority of individuals with IMCMA although the development of long-term tolerance has not been established. A major drawback of MOIT is the frequency of adverse effects, although most are mild and self-limited. The use of parenteral epinephrine is not infrequent. Because there are no standardized protocols, guidelines would be required prior to incorporating desensitization into clinical practice.
Eleven completed, randomised trials comparing intravenous glycerol and control were considered. Analysis of death during the scheduled treatment period for acute ischaemic and/or haemorrhagic stroke was possible in 10 trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (odds ratio (OR) 0.78, 95% confidence intervals (CI) 0.58 to 1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (OR 0.65, 95% CI 0.44 to 0.97). However, at the end of the scheduled follow-up period, there was no significant difference in the odds of death (OR 0.98, 95% CI 0.73 to 1.31). Functional outcome was reported in only two studies but there were non-significantly more patients who had a good outcome at the end of scheduled follow up (OR 0.73, 95% CI 0.37 to 1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment. This systematic review suggests a favourable effect of glycerol treatment on short term survival in patients with probable or definite ischaemic stroke but the confidence intervals were wide and the magnitude of the treatment effect may be only minimal. Due to the relatively small number of patients, and that the trials were performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke.
Twenty-seven studies (1,011 participants) were included. Three studies were rated as low risk of bias. Seven studies were rated as high risk of bias and 17 were rated as unclear risk of bias due to insufficient information. Seventeen trials compared different formulations of EN, 13 studies compared one or more elemental formulas to a non-elemental formula, three studies compared EN diets of similar protein composition but different fat composition, and one study compared non-elemental diets differing in glutamine enrichment. Meta-analysis of 11 trials (378 participants) demonstrated no difference in remission rates. Sixty-four per cent (134/210) of patients in the elemental group achieved remission compared to 62% (105/168) of patients in the non-elemental group (RR 1.02, 95% CI 0.88 to 1.18; GRADE very low quality). A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95% CI 0.91 to 1.18). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates. An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no difference in remission rates (RR 1.03; 95% CI 0.85 to 1.26). Very low fat content (< 3 g/1000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas. There was no difference between elemental and non-elemental diets in adverse event rates (RR 1.00, 95% CI 0.63 to 1.60; GRADE very low quality), or withdrawals due to adverse events (RR 1.29, 95% CI 0.80 to 2.09; GRADE very low quality). Common adverse events included nausea, vomiting, diarrhea and bloating. Ten trials compared EN to steroid therapy. Meta-analysis of eight trials (223 participants) demonstrated no difference in remission rates between EN and steroids. Fifty per cent (111/223) of patients in the EN group achieved remission compared to 72% (133/186) of patients in the steroid group (RR 0.77, 95% CI 0.58 to 1.03; GRADE very low quality). Subgroup analysis by age showed a difference in remission rates for adults but not for children. In adults 45% (87/194) of EN patients achieved remission compared to 73% (116/158) of steroid patients (RR 0.65, 95% CI 0.52 to 0.82; GRADE very low quality). In children, 83% (24/29) of EN patients achieved remission compared to 61% (17/28) of steroid patients (RR 1.35, 95% CI 0.92 to 1.97; GRADE very low quality). A per-protocol analysis produced similar results (RR 0.93, 95% CI 0.75 to 1.14). The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95% CI 0.70 to 0.95) and children (RR 1.43, 95% CI 1.03 to 1.97). There was no difference in adverse event rates (RR 1.39, 95% CI 0.62 to 3.11; GRADE very low quality). However, patients on EN were more likely to withdraw due to adverse events than those on steroid therapy (RR 2.95, 95% CI 1.02 to 8.48; GRADE very low quality). Common adverse events reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia. The most common reason for withdrawal was inability to tolerate the EN diet. Very low quality evidence suggests that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD. Very low quality evidence also suggests that EN may be more effective than steroids for induction of remission in children with active CD. Protein composition does not appear to influence the effectiveness of EN for the treatment of active CD. EN should be considered in pediatric CD patients or in adult patients who can comply with nasogastric tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided. Further research is required to confirm the superiority of corticosteroids over EN in adults. Further research is required to confirm the benefit of EN in children. More effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a nasogastric tube as this may lead to increased patient adherence with this therapy
We included 6 studies (2 full reports, 2 abstracts, 1 brief communication, and 1 letter), with a total of 544 participants. Risk of bias was unclear in several studies because of insufficient reporting. Five studies compared FAE with placebo, and one study compared FAE with methotrexate. All studies reported data at 12 to 16 weeks, and we identified no longer-term studies. When FAE were compared with placebo, we could not perform meta-analysis for the primary outcome of PASI score because the three studies that assessed this outcome reported the data differently, although all studies reported a significant reduction in PASI scores with FAE. Only 1 small study designed for psoriatic arthritis reported on the other primary outcome of participants discontinuing treatment due to adverse effects (2 of 13 participants on FAE compared with none of the 14 participants on placebo; risk ratio (RR) 5.36, 95% confidence interval (CI) 0.28 to 102.1; 27 participants; very low-quality evidence). However, these findings are uncertain due to indirectness and a very wide confidence interval. Two studies, containing 247 participants and both only reported as abstracts, allowed meta-analysis for PASI 50, which showed superiority of FAE over placebo (RR 4.55, 95% CI 2.80 to 7.40; low-quality evidence), with a combined PASI 50 of 64% in those given FAE compared with a PASI 50 of 14% for those on placebo, representing a number needed to treat to benefit of 2. The same studies reported more participants achieving PASI 75 with FAE, but we did not pool the data because of significant heterogeneity; none of the studies measured PASI 90. One study reported significant improvement in participants' quality of life (QoL) with FAE, measured with Skindex-29. However, we could not compute the mean difference because of insufficient reporting in the abstract. More participants experienced adverse effects, mainly gastrointestinal disturbance and flushing, on FAE (RR 4.72, 95% CI 2.45 to 9.08; 1 study, 99 participants; moderate-quality evidence), affecting 76% of participants given FAE and 16% of the placebo group (representing a number needed to treat to harm of 2). The other studies reported similar findings or did not report adverse effects fully. One study of 54 participants compared methotrexate (MTX) with FAE. PASI score at follow-up showed superiority of MTX (mean Difference (MD) 3.80, 95% CI 0.68 to 6.92; 51 participants; very low-quality evidence), but the difference was not significant after adjustment for baseline disease severity. The difference between groups for the proportion of participants who discontinued treatment due to adverse effects was uncertain because of imprecision (RR 0.19, 95% CI 0.02 to 1.53; 1 study, 51 participants; very low-quality evidence). Overall, the number of participants experiencing common nuisance adverse effects was not significantly different between the 2 groups, with 89% of the FAE group affected compared with 100% of the MTX group (RR 0.89, 95% CI 0.77 to 1.03; 54 participants; very low-quality evidence). Flushing was more frequent in those on FAE, with 13 out of 27 participants affected compared with 2 out of 27 given MTX. There was no significant difference in the number of participants who attained PASI 50, 75, and 90 in the 2 groups (very low-quality evidence) whereas this study did not measure the effect of treatments on QoL. The included studies reported no serious adverse effects of FAE and were too small and of limited duration to provide evidence about rare or delayed effects. Evidence suggests that FAE are superior to placebo and possibly similar in efficacy to MTX for psoriasis; however, the evidence provided in this review was limited, and it must be noted that four out of six included studies were abstracts or brief reports, restricting study reporting. FAE are associated with nuisance adverse effects, including flushing and gastrointestinal disturbance, but short-term studies reported no serious adverse effects.
We found no additional RCTs for inclusion in this update. This review includes one RCT dating from the 1960s with an overall high risk of bias. The RCT included 2307 healthy participants, all of whom were included in analyses. This trial compared the effect of an adenovirus vaccine against placebo. No statistically significant difference in common cold incidence was found: there were 13 (1.14%) events in 1139 participants in the vaccines group and 14 (1.19%) events in 1168 participants in the placebo group (risk ratio 0.95, 95% confidence interval 0.45 to 2.02; P = 0.90). No adverse events related to the live vaccine were reported. The quality of the evidence was low due to limitations in methodological quality and a wide 95% confidence interval. This Cochrane Review was based on one study with low-quality evidence. We found no conclusive results to support the use of vaccines for preventing the common cold in healthy people compared with placebo. We identified a need for well-designed, adequately powered RCTs to investigate vaccines for the common cold in healthy people. Any future trials on medical treatments for preventing the common cold should assess a variety of virus vaccines for this condition. Outcome measures should include common cold incidence, vaccine safety, and mortality related to the vaccine.
We included four RCTs involving 438 patients (220 patients in the drain group and 218 in the no-drain group). There was no evidence of a difference between the two groups in mortality (RR 1.73, 95% CI 0.38 to 7.84); re-operations (RR 2.49, 95% CI 0.71 to 8.74); post-operative complications (pneumonia: RR 1.18, 95% CI 0.55 to 2.54; wound infection: RR 1.23, 95% CI 0.47 to 3.23; intra-abdominal abscess: RR 1.27, 95% CI 0.29 to 5.51; anastomotic leak: RR 0.93, 95% CI 0.06 to 14.47); or initiation of soft diet (MD 0.15 days, 95% CI -0.07 to 0.37). However, the addition of a drain prolonged the operation time (MD 9.07 min, 95% CI 2.56 to 15.57) and post-operative hospital stay (MD 0.69 day, 95% CI 0.18 to 1.21) and led to drain-related complications. Additionally, we should note that 30-day mortality and re-operations are very rare events and, as a result, very large numbers of patients would be required to make any sensible conclusions about whether the two groups were similar. The overall quality of the evidence according to the GRADE approach was 'very low' for mortality and re-operations, and 'low' for post-operative complications, operation time, and post-operative length of stay. We found no convincing evidence to support routine drain use after gastrectomy for gastric cancer.
The overall quality of the evidence was low to very low. The main limitations were serious risk of bias related to blinding of participants and personnel, indirectness and imprecision. We identified 16 RCTs comparing a device versus no treatment (two studies; 90 women), hormonal treatment versus no treatment or placebo (two studies; 136 women), device combined with hormonal treatment versus no treatment (one study; 20 women), barrier gel versus no treatment (five studies; 464 women), device with graft versus device without graft (three studies; 190 women), one type of device versus another device (one study; 201 women), gel combined with hormonal treatment and antibiotics versus hormonal treatment with antibiotics (one study; 52 women) and device combined with gel versus device (one study; 120 women). The total number of participants was 1273, but data on 1133 women were available for analysis. Only two of 16 studies included 100% infertile women; in all other studies, the proportion was variable or unknown. No study reported live birth, but some (five studies) reported outcomes that were used as surrogate outcomes for live birth (term delivery or ongoing pregnancy). Anti-adhesion therapy versus placebo or no treatment following operative hysteroscopy. There was insufficient evidence to determine whether there was a difference between the use of a device or hormonal treatment compared to no treatment or placebo with respect to term delivery or ongoing pregnancy rates (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.42 to 2.12; 107 women; 2 studies; I² = 0%; very-low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without hormonal treatment or hormonal treatment or barrier gels compared with no treatment or placebo (OR 0.35, 95% CI 0.21 to 0.60; 560 women; 8 studies; I² = 0%; low-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 5 to 17). Comparisons of different anti-adhesion therapies following operative hysteroscopy It was unclear whether there was a difference between the use of a device combined with graft versus device only for the outcome of ongoing pregnancy (OR 1.48, 95% CI 0.57 to 3.83; 180 women; 3 studies; I² = 0%; low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without graft/gel or gel combined with hormonal treatment and antibiotics compared with using a device only or hormonal treatment combined with antibiotics, but the findings of this meta-analysis were affected by evidence quality (OR 0.55, 95% CI 0.36 to 0.83; 451 women; 5 studies; I² = 0%; low-quality evidence). Implications for clinical practice The quality of the evidence ranged from very low to low. The effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for research More research is needed to assess the comparative safety and (cost-)effectiveness of different anti-adhesion treatments compared to no treatment or other interventions for improving key reproductive outcomes in subfertile women.
Of the 556 potentially relevant studies only two met the inclusion criteria. One of those was excluded as the trial was abandoned prematurely and reported only preliminary results. The only analysed trial enrolled 551 participants receiving first-line chemotherapy (methotrexate) followed by whole brain radiotherapy (WBR) or receiving chemotherapy only (methotrexate followed by cytarabine in case of incomplete response). In this non-inferiority trial, the intention-to-treat (ITT) population consisted of 411 participants and the per-protocol (PP) population of 318 participants. We judged the potential for risk of bias in this open-label study as moderate. The estimated effect of chemotherapy plus WBR on survival was similar to that with chemotherapy alone but due to a wide CI we could not rule out the superiority of either therapy. This applied to both the ITT population (HR 1.01, 95% CI 0.79 to 1.30; P = 0.94) and the PP population (HR 1.06, 95% CI 0.80 to 1.40; P = 0.71) (moderate-quality evidence). Due to the low number of participants and a risk of detection bias we found low-quality evidence for an improvement in progression-free survival in participants in the ITT population receiving WBR in addition to chemotherapy (HR 0.79, 95% CI 0.63 to 0.99; P = 0.041). An improvement in PFS was also observed with WBR plus chemotherapy in participants in the PP population, but the CI was slightly wider and the result not significant (HR 0.82,95% CI 0.64 to 1.07; P = 0.14). Treatment-related mortality and health-related quality of life were not evaluated. Treatment-related neurotoxicity was assessed clinically in 79 participants, revealing signs of neurotoxicity in 49% of those receiving chemotherapy plus radiotherapy and in 26% of those receiving chemotherapy only (RR 1.85, 95% CI 0.98 to 3.48; P = 0.054) (very-low-quality evidence). In summary, the currently available evidence (one RCT) is not sufficient to conclude that WBR plus chemotherapy and chemotherapy alone have similar effects on overall survival in people with PCNSL. The findings suggest that the addition of radiotherapy (WBR) to chemotherapy may increase progression-free survival, but may also increase the incidence of neurotoxicity compared to chemotherapy only (methotrexate monotherapy). As the role of chemoradiotherapy in the treatment of PCNSL remains unclear, further prospective, randomised trials are needed before definitive conclusions can be drawn.
There are no identifiable studies that have evaluated the association between parenteral calcium supplementation in critically ill ICU patients and the following outcomes: mortality, multiple organ dysfunction, ICU and hospital length of stay, costs, and complications of calcium administration. Serum ionized calcium concentration was reported in 5 studies (12 trial arms, 159 participants). These trials showed a small but significant increase in serum ionized calcium concentration after calcium administration. These trials showed considerable statistical heterogeneity and differed extensively in the population studied (adult versus neonate), the indication (hypocalcemia versus prophylaxis) and threshold of hypocalcemia for which parenteral calcium was administered, and the timing of subsequent measurement of serum ionized calcium concentration to the extent that we consider a pooled estimate almost inappropriate. There is no clear evidence that parenteral calcium supplementation impacts the outcome of critically ill patients.
We included 14 studies (in 18 trial reports), involving 1047 pregnant women at risk of preterm birth with 1077 newborns. However, three of the included studies did not report on this review's outcomes of interest. We carried out two main comparisons: ambroxol versus antenatal corticosteroids (betamethasone); and ambroxol versus placebo or no treatment. Seven RCTs provided data for our comparison of ambroxol versus corticosteroid (betamethasone) and two trials contributed data to our comparison of ambroxol compared to placebo or no treatment. The included studies were generally judged as having either 'low' risk of bias or 'unclear' risk of bias (because the trial reports provided insufficient details about methods of sequence generation, allocation concealment and blinding). Primary outcomes There was no clear evidence of a difference in the incidence of RDS among newborns born to women who received ambroxol when compared to newborns of women who were given the corticosteroid, betamethasone (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07, seven RCTs, 728 women/758 newborns, moderate quality evidence) or placebo/no treatment (average RR 0.74; 95% CI 0.46 to 1.20, two studies, 204 women/204 newborns,T2= 0.07; I2= 53%, low-quality evidence). Results were imprecise and consistent with appreciable benefit as well as negligible effect. Similarly, there was no clear evidence of a difference in the rates of perinatal mortality between the group of women who received ambroxol and women in the corticosteroid (betamethasone) group (RR 0.51, 95% CI 0.23 to 1.12, six studies, 648 women/657 newborns, moderate quality evidence) or the placebo/no treatment group (RR 0.61; 95% CI 0.19 to 1.98, one study, 116 women/116 newborns, low-quality evidence). In terms of maternal adverse effects, there was no clear differences (in nausea or vomiting) between those women who received ambroxol compared to either those women who received corticosteroids (betamethasone) (average RR 3.45; 95% CI 0.34 to 35.51, three studies, 305 women, T2= 2.82; I2= 67%, very low-quality evidence), or women who received placebo or no treatment (RR 1.79; 95% CI 0.45 to 7.13, one study, 116 women, low-quality evidence). No other adverse effects (e.g. diarrhoea, gastric irritation and headache) were reported in the included studies. Secondary outcomes For the review's secondary outcomes, none of the included studies reported on the incidence of bronchopulmonary dysplasia, periventricular haemorrhage, necrotising enterocolitis or rate of maternal mortality. One small trial (involving 88 women) comparing ambroxol with placebo or no treatment, reported no difference between groups in terms of the need for mechanical ventilation in the neonate (RR 0.94; 95% CI 0.73 to 1.21, 88 women/88 babies, low-quality evidence) or the administration of pulmonary surfactant (RR 1.19; 95% CI 0.61 to 2.30, one RCT, 88 women/88 babies, low-quality evidence). This review is based on very low to moderate quality evidence from 14 small trials (many are published in the form of conference abstracts with minimal methodological details provided). There is insufficient evidence to support or refute the practice of giving ambroxol to women at risk of preterm birth for preventing neonatal RDS, perinatal mortality and adverse effects. More research is needed in order to fully evaluate the benefits and risks of this intervention.
We included 11 cohort studies, evaluating a total of 6502 participants undergoing 7018 procedures: 2529 underwent a nipple-sparing mastectomy (NSM), 818 underwent skin-sparing mastectomy (SSM) and 3671 underwent traditional mastectomy, also known as modified radical mastectomy (MRM). No participants underwent areola-sparing mastectomy. There was a high risk of confounding for all reported outcomes. For overall survival, the hazard ratio (HR) for NSM compared to SSM was 0.70 (95% CI 0.28 to 1.73; 2 studies; 781 participants) and the HR for NSM compared to MRM was 0.72 (95% CI 0.46 to 1.13; 2 studies, 1202 participants). Local recurrence was evaluated in two studies, the HR for NSM compared to MRM was 0.28 (95% CI 0.12 to 0.68; 2 studies, 1303 participants). The overall risk of complications was different in NSM when compared to other types of mastectomy in general (RR 0.10, 95% CI 0.01 to 0.82, 2 studies, P = 0.03; 1067 participants). With respect to skin necrosis, there was no evidence of a difference with NSM compared to other types of mastectomy, but the confidence interval was wide (RR 4.22, 95% CI 0.59 to 30.03, P = 0.15; 4 studies, 1948 participants). We observed no difference among the three types of mastectomy with respect to the risk of local infection (RR 0.95, 95% CI 0.44 to 2.09, P = 0.91, 2 studies; 496 participants). Meta-analysis was not possible when assessing cosmetic outcomes and quality of life, but in general the NSM studies reported a favourable aesthetic result and a gain in quality of life compared with the other types of mastectomy. The quality of evidence was considered very low for all outcomes due to the high risk of selection bias and wide confidence intervals. The findings from these observational studies of very low-quality evidence were inconclusive for all outcomes due to the high risk of selection bias.
We identified five studies (one cluster RCT, three RCTs and one NRCT), evaluating the effectiveness of dental auxiliaries compared with dentists in providing dental care traditionally provided by dentists, eligible for inclusion in this review. The included studies, which involved 13 dental auxiliaries, six dentists, and more than 1156 participants, evaluated two clinical tasks/techniques: placement of preventive resin fissure sealants and the atraumatic restorative technique (ART). Two studies were conducted in the US, and one each in Canada, Gambia and Singapore. Of the four studies evaluating effectiveness in placing preventive resin fissure sealants, three found no evidence of a difference in retention rates of those placed by dental auxiliaries and dentists over a range of follow-up periods (six to 24 months). One study found that fissure sealants placed by a dental auxiliary had lower retention rates than one placed by a dentist after 48 months (9.0% with auxiliary versus 29.1% with dentist). The same study reported that the net reduction after 48 months in the number teeth exhibiting caries (dental decay) was lower for teeth treated by the dental auxiliary than the dentist (3 with auxiliary versus 60 with dentist, P value < 0.001). One study showed no evidence of a difference in dental decay after treatment with fissure sealants between groups. The one study comparing the effectiveness of dental auxiliaries and dentists in performing ART reported no difference in survival rates of the restorations (fillings) after 12 months. All studies were at high risk of bias and the overall quality of the evidence was very low, as assessed using the GRADE approach. In addition, four of the included studies were more than 20 years old; the materials used and the techniques assessed were out of date. We found no eligible studies comparing the effectiveness of dental auxiliaries and dentists in the diagnosis of oral diseases and conditions, in delivering oral health education and other aspects of health promotion, or studies assessing participants' perspectives including the acceptability of care received. None of the included studies reported adverse effects. In addition, we found no studies comparing the costs and cost-effectiveness of dental auxiliaries and dentists, their impact on access and equity of access to care that met the pre-specified inclusion criteria. We only identified five studies for inclusion in this review, all of which were at high risk of bias and four were published more than 20 years ago, highlighting the paucity of high-quality evaluations of the relative effectiveness, cost-effectiveness and safety of dental auxiliaries compared with dentists in performing clinical tasks. No firm conclusions could be drawn from the present review about the relative effectiveness of dental auxiliaries and dentists.
At present, eligible first line trials for this meta-analysis were available for bevacizumab (5 trials including 3101 patients) and vatalanib (1 trial which included 1168 patients). The overall HR´s for PFS (0.61, 95% CI 0.45 - 0.83) and OS (0.81, 95% 0.73 - 0.90) for the comparison of first-line chemotherapy, with or without bevacizumab, confirms significant benefits in favour of the patients treated with bevacizumab. However, the effect on PFS shows significant heterogeneity. For second-line chemotherapy, with or without bevacizumab, a benefit in both PFS (HR 0.61, 95% CI 0.51 - 0.73) and OS (HR 0.75, 95% CI 0.63-0.89) was demonstrated in a single, randomized trial. While differences in treatment-related deaths and 60-day mortality were not significant, higher incidences in grade III/IV hypertension, arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab. For valatanib, currently available data showed a non-significant benefit in PFS and OS. The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.
Ten studies were included in the review. Selected studies addressed different psychosocial interventions for five distinct disorders or health complaints. There is good evidence that problem-solving treatment by general practitioners is effective for major depression. The evidence concerning the remaining interventions for other health complaints (reattribution or cognitive behavioural group therapy for somatisation, cognitive behavioural therapy for unexplained fatigue, counselling for smoking cessation, behavioural interventions to reduce alcohol reduction) is either limited or conflicting. In general, there is little available evidence on the use of psychosocial interventions by general practitioners. Of the psychosocial interventions reviewed, problem-solving treatment for depression may offer promise, although a stronger evidence-base is required and the effectiveness in routine practice remains to be demonstrated. More research is required to improve the evidence-base on this subject.
We included eleven RCTs involving 1836 caregiver participants. Nine interventions were delivered directly to the caregiver. Seven of these provided support in the caring role, another involved a family life review, and one grief therapy. None provided practical support. The other two interventions aimed to support caregivers indirectly via patient care. Overall the risk of bias is unclear, as all trials under-reported methods. There is low quality evidence that interventions directly supporting the caregiver significantly reduce psychological distress in the short term (8 trials: standardised mean difference (SMD) -0.15; 95% confidence interval (CI) -0.28 to -0.02). There is also low quality evidence that these interventions in the short term may marginally improve coping skills and quality of life, but neither results were statistically significant (7 trials: SMD -0.05; 95% CI -0.24 to 0.14; 6 trials: SMD 0.08; 95% CI -0.11 to 0.26, respectively). One study assessed physical outcomes, specifically sleep improvement, and found no difference (median effect 0.00). No study measured health service use or adverse outcomes. In one study, however, a subgroup of intervention participants had higher levels of family conflict. Evidence was less clear on the indirect interventions. While both trials in this category found that supporting the patient may reduce psychological distress, none of the four assessments were statistically significant. There were no evaluations of coping with the caring role, quality of life, service use or adverse outcomes. In one trial there was no difference between trial arms in the proportion of caregivers reporting good physical health. There is evidence that supportive interventions may help reduce caregivers' psychological distress. These findings suggest that practitioners should enquire about the concerns of caregivers and should consider that they may benefit from additional support. There is, however, a need for further research to explore the benefits identified, and to assess the interventions' effects on physical health, and potential harms. Trials need to report their methods fully.
We included six randomised controlled trials (RCTs) with a total of 822 participants. Two trials compared liquid enema reduction plus glucagon versus liquid enema alone. One trial compared liquid enema plus dexamethasone versus liquid enema alone. Another trial compared air enema plus dexamethasone versus air enema alone, and two trials compared use of liquid enema versus air enema.  We identified three ongoing trials. We judged all included trials to be at risk of bias owing to omissions in reported methods. We judged five of six trials as having high risk of bias in at least one domain. Therefore, the quality of the evidence (GRADE) for outcomes was low. Interventions and data presentation varied greatly across trials; therefore meta-analysis was not possible for most review outcomes. Enema plus glucagon versus enema alone It is uncertain whether use of glucagon improves the rate of successful reduction of intussusception when compared with enema alone (reported in two trials, 218 participants; RR 1.09, 95% CI 0.94 to 1.26;low quality of evidence). No trials in this comparison reported on the number of children with bowel perforation(s) nor on the number of children with recurrent intussusception. Enema plus dexamethasone versus enema alone Use of the adjunct, dexamethasone, may be beneficial in reducing intussusception recurrence with liquid or air enema (two trials, 299 participants; RR 0.14, 95% CI 0.03 to 0.60; low quality of evidence). This equates to a number needed to treat for an additional beneficial outcome of 13 (95% CI 8 to 37). It is uncertain whether use of the adjunct, dexamethasone, improves the rate of successful reduction of intussusception when compared with enema alone (reported in two trials, 356 participants; RR 1.01, 95% CI 0.92 to 1.10;low quality of evidence). Air enema versus liquid enema Air enema may be more successful than liquid enema for reducing intussusception (two trials, 199 participants; RR 1.28, 95% CI 1.10 to 1.49; low quality of evidence). This equates to a number needed to treat for an additional beneficial outcome of 6 (95% CI 4 to 19). No trials in this comparison reported on the number of children with bowel perforation(s) or on the number of children with recurrent intussusception nor any intraoperative complications, such as bowel perforation, or other adverse effects. Only one trial reported postoperative complications, but owing to the method of reporting used, a quantitative analysis was not possible. We identified no studies that exclusively evaluated surgical interventions for management of intussusception. This review identified a small number of trials that assessed a variety of interventions. All included trials provided evidence of low quality and were subject to serious concerns about imprecision, high risk of bias, or both. Air enema may be superior to liquid enema for successfully reducing intussusception in children; however, this finding is based on a few studies including small numbers of participants. Dexamethasone as an adjuvant may be more effective in reducing intussusception recurrence rates following air enema or liquid enema, but these results are also based on a few studies of small numbers of participants. This review highlights several points that need to be addressed in future studies, including reducing the risk of bias and including relevant outcomes. Specifically, surgical trials are lacking, and future research is needed to address this evidence gap.
We included 10 studies that analysed a total of 5903 participants. One study was assessed as being at low risk of bias, two were assessed as being at unclear risk of bias, with the remaining seven being at high risk of bias. The main finding of the review was that, over 2.5 to 3 years of use, a fluoride toothpaste containing 10% xylitol may reduce caries by 13% when compared to a fluoride-only toothpaste (PF -0.13, 95% CI -0.18 to -0.08, 4216 children analysed, low-quality evidence). The remaining evidence on children, from small single studies with risk of bias issues and great uncertainty associated with the effect estimates, was insufficient to determine a benefit from xylitol products. One study reported that xylitol syrup (8 g per day) reduced caries by 58% (95% CI 33% to 83%, 94 infants analysed, low quality evidence) when compared to a low-dose xylitol syrup (2.67 g per day) consumed for 1 year. The following results had 95% CIs that were compatible with both a reduction and an increase in caries associated with xylitol: xylitol lozenges versus no treatment in children (very low quality body of evidence); xylitol sucking tablets versus no treatment in infants (very low quality body of evidence); xylitol tablets versus control (sorbitol) tablets in infants (very low quality body of evidence); xylitol wipes versus control wipes in infants (low quality body of evidence). There was only one study investigating the effects of xylitol lozenges, when compared to control lozenges, in adults (low quality body of evidence). The effect estimate had a 95% CI that was compatible with both a reduction and an increase in caries associated with xylitol. Four studies reported that there were no adverse effects from any of the interventions. Two studies reported similar rates of adverse effects between study arms. The remaining studies either mentioned adverse effects but did not report any usable data, or did not mention them at all. Adverse effects include sores in the mouth, cramps, bloating, constipation, flatulence, and loose stool or diarrhoea. We found some low quality evidence to suggest that fluoride toothpaste containing xylitol may be more effective than fluoride-only toothpaste for preventing caries in the permanent teeth of children, and that there are no associated adverse-effects from such toothpastes. The effect estimate should be interpreted with caution due to high risk of bias and the fact that it results from two studies that were carried out by the same authors in the same population. The remaining evidence we found is of low to very low quality and is insufficient to determine whether any other xylitol-containing products can prevent caries in infants, older children, or adults.
We found one RCT and one quasi-RCT that met the inclusion criteria after independent and duplicate review of the search results. The studies used different anti-VEGF agents and different study groups which were not directly comparable. One multi-centre RCT (BRAVO) conducted in the USA randomised 397 individuals and compared monthly intravitreal ranibizumab (0.3 mg and 0.5 mg) injections with sham injection. The study only included individuals with non-ischaemic BRVO. Although repeated injections of ranibizumab appeared to have a favourable effect on the primary outcome, approximately 50% of the ranibizumab 0.3 mg group and 45% of the ranibizumab 0.5 mg group received rescue laser treatment which may have an important effect on the primary outcome. In addition, during the six-month observation period 93.5% of individuals in the sham group received intravitreal ranibizumab (0.5 mg). This cross-over design limits the ability to compare the long-term impact of ranibizumab versus a pure control group. The second trial was a small study (n = 30) from Italy with limitations in study design that reported a benefit of as-required intravitreal bevacizumab (1.25 mg) over laser photocoagulation in MO secondary to BRVO. We present the evidence from these trials and other interventional case series. The available RCT evidence suggests that repeated treatment of non-ischaemic MO secondary to BRVO with the anti-VEGF agent ranibizumab may improve clinical and visual outcomes at six and 12 months. However, the frequency of re-treatment has not yet been determined and the impact of prior or combined treatment with laser photocoagulation on the primary outcome is unclear. Results from ongoing studies should assess not only treatment efficacy but also, the number of injections needed for maintenance and long-term safety and the effect of any prior treatment.
We included 25 studies (712 participants). Three studies were parallel RCTs and the others were cross-over RCTs. Nineteen studies compared fixed reduction of dialysate temperature (below 36°C) and standard dialysate temperature (37°C to 37.5°C). Most studies were of unclear or high risk of bias. Compared with standard dialysate, it is uncertain whether fixed reduction of dialysate temperature improves IDH rate (8 studies, 153 participants: rate ratio 0.52, 95% CI 0.34 to 0.80; very low certainty evidence); however, it might increase the discomfort rate compared with standard dialysate (4 studies, 161 participants: rate ratio 8.31, 95% CI 1.86 to 37.12; very low certainty evidence). There were no reported dropouts due to adverse events. No study reported death, acute coronary syndrome or stroke. Three studies compared isothermal dialysate and thermoneutral dialysate. Isothermal dialysate might improve the IDH rate compared with thermoneutral dialysate (2 studies, 133 participants: rate ratio 0.68, 95% CI 0.60 to 0.76; I2 = 0%; very low certainty evidence). There were no reports of discomfort rate (1 study) or dropouts due to adverse events (2 studies). No study reported death, acute coronary syndrome or stroke. Reduction of dialysate temperature may prevent IDH, but the conclusion is uncertain. Larger studies that measure important outcomes for HD patients are required to assess the effect of reduction of dialysate temperature. Six ongoing studies may provide much-needed high quality evidence in the future.
This systematic review identified 12 randomized controlled trials (RCTs) including 774 patients that assessed melatonin for treating preoperative anxiety, postoperative anxiety or both. Four of the 12 studies compared melatonin, placebo and midazolam, whereas the remaining eight studies compared melatonin and placebo only. The quality of the evidence for our primary outcome (melatonin versus placebo for preoperative anxiety) was high. More than half of the included studies had a low risk of selection bias and at least 75% of the included studies had a low risk of attrition, performance and detection bias. Most of the included studies had an unclear risk of reporting bias. Eight out the 10 studies that assessed the effect of melatonin on preoperative anxiety using a visual analogue scale (VAS) (ranging from 0 to 100 mm, higher scores indicate greater anxiety) showed a reduction compared to placebo. The reported estimate of effect (relative effect -13.36, 95% confidence interval (CI) -16.13 to -10.58; high quality evidence) was based on a meta-analysis of seven studies. Two studies did not show any difference between melatonin and placebo. Two studies comparing melatonin with midazolam using a VAS found no evidence of a difference in preoperative anxiety between the two groups (relative effect -1.18, 95% CI -2.59 to 0.23; low quality evidence). Eight studies assessed the effect of melatonin on postoperative anxiety. Four of these studies measuring postoperative anxiety 90 minutes postoperatively using a VAS did not find any evidence of a difference between melatonin and placebo (relative effect -3.71, 95% CI -9.26 to 1.84). Conversely, two studies showed a reduction of postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) when comparing melatonin with placebo (relative effect -5.31, 95% CI -8.78 to -1.84; moderate quality evidence). Two studies comparing melatonin with midazolam using a VAS did not find any evidence of a difference between the two groups in postoperative anxiety (relative effect -2.02, 95% CI -5.82 to 1.78). When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults (measured 50 to 100 minutes after administration). The effect of melatonin on postoperative anxiety (measured 90 minutes and 6 hours after surgery) in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.
We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials. In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.
Thirty-one studies fulfilled the inclusion criteria, with a total of 4662 participants (of which 4522 were receiving the drugs relevant to our comparison) and presented data that could be used for at least one comparison. The trial centres were located in Europe (especially Scandinavia), Japan and Northern America. When comparing perphenazine with placebo, for our primary outcome of clinical response, results favoured perphenazine with significantly more people receiving placebo rated as either 'no better or deterioration' for global state than people receiving perphenazine (1 RCT, n = 61 RR 0.32 CI 0.13 to 0.78, very low quality evidence). More people receiving placebo relapsed, although not a statistically significant number (1 RCT, n = 48, RR 0.14 CI 0.02 to 1.07, very low quality evidence). Death was not reported in the perphenazine versus placebo comparison. Experiences of dystonia were equivocal between groups (1 RCT, n = 48, RR 1.00 CI 0.07 to 15.08, very low quality evidence); other outcomes not reported in this comparison include serious adverse events, economic outcomes, and service use and hospitalisation. For the comparison of perphenazine versus any other antipsychotic drugs, no real differences in effect between the drugs were found. There was no significant difference between groups for those considered 'no better or deterioration' (17 RCTs, n = 1879, RR 1.04 CI 0.91 to 1.17, very low quality evidence). For mental state outcome of 'no effect' of the study drug, there was again no significant difference between groups (4 RCTs, n = 383, RR 1.24 CI 0.61 to 2.52, very low quality evidence). Death was not reported in any of the included studies. There was no significant difference in rates of dystonia with perphenazine versus any other antipsychotic drugs (4 RCTs, n = 416, RR 1.36 CI 0.23 to 8.16, very low quality evidence), nor was there a significant difference between groups for serious adverse events (2 RCTs, n = 1760, RR 0.98 CI 0.68 to 1.41, very low quality evidence). Although perphenazine has been used in randomised trials for more than 50 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. All data for the main outcomes in this review were of very low quality evidence. At best we can say that perphenazine showed similar effects and adverse events as several of the other antipsychotic drugs. Since perphenazine is a relatively inexpensive and frequently used compound, further trials are justified to clarify the properties of this classical antipsychotic drug.
We included six Cochrane Reviews, one of which compared any type of chest physiotherapy with no chest physiotherapy or coughing alone and the remaining five reviews included head-to-head comparisons of different airway clearance techniques. All the reviews were considered to have a low risk of bias. However, the individual trials included in the reviews often did not report sufficient information to adequately assess risk of bias. Many trials did not sufficiently report on outcome measures and had a high risk of reporting bias. We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV1, except for reporting no difference between PEP therapy and oscillating devices after six months of treatment, mean difference -1.43% predicted (95% confidence interval -5.72 to 2.87); the quality of the body of evidence was graded as moderate. The quality of the body of evidence comparing different airway clearance techniques for other outcomes was either low or very low. There is little evidence to support the use of one airway clearance technique over another. People with cystic fibrosis should choose the airway clearance technique that best meets their needs, after considering comfort, convenience, flexibility, practicality, cost, or some other factor. More long-term, high-quality randomised controlled trials comparing airway clearance techniques among people with cystic fibrosis are needed.
36 trials were included but most were small and of duration less than three months. Nine trials were of six months duration (2016 patients). These longer trials were the more recent trials and generally were of adequate size, and conducted to a reasonable standard. Most trials tested the same standardised preparation of Ginkgo biloba, EGb 761, at different doses, which are classified as high or low. The results from the more recent trials showed inconsistent results for cognition, activities of daily living, mood, depression and carer burden. Of the four most recent trials to report results three found no difference between Ginkgo biloba and placebo, and one reported very large treatment effects in favour of Ginkgo biloba. There are no significant differences between Ginkgo biloba and placebo in the proportion of participants experiencing adverse events. A subgroup analysis including only patients diagnosed with Alzhiemer's disease (925 patients from nine trials) also showed no consistent pattern of any benefit associated with Ginkgo biloba. Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.
We included three randomised trials with 261 participants (mean age: 60 years) comparing RFCA (159 participants) to antiarrhythmic drugs (102) for non-paroxysmal atrial fibrillation. We generally assessed the included studies as having low or unclear risk of bias across multiple domains, with reported outcomes generally lacking precision due to low event rates. Evidence showed that RFCA was superior to antiarrhythmic drugs in achieving freedom from atrial arrhythmias (RR 1.84, 95% CI 1.17 to 2.88; 3 studies, 261 participants; low-quality evidence), reducing the need for cardioversion (RR 0.62, 95% CI 0.47 to 0.82; 3 studies, 261 participants; moderate-quality evidence), and reducing cardiac-related hospitalisation (RR 0.27, 95% CI 0.10 to 0.72; 2 studies, 216 participants; low-quality evidence) at 12 months follow-up. There was substantial uncertainty surrounding the effect of RFCA regarding significant bradycardia (or need for a pacemaker) (RR 0.20, 95% CI 0.02 to 1.63; 3 studies, 261 participants; low-quality evidence), periprocedural complications, and other safety outcomes (RR 0.94, 95% CI 0.16 to 5.68; 3 studies, 261 participants; very low-quality evidence). In people with non-paroxysmal atrial fibrillation, evidence suggests a superiority of RFCA to antiarrhythmic drugs in achieving freedom from atrial arrhythmias, reducing the need for cardioversion, and reducing cardiac-related hospitalisations. There was uncertainty surrounding the effect of RFCA with significant bradycardia (or need for a pacemaker), periprocedural complications, and other safety outcomes. Evidence should be interpreted with caution, as event rates were low and quality of evidence ranged from moderate to very low.
Three trials involving 104 people were included. We classified one study as having low risk of bias; the others had some limitations and we classified them as having high risk of bias. Two studies (one with low risk of bias and the other with high risk of bias) applied progressive resistance training (PRT) combined with range of motion exercises and stretching; the comparison group received standard care. Pooled data demonstrated that PRT can improve shoulder pain (mean difference (MD) -6.26; 95% confidence interval (CI) -12.20 to -0.31) and shoulder disability (MD -8.48; 95% CI -15.07 to -1.88), both measured using the Shoulder Pain and Disability Index (SPADI) (range 0 to 100). Similarly, secondary outcomes were also improved: active range of motion for external rotation (MD 14.51 degrees; 95% CI 7.87 to 21.14), passive range of motion for abduction (MD 7.65 degrees; 95% CI 0.64 to 14.66), forward flexion (MD 6.20 degrees; 95% CI 0.69 to 11.71), external rotation (MD 7.17 degrees; 95% CI 2.20 to 12.14) and horizontal abduction (MD 7.34 degrees; 95% CI 2.86 to 11.83). Strength and resistance of scapular muscles was assessed in one study and the results showed a statistically significant benefit of PRT. The studies did not demonstrate a statistically significant difference in quality of life. Only two non-serious adverse events were described in the PRT group compared with none in the standard care group. One study with high risk of bias used a broad spectrum of techniques including free active exercises, stretching and postural care for a period of three months following surgery. This study did not demonstrate a difference between the exercise group and routine postoperative physiotherapy care in shoulder function and quality of life, but serious methodological limitations could explain this. No serious adverse events were reported. Limited evidence from two RCTs demonstrated that PRT is more effective than standard physiotherapy treatment for shoulder dysfunction in patients treated for head and neck cancer, improving pain, disability and range of motion of the shoulder joint, but it does not improve quality of life. However, although statistically significant the measured benefits of the intervention may be small. Other exercise regimes were not shown to be effective compared to routine postoperative physiotherapy. Further studies which apply other exercise interventions in head and neck cancer patients in the early postoperative and radiotherapy period are needed, with long-term follow-up.
We included two trials that recruited a total of 234 women. The overall risk of bias was low for the two studies. Both studies compared Bishop score withTVUS. The two included studies did not show any clear difference between the Bishop score and TVUS groups for the following main outcomes: vaginal birth (RR 1.07, 95% CI 0.92 to 1.25, moderate quality evidence), caesarean delivery (RR 0.81, 95% CI 0.49 to 1.34, moderate quality evidence), neonatal admission into neonatal intensive care unit (RR 1.67, 95% CI 0.41 to 6.71, moderate quality evidence). Both studies only provided median data in relation to induction-delivery interval and reported no clear difference between the Bishop and TVUS groups. Perinatal mortality was not reported in the included studies. For the review's secondary outcomes, the need for misoprostol for cervical ripening was more frequent in the TVUS group compared to the Bishop score group (RR 0.52, 95% CI 0.41 to 0.66, two studies, 234 women, moderate quality evidence). In contrast, there were no clear differences between the Bishop scope and TVUS groups in terms of meconium staining of the amniotic fluid, fetal heart rate abnormality in labour, and Apgar score less than seven. Only one trial reported median data on the induction-delivery interval and induction to active phase interval, the trialist reported no difference between the Bishop group and the TVUS group for this outcome. Neither of the included studies reported on uterine rupture. Moderate quality evidence from two small RCTs involving 234 women that compared two different methods for assessing pre-induction cervical ripening (Bishop score and TVUS) did not demonstrate superiority of one method over the other in terms of the main outcomes assessed in this review. We did not identify any data relating to perinatal mortality. Whilst use of TVUS was associated with an increased need for misoprostol for cervical ripening, both methods could be complementary. The choice of a particular method of assessing pre-induction cervical ripening may differ depending on the environment and need where one is practicing since some methods (i.e. TVUS) may not be readily available and affordable in resource-poor settings where the sequelae of labour and its management is prevalent. The evidence in this review is based on two studies that enrolled a small number of women and there is insufficient evidence to support the use of TVUS over the standard digital vaginal assessment in pre-induction cervical ripening. Further adequately powered RCTs involving TVUS and the Bishop score and including other methods of pre-induction cervical ripening assessment are warranted. Such studies need to address uterine rupture, perinatal mortality, optimal cut-off value of the cervical length and Bishop score to classify women as having favourable or unfavourable cervices and cost should be included as an outcome.
The search identified 1178 potentially relevant titles; however, there were no published studies that were specifically designed to answer this question. Two studies met criteria for inclusion in the review and 98 children were included in the meta-analysis. There was no significant difference between groups in the proportion of children 'not cured' at follow-up (primary outcome measure), with a pooled odds ratio (OR) of 0.61 (95% confidence interval (CI) 0.24 to 1.55). However, the included studies were limited in their ability to answer the review question by the fact that all participants were infants, post acute bronchiolitis illness, and cough duration at the start of study medication was ill-defined. There is currently no evidence to support the use of ICS for treatment of subacute cough in children. However, this systematic review is limited by the small number of studies available for analysis and the size, quality and design of these studies. Further well-designed RCTs are required to support or refute the efficacy of treatment with ICS in children with subacute cough.
A single RCT met the inclusion criteria. Our 2018 search update identified no additional trials. The included trial evaluated BIG-IV for the treatment of infant botulism and included 59 treatment participants and 63 control participants. The control group received a control immune globulin that did not have an effect on botulinum toxin. Participants were followed during the length of their hospitalization to measure the outcomes of interest. There was some violation of intention-to-treat principles, and possibly some between-treatment group imbalances among participants admitted to the intensive care unit and mechanically ventilated, but otherwise the risk of bias was low. There were no deaths in either group, making any treatment effect on mortality inestimable. There was a benefit in the treatment group on mean duration of hospitalization (BIG-IV: 2.60 weeks, 95% confidence interval (CI) 1.95 to 3.25; control: 5.70 weeks, 95% CI 4.40 to 7.00; mean difference (MD) -3.10 weeks, 95% CI -4.52 to -1.68; moderate-certainty evidence); mechanical ventilation (BIG-IV: 1.80 weeks, 95% CI 1.20 to 2.40; control: 4.40 weeks, 95% CI 3.00 to 5.80; MD -2.60 weeks, 95% CI -4.06 to -1.14; low-certainty evidence); and tube or parenteral feeding (BIG-IV: 3.60 weeks, 95% CI 1.70 to 5.50; control: 10.00 weeks, 95% CI 6.85 to 13.15; MD -6.40 weeks, 95% CI -10.00 to -2.80; moderate-certainty evidence), but not on proportion of participants with adverse events or complications (BIG-IV: 63.08%; control: 68.75%; risk ratio 0.92, 95% CI 0.72 to 1.18; absolute risk reduction 0.06, 95% CI 0.22 to -0.11; moderate-certainty evidence). We found low- and moderate-certainty evidence supporting the use of BIG-IV in infant intestinal botulism. A single RCT demonstrated that BIG-IV probably decreases the duration of hospitalization; may decrease the duration of mechanical ventilation; and probably decreases the duration of tube or parenteral feeding. Adverse events were probably no more frequent with immune globulin than with placebo. Our search did not reveal any evidence examining the use of other medical treatments including serum trivalent botulism antitoxin.
This updated review included 24 studies; six additional studies added 1001 participants involved in comparisons of ketoprofen or dexketoprofen and placebo, with a 12% increase in participants taking ketoprofen and a 65% increase for dexketoprofen. Most participants (70%) were women. Dental studies typically involved young participants (mean age 20 to 30 years); other types of surgery involved older participants (mean age 37 to 68 years). Overall, we judged the studies at high risk of bias only for small size, which can lead to an overestimation of benefit. Ketoprofen doses ranged between 6.5 mg and 150 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual ketoprofen oral dose of 50 mg was 57%, compared to 23% with placebo, giving an NNT of 2.9 (95% CI 2.4 to 3.7) (RR 2.5, 95% CI 2.0 to 3.1; 594 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 1.8) than other surgery (NNT 4.2). The proportion of participants using rescue medication within six hours was lower with ketoprofen (32%) than with placebo (75%), giving a number needed to treat to prevent use of rescue medication (NNTp) of 2.3 (95% CI 1.8 to 3.1); 263 participants; 4 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with ketoprofen (18%) and placebo (11%) (RR 1.6, 95% CI 0.98 to 2.8; 342 participants; 5 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence). Dexketoprofen doses ranged between 5 mg and 100 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual dexketoprofen oral dose of 20 mg or 25 mg was 52%, compared to 27% with placebo, giving an NNT of 4.1 (95% CI 3.3 to 5.2) (RR 2.0, 95% CI 1.6 to 2.2; 1177 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 2.7) than other surgery (NNT 5.7). The proportion of participants using rescue medication within six hours was lower with dexketoprofen (47%) than placebo (69%), giving an NNTp of 4.7 (95% CI 3.3 to 8.0); 445 participants; 5 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with dexketoprofen (14%) and placebo (10%) (RR 1.4, 95% CI 0.89 to 2.2; 536 participants, 6 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence). Ketoprofen at doses of 25 mg to 100 mg is an effective analgesic in moderate to severe acute postoperative pain with an NNT for at least 50% pain relief of 2.9 with a 50 mg dose. This is similar to that of commonly used NSAIDs such as ibuprofen (NNT 2.5 for 400 mg dose) and diclofenac (NNT 2.7 for 50 mg dose). Dexketoprofen is also effective with an NNT of 4.1 in the dose range 10 mg to 25 mg. Differential efficacy between dental surgery and other types of surgery seen for both drugs is unusual. Both drugs were well tolerated in single doses.
A total of 33 trials (including 11 from the original 2008 review) involving 7453 participants were included in this review, with 28 trials providing suitable data for entry into meta-analysis. Although the interventions provided in these studies were very different from one study to another (participant numbers, duration of intervention, group versus individual intervention, setting), most of the studies were based on recognisable theoretical models, and we tried to be inclusive in considering the wide variety of available culturally appropriate health education. Glycaemic control (as measured by glycosylated haemoglobin A1c (HbA1c)) showed improvement following culturally appropriate health education at three months (mean difference (MD) -0.4% (95% confidence interval (CI) -0.5 to -0.2); 14 trials; 1442 participants; high-quality evidence) and at six months (MD -0.5% (95% CI -0.7 to -0.4); 14 trials; 1972 participants; high-quality evidence) post intervention compared with control groups who received 'usual care'. This control was sustained to a lesser extent at 12 months (MD -0.2% (95% CI -0.3 to -0.04); 9 trials; 1936 participants) and at 24 months (MD -0.3% (95% CI -0.6 to -0.1); 4 trials; 2268 participants; moderate-quality evidence) post intervention. Neutral effects on health-related quality of life measures were noted and there was a general lack of reporting of adverse events in most studies — the other two primary outcomes for this review. Knowledge scores showed improvement in the intervention group at three (standardised mean difference (SMD) 0.4 (95% CI 0.1 to 0.6), six (SMD 0.5 (95% CI 0.3 to 0.7)) and 12 months (SMD 0.4 (95% CI 0.1 to 0.6)) post intervention. A reduction in triglycerides of 24 mg/dL (95% CI -40 to -8) was observed at three months, but this was not sustained at six or 12 months. Neutral effects on total cholesterol, low-density lipoprotein (LDL) cholesterol or high-density lipoprotein (HDL) cholesterol were reported at any follow-up point. Other outcome measures (blood pressure, body mass index, self-efficacy and empowerment) also showed neutral effects compared with control groups. Data on the secondary outcomes of diabetic complications, mortality and health economics were lacking or were insufficient. Because of the nature of the intervention, participants and personnel delivering the intervention were rarely blinded, so the risk of performance bias was high. Also, subjective measures were assessed by participants who self-reported via questionnaires, leading to high bias in subjective outcome assessment. Culturally appropriate health education has short- to medium-term effects on glycaemic control and on knowledge of diabetes and healthy lifestyles. With this update (six years after the first publication of this review), a greater number of RCTs were reported to be of sufficient quality for inclusion in the review. None of these studies were long-term trials, and so clinically important long-term outcomes could not be studied. No studies included an economic analysis. The heterogeneity of the studies made subgroup comparisons difficult to interpret with confidence. Long-term, standardised, multi-centre RCTs are needed to compare different types and intensities of culturally appropriate health education within defined ethnic minority groups, as the medium-term effects could lead to clinically important health outcomes, if sustained.
No trials were included. Primary healthcare interventions and a strong family and social support network are invaluable to parents and families around the time a baby dies. However, due to the lack of high-quality randomised trials conducted in this area, the true benefits of currently existing interventions aimed at providing support for mothers, fathers and families experiencing perinatal death is unclear. Further, the currently available evidence around the potential detrimental effects of some interventions (e.g. seeing and holding a deceased baby) remains inconclusive at this point in time. However, some well-designed descriptive studies have shown that, under the right circumstances and guided by compassionate, sensitive, experienced staff, parents' experiences of seeing and holding their deceased baby is often very positive. The sensitive nature of this topic and small sample sizes, make it difficult to develop rigorous clinical trials. Hence, other research designs may further inform practice in this area. Where justified, methodologically rigorous trials are needed. However, methodologically rigorous trials should be considered comparing different approaches to support.
There were eight included studies: three studies had a low risk of bias and five studies had high risk of bias. The studies compared ergot alkaloids with no uterotonic agents, with a total of 2031 women in the ergot alkaloids group and 1978 women in the placebo or no treatment group. Seven studies used the IV/IM route of administration and one study used the oral route. Ergot alkaloids (any route of administration) versus no uterotonic agents Use of ergot alkaloids in the third stage of labour decreased mean blood loss (mean difference (MD) -80.52 mL, 95% confidence interval (CI) -96.39 to -64.65 mL; women = 2718; studies = 3; moderate-quality evidence); decreased PPH of at least 500 mL (average risk ratio (RR) 0.52, 95% CI 0.28 to 0.94; women = 3708; studies = 5; I2 = 83%; low-quality evidence); increased maternal haemoglobin concentration (g/dL) at 24 to 48 hours postpartum (MD 0.50 g/dL, 95% CI 0.38 to 0.62; women = 1429; studies = 1; moderate-quality evidence); and decreased the use of therapeutic uterotonics (average RR 0.37, 95% CI 0.15 to 0.90; women = 2698; studies = 3; I2 = 89%; low-quality evidence). There were no clear differences between groups in severe PPH of at least 1000 mL (average RR 0.32, 95% CI 0.04 to 2.59; women = 1718; studies = 2; I2 = 74%; very low-quality evidence). The risk of retained placenta or manual removal of the placenta, or both, were inconsistent with high heterogeneity. Ergot alkaloids increased the risk of elevated blood pressure (average RR 2.60, 95% CI 1.03 to 6.57: women = 2559; studies = 3; low-quality evidence) and pain after birth requiring analgesia (RR 2.53, 95% CI 1.34 to 4.78: women = 1429; studies = 1; moderate-quality evidence) but there were no differences between groups in vomiting, nausea, headache or eclamptic fit. Results for IV/IM ergot alkaloids versus no uterotonic agents were similar to those for the main comparison of ergot alkaloids administered by any route, since most of the studies (seven of eight) used the IV/IM route. Only one small study (289 women) compared oral ergometrine with placebo and it showed no benefit of ergometrine over placebo. No maternal adverse effects were reported. None of the studies reported on any of our prespecified neonatal outcomes Prophylactic IM or IV injections of ergot alkaloids may be effective in reducing blood loss, reducing PPH (estimated blood loss of at least 500 mL), and increasing maternal haemoglobin. Ergot alkaloids may also decrease the use of therapeutic uterotonics, but adverse effects may include elevated blood pressure and pain after birth requiring analgesia. There were no differences between groups in terms of other adverse effects (vomiting, nausea, headache or eclamptic fit). There is a lack of evidence on the effects of ergot alkaloids on severe PPH, and retained or manual removal of placenta. There is also a lack of evidence on the oral route of administration of ergot alkaloids.
Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF ≤40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo. Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone. Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]). In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone.
The search identified 183 references but only five studies (total n=210) met the inclusion criteria. All of the studies were on inpatient populations and compared the intervention with standard inpatient care. One study had drama therapy as the intervention, one had role-playing, one had a social drama group and two used psychodrama. Two of the included studies were Chinese and it is difficult to know whether psychodrama and indeed inpatient psychiatric care in China is comparable with the drama interventions and inpatient care in the other included studies. There were no significant findings about the value of drama interventions for keeping inpatients engaged in treatment. Due to poor reporting very little data from the five studies could be used and there were no conclusive findings about the harms or benefits of drama therapy for inpatients with schizophrenia. Randomised studies are possible in this field. The use of drama therapy for schizophrenia and schizophrenia-like illnesses should continue to be under evaluation as its benefits, or harms, are unclear.
We included two trials involving 754 participants. One new trial of 660 participants showed the same success rate of vacuum procedure of 98.2% by both methods (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.98 to 1.02). The two included trials showed significant reductions in the time between applying the vacuum cup and delivery, (one trial (74 women): mean difference (MD) -6.10 minutes, 95% CI -8.83 to -3.37 and the other trial (660 women): with median difference -4.4 minutes, 95% CI -4.8 to -4.0). The two included trials showed no significant difference in detachment rate (RR 0.85, 95% CI 0.38 to 1.86, 2 studies, 754 women), no significant difference in Apgar score below seven at one minute (RR 1.04, 95% CI 0.51 to 2.09) and five minutes (RR 1.00, 95% CI 0.29 to 3.42), no significant differences in scalp abrasions or lacerations, cephalhematoma, subgaleal hemorrhage and hyperbilirubinemia. There were no significant differences between the two methods in all secondary outcomes. The rapid negative pressure application for vacuum assisted vaginal birth reduces duration of the procedure whilst there is no evidence of differences in maternal and neonatal outcomes. Rapid method of negative application should be recommended for vacuum extraction assisted vaginal delivery.
We identified five randomised, double-blind studies with 1501 participants, but only four had been published and had relevant outcome data. These four studies were of high quality, although two of the studies were small. Both ibuprofen 200 mg + caffeine 100 mg and ibuprofen 100 mg + caffeine 100 mg produced significantly more participants than placebo who achieved at least 50% of maximum pain relief over six hours, and both doses significantly reduced remedication rates (moderate quality evidence). For at least 50% of maximum pain relief, the NNT was 2.1 (95% confidence interval 1.8 to 2.5) for ibuprofen 200 mg + caffeine 100 mg (four studies, 334 participants) and 2.4 (1.9 to 3.1) for ibuprofen 100 mg + caffeine 100 mg (two studies, 200 participants) (moderate quality evidence). These values were close to those predicted by published models for combination analgesics in acute pain, and were supported by low (good) NNT values for prevention of remedication. Adverse event rates were low, and no sensible analysis was possible. For ibuprofen 200 mg + caffeine 100 mg particularly, the low NNT value is among the lowest (best) values for analgesics in this pain model. The combination is not commonly available, but can be probably be achieved by taking a single 200 mg ibuprofen tablet with a cup of modestly strong coffee or caffeine tablets. In principle, this can deliver good analgesia at lower doses of ibuprofen.
One single-centred trial (46 participants) was identified comparing a topical steroid (betamethasone) given as nasal drops to placebo. Treatment was given twice daily for six weeks; 22 participants received the active drug. Subjective symptom scores, change in polyp size, and side effects were assessed. There was no difference in nasal symptom scores between the treatment and placebo groups. Betamethasone was effective in reducing the size of polyps, but was associated with increased reports of mild side effects, nasal bleeding and discomfort. Risk of bias was high since over 50% of people enrolled did not complete the study. Follow-up of participants was short (six weeks) also reducing the significance of the results for clinical practice. This review suggests topical steroids for nasal polyposis in people with cystic fibrosis have no demonstrable effect on subjective nasal symptom scores. They have some effect in reducing the size of the polyps, but due to the small sample size, poor completion rates and lack of follow-up, the trial is at high risk of bias and evidence for efficacy is limited. Overall there is no clear evidence for using topical steroids in people with cystic fibrosis and nasal polyposis. A well-designed randomised controlled trial of adequate power and long-term follow-up is needed. Validated measures of symptoms and physical findings should be performed and quality of life issues addressed.
Of the 83 studies identified, 15 studies which included 487 participants, met the inclusion criteria. The numbers in each study ranged from nine up to 72 participants; two studies were in adults, seven were in children and adolescents and six studies included all age ranges. Four studies of hospitalised participants lasted less than one month and 11 studies were outpatient-based, lasting between two months and three years. The studies included participants with a wide range of disease severity and employed differing levels of supervision with a mixture of types of training. There was also wide variation in the quality of the included studies. This systematic review shows very low- to low-quality evidence from both short- and long-term studies that in people with cystic fibrosis aerobic or anaerobic physical exercise training (or a combination of both) has a positive effect on aerobic exercise capacity, pulmonary function and health-related quality of life. No study reported on mortality; two studies reported on adverse events (moderate-quality evidence); one of each study reported on pulmonary exacerbations (low-quality evidence) and diabetic control (very low-quality evidence). Although improvements were not consistent between studies and ranged from no effects to clearly positive effects, the most consistent effects of the heterogeneous exercise training modalities and durations were found for maximal aerobic exercise capacity (in four out of seven studies) with unclear effects on forced expiratory volume in one second (in two out of 11 studies) and health-related quality of life (in two out of seven studies). Evidence about the efficacy of physical exercise training in cystic fibrosis from 15 small studies with low to moderate methodological quality is limited. Exercise training is already part of regular outpatient care offered to most people with cystic fibrosis, and since there is some evidence for beneficial effects on aerobic fitness and no negative side effects exist, there is no reason to actively discourage this. The benefits from including physical exercise training in an individual's regular care may be influenced by the type and duration of the training programme. High-quality randomised controlled trials are needed to comprehensively assess the benefits of exercise programmes in people with cystic fibrosis and the relative benefits of the addition of aerobic versus anaerobic versus a combination of both types of physical exercise training to the care of people with cystic fibrosis.
We identified six RCTs with a total of 218 participants randomised, one trial awaiting classification and five ongoing trials. All trials were conducted in participants at high risk of CVD, two trials examined CoQ10 supplementation alone and four examined CoQ10 supplementation in patients on statin therapy; we analysed these separately. All six trials were small-scale, recruiting between 20 and 52 participants; one trial was at high risk of bias for incomplete outcome data and one for selective reporting; all studies were unclear in the method of allocation and therefore for selection bias. The dose of CoQ10 varied between 100 mg/day and 200 mg/day and the duration of the interventions was similar at around three months. No studies reported mortality or non-fatal cardiovascular events. None of the included studies provided data on adverse events. Two trials examined the effect of CoQ10 on blood pressure. For systolic blood pressure we did not perform a meta-analysis due to significant heterogeneity. In one trial CoQ10 supplementation had no effect on systolic blood pressure (mean difference (MD) -1.90 mmHg, 95% confidence interval (CI) -13.17 to 9.37, 51 patients randomised). In the other trial there was a statistically significant reduction in systolic blood pressure (MD -15.00 mmHg, 95% CI -19.06 to -10.94, 20 patients randomised). For diastolic blood pressure we performed a random-effects meta-analysis, which showed no evidence of effect of CoQ10 supplementation when these two small trials were pooled (MD -1.62 mmHg, 95% CI -5.2 to 1.96). One trial (51 patients randomised) looked at the effect of CoQ10 on lipid levels. The trial showed no evidence of effect of CoQ10 supplementation on total cholesterol (MD 0.30 mmol/L, 95% CI -0.10 to 0.70), high-density lipoprotein (HDL)-cholesterol (MD 0.02 mmol/L, 95% CI -0.13 to 0.17) or triglycerides (MD 0.05 mmol/L, 95% CI -0.42 to 0.52). Of the four trials that investigated CoQ10 supplementation in patients on statin therapy, three of them showed that simultaneous administration of CoQ10 did not significantly influence lipid levels or systolic blood pressure levels between the two groups. The fourth trial showed a significant increase in the change in total and low-density lipoprotein (LDL)-cholesterol at three months across the four arms of the trial (α-tocopherol, CoQ10, CoQ10 + α-tocopherol and placebo), however the way in which the data were presented meant that we were unable to determine if there was any significant difference between the CoQ10 only and placebo arms. In contrast, there was no significant difference in the change in HDL-cholesterol and triglycerides after three months between the four arms of the trial. There are very few studies to date examining CoQ10 for the primary prevention of CVD. The results from the ongoing studies will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution and further high quality trials with longer-term follow-up are needed to determine the effects on cardiovascular events.
Eight studies involving 262 participants were included in the review. Participants had stable asthma, with severity ranging from mild to severe. All studies were randomised trials, three studies had high withdrawal rates. Participants were between five to 18 years of age, and in seven studies swimming training varied from 30 to 90 minutes, two to three times a week, over six to 12 weeks. The programme in one study gave 30 minutes training six times per week. The comparison was usual care in seven studies and golf in one study. Chlorination status of swimming pool was unknown for four studies. Two studies used non-chlorinated pools, one study used an indoor chlorinated pool and one study used a chlorinated but well-ventilated pool. No statistically significant effects were seen in studies comparing swimming training with usual care or another physical activity for the primary outcomes; quality of life, asthma control, asthma exacerbations or use of corticosteroids for asthma. Swimming training had a clinically meaningful effect on exercise capacity compared with usual care, measured as maximal oxygen consumption during a maximum effort exercise test (VO2 max) (two studies, n = 32), with a mean increase of 9.67 mL/kg/min; 95% confidence interval (CI) 5.84 to 13.51. A difference of equivalent magnitude was found when other measures of exercise capacity were also pooled (four studies, n = 74), giving a standardised mean difference (SMD) 1.34; 95% CI 0.82 to 1.86. Swimming training was associated with small increases in resting lung function parameters of varying statistical significance; mean difference (MD) for FEV1 % predicted 8.07; 95% CI 3.59 to 12.54. In sensitivity analyses, by risk of attrition bias or use of imputed standard deviations, there were no important changes on effect sizes. Unknown chlorination status of pools limited subgroup analyses. Based on limited data, there were no adverse effects on asthma control or occurrence of exacerbations. This review indicates that swimming training is well-tolerated in children and adolescents with stable asthma, and increases lung function (moderate strength evidence) and cardio-pulmonary fitness (high strength evidence). There was no evidence that swimming training caused adverse effects on asthma control in young people 18 years and under with stable asthma of any severity. However whether swimming is better than other forms of physical activity cannot be determined from this review. Further adequately powered trials with longer follow-up periods are needed to better assess the long-term benefits of swimming.
Only one small study (n = 44) fulfilled the inclusion criteria. Results suggested that cell salvage did not affect mortality overall (death rates were 67% (14/21 participants) in the cell salvage group and 65% (15/23) in the control group) (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.31 to 3.72). For individuals with abdominal injury, mortality was also similar in both groups (OR 0.48, 95% CI 0.11 to 2.10). Less donor blood was needed for transfusion within the first 24 hours postinjury in the cell salvage group compared with the control group (mean difference (MD) -4.70 units, 95% CI -8.09 to -1.31). Adverse events, notably postoperative sepsis, did not differ between groups (OR 0.54, 95% CI 0.11 to 2.55). Cost did not notably differ between groups (MD -177.81, 95% CI -452.85 to 97.23, measured in GBP in 2002). Evidence for the use of cell salvage in individuals undergoing abdominal or thoracic trauma surgery remains equivocal. Large, multicentre, methodologically rigorous trials are needed to assess the relative efficacy, safety and cost-effectiveness of cell salvage in different surgical procedures in the emergency context.
Nineteen randomised studies (2728 participants) of concurrent chemoradiotherapy versus radiotherapy alone were included. Chemoradiotherapy significantly reduced overall risk of death (HR 0.71, 95% CI 0.64 to 0.80; I2 0%; 1607 participants) and overall progression-free survival at any site (HR 0.69, 95% CI 0.58 to 0.81; I2 45%; 1145 participants). Incidence of acute oesophagitis, neutropenia and anaemia were significantly increased with concurrent chemoradiation.  Six trials (1024 patients) of concurrent versus sequential chemoradiation were included. A significant benefit of concurrent treatment was shown in overall survival (HR 0.74, 95% CI 0.62 to 0.89; I2 0%; 702 participants). This represented a 10% absolute survival benefit at 2 years. More treatment-related deaths (4% vs 2%) were reported in the concurrent arm without statistical significance (RR 2.02, 95% CI 0.90 to 4.52; I2 0%; 950 participants). There was increased severe oesophagitis with concurrent treatment (RR 4.96, 95%CI 2.17 to 11.37; I2 66%; 947 participants). This update of the review published in 2004 incorporates additional trials and more mature data. It demonstrates the benefit of concurrent chemoradiation over radiotherapy alone or sequential chemoradiotherapy. Patient selection is an important consideration in view of the added toxicity of concurrent treatment. Uncertainty remains as to how far this is purely due to a radiosensitising effect and whether similar benefits could be achieved by using modern radiotherapy techniques and more dose intensive accelerated and/ or hyperfractionated radiotherapy regimens.
This systematic review now has 21 included studies (four of which we added in the 2016 update), two studies awaiting assessment, and 47 excluded studies. In total, data for meta-analyses were available in 21 trials (n = 6218 women), of which only four reported live births. UGET was associated with an increased chance of a live birth/ongoing pregnancy compared with CTET (OR 1.47, 95% CI 1.30 to 1.65; 13 trials; n = 5859 women; I2 = 74%; low-quality evidence). Sensitivity analysis by including only trials with low risk of selection bias or by using a random-effects model did not alter the effect. We estimate that for women with a chance of a live birth/ongoing pregnancy of 23% using CTET, this would increase to between 28% and 33% using UGET. We considered the quality of the evidence using GRADE methodology to be low. UGET was associated with an increase in the chance of a clinical pregnancy (OR 1.31, 95% CI 1.17 to 1.45; 20 trials; n = 6711 women; I2 = 42%; moderate-quality evidence). We identified no differences between groups for the incidence of adverse events including multiple pregnancy, ectopic pregnancy, or miscarriage. These events were relatively rare, and sample sizes limited the ability to detect such differences. The evidence suggests ultrasound guidance improves the chance of live birth/ongoing and clinical pregnancies compared with clinical touch, without increasing the chance of multiple pregnancy, ectopic pregnancy, or miscarriage. Methodological limitations included: only four studies reporting details of both computerised randomisation techniques and adequate allocation concealment, only four studies reported on the outcome of live birth, and none of the nine studies that reported on ongoing pregnancy reported on live birth, suggesting possible reporting bias. Adequate reporting of randomisation and allocation concealment will improve the quality of future studies. The primary outcome measure of future studies should be the reporting of live births per woman randomised.
We included six relevant trials undertaken between 1969 and 1980. We found no significant difference in death (n = 175, 1 RCT, RR in the longer term 0.42, CI 0.10 to 1.83, very low quality evidence). In the long term, there was no difference in improvement of mental state (n = 61, 1 RCT, RR 3.39, CI 0.76 to 15.02, very low quality evidence). There was no difference in readmission to hospital (n = 651, 4 RCTs, RR by the long term 1.26, CI 1.00 to 1.57, low quality evidence). Data for leaving the study prematurely by the longer term showed no difference (n = 229, 2 RCTs, (RR 0.77, CI 0.34 to 1.77, low quality evidence). There was a significant difference favouring short stay (P = 0.01) in numbers of participants with delayed discharge from hospital exceeding the time planned in study (n = 404, 3 RCTs, RR in the longer term 0.54, CI 0.33 to 0.88, low quality evidence). There was no difference in numbers of participants lost to follow-up (n = 404, 3 RCTs, RR by the longer term 1.07, CI 0.70 to 1.62, low quality evidence). Finally, there was a significant difference favouring short-stay hospitalisation for social functioning, including unemployment, unable to housekeep, or unknown employment status (n = 330, 2 RCTs, RR by longer term 0.61, CI 0.50 to 0.76, very low quality evidence). The effects of hospital care and the length of stay is important for mental health policy. We found limited low and very low quality data which were all over 30 years old. Outcomes from these studies do suggest that a planned short-stay policy does not encourage a 'revolving door' pattern of admission and disjointed care for people with serious mental illness. More large, well-designed and reported trials are justified especially where a short-stay policy is not routine care.
Four trials met the inclusion criteria, with a total of 3198 children under five years of age, and were conducted in Afghanistan, Spain, and the USA. Prevalence of vitamin D deficiency varied widely in these populations (range: 73.1% in Afghanistan, 10 to 12% in USA, and 6.2% in Spain). The included trials evaluated mortality (two trials), pneumonia incidence (two trials), diarrhoea incidence (two trials), hospitalization (two trials), and mean serum vitamin D concentrations (four trials). We do not know whether vitamin D supplementation impacts on all-cause mortality because this outcome was underpowered due to few events (risk ratio (RR) 1.43, 95% confidence interval (CI) 0.54 to 3.74; one trial, 3046 participants, low quality evidence). For pneumonia, episodes of 'radiologically confirmed' first or only episode of pneumonia were little different in the supplemented and unsupplemented group (Rate Ratio: 1.06, 95% confidence interval (CI) 0.89 to 1.26; two trials, 3134 participants, moderate quality evidence), and similarly for children with confirmed or unconfirmed pneumonia (RR 0.95, 95% CI 0.87 to 1.04; one trial, 3046 participants). In these two trials there were no obvious differences between supplemented and unsupplemented children regarding episodes of diarrhoea. In the single large trial from Afghanistan, the trial authors reported that vitamin D supplementation was associated with an increase in repeat episodes of pneumonia confirmed by chest radiograph (RR 1.69, 95% CI 1.28 to 2.21; one trial, 3046 participants), but not reflected in the outcome of confirmed or unconfirmed pneumonia (RR 1.06, 95% CI 1.00 to 1.13; one trial, 3046 participants). For hospital admission measured in one small trial, there was no difference detected (RR 0.86, 95% CI 0.20 to 3.62; one trial, 88 participants; very low quality evidence). The mean serum vitamin D concentrations were higher in supplemented compared to unsupplemented children at the end of supplementation (MD 7.72 ng/mL, 95% CI 0.50 to 14.93; four trials, 266 participants, low quality evidence). These results were driven primarily by two smaller trials with large magnitudes of effect. In the other two bigger trials, serum vitamin D concentrations were elevated in the intervention group for most of the trial duration but not at the end of supplementation. This may be due to time elapsed at measurement from the last dose, incomplete compliance, or increased need of vitamin D with infant age. We did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality (due to TB, diarrhoea, or malaria). Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.
Twenty one randomised trials with a total of 1371 children met the inclusion criteria. Sample sizes were generally small. All studies but one investigated children with functional faecal incontinence. Interventions varied amongst trials and few outcomes were shared by trials addressing the same comparisons. Combined results of nine trials showed higher rather than lower rates of persisting symptoms of faecal incontinence up to 12 months when biofeedback was added to conventional treatment (OR 1.11 CI 95% 0.78 to 1.58). This result was consistent with that of two trials with longer follow-up (OR 1.31 CI 95% 0.80 to 2.15). In one trial the adjunct of anorectal manometry to conventional treatment did not result in higher success rates in chronically constipated children (OR 1.40 95% CI 0.72 to 2.73 at 24 months). In one small trial the adjunct of behaviour modification to laxative therapy was associated with a significant reduction in children's soiling episodes at both the three month (OR 0.14 CI 95% 0.04 to 0.51) and the 12 month assessment (OR 0.20 CI 95% 0.06 to 0.65). There is no evidence that biofeedback training adds any benefit to conventional treatment in the management of functional faecal incontinence in children. There was not enough evidence on which to assess the effects of biofeedback for the management of organic faecal incontinence. There is some evidence that behavioural interventions plus laxative therapy, rather than laxative therapy alone, improves continence in children with functional faecal incontinence associated with constipation.
We identified three eligible RCTs and five CTs, including participants aged 11 to 14 years, who were non-smokers at baseline. Of the eight trials identified, six had analyzable data relevant for this review, which contributed to meta-analyses (7275 participants in total: 4003 intervention; 3272 control; 2484 participants after adjusting for clustering). All except one of the studies tested the 'Smokefree Class Competition' (SFC), which has been widely implemented throughout Europe. In this competition, classes with youth generally between the ages of 11 and 14 years commit to being smoke-free for a six-month period, and report their smoking status regularly. If 90% or more of the class are non-smokers at the end of the six months, the class goes into a competition to win prizes. The one study that was not a trial of the SFC was a controlled trial in which schools in two communities were assigned to the intervention, with schools in a third community acting as controls. Students in the intervention community with lower smoking rates at the end of the project (one school year) received rewards. Most studies resulted in statistically non-significant results. Only one study of the SFC reported a significant effect of the competition on the prevention of smoking at the longest follow-up. However, this study was at risk of multiple biases, and when we calculated the adjusted risk ratio (RR) we no longer detected a statistically significant difference. The pooled RR for the more robust RCTs (3 studies, n = 3056 participants/1107 adjusted for clustering) suggests that there is no statistically significant effect of incentives, in the form of the SFC, to prevent smoking initiation among children and adolescents in the long term (RR 1.00, 95% confidence interval (CI) 0.84 to 1.19). Pooled results from the non-randomized trials also did not detect a significant effect of the SFC, and we were unable to extract data on our outcome of interest from the one trial that did not study the SFC. There is little robust evidence to suggest that unintended consequences (such as making false claims about their smoking status and bullying of smoking students) are consistently associated with such interventions, although this has not been the focus of much research. There was insufficient information to assess the dose-response relationship or to report costs of incentives for preventing smoking uptake. We judged the included RCTs to be at unclear risk of bias, and the non-RCTs to be at high risk of bias. Using GRADE, we rated the overall quality of the evidence for our primary outcome as 'low' (for RCTs) and 'very low' (for non-RCTs), because of imprecision (all studies had wide confidence intervals), and for the risks of bias identified. We further downgraded the non-RCT evidence, due to issues with the non-RCT study design, likely to introduce further bias. The very limited evidence currently available suggests that incentive programmes do not prevent smoking initiation among youth. However, there are relatively few published studies and these are of variable quality. In addition, trials included in the meta-analyses were all studies of the SFC, which distributed small to moderately-sized prizes to whole classes, usually through a lottery system. It is therefore possible that other incentive programmes could be more successful at preventing smoking uptake in young people. Future studies might investigate the efficacy of a wider range of incentives, including those given to individual participants to prevent smoking uptake, whilst considering both the effect of incentives on smoking initiation and the progression to smoking. It would be useful if incentives were evaluated in varying populations from different socioeconomic and ethnic backgrounds, and if intervention components were described in detail.
Three randomized controlled trials were identified. One was of good methodological quality (Markowitz 2000). This study looked at the use of 6-mercaptopurine (6-MP) as a steroid sparing agent. No difference in linear growth was observed between the intervention and placebo groups, although the total steroid dose received over the 18 month follow up period was reduced in the group receiving 6-MP. The two remaining randomized controlled trials (Sanderson 1987; Thomas 1993a) consider the use of enteral feeding versus corticosteroids for induction of remission, with height velocity standard deviation score at 6 months as an outcome measure. Although of less rigorous methodological quality, the results of these studies are discussed in detail in the review. In both studies height velocity standard deviation scores were significantly increased in the enteral feeding group compared with the corticosteroid group. In addition to these randomized controlled trials, a body of lower quality evidence does exist relevant to two other important interventions; the use of supplemental enteral nutrition (Morin 1980; Belli 1988; Israel 1995) and the judicious use of surgical interventions in pre-pubertal children with refractory disease (Alperstein 1985; Lipson 1990; McLain 1990). Newer treatments, such as infliximab, are now becoming more widely used and may offer advantages in promoting growth. These effects are as yet unstudied. This review highlights the need for large, multi centre studies of the different treatment options in paediatric Crohn's disease and the importance of standardised measurements of growth, such as height velocity standard deviation scores and height standard deviation scores as outcome measures.
This review included 18 double-blind placebo-controlled trials with a total of 2456 participants. Five trials were assessed at unclear risk of bias, thirteen at high risk, and none at low risk of bias. Compared to placebo, antibiotics probably reduce the risk of infection in patients undergoing third molar extraction(s) by approximately 70% (RR 0.29 (95% CI 0.16 to 0.50) P < 0.0001, 1523 participants, moderate quality evidence) which means that 12 people (range 10-17) need to be treated with antibiotics to prevent one infection following extraction of impacted wisdom teeth. There is evidence that antibiotics may reduce the risk of dry socket by 38% (RR 0.62 (95% CI 0.41 to 0.95) P = 0.03, 1429 participants, moderate quality evidence) which means that 38 people (range 24-250) need to take antibiotics to prevent one case of dry socket following extraction of impacted wisdom teeth. There is also some evidence that patients who have prophylactic antibiotics may have less pain (MD -8.17 (95% CI -11.90 to -4.45) P < 0.0001, 372 participants, moderate quality evidence ) overall 7 days after the extraction compared to those receiving placebo, which may be a direct result of the lower risk of infection. There is no evidence of a difference between antibiotics and placebo in the outcomes of fever (RR 0.34, 95% CI 0.06 to 1.99), swelling (RR 0.92, 95% CI 0.65 to 1.30) or trismus (RR 0.84, 95% CI 0.42 to 1.71) 7 days after tooth extraction. Antibiotics are associated with an increase in generally mild and transient adverse effects compared to placebo (RR 1.98 (95% CI 1.10 to 3.59) P = 0.02) which means that for every 21 people (range 8-200) who receive antibiotics, an adverse effect is likely. Although general dentists perform dental extractions because of severe dental caries or periodontal infection, there were no trials identified which evaluated the role of antibiotic prophylaxis in this group of patients in this setting. All of the trials included in this review included healthy patients undergoing extraction of impacted third molars, often performed by oral surgeons. There is evidence that prophylactic antibiotics reduce the risk of infection, dry socket and pain following third molar extraction and result in an increase in mild and transient adverse effects. It is unclear whether the evidence in this review is generalisable to those with concomitant illnesses or immunodeficiency, or those undergoing the extraction of teeth due to severe caries or periodontitis. However, patients at a higher risk of infection are more likely to benefit from prophylactic antibiotics, because infections in this group are likely to be more frequent, associated with complications and be more difficult to treat. Due to the increasing prevalence of bacteria which are resistant to treatment by currently available antibiotics, clinicians should consider carefully whether treating 12 healthy patients with antibiotics to prevent one infection is likely to do more harm than good.
We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi2 = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054). In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.
Twenty-two small trials involving 2676 people were included. One trial was placebo controlled, 18 compared two or more drug treatments, three compared treatment regimens, and one compared different drug vehicles. Fewer treatment failures occurred by day seven with oral ivermectin compared with placebo in one small trial (55 participants). Topical permethrin appeared more effective than oral ivermectin (140 participants, 2 trials), topical crotamiton (194 participants, 2 trials), and topical lindane (753 participants, 5 trials). Permethrin also appeared more effective in reducing itch persistence than either crotamiton (94 participants, 1 trial) or lindane (490 participants, 2 trials). No difference was detected between permethrin (a synthetic pyrethroid) and a natural pyrethrin-based topical treatment (40 participants, 1 trial), and between permethrin and benzyl benzoate (53 participants, 1 trial), however both these trials were small. No significant difference was detected in the number of treatment failures between crotamiton and lindane (100 participants, 1 trial), lindane and sulfur (68 participants, 1 trial), benzyl benzoate and sulfur (158 participants, 1 trial), and benzyl benzoate and natural synergized pyrethrins (240 participants, 1 trial); all were topical treatments. No trials of malathion were identified. No serious adverse events were reported. A number of trials reported skin reactions in participants randomized to topical treatments. There were occasional reports of headache, abdominal pain, diarrhoea, vomiting, and hypotension. Topical permethrin appears to be the most effective treatment for scabies. Ivermectin appears to be an effective oral treatment. More research is needed on the effectiveness of malathion, particularly when compared to permethrin, and on the management of scabies in an institutional setting and at a community level.
Thirteen trials recruiting 34,980 women were included in the systematic review. Risk of bias was low for allocation concealment and selective reporting, unclear for random sequence generation and incomplete outcome data and high for blinding of both outcome assessment and participants and personnel. There was no difference in antenatal, obstetric and neonatal outcome or morbidity in screened versus control groups. Routine late pregnancy ultrasound was not associated with improvements in overall perinatal mortality. There is little information on long-term substantive outcomes such as neurodevelopment. There is a lack of data on maternal psychological effects. Overall, the evidence for the primary outcomes of perinatal mortality, preterm birth less than 37 weeks, induction of labour and caesarean section were assessed to be of moderate or high quality with GRADE software. There was no association between ultrasound in late pregnancy and perinatal mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.67 to 1.54; participants = 30,675; studies = eight; I² = 29%), preterm birth less than 37 weeks (RR 0.96, 95% CI 0.85 to 1.08; participants = 17,151; studies = two; I² = 0%), induction of labour (RR 0.93, 95% CI 0.81 to 1.07; participants = 22,663; studies = six; I² = 78%), or caesarean section (RR 1.03, 95% CI 0.92 to 1.15; participants = 27,461; studies = six; I² = 54%). Three additional primary outcomes chosen for the 'Summary of findings' table were preterm birth less than 34 weeks, maternal psychological effects and neurodevelopment at age two. Because none of the included studies reported these outcomes, they were not assessed for quality with GRADE software. Based on existing evidence, routine late pregnancy ultrasound in low-risk or unselected populations does not confer benefit on mother or baby. There was no difference in the primary outcomes of perinatal mortality, preterm birth less than 37 weeks, caesarean section rates, and induction of labour rates if ultrasound in late pregnancy was performed routinely versus not performed routinely. Meanwhile, data were lacking for the other primary outcomes: preterm birth less than 34 weeks, maternal psychological effects, and neurodevelopment at age two, reflecting a paucity of research covering these outcomes. These outcomes may warrant future research.
Eleven RCTs involving 808 participants met the inclusion criteria. The methodological quality of the included studies was variable and most of the predefined outcomes were reported by only one or two studies, therefore the quality of the evidence was low. Five studies with a total of 405 patients reported the incidence of DVT. In the CPM group (205 patients) 36 developed DVT (18%) compared to 29 (15%) in the control group (200 patients). The results of the meta-analysis showed no evidence that CPM had any effect on preventing VTE after TKA (RR 1.22, 95% CI 0.84 to 1.79). One trial (150 participants) did not find PE in any of the patients during hospitalisation or in the subsequent three months. PE was not reported in the other included studies. None of the trials reported deaths among the included participants. There is not enough evidence from the available RCTs to conclude that CPM reduces VTE after TKA. We cannot assess the effect of CPM on mortality because no such events occurred amongst the participants of these trials. The quality of the evidence was low. The results are supported by only a small number of studies, most of which are of low to moderate quality.
For TTP, we found six RCTs (331 participants) evaluating PE with FFP as the control. Interventions tested included antiplatelet therapy (APT) plus PE with FFP, FFP transfusion and PE with cryosupernatant plasma (CSP). Two studies compared plasma infusion (PI) to PE with FFP and showed a significant increase in failure of remission at two weeks (RR 1.48, 95% 1.12 to 1.96) and all-cause mortality (RR 1.91, 95% 1.09 to 3.33) in the PI group. Seven RCTs were undertaken in children with HUS. None of the assessed interventions used (FFP transfusion, heparin with or without urokinase or dipyridamole, shiga toxin binding protein and steroids) were superior to supportive therapy alone, for all-cause mortality, neurological/extrarenal events, renal biopsy changes, proteinuria or hypertension at the last follow-up visit. Bleeding was significantly higher in those receiving anticoagulation therapy compared to supportive therapy alone (RR 25.89, 95% CI 3.67 to 182.83). PE with FFP is still the most effective treatment available for TTP. For patients with HUS, supportive therapy including dialysis is still the most effective treatment. All studies in HUS have been conducted in the diarrhoeal form of the disease. There were no RCTs evaluating the effectiveness of any interventions on patients with atypical HUS who have a more chronic and relapsing course.
Nine randomised clinical trials with 879 participants fulfilled our inclusion criteria. All trials were at high risk of bias, and we rated the evidence as low to very low quality. All of the included trials compared combined external beam radiotherapy plus chemoembolisation versus chemoembolisation alone in people with unresectable hepatocellular carcinoma; moreover, three of the trials compared external beam radiotherapy alone versus chemoembolisation alone. All trials were conducted in China. The median age in most of the included trials was around 52 years, and most trial participants were male. The median follow-up duration ranged from one to three years. None of the trials reported data on cancer-related mortality, quality of life, serious adverse events, or time to progression of the tumour. For the comparison of radiotherapy plus chemoembolisation versus chemoembolisation alone, the risk ratio for one-year all-cause mortality was 0.51 (95% confidence interval (CI) 0.41 to 0.62; P < 0.001; 9 trials; low-quality evidence); for complete response rate was 2.14 (95% CI 1.47 to 3.13; P < 0.001; 7 trials; low-quality evidence); and for overall response rate defined as complete response plus partial response was 1.58 (95% CI 1.40 to 1.78; P < 0.001; 7 trials; low-quality evidence), all in favour of combined treatment with external beam radiotherapy plus transarterial chemoembolisation and seemingly supported by our Trial Sequential Analysis. Additionally, the combined treatment was associated with a higher risk of elevated total bilirubin and elevated alanine aminotransferase. The risk ratio for the risk of elevated alanine aminotransferase was 1.41 (95% CI 1.08 to 1.84; P = 0.01; very low-quality evidence), while for elevated total bilirubin it was 2.69 (95% CI 1.34 to 5.40; P = 0.005; very low-quality evidence). For the comparison of radiotherapy versus chemoembolisation, the risk ratio for one-year all-cause mortality was 1.21 (95% CI 0.97 to 1.50; 3 trials; I2 = 0%; very low-quality evidence) which was not supported by our Trial Sequential Analysis. In addition, we found seven ongoing randomised clinical trials evaluating different external beam radiotherapy techniques for people with unresectable hepatocellular carcinoma. We found very low- and low-quality evidence suggesting that combined external beam radiotherapy and chemoembolisation may be associated with lower mortality and increased complete and overall response rates, despite an increased toxicity as expressed by a higher rise of bilirubin and alanine aminotransferase. A high risk of systematic errors (bias) as well as imprecision and inconsistency suggest that these findings should be considered cautiously and that high-quality trials are needed to assess further the role of external beam radiotherapy for unresectable hepatocellular carcinoma.
We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion. In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence). The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low. There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis. Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.
We included nine RCTs (1242 participants and 426 surrogate decision-makers) in this review. The meta-analysis included seven studies (876 participants). Participants' mean ages ranged from 62 to 82 years, and 53% to 100% of the studies' participants were men. All included studies took place in the US or the UK. Only one study reported concordance between participants' preferences and end-of-life care, and it enrolled people with heart failure or renal disease. Owing to one study with small sample size, the effects of ACP on concordance between participants' preferences and end-of-life care were uncertain (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.91 to 1.55; participants = 110; studies = 1; very low-quality evidence). It corresponded to an assumed risk of 625 per 1000 participants receiving usual care and a corresponding risk of 744 per 1000 (95% CI 569 to 969) for ACP. There was no evidence of a difference in quality of life between groups (standardised mean difference (SMD) 0.06, 95% CI –0.26 to 0.38; participants = 156; studies = 3; low-quality evidence). However, one study, which was not included in the meta-analysis, showed that the quality of life score improved by 14.86 points in the ACP group compared with 11.80 points in the usual care group. Completion of documentation by medical staff regarding discussions with participants about ACP processes may have increased (RR 1.68. 95% CI 1.23 to 2.29; participants = 92; studies = 2; low-quality evidence). This corresponded to an assumed risk of 489 per 1000 participants with usual care and a corresponding risk of 822 per 1000 (95% CI 602 to 1000) for ACP. One study, which was not included in the meta-analysis, also showed that ACP helped to improve documentation of the ACP process (hazard ratio (HR) 2.87, 95% CI 1.09 to 7.59; participants = 232). Three studies reported that implementation of ACP led to an improvement of participants' depression (SMD –0.58, 95% CI –0.82 to –0.34; participants = 278; studies = 3; low-quality evidence). We were uncertain about the effects of ACP on the quality of communication when compared to the usual care group (MD –0.40, 95% CI –1.61 to 0.81; participants = 9; studies = 1; very low-quality evidence). We also noted an increase in all-cause mortality in the ACP group (RR 1.32, 95% CI 1.04 to 1.67; participants = 795; studies = 5). The studies did not report participants' satisfaction with care/treatment and caregivers' satisfaction with care/treatment. ACP may help to increase documentation by medical staff regarding discussions with participants about ACP processes, and may improve an individual's depression. However, the quality of the evidence about these outcomes was low. The quality of the evidence for each outcome was low to very low due to the small number of studies and participants included in this review. Additionally, the follow-up periods and types of ACP intervention were varied. Therefore, further studies are needed to explore the effects of ACP that consider these differences carefully.
We included eight RCTs (702 women at high risk of developing OHSS). The quality of evidence was low or very low. The main limitations were failure to report live birth, risk of bias due to lack of information about study methods, and imprecision due to low event rates and lack of data. Four of the studies were published only as abstracts, and provided limited data. Coasting versus no coasting Rates of OHSS were lower in the coasting group (OR 0.11, 95% CI 0.05 to 0.24; I² = 0%, two RCTs; 207 women; low-quality evidence), suggesting that if 45% of women developed moderate or severe OHSS without coasting, between 4% and 17% of women would develop it with coasting. There were too few data to determine whether there was a difference between the groups in rates of live birth (OR 0.48, 95% CI 0.14 to 1.62; one RCT; 68 women; very low-quality evidence), clinical pregnancy (OR 0.82, 95% CI 0.46 to 1.44; I² = 0%; two RCTs; 207 women; low-quality evidence), multiple pregnancy (OR 0.31, 95% CI 0.12 to 0.81; one RCT; 139 women; low-quality evidence), or miscarriage (OR 0.85, 95% CI 0.25 to 2.86; I² = 0%; two RCTs; 207 women; very low-quality evidence). Coasting versus EUFA There were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 0.98, 95% CI 0.34 to 2.85; I² = 0%; 2 RCTs; 83 women; very low-quality evidence), or clinical pregnancy (OR 0.67, 95% CI 0.25 to 1.79; I² = 0%; 2 RCTs; 83 women; very low-quality evidence); no studies reported live birth, multiple pregnancy, or miscarriage. Coasting versus antagonist One RCT (190 women) reported this comparison, and no events of OHSS occurred in either arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.74, 95% CI 0.42 to 1.31; one RCT; 190 women; low-quality evidence), or multiple pregnancy rates (OR 1.00, 95% CI 0.43 to 2.32; one RCT; 98 women; very low-quality evidence); the study did not report live birth or miscarriage. Coasting versus FSH co-trigger Rates of OHSS were higher in the coasting group (OR 43.74, 95% CI 2.54 to 754.58; one RCT; 102 women; very low-quality evidence), with 15 events in the coasting arm and none in the FSH co-trigger arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.92, 95% CI 0.43 to 2.10; one RCT; 102 women; low-quality evidence). This study did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage, but stated that there was no significant difference between the groups. Coasting versus cabergoline There were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 1.98, 95% CI 0.09 to 5.68; P = 0.20; I² = 72%; two RCTs; 120 women; very low-quality evidence), with 11 events in the coasting arm and six in the cabergoline arm. The evidence suggested that coasting was associated with lower rates of clinical pregnancy (OR 0.38, 95% CI 0.16 to 0.88; P = 0.02; I² =0%; two RCTs; 120 women; very low-quality evidence), but there were only 33 events altogether. These studies did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage. There was low-quality evidence to suggest that coasting reduced rates of moderate or severe OHSS more than no coasting. There was no evidence to suggest that coasting was more beneficial than other interventions, except that there was very low-quality evidence from a single small study to suggest that using FSH co-trigger at the time of HCG administration may be better at reducing the risk of OHSS than coasting. There were too few data to determine clearly whether there was a difference between the groups for any other outcomes.
We found no randomised clinical trials comparing cryotherapy versus no intervention or versus systemic treatments; however, we identified one randomised clinical trial comparing cryotherapy with conventional surgery. The trial was conducted in Ukraine. The trial included 123 participants with solitary, or multiple unilobar or bilobar liver metastases; 63 participants received cryotherapy and 60 received conventional surgery. There were 36 women and 87 men. The primary sites for the metastases were colon and rectum (66.6%), stomach (7.3%), breast (6.5%), skin (4.9%), ovaries (4.1%), uterus (3.3%), kidney (3.3%), intestines (1.6%), pancreas (1.6%), and unknown (0.8%). The trial was not reported sufficiently enough to assess the risk of bias of the randomisation process, allocation concealment, or presence of blinding. It was also not possible to assess incomplete outcome data and selective outcome reporting bias. The certainty of evidence was low because of risk of bias and imprecision. The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. The calculated by us relative risk (RR) with 95% Confidence Interval (CI) was: RR 0.88, 95% CI 0.77 to 1.02. We judged the evidence as low-certainty evidence. Regarding adverse events and complications, separately and in total, our calculation showed no evidence of a difference in recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (RR 0.90, 95% CI 0.80 to 1.01; low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, the authors did not report whether there was any evidence of a difference. There were no intervention-related mortality or bile leakages. We identified no evidence for health-related quality of life, cancer mortality, or time to progression of liver metastases. The study reported tumour response in terms of the carcinoembryonic antigen level in 69% of participants, and reported results in the form of a graph for 30% of participants. The carcinoembryonic antigen level was lower in the cryotherapy group, and decreased to normal values faster in comparison with the control group (P < 0.05). Funding: the trial did not provide information on funding. The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.
The review included five studies with 430 participants. Studies varied in the preparations of valproate, mean doses (480 mg/day to 1000 mg/day), duration of treatment (three weeks to six weeks), and outcome measures used. The studies were generally well conducted although some methodological information was missing and one study was at high risk of attrition bias. The quality of evidence related to our primary efficacy outcome of agitation varied from moderate to very low. We found moderate-quality evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108) and with the BPRS agitation factor (range 0 to 18). They found that there was probably little or no effect of valproate treatment over six weeks (total BPRS: mean difference (MD) 0.23, 95% confidence interval (CI) –2.14 to 2.59; 202 participants, 2 studies; BPRS agitation factor: MD –0.67, 95% CI –1.49 to 0.15; 202 participants, 2 studies). Very low-quality evidence from three studies which measured agitation with the Cohen-Mansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on agitation. There was variable quality evidence on other behaviour outcomes reported in single studies of no difference between groups or a benefit for the placebo group. Three studies, which measured cognitive function using the Mini-Mental State Examination (MMSE), found little or no effect of valproate over six weeks, but we were uncertain about this result because the quality of the evidence was very low. Two studies that assessed functional ability using the Physical Self-Maintenance Scale (PSMS) (range 6 to 30) found that there was probably slightly worse function in the valproate-treated group, which was of uncertain clinical importance (MD 1.19, 95% CI 0.40 to 1.98; 203 participants, 2 studies; moderate-quality evidence). Analysis of adverse effects and serious adverse events (SAE) indicated a higher incidence in valproate-treated participants. A meta-analysis of three studies showed that there may have been a higher rate of adverse effects among valproate-treated participants than among controls (odds ratio (OR) 2.02, 95% CI 1.30 to 3.14; 381 participants, 3 studies, low-quality evidence). Pooled analysis of the number of SAE for the two studies that reported such data indicated that participants treated with valproate preparations were more likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies), but the very low quality of the data made it difficult to draw any firm conclusions regarding SAEs. Individual adverse events that were more frequent in the valproate-treated group included sedation, gastrointestinal symptoms (nausea, vomiting, and diarrhoea), and urinary tract infections. This updated review corroborates earlier findings that valproate preparations are probably ineffective in treating agitation in people with dementia, but are associated with a higher rate of adverse effects, and possibly of SAEs. On the basis of this evidence, valproate therapy cannot be recommended for management of agitation in dementia. Further research may not be justified, particularly in light of the increased risk of adverse effects in this often frail group of people. Research would be better focused on effective non-pharmacological interventions for this patient group, or, for those situations where medication may be needed, further investigation of how to use other medications as effectively and safely as possible.
One new study was identified for this 2018 update, bringing the total number of included studies to two and the total number of participants to 451. Both trials discharged patients randomised to the outpatient group within 36 hours of initial triage and both followed participants for 90 days. One study compared the same treatment regimens in both outpatient and inpatient groups, and the other study used different treatment regimes. There was no clear difference in treatment effect for the outcomes of short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49; low-quality evidence), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99, low-quality evidence), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30; low-quality evidence) and at 90 days (RR 6.88, 95% CI 0.36 to 132.14, P = 0.20; low-quality evidence), minor bleeding (RR 1.08, 95% CI 0.07 to 16.79; P = 0.96, low-quality evidence), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51, low-quality evidence), and participant satisfaction (RR 0.97, 95% CI 0.90 to 1.04, P = 0.39; moderate-quality evidence). We downgraded the quality of the evidence because the CIs were wide and included treatment effects in both directions, the sample sizes and numbers of events were small, and because the effect of missing data and the absence of publication bias could not be verified. PE-related mortality, and adverse effects such as haemodynamic instability and compliance, were not assessed by the included studies. Currently, only low-quality evidence is available from two published randomised controlled trials on outpatient versus inpatient treatment in low-risk patients with acute PE. The studies did not provide evidence of any clear difference between the interventions in overall mortality, bleeding and recurrence of PE.
Five studies were included with a total of 176 participants (71 people participated in water-based exercise training and 54 in land-based exercise training; 51 completed no exercise training). All studies compared supervised water-based exercise training versus land-based exercise training and/or no exercise training in people with COPD (with average forced expiratory volume in one second (FEV1) %predicted ranging from 39% to 62%). Sample sizes ranged from 11 to 53 participants. The exercise training programmes lasted from four to 12 weeks, and the mean age of participants ranged from 57 to 73 years. A moderate risk of bias was due to lack of reporting of randomisation, allocation and blinding procedures in some studies, as well as small sample sizes. Compared with no exercise, water-based exercise training improved the six-minute walk distance (mean difference (MD) 62 metres; 95% confidence interval (CI) 44 to 80 metres; three studies; 99 participants; moderate quality evidence), the incremental shuttle walk distance (MD 50 metres; 95% CI 20 to 80 metres; one study; 30 participants; high quality evidence) and the endurance shuttle walk distance (MD 371 metres; 95% CI 121 to 621 metres; one study; 30 participants; high quality evidence). Quality of life was also improved after water-based exercise training compared with no exercise (standardised mean difference (SMD) -0.97, 95% CI -0.37 to -1.57; two studies; 49 participants; low quality evidence). Compared with land-based exercise training, water-based exercise training did not significantly change the six-minute walk distance (MD 11 metres; 95% CI -11 to 33 metres; three studies; 62 participants; moderate quality evidence) or the incremental shuttle walk distance (MD 9 metres; 95% CI -15 to 34 metres; two studies; 59 participants; low quality evidence). However, the endurance shuttle walk distance improved following water-based exercise training compared with land-based exercise training (MD 313 metres; 95% CI 232 to 394 metres; two studies; 59 participants; moderate quality evidence). No significant differences were found between water-based exercise training and land-based exercise training for quality of life, as measured by the St George's Respiratory Questionnaire or by three of four domains of the Chronic Respiratory Disease Questionnaire (CRDQ); however, the fatigue domain of the CRDQ showed a statistically significant difference in favour of water-based exercise (MD -3.00; 95% CI -5.26 to -0.74; one study; 30 participants). Only one study reported long-term outcomes after water-based exercise training for quality of life and body composition, and no significant change was observed between baseline results and six-month follow-up results. One minor adverse event was reported for water-based exercise training (based on reporting from two studies; 20 participants). Impact of disease severity could not be examined because data were insufficient. There is limited quality evidence that water-based exercise training is safe and improves exercise capacity and quality of life in people with COPD immediately after training. There is limited quality evidence that water-based exercise training offers advantages over land-based exercise training in improving endurance exercise capacity, but we remain uncertain as to whether it leads to better quality of life. Little evidence exists examining the long-term effect of water-based exercise training.
We included nine short-term RCTs (duration 12 weeks or less) in the analysis (345 participants; age range 18 to 76 years). Participants were exposed to a variety of traumas, ranging from assault, traffic accidents and work accidents to cardiac surgery and septic shock. Seven studies were conducted at single centres. The seven RCTs included four hydrocortisone studies, three propranolol studies (of which one study had a third arm investigating gabapentin), and single trials of escitalopram and temazepam. Outcome assessment measures included the Clinician-Administered PTSD Scale (CAPS), the 36-Item Short-Form Health Survey (SF-36) and the Center for Epidemiological Studies – Depression Scale (CES-D). In four trials with 165 participants there was moderate quality evidence for the efficacy of hydrocortisone in preventing the onset of PTSD (risk ratio (RR) 0.17; 95% confidence interval (CI) 0.05 to 0.56; P value = 0.004), indicating that between seven and 13 patients would need to be treated with this agent in order to prevent the onset of PTSD in one patient. There was low quality evidence for preventing the onset of PTSD in three trials with 118 participants treated with propranolol (RR 0.62; 95% CI 0.24 to 1.59; P value = 0.32). Drop-outs due to treatment-emergent side effects, where reported, were low for all of the agents tested. Three of the four RCTs of hydrocortisone reported that medication was more effective than placebo in reducing PTSD symptoms after a median of 4.5 months after the event. None of the single trials of escitalopram, temazepam and gabapentin demonstrated evidence that medication was superior to placebo in preventing the onset of PTSD. Seven of the included RCTs were at a high risk of bias. Differential drop-outs between groups undermined the results of three studies, while one study failed to describe how the allocation of medication was concealed. Other forms of bias that might have influenced study results included possible confounding through group differences in concurrent medication and termination of the study based on treatment response. There is moderate quality evidence for the efficacy of hydrocortisone for the prevention of PTSD development in adults. We found no evidence to support the efficacy of propranolol, escitalopram, temazepam and gabapentin in preventing PTSD onset. The findings, however, are based on a few small studies with multiple limitations. Further research is necessary in order to determine the efficacy of pharmacotherapy in preventing PTSD and to identify potential moderators of treatment effect.
Nineteen studies involving 1120 women were eligible for inclusion.  Antibiotic versus antibiotic (10 trials, 430 women): During active prophylaxis the rate range of microbiological recurrence patient-year (MRPY) was 0 to 0.9 person-year in the antibiotic group against 0.8 to 3.6 with placebo. The RR of having one microbiological recurrence (MR) was 0.21 (95% CI 0.13 to 0.34), favouring antibiotic and the NNT was 1.85. For clinical recurrences (CRPY) the RR was 0.15 (95% CI 0.08 to 0.28). The NNT was 1.85. The RR of having one MR after prophylaxis was 0.82 (95% CI 0.44 to 1.53). The RR for severe side effects was 1.58 (95% CI 0.47 to 5.28) and for other side effects the RR was 1.78 (CI 1.06 to 3.00) favouring placebo. Side effects included vaginal and oral candidiasis and gastrointestinal symptoms. Antibiotic versus antibiotic (eight trials, 513 women): These trials were not pooled. Weekly perfloxacin was more effective than monthly. The RR for MR was 0.31(95% CI 0.19 to 0.52). There was no significant difference in MR between continuous daily and postcoital ciprofloxacin. Continuous antibiotic prophylaxis for 6-12 months reduced the rate of UTI during prophylaxis when compared to placebo. After prophylaxis two studies showed no difference between groups. There were more adverse events in the antibiotic group. One RCT compared postcoital versus continuous daily ciprofloxacin and found no significant difference in rates of UTIs, suggesting that postcoital treatment could be offered to woman who have UTI associated with sexual intercourse.
Six RCT's (n=483), with 8-16 weeks follow-up, met our inclusion criteria. Meta-analysis of five trials (n=425) with adequate data indicated that potassium supplementation compared to control resulted in a large but statistically non-significant reductions in SBP (mean difference: -11.2, 95% CI: -25.2 to 2.7) and DBP (mean difference: -5.0, 95% CI: -12.5 to 2.4). The substantial heterogeneity between trials was not explained by potassium dose, quality of trials or baseline blood pressure. Excluding one trial in an African population with very high baseline blood pressure resulted in smaller overall reductions in blood pressure (SBP mean difference: -3.9, 95% CI: -8.6 to 0.8; DBP mean difference: -1.5, 95% CI: -6.2 to 3.1). Further sensitivity analysis restricted to two high quality trials (n=138) also found non-significant reductions in blood pressure (SBP mean difference: -7.1, 95% CI: -19.9 to 5.7; DBP mean difference: -5.5, 95% CI: -14.5 to 3.5). Potassium supplementation has no statistically significant effect on blood pressure. Due to small number of participants in the two high quality trials, the short duration of follow-up, and the unexplained heterogeneity between trials, the evidence about the effect of potassium supplementation on blood pressure is not conclusive. Further high quality RCTs of longer duration are required to clarify whether potassium supplementation can reduce blood pressure and improve health outcomes.
No additional trials could be included in this update. One trial at low risk of bias evaluating oral penicillin in combination with analgesics versus placebo with analgesics, involving 40 participants was included in a former update of the review. The certainty of the evidence was rated low for the different outcomes. Our primary outcome was patient-reported pain (intensity/duration) and pain relief. There was a close parallel distribution of the pain ratings in both the intervention (median 6.0, interquartile range (IQR) 10.5), and for placebo (median 6.0, IQR 9.5) over the seven-day study period. There was insufficient evidence to claim or refute a benefit for penicillin for pain intensity. There was no significant difference in the mean total number of ibuprofen tablets over the study period: 9.20 (standard deviation (SD) 6.02) in the penicillin group versus 9.60 (SD 6.34) in the placebo group; mean difference -0.40 (95% confidence interval (CI) -4.23 to 3.43; P = 0.84). This applied equally for the mean total number of Tylenol tablets: 6.90 (SD 6.87) used in the penicillin group versus 4.45 (SD 4.82) in the placebo group; mean difference 2.45 (95% CI -1.23 to 6.13; P = 0.19). Our secondary outcome on reporting of adverse events was not addressed in this study. This Cochrane Review which was based on one low-powered small sample trial assessed as at low risk of bias, illustrates that there is insufficient evidence to determine whether antibiotics reduce pain or not compared to not having antibiotics. The results of this review confirm the necessity for further larger sample and methodologically sound trials that can provide additional evidence as to whether antibiotics, prescribed in the preoperative phase, can affect treatment outcomes for irreversible pulpitis.
Information on cognitive function at the start of a study was available on 4080 participants randomised in three trials. Cognitive function data were available on 3536 participants at final follow-up. In two studies participants received gel capsules containing either omega-3 PUFA (the intervention) or olive or sunflower oil (placebo) for six or 24 months. In one study, participants received margarine spread for 40 months; the margarine for the intervention group contained omega-3 PUFA. Two studies had cognitive health as their primary outcome; one study of cardiovascular disease included cognitive health as an additional outcome. None of the studies examined the effect of omega-3 PUFA on incident dementia. In two studies involving 3221 participants there was no difference between the omega-3 and placebo group in mini-mental state examination score at final follow-up (following 24 or 40 months of intervention); MD -0.07 (95% CI -0.25 to 0.10). In two studies involving 1043 participants, other tests of cognitive function such as word learning, digit span and verbal fluency showed no beneficial effect of omega-3 PUFA supplementation. Participants in both the intervention and control groups experienced either small or no cognitive declines during the studies. The main reported side-effect of omega-3 PUFA supplementation was mild gastrointestinal problems. Overall, minor adverse events were reported by fewer than 15% of participants, and reports were balanced between intervention groups. Adherence to the intervention was on average over 90% among people who completed the trials. All three studies included in this review are of high methodological quality. Direct evidence on the effect of omega-3 PUFA on incident dementia is lacking. The available trials showed no benefit of omega-3 PUFA supplementation on cognitive function in cognitively healthy older people. Omega-3 PUFA supplementation is generally well tolerated with the most commonly reported side-effect being mild gastrointestinal problems. Further studies of longer duration are required. Longer-term studies may identify greater change in cognitive function in study participants which may enhance the ability to detect the possible effects of omega-3 PUFA supplementation in preventing cognitive decline in older people.
An updated literature search performed in July 2008 did not identify any new trials. Only two randomized controlled trials were identified that satisfied the inclusion criteria. These two trials could not be pooled for analysis because of major differences in design and patient populations. In the first trial, 11 patients received intravenous cyclosporine (4 mg/kg) and 9 received placebo. Two of 11 in the treatment group failed to respond to therapy compared with nine of nine in the placebo group (RR 0.18, 95% CI 0.05 - 0.64). However, 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively and follow-up was less than a month. In the second trial 15 patients were treated with intravenous cyclosporine and 15 with intravenous methylprednisolone. Five of 15 patients in the cyclosporine group failed to respond to therapy as compared to 7/15 in the methylprednisolone group (RR 0.71, 95% CI 0.29 - 1.75). After 1 year 7/9 responders in the cyclosporine group were still in remission compared with 4/8 in the steroid group (p > 0.05) and the colectomy rate was similar in both groups. The mean time to response in the cyclosporine group in the 2 trials was short (7 days and 5.2 days). These results should be interpreted with caution given the small numbers of trials and patients evaluated for comparison, and limited follow-up (few weeks in one trial to a year in the other). The precise assessment of the occurrence of adverse events was difficult because the trials described different adverse reactions, which reversed after discontinuation of cyclosporine. There was no evidence in the trials reviewed that cyclosporine was more effective than standard treatment for preventing colectomy but this effect cannot be excluded due to the small sample size and rarity of this outcome. Additional limitations of current research include lack of data on quality of life, costs and long-term results of cyclosporine therapy. There is limited evidence that cyclosporine is more effective than standard treatment alone for severe ulcerative colitis. The relatively quick response makes the short-term use of cyclosporine potentially attractive, but the long-term benefit is unclear, when adverse events such as cyclosporine-induced nephrotoxicity may become more obvious. There is a need for additional research on quality of life, costs and long-term results from cyclosporine therapy in severe ulcerative colitis.
Ten trials met the inclusion criteria. PEDro quality ratings ranged from 6/10 to 10/10. Concentration of BoNT-A ranged from 50U/1.0ml to 200U/1.0ml saline with doses of 0.5U to 16U/kg body weight and total doses of 220 to 410 Units (Botox®). A combination of BoNT-A and occupational therapy is more effective than occupational therapy alone in reducing impairment, improving activity level outcomes and goal achievement, but not for improving quality of life or perceived self-competence. When compared with placebo or no treatment, there is moderate evidence that BoNT-A alone is not effective. This systematic review found high level evidence supporting the use of BoNT-A as an adjunct to managing the upper limb in children with spastic CP. BoNT-A should not be used in isolation but should be accompanied by planned occupational therapy. Further research is essential to identify children most likely to respond to BoNT-A injections, monitor longitudinal outcomes, determine timing and effect of repeated injections and the most effective dosage, dilution and volume schedules. The most effective adjunct therapies including frequency and intensity of delivery also requires investigation.
We included three trials examining pulmonary exacerbations (171 participants) and two trials examining long-term therapy (85 participants). We regarded the most important outcomes as quality of life and lung function. The analysis did not identify any statistically significant difference between oral anti-pseudomonal antibiotics and other treatments for these outcome measures for either pulmonary exacerbations or long-term treatment. One of the included trials reported significantly better lung function when treating a pulmonary exacerbation with ciprofloxacin when compared with intravenous treatment; however, our analysis did not confirm this finding. We found no evidence of difference between oral anti-pseudomonal antibiotics and other treatments regarding adverse events or development of antibiotic resistance, but trials were not adequately powered to detect this. None of the studies had a low risk of bias from blinding which may have an impact particularly on subjective outcomes such as quality of life. The risk of bias for other criteria could not be clearly stated across the studies. We found no conclusive evidence that an oral anti-pseudomonal antibiotic regimen is more or less effective than an alternative treatment for either pulmonary exacerbations or long-term treatment of chronic infection with P. aeruginosa. Until results of adequately-powered future trials are available, treatment needs to be selected on a pragmatic basis, based upon any available non-randomised evidence, the clinical circumstances of the individual, the known effectiveness of drugs against local strains and upon individual preference.
We identified six randomised controlled trials including a total of 262 participants. Four studies were conducted with primary school or kindergarten teachers, one with student teachers and one with telemarketers. Three studies found similar self-reported vocal symptoms between those who attended direct voice training and those who were in a no intervention control group (standardised mean difference (SMD) 0.27; 95% CI -0.12 to 0.66). Two studies found similar self-reported vocal symptoms between those who attended indirect voice training and those who were in a no intervention control group (SMD 0.44; 95% CI -0.03 to 0.92). One study found similar scores on the Voice Handicap Index for those who had direct and indirect voice training combined and for those who had no intervention. Two studies compared a combination of direct and indirect voice training with indirect voice training only. Both studies found similar scores for self-reported phonation difficulty (mean difference -5.55; 95% CI -23.75 to 12.66) in both groups. The evidence for all comparisons was rated as low quality. No work-directed studies were found. No studies evaluated the effectiveness of prevention in terms of sick leave or number of diagnosed voice disorders. We found no evidence that either direct or indirect voice training or the two combined are effective in improving self-reported vocal functioning when compared to no intervention. The current practice of giving training to at-risk populations for preventing the development of voice disorders is therefore not supported by definitive evidence of effectiveness. Larger and methodologically better trials are needed with outcome measures that better reflect the aims of interventions.
We included 11 trials involving 904 adults, published between 1990 and 2014. Eight studies were conducted in the USA, and one each in Canada, Spain and Turkey. Sample sizes ranged from 20 to 154 participants aged between 18 and 85 years old. The proportion of female participants varied between 52% and 100%. The duration of follow-up in the studies varied from seven days to 12 months. The exercise type most prescribed for the intervention was aerobic (walking in 70% of the studies, or bicycle riding or treadmill) at least five times a week. Duration was 30 to 45 minutes at moderate intensity. Participants were supervised in 90% of the studies. For four of the primary outcomes the results did not differ significantly and all were low-quality evidence (number of ARI episodes per person per year, rate ratio 0.91 (95% confidence interval (CI) 0.59 to 1.42); proportion of participants who experienced at least one ARI over the study period, risk ratio 0.76 (95% CI 0.57 to 1.01); severity of ARI symptoms, mean difference (MD) -110 (95% CI -324 to 104); and number of symptom days in the follow-up period, MD -2.1 days (95% CI -4.4 to 0.3)). However, one primary outcome, the number of symptom days per episode of illness, was reduced in those participants who exercised (MD -1.1 day, 95% CI -1.7 to -0.5, moderate-quality evidence). We found no significant differences for the secondary outcomes (laboratory parameters (blood lymphocytes, salivary secretory immunoglobulin and neutrophils); quality of life outcomes; cost-effectiveness and exercise-related injuries). There was good adherence to the intervention with no difference between the exercise and non-exercise groups. We rated the quality of evidence for the primary outcomes as low for most outcomes using the GRADE criteria: allocation concealment was not reported and there was a lack of blinding; in addition, there was imprecision (the CI is very wide because of a small number of participants) and inconsistency, which may be due to differences in study design. We cannot determine whether exercise is effective at altering the occurrence, severity or duration of acute respiratory infections. One analysis of four trials suggests that the number of days of illness per episode of infection might be reduced by exercise. The small size of the studies, risk of bias and heterogeneous populations trialled all contribute to the uncertainty. Larger studies, with less risk of bias from patient selection, blinding of outcomes assessors, reporting of all outcomes measured and with registration of study protocols, are required to settle the question.
We were able to include six studies (586 participants). Non-standard care consisted solely of another type of exercise programme. All outcomes were short term (less than six months). There was a clear difference in the outcome leaving the study early (6 RCTs, n=586, RR 0.64 CI 0.49 to 0.83, medium quality evidence) in favour of the yoga group. There were no clear differences between groups for the remaining outcomes. These included mental state (improvement in Positive and Negative Syndrome Scale, 1 RCT, n=84, RR 0.81 CI 0.62 to 1.07, low quality evidence), social functioning (improvement in Social Occupational Functioning Scale, 1 RCT, n=84, RR 0.90 CI 0.78 to 1.04, low quality evidence), quality of life (mental health) (average change 36-Item Short Form Survey (SF-36) quality-of-life sub-scale, 1 RCT, n=69, MD -5.30 CI -17.78 to 7.18, low quality evidence), physical health, (average change WHOQOL-BREF physical-health sub-scale, 1 RCT, n=69, MD 9.22 CI -0.42 to 18.86, low quality evidence). Only one study reported adverse effects, finding no incidence of adverse events in either treatment group. There were a considerable number of missing outcomes, which included relapse, change in cognition, costs of care, effect on standard care, service intervention, disability, and activities of daily living. We found minimal differences between yoga and non-standard care, the latter consisting of another exercise comparator, which could be broadly considered aerobic exercise. Outcomes were largely based on single studies with limited sample sizes and short-term follow-up. Overall, many outcomes were not reported and evidence presented in this review is of low to moderate quality - too weak to indicate that yoga is superior or inferior to non-standard care control for management of people with schizophrenia.
Five small heterogeneous randomised controlled trials, all at high risk of performance bias and most at risk of at least one other type of bias, were included. These involved approximately 200 participants with a diagnosis of patellofemoral pain syndrome. All compared taping versus control (no or placebo taping) and all included one or more co-interventions given to both taping and control group participants; this was prescribed exercise in four trials. The intensity and length of treatment was very varied: for example, length of treatment ranged from one week in one trial to three months in another. A meta-analysis of the visual analogue scale (VAS) pain data (scale 0 to 10: worst pain), measured in different ways, from four trials (data from 161 knees), found no statistically or clinically significant difference between taping and non taping in pain at the end of the treatment programmes (mean difference (MD) -0.15; 95% confidence interval (CI) -1.15 to 0.85; random-effects model used given the significant heterogeneity (P < 0.0001)). Data for other outcomes measuring function and activities of daily living were from single trials only and gave contradictory results. The currently available evidence from trials reporting clinically relevant outcomes is low quality and insufficient to draw conclusions on the effects of taping, whether used on its own or as part of a treatment programme. Further research involving large, preferably multi-centre, good quality and well reported randomised controlled trials that measure clinically important outcomes and long-term results is warranted. Before this, consensus is required on the diagnosis of patellofemoral pain syndrome, the standardisation of outcome measurement and an acceptable approach for patellar taping.
19 publications describing 10 trials of adults were included in the review. Studies that compared reduced dose (mean 60% reduction) ICS/LABA combination to a fixed moderate/high dose ICS found no significant difference in severe exacerbations requiring oral corticosteroids (RR 1.0, 95%CI 0.76 to 1.32), withdrawal due to worsening asthma (RR 0.82, 95%CI 0.5 to 1.35) or airway inflammation. There were also significant improvements in FEV1 (change from baseline WMD 0.10, 95%CI 0.07 to 0.12), morning & evening PEF and percent rescue free days with LABA. Two studies provided outcomes for a reduced/tapering ICS dose comparison. More participants receiving the LABA/reduced ICS combination achieved a reduction in ICS dose reaching significance in one study. A significant reduction of 253 mcg BDP was achieved in one study. In adults with asthma, using moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. The addition of LABA permits more participants on minimum maintenance ICS to reduce ICS. The precise magnitude of the ICS dose reduction requires further study.
Twenty-one RCTs were included, with a total of 2538 participants randomised to low GI intervention (1288) or high GI (1250). All 21 included studies reported the effect of low GI diets on risk factors for cardiovascular disease, including blood lipids and blood pressure. Twenty RCTs (18 of which were newly included in this version of the review) included primary prevention populations (healthy individuals or those at high risk of CVD, with mean age range from 19 to 69 years) and one RCT was in those diagnosed with pre-existing CVD (a secondary prevention population, with mean age 26.9 years). Most of the studies did not have an intervention duration of longer than six months. Difference in GI intake between comparison groups varied widely from 0.6 to 42. None of the included studies reported the effect of low GI dietary intake on cardiovascular mortality and cardiovascular events such as fatal and nonfatal myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke. The unclear risk of bias of most of the included studies makes overall interpretation of the data difficult. Only two of the included studies (38 participants) reported on adverse effects and did not observe any harms (low-quality evidence). There is currently no evidence available regarding the effect of low GI diets on cardiovascular disease events. Moreover, there is currently no convincing evidence that low GI diets have a clear beneficial effect on blood lipids or blood pressure parameters.
We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children. While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over-the-counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use - in particular the increased risks for children - these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions. This review has highlighted the absence of any randomised controlled trials evaluating codeine-based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological-based management practices continue to be advocated for children with chronic cough.
Two studies compared corticosteroids to placebo and six studies compared corticosteroids to 5-ASA. Corticosteroids were found to be significantly more effective than placebo at inducing remission in CD (RR 1.99; 95% CI 1.51 to 2.64; P < 0.00001). Corticosteroids were found to be more effective than 5-ASA at inducing remission in studies with long follow-up duration (i.e. > 15 weeks; RR 1.65; 95% CI 1.33 to 2.03; P < 0.00001). Corticosteroids induced adverse events in a higher proportion of patients than placebo (RR 4.89; 95% CI 1.98 to 12.07; P = 0.0006), or low-dose 5-ASA (RR 2.38; 95% CI 1.34 to 4.25; P = 0.003). No difference existed in the proportion of patients experiencing adverse events when steroids were compared to high-dose 5-ASA. Steroids did not induce more study withdrawals due to adverse events than either placebo or 5-ASA. Corticosteroids are effective for induction of remission in patients with CD, particularly when used for more than 15 weeks. Although corticosteroids cause more adverse events than either placebo or low-dose 5-ASA, these adverse events did not lead to increased study withdrawal in the included studies. Further information is required to determine the optimal duration of treatment and tapering protocol to maximize the efficacy of treatment with corticosteroids. Additionally, further study is required to determine whether corticosteroids are more effective in patients with certain phenotypes or when administered intravenously.
We identified a total of 13 randomized trials involving 2362 participants. Ten trials (2122 participants) reported sufficient detail on survival to be included in a meta-analysis for the primary outcome. Preoperative chemotherapy improves overall survival (HR 0.88, 95% confidence interval (CI) 0.80 to 0.96) and is associated with a significantly higher rate of complete (R0) resection (RR 1.11, 95% CI 1.03 to 1.19). No evidence suggests that the overall rate of resection (RR 0.96, 95% CI 0.92 to 1.01), tumor recurrence (RR 0.81, 95% CI 0.54 to 1.22) or nonfatal complications (RR 0.90; 95% CI 0.76 to 1.06) was different for preoperative chemotherapy compared with surgery alone. Trials reported risks of toxicity with chemotherapy that ranged from 11% to 90%. In summary, preoperative chemotherapy plus surgery offers a survival advantage compared with surgery alone for patients with resectable thoracic esophageal cancer, but the evidence is of moderate quality. Some evidence of toxicity and preoperative mortality have been associated with chemotherapy.
Twenty-one RCTs were identified that involved non-surgical management of chronic pelvic pain: 13 trials were included in the review, and eight were excluded. The studies included a total of 750 women—406 women in the intervention groups and 344 in the control groups. Included studies had high attrition rates, and investigators often did not blind adequately or did not clearly describe randomisation procedures. Medical treatment versus placebo Progestogen (medroxyprogesterone acetate (MPA)) was more effective than placebo at the end of treatment in terms of the number of women achieving a greater than 50% reduction in visual analogue scale (VAS) pain score immediately after treatment (Peto OR 3.00, 95% CI 1.70 to 5.31, two studies, n = 204, I2 = 22%, moderate-quality evidence). Evidence of benefit was maintained up to nine months after treatment (Peto OR 2.09, 95% CI 1.18 to 3.71, two studies, n = 204, I2 = 0%, moderate-quality evidence). Women treated with progestogen reported more adverse effects (e.g. weight gain, bloatedness) than those given placebo (high-quality evidence). The estimated effect of lofexidine on pain outcomes when compared with placebo was compatible with benefit and harm (Peto OR 0.42, 95% CI 0.11 to 1.61, one study, 39 women, low-quality evidence). Women in the lofexidine group reported more adverse effects (including drowsiness and dry mouth) than women given placebo (moderate-quality evidence). Head-to-head comparisons of medical treatments Head-to-head comparisons showed that women taking goserelin had greater improvement in pelvic pain score (MD 3, 95% CI 2.08 to 3.92, one study, n = 47, moderate-quality evidence) at one year than those taking progestogen. Women taking gabapentin had a lower VAS pain score than those taking amytriptyline (MD -1.50, 95% CI -2.06 to -0.94, n = 40, low-quality evidence). Study authors reported that no statistically significant difference was observed in the rate of adverse effects among women taking gabapentin compared with women given amytriptyline. The study comparing goserelin versus progestogen did not report on adverse effects. Psychological treatment Women who underwent reassurance ultrasound scans and received counselling were more likely to report improved pain than those treated with a standard 'wait and see' policy (Peto OR 6.77, 95% CI 2.83 to 16.19, n = 90, low-quality evidence). Significantly more women who had writing therapy as a disclosure reported improvement in pain than those in the non-disclosure group (Peto OR 4.47, 95% CI 1.41 to 14.13, n = 48, very low-quality evidence). No difference between groups in pain outcomes was noted when other psychological therapies were compared with standard care or placebo (quality of evidence ranged from very low to low). Studies did not report on adverse effects. Complementary therapy Distension of painful pelvic structures was more effective for pain when compared with counselling (MD 35.8, 95% CI 23.08 to 48.52 on a zero to 100 scale, one study, n = 48, moderate-quality evidence). No difference in pain levels was observed when magnetic therapy was compared with use of a control magnet (very low-quality evidence). Studies did not report on adverse effects. The results of studies examining psychological and complementary therapies could not be combined to yield meaningful results. Evidence of moderate quality supports progestogen as an option for chronic pelvic pain, with efficacy reported during treatment. In practice, this option may be most acceptable among women unconcerned about progestogenic adverse effects (e.g. weight gain, bloatedness—the most common adverse effects). Although some evidence suggests possible benefit of goserelin when compared with progestogen, gabapentin as compared with amytriptyline, ultrasound versus 'wait and see' and writing therapy versus non-disclosure, the quality of evidence is generally low, and evidence is drawn from single studies. Given the prevalence and healthcare costs associated with chronic pelvic pain in women, RCTs of other medical, lifestyle and psychological interventions are urgently required.
A single study was included for analysis in this review. This study compared the use of telemedicine (Baby Carelink) for parents and families of infants in the NICU with a control group without access to this programme and assessed the length of hospital stay for the infants and family satisfaction in multiple components of infant care. The study shows no difference in the length of hospital stay (average length of stay: telemedicine group: 68.5 days (standard deviation (SD) 28.3 days), control group: 70.6 days (SD 35.6 days), MD -2.10 days (95% confidence interval: -18.85 to 14.65 days). There was insufficient information for further analysis of measures of family satisfaction. There is insufficient evidence to support or refute the use of telemedicine technology to support the parents of high-risk newborn infants receiving intensive care. Clinical trials are needed to assess the application of telemedicine to support parents and families of infants in NICU with length of hospital stay and their perception of NICU care as the major outcomes.
We pooled data from 14 trials of 1109 participants in a meta-analysis. Moderate quality evidence suggests that post-pyloric feeding is associated with low rates of pneumonia compared with gastric tube feeding (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.51 to 0.84). Low-quality evidence shows an increase in the percentage of total nutrient delivered to the patient by post-pyloric feeding (mean difference (MD) 7.8%, 95% CI 1.43 to 14.18). Evidence of moderate quality revealed no differences in duration of mechanical ventilation or in mortality. Intensive care unit (ICU) length of stay was similar between the two groups. The effect on the time required to achieve the full nutrition target was uncertain (MD -1.99 hours 95% CI -10.97 to 6.99) (very low-quality evidence). We found no evidence suggesting an increase in the rate of complications during insertion or maintenance of the tube in the post-pyloric group (RR 0.51, 95% CI 0.19 to 1.364; RR1.63, 95% CI 0.93 to 2.86, respectively); evidence was assessed as being of low quality for both. Risk of bias was generally low in most studies, and review authors expressed concern regarding lack of blinding of the caregiver in most trials. We found moderate-quality evidence of a 30% lower rate of pneumonia associated with post-pyloric feeding and low-quality evidence suggesting an increase in the amount of nutrition delivered to these participants. We do not have sufficient evidence to show that other clinically important outcomes such as duration of mechanical ventilation, mortality and length of stay were affected by the site of tube feeding. Low-quality evidence suggests that insertion of a post-pyloric feeding tube appears to be safe and was not associated with increased complications when compared with gastric tube insertion. Placement of the post-pyloric tube can present challenges; the procedure is technically difficult, requiring expertise and sophisticated radiological or endoscopic assistance. We recommend that use of a post-pyloric feeding tube may be preferred for ICU patients for whom placement of the post-pyloric feeding tube is feasible. Findings of this review preclude recommendations regarding the best method for placing the post-pyloric feeding tube. The clinician is left with this decision, which should be based on the policies of institutional facilities and should be made on a case-by-case basis. Protocols and training for bedside placement by physicians or nurses should be evaluated.
We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)-10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity. We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias. We did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI -11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI -1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence). We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence). Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI -1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI -0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants). Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo. For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants). None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs.
Our search resulted in 1663 potentially relevant references, of which we included three trials with 14 publications, assessing 398 patients. Overall, we judged the quality of the trials as moderate. The trials were all reported as randomised controlled and open-label. We included two RCTs assessing the effect of HDCT followed by ASCT compared with conventional chemotherapy in a meta-analysis. The number of studies was very low, therefore, the quantification of heterogeneity was not reliable. We included one further RCT (one assessing additional SHDCT followed by ASCT versus HDCT followed by ASCT), which was not compatible with our meta-analysis. For this trial, we performed further analyses. Two trials showed a non-statistically significant trend that HDCT followed by ASCT compared to conventional chemotherapy increases OS (HR 0.67; 95% CI 0.41 to 1.07; P value = 0.10, 157 patients, moderate quality of evidence). However, the increase in PFS was statistically significant for people treated with HDCT followed by ASCT (HR 0.55; 95% CI 0.35 to 0.86; P value = 0.009, 157 patients, moderate quality of evidence). Adverse events were reported in one trial only and did not differ statistically significant between the treatment arms. We were not able to draw conclusions regarding treatment-related mortality (TRM) because of insufficient evidence (RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence). For the second comparison, SHDCT plus HDCT followed by ASCT versus HDCT followed by ASCT there was no difference between the treatment arms regarding OS (HR 0.93; 95% CI 0.5 to 1.74; P value = 0.816, three-year OS: 80% SHDCT versus 87% HDCT, 241 patients), or PFS (HR 0.87; 95% CI 0.58 to 1.30; P value = 0.505, 241 patients). Seven patients died in the SHDCT arm and one in the HDCT arm due to increased toxicity of the treatment. Adverse events were increased with SHDCT plus HDCT followed by ASCT after two cycles of dexamethasone plus high-dose cytarabine plus cisplatin (DHAP) (88% SHDCT versus 45% HDCT, 223 patients, P value < 0.00001). Overall, more statistically significant World Health Organization (WHO) grade 3/4 infections occurred with SHDCT (48% SHDCT versus 33% HDCT; P value = 0.002, 223 patients). The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect. Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.
Seven clinical studies totalling 12,223 participants with COPD were included in the review. The studies used similar designs and were generally of good methodological quality. Inclusion criteria for RCTs were similar across the included studies, although studies varied in terms of smoking history and COPD severity of participants. They compared tiotropium (which was delivered by HandiHaler in all studies) with salmeterol (four studies, 8936 participants), formoterol (one study, 431 participants) and indacaterol (two studies, 2856 participants). All participants were instructed to discontinue anticholinergic or long-acting beta2-agonist bronchodilators during treatment, but could receive inhaled corticosteroids (ICS) at a stable dose. Study duration ranged from 3 to 12 months. We extracted data for 11,223 participants. In general, the treatment groups were well matched at baseline. Overall, the risk of bias across the included RCTs was low. In the analysis of the primary outcomes in this review, a high level of heterogeneity amongst studies meant that we did not pool data for St George's Respiratory Questionnaire quality of life score. Subgroup analyses based on the type of LABA found statistically significant differences among effects on quality of life depending on whether tiotropium was compared with salmeterol, formoterol or indacaterol. Tiotropium reduced the number of participants experiencing one or more exacerbations compared with LABA (odds ratio (OR) 0.86; 95% confidence interval (CI) 0.79 to 0.93). For this outcome, there was no difference seen among the different types of LABA. There was no statistical difference in mortality observed between the treatment groups. For secondary outcomes, tiotropium was associated with a reduction in the number of COPD exacerbations leading to hospitalisation compared with LABA treatment (OR 0.87; 95% 0.77 to 0.99), but not in the overall rate of all-cause hospitalisations. There was no statistically significant difference in forced expiratory volume in one second (FEV1) or symptom score between tiotropium and LABA-treated participants. There was a lower rate of non-fatal serious adverse events recorded with tiotropium compared with LABA (OR 0.88; 95% CI 0.78 to 0.99). The tiotropium group was also associated with a lower rate of study withdrawals (OR 0.89; 95% CI 0.81 to 0.99). We identified six full economic evaluations assessing the cost and cost-effectiveness of tiotropium and salmeterol. The studies were based on an economic model or empirical analysis of clinical data from RCTs. They all looked at maintenance costs and the costs for COPD exacerbations, including respiratory medications and hospitalisations. The setting for the evaluations was primary and secondary care in the UK, Greece, Netherlands, Spain and USA. All the studies estimated tiotropium to be superior to salmeterol based on better clinical outcomes (exacerbations or quality of life) and/or lower total costs. However, the authors of all evaluations reported there was substantial uncertainty around the results. In people with COPD, the evidence is equivocal as to whether or not tiotropium offers greater benefit than LABAs in improving quality of life; however, this is complicated by differences in effect among the LABA types. Tiotropium was more effective than LABAs as a group in preventing COPD exacerbations and disease-related hospitalisations, although there were no statistical differences between groups in overall hospitalisation rates or mortality during the study periods. There were fewer serious adverse events and study withdrawals recorded with tiotropium compared with LABAs. Symptom improvement and changes in lung function were similar between the treatment groups. Given the small number of studies to date, with high levels of heterogeneity among them, one approach may be to give a COPD patient a substantial trial of tiotropium, followed by a LABA (or vice versa), then to continue prescribing the long-acting bronchodilator that the patient prefers. Further studies are needed to compare tiotropium with different LABAs, which are currently ongoing. The available economic evidence indicates that tiotropium may be cost-effective compared with salmeterol in several specific settings, but there is considerable uncertainty around this finding.
Our searches identified over 1700 records, from which we include 24 completed studies (three RCTs, two of which were eligible for our cessation meta-analysis, and 21 cohort studies). Eleven of these studies are new for this version of the review. We identified 27 ongoing studies. Two RCTs compared EC with placebo (non-nicotine) EC, with a combined sample size of 662 participants. One trial included minimal telephone support and one recruited smokers not intending to quit, and both used early EC models with low nicotine content and poor battery life. We judged the RCTs to be at low risk of bias, but under the GRADE system we rated the overall quality of the evidence for our outcomes as ‘low’ or ‘very low’, because of imprecision due to the small number of trials. A ‘low’ grade means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. A ‘very low’ grade means we are very uncertain about the estimate. Participants using an EC were more likely to have abstained from smoking for at least six months compared with participants using placebo EC (RR 2.29, 95% CI 1.05 to 4.96; placebo 4% versus EC 9%; 2 studies; 662 participants. GRADE: low). The one study that compared EC to nicotine patch found no significant difference in six-month abstinence rates, but the confidence intervals do not rule out a clinically important difference (RR 1.26, 95% CI 0.68 to 2.34; 584 participants. GRADE: very low). Of the included studies, none reported serious adverse events considered related to EC use. The most frequently reported AEs were mouth and throat irritation, most commonly dissipating over time. One RCT provided data on the proportion of participants experiencing any adverse events. The proportion of participants in the study arms experiencing adverse events was similar (ECs vs placebo EC: RR 0.97, 95% CI 0.71 to 1.34 (298 participants); ECs vs patch: RR 0.99, 95% CI 0.81 to 1.22 (456 participants)). The second RCT reported no statistically significant difference in the frequency of AEs at three- or 12-month follow-up between the EC and placebo EC groups, and showed that in all groups the frequency of AEs (with the exception of throat irritation) decreased significantly over time. There is evidence from two trials that ECs help smokers to stop smoking in the long term compared with placebo ECs. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated 'low' by GRADE standards. The lack of difference between the effect of ECs compared with nicotine patches found in one trial is uncertain for similar reasons. None of the included studies (short- to mid-term, up to two years) detected serious adverse events considered possibly related to EC use. The most commonly reported adverse effects were irritation of the mouth and throat. The long-term safety of ECs is unknown. In this update, we found a further 15 ongoing RCTs which appear eligible for this review.
We included nine trials with 469 women. A diverse set of medications and regimens were studied in these trials, making the comparisons available for meta-analysis limited. The comparisons draw data from six trials with 383 participants. All trials were relatively small and had several aspects of unclear risk of bias with few of this review's outcomes reported. Due to this, no data from three trials were able to be used despite them meeting inclusion criteria. We carried out four comparisons: isosorbide mononitrate or dinitrate compared with misoprostol; misoprostol compared with placebo; chemical dilation (use of medications) compared with mechanical dilation; and any cervical preparation compared with placebo. None of the included studies reported data on the review's primary outcome: cervical or uterine injury (perforation, laceration, creation of a false passage). No clear difference was shown between isosorbide compounds and misoprostol for the outcome need for manual cervical dilation (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.10 to 5.64; three trials, 150 women; Tau² = 2.11; I² = 69%), however the data were heterogenous. In terms of adverse effects, misoprostol was associated with more vomiting (RR 0.11, 95% CI 0.01 to 0.85; two trials, 120 women), however there were no clear differences between isosorbide compounds and misoprostol in relation to other reported adverse effects (headache, nausea or hypotension). The dosing regimens differed in terms of dose, number of administrations and route of administration in the different trials. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators in a single trial (65 women) that measured difficulty in cervical dilation, excessive bleeding and adverse effects. Misoprostol was shown to be more effective than placebo for cervical ripening (reduced need for manual cervical dilation) (RR 0.14, 95% CI 0.08 to 0.26; one trial, 120 women), and surgical time was reduced when misoprostol was used (mean difference (MD) -3.15, 95% CI -3.59 to -2.70; one trial, 120 women). However, compared to placebo, misoprostol, was associated with more abdominal pain (RR 29.00, 95% CI 1.77 to 475.35; one trial, 120 women), although no clear differences in the risk of other adverse effects (nausea, vomiting, headache or fever) were observed between groups. There was no clear differences between chemical dilation and mechanical dilators for the outcomes: difficulty in cervical dilation, excessive bleeding or adverse effects. Compared with placebo, any cervical preparation reduced the need for manual cervical dilatation (average RR 0.25, 95% CI 0.07 to 0.89; two trials, 168 women; Tau² = 0.67; I² = 81%), and reduced surgical time (MD -2.55, 95% CI -3.67 to -1.43, two trials, 168 women; Tau² = 0.63; I² = 96%). None of the included trials reported on the review's other secondary outcomes, including: injury to bladder or bowel, miscarriage/preterm birth in a subsequent pregnancy, analgesia use after administration of ripening agent but before surgery, or analgesia use after surgery. This review found no evidence to evaluate cervical ripening prior to first trimester surgical evacuation for miscarriage for reducing the rate of cervical or uterine injury, however, this may be because these outcomes are very rare. Cervical preparation was shown to reduce the need for manual cervical dilatation compared with placebo. Misoprostol and isosorbide mononitrate and dinitrate were similarly effective in ripening the cervix, however there was more vomiting with misoprostol. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators. The nine studies included in this review were small and the methodological quality of the trials was mixed, and for the most part, not well-described; thus any conclusions drawn from the data included in this review must be treated with caution. Consequently, large, high-quality trials are required to determine whether the benefits of this treatment outweigh the risks. Further research should be powered to assess the rate of cervical and uterine injury between interventions. Future research should also guide clinicians in deciding whether the benefits of reduced manual cervical dilatation outweigh the risks of adverse effects associated with these agents (nausea, vomiting, headache, fever, diarrhoea and pain). Women's satisfaction and outcomes of future pregnancies should also be assessed.
Seven studies with a total of 578 patients were included in the first comparison: mean percentage of rebleeding in H. pylori eradication therapy group was 2.9%, and in the non-eradication therapy group without subsequent long-term maintenance antisecretory therapy it was 20% (OR 0.17, 95% CI 0.10 to 0.32; there was no statistical evidence of heterogeneity; NNT was 7, 95% CI 5 to 11). Three studies with a total of 470 patients were included in the second comparison: mean percentage of rebleeding in H. pylori eradication therapy group was 1.6%, and in non-eradication therapy group with long-term maintenance antisecretory therapy it was 5.6% (OR 0.24, 95% CI 0.09 to 0.67; heterogeneity was not demonstrated; NNT was 20, 95% CI 12 to 100). Subgroup analyses were carried out to examine the effect of NSAIDS and of excluding H.pylori eradication failures from the analyses. Treatment of H. pylori infection is more effective than antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) in preventing recurrent bleeding from peptic ulcer. All patients with peptic ulcer bleeding should be tested for H. pylori infection, and eradication therapy should be prescribed to H. pylori-positive patients.
We included a total of 27 trials, and 26 trials involving 15,858 women provided usable outcome data for analysis. These trials were conducted in 17 different countries: 13 trials were conducted in high-income settings; 13 trials in middle-income settings; and no studies in low-income settings. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (average RR 1.08, 95% confidence interval (CI) 1.04 to 1.12; 21 trials, 14,369 women; low-quality evidence) and less likely to report negative ratings of or feelings about their childbirth experience (average RR 0.69, 95% CI 0.59 to 0.79; 11 trials, 11,133 women; low-quality evidence) and to use any intrapartum analgesia (average RR 0.90, 95% CI 0.84 to 0.96; 15 trials, 12,433 women). In addition, their labours were shorter (MD -0.69 hours, 95% CI -1.04 to -0.34; 13 trials, 5429 women; low-quality evidence), they were less likely to have a caesarean birth (average RR 0.75, 95% CI 0.64 to 0.88; 24 trials, 15,347 women; low-quality evidence) or instrumental vaginal birth (RR 0.90, 95% CI 0.85 to 0.96; 19 trials, 14,118 women), regional analgesia (average RR 0.93, 95% CI 0.88 to 0.99; 9 trials, 11,444 women), or a baby with a low five-minute Apgar score (RR 0.62, 95% CI 0.46 to 0.85; 14 trials, 12,615 women). Data from two trials for postpartum depression were not combined due to differences in women, hospitals and care providers included; both trials found fewer women developed depressive symptomatology if they had been supported in birth, although this may have been a chance result in one of the studies (low-quality evidence). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, such as admission to special care nursery (average RR 0.97, 95% CI 0.76 to 1.25; 7 trials, 8897 women; low-quality evidence), and exclusive or any breastfeeding at any time point (average RR 1.05, 95% CI 0.96 to 1.16; 4 trials, 5584 women; low-quality evidence). Subgroup analyses suggested that continuous support was most effective at reducing caesarean birth, when the provider was present in a doula role, and in settings in which epidural analgesia was not routinely available. Continuous labour support in settings where women were not permitted to have companions of their choosing with them in labour, was associated with greater likelihood of spontaneous vaginal birth and lower likelihood of a caesarean birth. Subgroup analysis of trials conducted in high-income compared with trials in middle-income countries suggests that continuous labour support offers similar benefits to women and babies for most outcomes, with the exception of caesarean birth, where studies from middle-income countries showed a larger reduction in caesarean birth. No conclusions could be drawn about low-income settings, electronic fetal monitoring, the timing of onset of continuous support or model of support. Risk of bias varied in included studies: no study clearly blinded women and personnel; only one study sufficiently blinded outcome assessors. All other domains were of varying degrees of risk of bias. The quality of evidence was downgraded for lack of blinding in studies and other limitations in study designs, inconsistency, or imprecision of effect estimates. Continuous support during labour may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labour, and decreased caesarean birth, instrumental vaginal birth, use of any analgesia, use of regional analgesia, low five-minute Apgar score and negative feelings about childbirth experiences. We found no evidence of harms of continuous labour support. Subgroup analyses should be interpreted with caution, and considered as exploratory and hypothesis-generating, but evidence suggests continuous support with certain provider characteristics, in settings where epidural analgesia was not routinely available, in settings where women were not permitted to have companions of their choosing in labour, and in middle-income country settings, may have a favourable impact on outcomes such as caesarean birth. Future research on continuous support during labour could focus on longer-term outcomes (breastfeeding, mother-infant interactions, postpartum depression, self-esteem, difficulty mothering) and include more woman-centred outcomes in low-income settings.
Twenty-eight trials, involving almost 17,000 women, contributed data to the review. Overall, women who received a psychosocial or psychological intervention were significantly less likely to develop postpartum depression compared with those receiving standard care (average RR 0.78, 95% confidence interval (CI) 0.66 to 0.93; 20 trials, 14,727 women). Several promising interventions include: (1) the provision of intensive, individualised postpartum home visits provided by public health nurses or midwives (RR 0.56, 95% CI 0.43 to 0.73; two trials, 1262 women); (2) lay (peer)-based telephone support (RR 0.54, 95% CI 0.38 to 0.77; one trial, 612 women); and (3) interpersonal psychotherapy (standardised mean difference -0.27, 95% CI -0.52 to -0.01; five trials, 366 women). Professional- and lay-based interventions were both effective in reducing the risk to develop depressive symptomatology. Individually-based interventions reduced depressive symptomatology at final assessment (RR 0.75, 95% CI 0.61 to 0.92; 14 trials, 12,914 women) as did multiple-contact interventions (RR 0.78, 95% CI 0.66 to 0.93; 16 trials, 11,850 women). Interventions that were initiated in the postpartum period also significantly reduced the risk to develop depressive symptomatology (RR 0.73, 95% CI 0.59 to 0.90; 12 trials, 12,786 women). Identifying mothers 'at-risk' assisted the prevention of postpartum depression (RR 0.66, 95% CI 0.50 to 0.88; eight trials, 1853 women). Overall, psychosocial and psychological interventions significantly reduce the number of women who develop postpartum depression. Promising interventions include the provision of intensive, professionally-based postpartum home visits, telephone-based peer support, and interpersonal psychotherapy.
Eight studies met the inclusion criteria involving 394 participants with AsPD. Data were available from four studies involving 274 participants with AsPD. No study set out to recruit participants solely on the basis of having AsPD, and in only one study was the sample entirely of AsPD participants. Eight different drugs were examined in eight studies. Study quality was relatively poor. Inadequate reporting meant the data available were generally insufficient to allow any independent statistical analysis. The findings are limited to descriptive summaries based on analyses carried out and reported by the trial investigators. All the available data were derived from unreplicated single reports. Only three drugs (nortriptyline, bromocriptine, phenytoin) were effective compared to placebo in terms of improvement in at least one outcome. Nortriptyline was reported in one study as superior for men with alcohol dependency on mean number of drinking days and on alcohol dependence, but not for severity of alcohol misuse or on the patient's or clinician's rating of drinking. In the same study, both nortriptyline and bromocriptine were reported as superior to placebo on anxiety on one scale but not on another. In one study, phenytoin was reported as superior to placebo on the frequency and intensity of aggressive acts in male prisoners with impulsive (but not premeditated) aggression. In the remaining two studies, both amantadine and desipramine were not superior to placebo for adults with opioid and cocaine dependence, and desipramine was not superior to placebo for men with cocaine dependence. The body of evidence summarised in this review is insufficient to allow any conclusion to be drawn about the use of pharmacological interventions in the treatment of antisocial personality disorder.
Thirteen trials with 2197 participants met the inclusion criteria: 11 trials investigated treatment regimens; two investigated prophylaxis regimens. The quality of the trials was variable. For eradicating Bordetella pertussis (B. pertussis) from the nasopharynx, short-term antibiotics (azithromycin for three to five days, or clarithromycin or erythromycin for seven days) were as effective as long-term (erythromycin for 10 to 14 days) (risk ratio (RR) 1.01; 95% confidence interval (CI) 0.98 to 1.04), but had fewer side effects (RR 0.66; 95% CI 0.52 to 0.83). Trimethoprim/sulphamethoxazole for seven days was also effective. Nor were there differences in clinical outcomes or microbiological relapse between short and long-term antibiotics. For preventing infection by treating contacts older than six months of age, antibiotics did not significantly improve clinical symptoms, nor the number of cases developing culture-positive B. pertussis. Side effects were reported with antibiotics and they varied from one antibiotic to another. Although antibiotics were effective in eliminating B. pertussis, they did not alter the subsequent clinical course of the illness. There is insufficient evidence to determine the benefits of prophylactic treatment of pertussis contacts.
Two trials with a total of 210 participants were included. Both trials were at some risk of performance bias. One trial had four intervention groups and the other had three. One trial found that foot orthoses when compared with flat insoles (control group) had better results at six weeks in knee pain (participants with global improvement: risk ratio 1.48, 95% confidence interval 1.11 to 1.99), but not at one year follow-up. Participants in the orthoses group reported significantly more minor adverse effects (e.g. rubbing, blistering) compared with the flat insole group (risk ratio 1.87, 95% confidence intervaI 1.21 to 2.91). Both trials in their comparisons of orthoses plus physiotherapy versus physiotherapy alone found no statistically significant differences between the two intervention groups in knee pain or function. Results for knee pain outcomes did not show significant differences between foot orthoses versus physiotherapy. Although participants in the physiotherapy group had consistently better results for the functional index questionnaire, the clinical relevance of these results is uncertain. While not robust, the available evidence does not reveal any clear advantage of foot orthoses over simple insoles or physiotherapy for patellofemoral pain. While foot orthoses may help relieve knee pain over the short term, the benefit may be marginal. Patients treated with orthoses are more likely to complain of mild adverse effects and discomfort.
Fifty-one studies were included. They used three different models, namely case management, shared care, and interdisciplinary teams. Six additional interventional strategies were used besides these models: (1) patient-held record, (2) telephone follow-up, (3) communication and case discussion between distant healthcare professionals, (4) change in medical record system, (5) care protocols, directives and guidelines, and (6) coordination of assessments and treatment. Based on the median effect size estimates, no significant difference in patient health-related outcomes was found between patients assigned to interventions and those assigned to usual care. A limited number of studies reported psychological health, satisfaction of providers, or process of care measures. However, they could not be regrouped to calculate median effect size estimates because of a high heterogeneity among studies. Results from this Cochrane review do not allow us to conclude on the effectiveness of included interventions to improve continuity of care on patient, healthcare provider or process of care outcomes. Future research should evaluate interventions that target an improvement in continuity as their primary objective and describe these interventions with the categories proposed in this review. Also of importance, continuity measures should be validated with persons with cancer who have been followed in various settings.
Our search identified 8299 articles (excluding duplicates). We examined the titles and abstracts of 1125 articles and the full-text versions of 97 articles. We included seven studies in our review, which reported data from 1491 children; all were conducted in hospital settings. Overall, study quality was moderate. In two studies the presence of chest pain more than doubled the probability of M. pneumoniae. Wheeze was 12% more likely to be absent in children with M. pneumoniae (pooled positive likelihood ratio (LR+) 0.76, 95% CI 0.60 to 0.97; pooled negative likelihood ratio (LR-) 1.12, 95% CI 1.02 to 1.23). Our sensitivity analysis showed that the presence of crepitations was associated with M. pneumoniae, but this finding was of borderline statistical significance (pooled LR+ 1.10, 95% CI 0.99 to 1.23; pooled LR- 0.66, 95% CI 0.46 to 0.96). M. pneumoniae cannot be reliably diagnosed in children and adolescents with community-acquired pneumonia based on clinical symptoms and signs. Although the absence of wheeze is a statistically significant diagnostic indicator, it does not have sufficient diagnostic value to guide empirical macrolide treatment. Data from two studies suggest that the presence of chest pain more than doubles the probability of M. pneumoniae. However, further research is needed to substantiate this finding. More high quality large-scale studies in primary care settings are needed to help develop prediction rules based on epidemiological data as well as clinical and baseline patient characteristics.
Six trials (343 participants) evaluated Eutectic Mixture of Local Anaesthetics (EMLA): lidocaine-prilocaine cream for the pain associated with ulcer debridement. The between-group difference in pain measured on a 100 mm scale was statistically significant in favour of EMLA (MD -20.65, 95% CI -12.19 to -29.11). No significant between-group differences in burning or itching were observed. Two trials (470 participants with venous leg ulcers) evaluated ibuprofen slow-release foam dressings for persistent venous leg ulcer pain. Compared with local best practice, significantly more participants in the ibuprofen dressing group achieved the outcome of >50% of the total maximum pain relief score between day 1 and day 5 than participants in the local best practice group (RR 1.63, 95% CI 1.24 to 2.15). The number needed to treat was 6 (95% CI 4 to 12). In the second trial, compared with an identical non-ibuprofen foam dressing, there was no statistically significant difference in the proportion of participants experiencing slight to complete pain relief on the first evening of treatment.Limited data were available to assess healing rates or adverse events. There is some evidence to suggest that ibuprofen dressings may offer pain relief to people with painful venous leg ulcers. EMLA (5%) appears to provide effective pain relief during the debridement of venous leg ulcers. Further research should consider standardised pain assessment methods and assess both the effect on ulcer healing and the impact of long term use of these treatments.
We reran the searches and included one new study (100 participants) in this updated review. In total, we included 11 studies with 829 participants, although most analyses were based on data from fewer participants and evidence of low quality. We noted substantial heterogeneity in the included trials. Thus, our results should be read with caution. It was not possible to combine trials for the primary outcome (LOER), but individual trials reported faster induction times (typically 24 to 82 seconds faster, 41 seconds (31.37 to 50.62)) with high initial concentration sevoflurane (six studies, 443 participants, low-quality evidence). Apnoea appeared to be more common in the high initial concentration sevoflurane group (risk ratio (RR) 3.14, 95% confidence interval (CI) 1.72 to 5.7, two studies, 160 participants, low-quality evidence). We found no evidence of differences between the two groups in the incidence of cough (odds ratio (OR) 1.23, 95% CI 0.53 to 2.81, eight studies, 589 participants, low-quality evidence), laryngospasm (OR 1.59, 95% CI 0.16 to 15.9, seven studies, 588 participants, low-quality evidence), breath holding (OR 1.16, 95% CI 0.47 to 2.83, five studies, 389 participants, low-quality evidence), patient movement (RR 1.14, 95% CI 0.69 to 1.89, five studies, 445 participants, low-quality evidence) or bradycardia (OR 0.8, 95% CI 0.22 to 2.88, three studies, 199 participants, low-quality evidence), and the overall incidence of complications was low. A high initial concentration sevoflurane technique probably offers more rapid induction of anaesthesia and a similar rate of complications, except for apnoea, which may be more common with a high initial concentration. However, this conclusion is not definitive because the included studies provided evidence of low quality.
Five RCTs met our inclusion criteria. Three trials aimed to improve adherence to a specific method of contraception amongst existing or new contraception users by comparing automated text message interventions versus standard care. Two trials aimed to improve both uptake and adherence, not limited to one method, in both users and non-users of contraception. No trials were at low risk of bias in all areas assessed. One trial in the USA reported improved self reported oral contraceptive (OC) continuation at six months from an intervention comprising a range of uni-directional and interactive text messages (RR 1.19, 95% CI 1.05 to 1.35). One trial in Cambodia reported increased self reported use of effective contraception at four months post abortion from an intervention comprising automated interactive voice messages and phone counsellor support (RR 1.39, 95% CI 1.17 to 1.66). One feasibility trial in the USA reported a lower mean number of days between scheduled and completed attendance for the first but not subsequent Depo-Provera appointments using clinic records from an intervention comprising reminders and healthy self management text messages (mean difference (MD) -8.60 days, 95% CI -16.74 to -0.46). Simple text message OC reminders had no effect on missed pills as assessed by electronic medication monitoring in a small trial in the USA (MD 0.5 missed pills, 95% CI -1.08 to 2.08). No effect on self reported contraception use was noted amongst isotretinoin users from an intervention that provided health information via two uni-directional text messages and mail (RR 1.26, 95% CI 0.84 to 1.89). One trial assessed potential adverse effects of the intervention and reported no evidence of road traffic accidents or domestic abuse. Our review provides limited evidence that interventions delivered by mobile phone can improve contraception use. Whilst evidence suggests that a series of interactive voice messages and counsellor support can improve post-abortion contraception, and that a mixture of uni-directional and interactive daily educational text messages can improve OC adherence, the cost-effectiveness and long-term effects of these interventions remain unknown. Further high-quality trials are required to robustly establish the effects of interventions delivered by mobile phone to improve contraception use.
Meta-analysis of the 5 cross-over studies found a reduction in SBP of 20.09 mmHg (95%CI:16.58-23.06,p<0.00001) and a 6.75 mmHg (95%CI:4.8-8.69,p<0.00001) reduction in DBP. These results were statistically significant and there was no evidence of heterogeneity between the studies. There may be a dose response effect with spironolactone up to 50 mg/day, but the confidence intervals around the mean end-of-study blood pressure for doses ranging 25-500 mg/day all overlapped. In other words, it appears that doses >50mg/day do not produce further reductions in either SBP or DBP. One cross-over study found that spironolactone 25 mg/day did not statistically significantly change SBP or DBP compared to placebo, SBP: -9.9 (95%CI:-21.15,1.35); DBP -2.34 (95%CI:-7.92,3.06). From the limited available evidence, spironolactone appears to lower blood pressure compared to placebo to a similar degree in patients with primary (essential) hypertension when doses of 100-500 mg/day are given. A dose of 25 mg/day did not statistically significantly reduce systolic or diastolic blood pressure, compared to placebo. Given the lack of a dose-response, coupled with a possible increased risk in adverse events with higher doses, doses of 25 to 100 mg/day are reasonable. There is no evidence of the effect of spironolactone on clinical outcomes in hypertensive patients.
The review included 26 cluster-randomised/quasi-randomised trials, covering a wide range of interventional packages, including two subsets from three trials. Assessment of risk of bias in these studies suggests concerns regarding insufficient information on sequence generation and regarding failure to adequately address incomplete outcome data, particularly from randomised controlled trials. We incorporated data from these trials using generic inverse variance method in which logarithms of risk ratio (RR) estimates were used along with the standard error of the logarithms of RR estimates. Our review showed a possible effect in terms of a reduction in maternal mortality (RR 0.80; 95% confidence interval (CI) 0.64 to 1.00, random-effects (11 studies, n = 167,311; random-effects, Tau² = 0.03, I² 20%). However, significant reduction was observed in maternal morbidity (average RR 0.75; 95% CI 0.61 to 0.92; four studies, n = 138,290; random-effects, Tau² = 0.02, I² = 28%); neonatal mortality (average RR 0.75; 95% CI 0.67 to 0.83; 21 studies, n = 302,646; random-effects, Tau² = 0.06, I² = 85%) including both early and late mortality; stillbirths (average RR 0.81; 95% CI 0.73 to 0.91; 15 studies, n = 201,181; random-effects, Tau² = 0.03, I² = 66%); and perinatal mortality (average RR 0.78; 95% CI 0.70 to 0.86; 17 studies, n = 282,327; random-effects Tau² = 0.04, I² = 88%) as a consequence of implementation of community-based interventional care packages. Community-based intervention packages also increased the uptake of tetanus immunisation by 5% (average RR 1.05; 95% CI 1.02 to 1.09; seven studies, n = 71,622; random-effects Tau² = 0.00, I² = 52%); use of clean delivery kits by 82% (average RR 1.82; 95% CI 1.10 to 3.02; four studies, n = 54,254; random-effects, Tau² = 0.23, I² = 90%); rates of institutional deliveries by 20% (average RR 1.20; 95% CI 1.04 to 1.39; 14 studies, n = 147,890; random-effects, Tau² = 0.05, I² = 80%); rates of early breastfeeding by 93% (average RR 1.93; 95% CI 1.55 to 2.39; 11 studies, n = 72,464; random-effects, Tau² = 0.14, I² = 98%), and healthcare seeking for neonatal morbidities by 42% (average RR 1.42; 95% CI 1.14 to 1.77, nine studies, n = 66,935, random-effects, Tau² = 0.09, I² = 92%). The review also showed a possible effect on increasing the uptake of iron/folic acid supplementation during pregnancy (average RR 1.47; 95% CI 0.99 to 2.17; six studies, n = 71,622; random-effects, Tau² = 0.26; I² = 99%). It has no impact on improving referrals for maternal morbidities, healthcare seeking for maternal morbidities, iron/folate supplementation, attendance of skilled birth attendance on delivery, and other neonatal care-related outcomes. We did not find studies that reported the impact of community-based intervention package on improving exclusive breastfeeding rates at six months of age. We assessed our primary outcomes for publication bias and observed slight asymmetry on the funnel plot for maternal mortality. Our review offers encouraging evidence that community-based intervention packages reduce morbidity for women, mortality and morbidity for babies, and improves care-related outcomes particularly in low- and middle-income countries. It has highlighted the value of integrating maternal and newborn care in community settings through a range of interventions, which can be packaged effectively for delivery through a range of community health workers and health promotion groups. While the importance of skilled delivery and facility-based services for maternal and newborn care cannot be denied, there is sufficient evidence to scale up community-based care through packages which can be delivered by a range of community-based workers.
We found no new studies. This updated review therefore includes four studies with 278 participants. Most analyses were based on data from few participants and low-quality evidence, so our results should be interpreted with caution. Deliberate hypotension with propofol did not decrease TBL (millilitres) when compared with inhalation anaesthetics in either children (1 study; 70 participants; very low-quality evidence), or adults (1 study; 88 participants; moderate-quality evidence). Propofol improved the quality of the surgical field by less than one category on a scale from 0 (no bleeding) to 5 (severe bleeding) (mean difference -0.64, 95% CI -0.91 to -0.37; 4 studies; 277 participants; low-quality evidence), but no difference in operation time was reported (3 studies; 214 participants; low-quality evidence). Failure to lower blood pressure to target was less common in the propofol group (risk ratio of failure with propofol 0.24, 95% CI 0.09 to 0.66; 1 study; 88 participants; moderate-quality evidence). Using propofol to achieve deliberate hypotension probably improves the surgical field, but the effect is small. Deliberate hypotension with propofol did not decrease TBL and the operation time. However, due to the very low quality of the evidence, this conclusion is not definitive. Randomized controlled trials with good-quality methodology and large sample size are required to investigate the effectiveness of deliberate hypotension with propofol for FESS.
We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a non-offending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged 'low risk of bias' with regards to sequence generation and only one study was judged 'low risk of bias' in relation to allocation concealment. All studies were judged 'high risk of bias' in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited. Depression, post-traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate' at best. Meta-analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post-traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2 = 0%; P value for heterogeneity = 0.84). No study reported adverse effects. The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.
Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias. We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo. Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference. When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. The identified studies comprehensively address the objectives of the present review. Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants. The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review. Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes. Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.
We found 12 eligible studies (1149 participants). In four studies, renal denervation was compared to sham procedure; one study compared a proximal ablation to a complete renal artery denervation; in the remaining, renal denervation was tested against standard or intensified antihypertensive therapy. None of the included trials was designed to look at hard clinical end points as primary outcomes. When compared to control, there was low quality evidence that renal denervation did not reduce the risk of myocardial infarction (4 studies, 742 participants; RR 1.31, 95% CI 0.45 to 3.84), ischaemic stroke (4 studies, 823 participants; RR 1.15, 95% CI 0.36 to 3.72), or unstable angina (2 studies, 201 participants; RR 0.63, 95% CI 0.08 to 5.06), and moderate quality evidence that it had no effect on 24-hour ambulatory blood pressure monitoring (ABPM) systolic BP (5 studies, 797 participants; MD 0.28 mmHg, 95% CI -3.74 to 4.29), diastolic BP (4 studies, 756 participants; MD 0.93 mmHg, 95% CI -4.50 to 6.36), office measured systolic BP (6 studies, 886 participants; MD -4.08 mmHg, 95% CI -15.26 to 7.11), or diastolic BP (5 studies, 845 participants; MD -1.30 mmHg, 95% CI -7.30 to 4.69). Furthermore, low quality evidence suggested that this procedure produced no effect on either serum creatinine (3 studies, 736 participants, MD 0.01 mg/dL; 95% CI -0.12 to 0.14), estimated glomerular filtration rate (eGFR), or creatinine clearance (4 studies, 837 participants; MD -2.09 mL/min, 95% CI -8.12 to 3.95). Based on low-quality evidence, renal denervation significantly increased bradycardia episodes compared to control (3 studies, 220 participants; RR 6.63, 95% CI 1.19 to 36.84), while the risk of other adverse events was comparable or not assessable. Data were sparse or absent for all cause mortality, hospitalisation, fatal cardiovascular events, quality of life, atrial fibrillation episodes, left ventricular hypertrophy, sleep apnoea severity, need for renal replacement therapy, and metabolic profile. The quality of the evidence was low for cardiovascular outcomes and adverse events and moderate for lack of effect on blood pressure and renal function. In patients with resistant hypertension, there is low quality evidence that renal denervation does not change major cardiovascular events, and renal function. There was moderate quality evidence that it does not change blood pressure and and low quality evidence that it caused an increaseof bradycardia episodes. Future trials measuring patient-centred instead of surrogate outcomes, with longer follow-up periods, larger sample size and more standardized procedural methods are necessary to clarify the utility of this procedure in this population.
Of the 1233 patients enrolled in nine identified trials, 622 were treated with staples and 611 with manual suture. The following main results were obtained.  a) Mortality, result based on 901 patients: RD -0.6%, 95% CI -2.8% to +1.6%.  b) Overall dehiscence, result based on 1233 patients: RD 0.2%, 95% CI -5.0% to +5.3%.  c) Clinical anastomotic dehiscence, result based on 1233 patients: RD -1.4%, 95% CI -5.2 to +2.3%.  d) Radiological anastomotic dehiscence, result based on 825 patients: RD 1.2%, 95% CI -4.8% to +7.3%.  e) Stricture, result based on 1042 patients: RD 4.6%, 95% CI 1.2% to 8.1%; NNT 17, 95% CI 12 to 31.  f) Anastomotic haemorrhage, result based on 662 patients: RD 2.7%, 95% CI -0.1% to +5.5%.  g) Reoperation, result based on 544 patients: RD 3.9%, 95% CI 0.3% to 7.4%.  h) Wound infection, result based on 567 patients: RD 1.0%, 95% CI -2.2% to +4.3%.  i) Anastomosis duration, result based on one study (159 patients): WMD -7.6 minutes, 95% CI -12.9 to -2.2 minutes.  j) Hospital stay, result based on one study (159 patients): WMD 2.0 days, 95% CI -3.27 to +7.2 days. The evidence found was insufficient to demonstrate any superiority of stapled over handsewn techniques in colorectal anastomosis surgery, regardless of the level of anastomosis. There were no randomised clinical trials comparing these two types of anastomosis in elective conditions in the last decade. The relevance of this research question has possibly lost its strength where elective surgery is concerned. However, in risk situations, such as emergency surgery, trauma and inflammatory bowel disease, new clinical trials are needed.
We included five studies (446 participants) in this review. Meta analysis of three studies comparing hydrogel dressings with basic wound contract dressings found significantly greater healing with hydrogel: risk ratio (RR) 1.80, 95% confidence interval (CI) 1.27 to 2.56. The three pooled studies had different follow-up times (12 weeks, 16 weeks and 20 weeks) and also evaluated ulcers of different severities (grade 3 and 4; grade 2 and grade unspecified). One study compared a hydrogel dressing with larval therapy and found no statistically significant difference in the number of ulcers healed and another found no statistically significant difference in healing between hydrogel and platelet-derived growth factor. There was also no statistically significant difference in number of healed ulcers between two different brands of hydrogel dressing. All included studies were small and at unclear risk of bias and there was some clinical heterogeneity with studies including different ulcer grades. No included studies compared hydrogel with other advanced wound dressings. There is some evidence to suggest that hydrogel dressings are more effective in healing (lower grade) diabetic foot ulcers than basic wound contact dressings however this finding is uncertain due to risk of bias in the original studies. There is currently no research evidence to suggest that hydrogel is more effective than larval therapy or platelet-derived growth factors in healing diabetic foot ulcers, nor that one brand of hydrogel is more effective than another in ulcer healing. No RCTs comparing hydrogel dressings with other advanced dressing types were found.
We included 20 studies of people with suspected rotator cuff tears (1147 shoulders), of which six evaluated MRI and US (252 shoulders), or MRA and US (127 shoulders) in the same people. Many studies had design flaws, with the potential for bias, thus limiting the reliability of their findings. Overall, the methodological quality of the studies was judged to be low or unclear. For each test, we observed considerable heterogeneity in study results, especially between studies that evaluated US for the detection of full thickness tears and studies that evaluated MRA for the detection of partial thickness tears. The criteria for a positive diagnostic test (index tests and reference standard) varied between studies. Meta-analyses were not possible for studies that assessed MRA for detection of any rotator cuff tears or partial thickness tears. We found no statistically significant differences in sensitivity or specificity between MRI and US for detecting any rotator cuff tears (P = 0.13), or for detecting partial thickness tears (P = 1.0). Similarly, for the comparison between MRI, MRA and US for detecting full thickness tears, there was no statistically significant difference in diagnostic performance (P = 0.7). For any rotator cuff tears, the summary sensitivity and specificity were 98% (95% CI 92% to 99%) and 79% (95% CI 68% to 87%) respectively for MRI (6 studies, 347 shoulders), and 91% (95% CI 83% to 95%) and 85% (95% CI 74% to 92%) respectively for US (13 studies, 854 shoulders). For full thickness tears, the summary sensitivity and specificity were 94% (95% CI 85% to 98%) and 93% (95% CI 83% to 97%) respectively for MRI (7 studies, 368 shoulders); 94% (95% CI 80% to 98%) and 92% (95% CI 83% to 97%) respectively for MRA (3 studies, 183 shoulders); and 92% (95% CI 82% to 96%) and 93% (95% CI 81% to 97%) respectively for US (10 studies, 729 shoulders). Because few studies were direct head-to-head comparisons, we could not perform meta-analyses restricted to these studies. The test comparisons for each of the three classifications of the target condition were therefore based on indirect comparisons which may be prone to bias due to confounding. MRI, MRA and US have good diagnostic accuracy and any of these tests could equally be used for detection of full thickness tears in people with shoulder pain for whom surgery is being considered. The diagnostic performance of MRI and US may be similar for detection of any rotator cuff tears. However, both MRI and US may have poor sensitivity for detecting partial thickness tears, and the sensitivity of US may be much lower than that of MRI. The strength of evidence for all test comparisons is limited because most studies were small, heterogeneous and methodologically flawed, and there were few comparative studies. Well designed studies that directly compare MRI, MRA and US for detection of rotator cuff tears are needed.
Ten included studies (11 publications) enrolled 480 participants with trigeminal neuralgia, diabetic neuropathy, and post stroke pain. Nine studies used a cross-over design, and one a parallel group design. Most of the studies were of short duration, lasting four weeks or less. No study provided first or second tier evidence for an efficacy outcome. Using third tier evidence, carbamazepine generally provided better pain relief than placebo in the three conditions studied, with some indication of pain improvement over mainly the short term, but with poorly defined outcomes, incomplete reporting, and in small numbers of participants. There were too few data in studies comparing carbamazepine with active comparators to draw any conclusions. In four studies 65% (113/173) of participants experienced at least one adverse event with carbamazepine, and 27% (47/173) with placebo; for every five participants treated, two experienced an adverse event who would not have done so with placebo. In eight studies 3% (8/268) of participants withdrew due to adverse events with carbamazepine, and none (0/255) with placebo. Serious adverse events were not reported consistently; rashes were associated with carbamazepine. Four deaths occurred in patients on carbamazepine, with no obvious drug association. Carbamazepine is probably effective in some people with chronic neuropathic pain, but with caveats. No trial was longer than four weeks, had good reporting quality, nor used outcomes equivalent to substantial clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.
We included eight randomised controlled trials with 1699 participants across three comparisons. This abstract focuses on the primary outcomes of this review only. Scheduled phosphodiesterase type 5 inhibitors (PDE5I) versus placebo or no treatment Scheduled PDE5I may have little or no effect on short-term (up to 12 months) self-reported potency (risk ratio (RR) 1.13, 95% confidence interval (CI) 0.91 to1.41; very low quality evidence), which corresponds to 47 more men with self-reported potency per 1000 (95% CI 33 fewer to 149 more) and short-term erectile function as assessed by a validated instrument (RR 1.11, 95% CI 0.80 to 1.55; very low quality evidence), which corresponds to 28 more men per 1000 (95% CI 50 fewer to 138 more), but we are very uncertain of both of these findings. Scheduled PDE5I may result in fewer serious adverse events compared to placebo (RR 0.32, 95% CI 0.11 to 0.94; low quality evidence), though this does not appear biologically plausible and may represent a chance finding. We are also very uncertain of this finding. We found no long-term (longer than 12 months) data for any of the three primary outcomes. Scheduled PDE5I versus on-demand PDE5I Daily PDE5I appears to result in little to no difference in both short-term and long-term (greater than 12 months) self-reported potency (short term: RR 0.97, 95% CI 0.62 to 1.53; long term: RR 1.00, 95% CI 0.60 to 1.67; both very low quality evidence); this corresponds to nine fewer men with self-reported short-term potency per 1000 (95% CI 119 fewer to 166 more) and zero fewer men with self-reported long-term potency per 1000 (95% CI 153 fewer to 257 more). We are very uncertain of these findings. Daily PDE5I appears to result in little to no difference in short-term and long-term erectile function (short term: RR 1.00, 95% CI 0.65 to 1.55; long term; RR 0.74, 95% CI 0.48 to 1.14; both very-low quality evidence), which corresponds to zero men with short-term erectile dysfunction per 1000 (95% CI 80 fewer to 125 more) and 119 fewer men with long-term erectile dysfunction per 1000 (95% CI 239 fewer to 64 more). We are very uncertain of these findings. Scheduled PDE5I may result in little or no effects on short-term adverse events (RR 0.69 95% CI 0.12 to 4.04; very low quality evidence), which corresponds to seven fewer men with short-term serious adverse events (95% CI 18 fewer to 64 more), but we are very uncertain of these findings. We found no long-term data for serious adverse events. Scheduled PDE5I versus scheduled intraurethral prostaglandin E1 At short-term follow-up, daily PDE5I may result in little or no effect on self-reported potency (RR 1.10, 95% CI 0.79, to 1.52; very low quality evidence), which corresponds to 46 more men per 1000 (95% CI 97 fewer to 241 more). Daily PDE5I may result in a small improvement of erectile function (RR 1.64, 95% CI 0.84 to 3.20; very low quality evidence), which corresponds to 92 more men per 1000 (95% CI 23 fewer to 318 more) but we are very uncertain of both these findings. We found no long-term (longer than 12 months) data for any of the three primary outcomes. We found no evidence for any other comparisons and were unable to perform any of the preplanned subgroup analyses based on nerve-sparing approach, age or baseline erectile function. Based on mostly very-low and some low-quality evidence, penile rehabilitation strategies consisting of scheduled PDE5I use following radical prostatectomy may not promote self-reported potency and erectile function any more than on demand use.
We included four studies with 149 randomized participants. We identified two studies awaiting classification for which we were unable to assess eligibility and one ongoing study. Participants differed in severity of illness as assessed by APACHE II scores in three studies and further differences existed between comparisons and methods. One study compared propofol versus no agent, one study compared different doses of propofol and two studies compared propofol versus a benzodiazepine (flunitrazepam, one study; midazolam, one study). All studies reported randomization and allocation concealment inadequately. We judged all studies to have high risk of performance bias from personnel who were unblinded. We noted that some study authors had blinded study outcome assessors and participants for relevant outcomes. It was not appropriate to combine data owing to high levels of methodological heterogeneity. One study comparing propofol with no agent (13 participants) measured quantity and quality of sleep using polysomnography; study authors reported no evidence of a difference in duration of sleep or sleep efficiency, and reported disruption to usual REM (rapid eye movement sleep) with propofol. One study comparing different doses of propofol (30 participants) measured quantity and quality of sleep by personnel using the Ramsay Sedation Scale; study authors reported that more participants who were given a higher dose of propofol had a successful diurnal rhythm, and achieved a greater sedation rhythmicity. Two studies comparing propofol with a different agent (106 participants) measured quantity and quality of sleep using the Pittsburgh Sleep Diary and the Hospital Anxiety and Depression Scale; one study reported fewer awakenings of reduced duration with propofol, and similar total sleep time between groups, and one study reported no evidence of a difference in sleep quality. One study comparing propofol with another agent (66 participants) measured quantity and quality of sleep with the Bispectral Index and reported longer time in deep sleep, with fewer arousals. One study comparing propofol with another agent (40 participants) reported higher levels of anxiety and depression in both groups, and no evidence of a difference when participants were given propofol. No studies reported adverse events. We used the GRADE approach to downgrade the certainty of the evidence for each outcome to very low. We identified sparse data with few participants, and methodological differences in study designs and comparative agents introduced inconsistency, and we noted that measurement tools were imprecise or not valid for purpose. We found insufficient evidence to determine whether administration of propofol would improve the quality and quantity of sleep in adults in the ICU. We noted differences in study designs, methodology, comparative agents and illness severity amongst study participants. We did not pool data and we used the GRADE approach to downgrade the certainty of our evidence to very low.
Seven pralidoxime RCTs were found. Three RCTs including 366 patients studied pralidoxime vs placebo and four RCTs including 479 patients compared two or more different doses. These trials found quite disparate results with treatment effects ranging from benefit to harm. However, many studies did not take into account several issues important for outcomes. In particular, baseline characteristics were not balanced, oxime doses varied widely, there were substantial delays to treatment, and the type of organophosphate was not taken into account. Only one RCT compared the World Health Organization (WHO) recommended doses with placebo. This trial showed no clinical benefits and a trend towards harm in all sub-groups, despite clear evidence that these doses reactivated acetylcholinesterase in the blood. Current evidence is insufficient to indicate whether oximes are harmful or beneficial. The WHO recommended regimen (30 mg/kg pralidoxime chloride bolus followed by 8 mg/kg/hr infusion) is not supported. Further RCTs are required to examine other strategies and regimens. There are many theoretical and practical reasons why oximes may not be useful, particularly for late presentations of dimethyl OP and those with a large excess of OP that simply re-inhibits reactivated enzymes. Future studies should screen for patient sub-groups that may benefit and may need flexible dosing strategies as clinical effectiveness and doses may depend on the type of OP.
Ten trials involving 617 patients satisfied the inclusion criteria. The interventions included low central venous pressure (CVP), autologous blood donation, haemodilution, haemodilution with controlled hypotension, and hypoventilation. Only one or two trials were included under most comparisons. All trials had a high risk of bias. There was no significant difference in the peri-operative mortality in any of the comparisons: low CVP versus no intervention (3 trials, 0/88 (0%) patients in the low CVP group versus 1/89 (1.1%) patients in the no intervention group); autologous blood donation versus no intervention (1 trial, 0/40 (0%) versus 0/39 (0%)); haemodilution versus no intervention (2 trials, 1/73 (1.4%) versus 3/77 (3.9%) in one of these trials); haemodilution with controlled hypotension versus no intervention (1 trial, 0/10 (0%) versus 0/10 (0%)); haemodilution with bovine haemoglobin (HBOC-201) versus haemodilution with hydroxy ethyl starch (HES) (1 trial, 1/6 (16.7%) versus 0/6 (0%)); hypoventilation versus no intervention (1 trial, 0/40 (0%) versus 0/39 (0%)). None of the trials reported long-term survival or quality of life. The risk ratio of requiring allogeneic blood transfusion was significantly lower in the haemodilution versus no intervention groups (3 trials, 16/115 (weighted proportion = 14.2%) versus 41/118 (34.7%), RR 0.41 (95% CI 0.25 to 0.66), P = 0.0003); and for haemodilution with controlled hypotension versus no intervention (1 trial, 0/10 (0%) versus 10/10 (100%), P < 0.0001). There were no significant differences in the allogeneic transfusion requirements in the other comparisons which reported this outcome, such as low CVP versus no intervention, autologous blood donation versus control, and hypoventilation versus no intervention. None of the interventions seemed to decrease peri-operative morbidity or offer any long-term survival benefit. Haemodilution shows promise in the reduction of blood transfusion requirements in liver resection surgery. However, there is a high risk of type I (erroneously concluding that an intervention is beneficial when it is actually not beneficial) and type II errors (erroneously concluding that an intervention is not beneficial when it is actually beneficial) because of the few trials included, the small sample size in each trial, and the high risk of bias in the trials. Further randomised clinical trials with low risk of bias and random errors that assess clinically important outcomes such as peri-operative mortality are necessary to assess any cardiopulmonary interventions aimed at decreasing blood loss and blood transfusion requirements in patients undergoing liver resections. Trials need to be designed to assess the effect of a combination of different interventions in liver resections.
Twelve trials involving 1283 participants wereincluded; 1226 participants were used in the analysis (724 in the early refeeding group and 502 in the late refeeding group). Nine trials described their allocation sequence, but only two used concealed allocation. One trial reported single-blinding but did not clearly identify the person who was blinded. Early refeeding meant intake during or immediately after start of rehydration, while late refeeding meant intake only 20 hours to 48 hours after start of rehydration. Significant heterogeneity was noted in the data for the duration of diarrhoea. There was no significant difference between the two refeeding groups in the number of participants who needed unscheduled intravenous fluids (six trials with 813 participants), who experienced episodes of vomiting (five trials with 466 participants), and who developed persistent diarrhoea (four trials with 522 participants). The mean length of hospital stay was also similar (two trials with 246 participants). There was no evidence that early refeeding increases the risk of unscheduled intravenous fluid use, episodes of vomiting, and development of persistent diarrhoea. No conclusion could be made regarding the duration of diarrhoea.
We included three small RCTs enrolling 79 participants. Two trials did not use a placebo in the control arms and the third trial used air placebo. Two included studies reported no mortality. We judged all three of the included studies to be at low risk or unclear risk across all risk of bias categories; we did not judge any of the studies to be at high risk of bias in any category. Our pooled analysis of the three trials revealed that duration of mechanical ventilation was not significantly different between the groups (mean difference (MD) -63.04, 95% confidence interval (CI) -130.43 to 4.35 hours) but duration of intensive care unit (ICU) stay was less in the surfactant group compared to the control group: MD -3.31, 95% CI -6.38 to -0.25 days. After excluding one trial which produced significant heterogeneity, the duration of mechanical ventilation and duration of ICU stay were significantly lower in the surfactant group compared to the control group: MD -28.99, 95% CI -40.10 to -17.87 hours; and MD -1.81, 95% CI -2.42 to -1.19 days, respectively. Use of surfactant had favourable effects on oxygenation and CO2 elimination. No adverse effects and no complications were observed in any of the three included studies. The level of evidence for duration of mechanical ventilation, duration of intensive care unit stay, oxygenation parameters, and carbon dioxide parameters was of moderate quality. Use of surfactant had favourable effects on duration of mechanical ventilation, duration of ICU stay, oxygenation, and CO2 elimination. However, the studies are few and small (n = 79) so available evidence is insufficient to establish the effectiveness of surfactant therapy for bronchiolitis in critically ill infants who require mechanical ventilation. There is a need for larger trials with adequate power and a cost-effectiveness analysis to evaluate the effectiveness of exogenous surfactant therapy for infants with bronchiolitis who require intensive care management.
A total of 16 studies were included. All studies reported on TAUS and EUS as separate tests and not as a combination of tests. All studies were at high or unclear risk of bias, ten studies had high applicability concerns in participant selection (because of inappropriate participant exclusions) or reference standards (because of lack of follow-up for non-operated polyps), and three studies had unclear applicability concerns in participant selection (because of high prevalence of gallbladder polyps) or index tests (because of lack of details on ultrasound equipment and performance). A meta-analysis directly comparing results of TAUS and EUS in the same population could not be performed because only limited studies executed both tests in the same participants. Therefore, the results below were obtained only from indirect test comparisons. There was significant heterogeneity amongst all comparisons (target conditions) on TAUS and amongst studies on EUS for differentiating true and pseudo polyps. Detection of gallbladder polyps: Six studies (16,260 participants) used TAUS. We found no studies on EUS. The summary sensitivity and specificity of TAUS for the detection of gallbladder polyps was 0.84 (95% CI 0.59 to 0.95) and 0.96 (95% CI 0.92 to 0.98), respectively. In a cohort of 1000 people, with a 6.4% prevalence of gallbladder polyps, this would result in 37 overdiagnosed and seven missed gallbladder polyps. Differentiation between true polyp and pseudo gallbladder polyp: Six studies (1078 participants) used TAUS; the summary sensitivity was 0.68 (95% CI 0.44 to 0.85) and the summary specificity was 0.79 (95% CI 0.57 to 0.91). Three studies (209 participants) used EUS; the summary sensitivity was 0.85 (95% CI 0.46 to 0.97) and the summary specificity was 0.90 (95% CI 0.78 to 0.96). In a cohort of 1000 participants with gallbladder polyps, with 10% having true polyps, this would result in 189 overdiagnosed and 32 missed true polyps by TAUS, and 90 overdiagnosed and 15 missed true polyps by EUS. There was no evidence of a difference between the diagnostic accuracy of TAUS and EUS (relative sensitivity 1.06, P = 0.70, relative specificity 1.15, P = 0.12). Differentiation between dysplastic polyps/carcinomas and adenomas/pseudo polyps of the gallbladder: Four studies (1,009 participants) used TAUS; the summary sensitivity was 0.79 (95% CI 0.62 to 0.90) and the summary specificity was 0.89 (95% CI 0.68 to 0.97). Three studies (351 participants) used EUS; the summary sensitivity was 0.86 (95% CI 0.76 to 0.92) and the summary specificity was 0.92 (95% CI 0.85 to 0.95). In a cohort of 1000 participants with gallbladder polyps, with 5% having a dysplastic polyp/carcinoma, this would result in 105 overdiagnosed and 11 missed dysplastic polyps/carcinomas by TAUS and 76 overdiagnosed and seven missed dysplastic polyps/carcinomas by EUS. There was no evidence of a difference between the diagnostic accuracy of TAUS and EUS (log likelihood test P = 0.74). Although TAUS seems quite good at discriminating between gallbladder polyps and no polyps, it is less accurate in detecting whether the polyp is a true or pseudo polyp and dysplastic polyp/carcinoma or adenoma/pseudo polyp. In practice, this would lead to both unnecessary surgeries for pseudo polyps and missed cases of true polyps, dysplastic polyps, and carcinomas. There was insufficient evidence that EUS is better compared to TAUS in differentiating between true and pseudo polyps and between dysplastic polyps/carcinomas and adenomas/pseudo polyps. The conclusions are based on heterogeneous studies with unclear criteria for diagnosis of the target conditions and studies at high or unclear risk of bias. Therefore, results should be interpreted with caution. Further studies of high methodological quality, with clearly stated criteria for diagnosis of gallbladder polyps, true polyps, and dysplastic polyps/carcinomas are needed to accurately determine diagnostic accuracy of EUS and TAUS.
Fifty-three studies with a total of more than 25,000 participants met the inclusion criteria. A large proportion of studies recruited people in healthcare settings or with specific health needs. Most studies provided NRT. Behavioural support was typically provided by specialists in cessation counselling, who offered between four and eight contact sessions. The planned maximum duration of contact was typically more than 30 minutes but less than 300 minutes. Overall, studies were at low or unclear risk of bias, and findings were not sensitive to the exclusion of any of the six studies rated at high risk of bias in one domain. One large study (the Lung Health Study) contributed heterogeneity due to a substantially larger treatment effect than seen in other studies (RR 3.88, 95% CI 3.35 to 4.50). Since this study used a particularly intensive intervention which included extended availability of nicotine gum, multiple group sessions and long term maintenance and recycling contacts, the results may not be comparable with the interventions used in other studies, and hence it was not pooled in other analyses. Based on the remaining 52 studies (19,488 participants) there was high quality evidence (using GRADE) for a benefit of combined pharmacotherapy and behavioural treatment compared to usual care, brief advice or less intensive behavioural support (RR 1.83, 95% CI 1.68 to 1.98) with moderate statistical heterogeneity (I² = 36%). The pooled estimate for 43 trials that recruited participants in healthcare settings (RR 1.97, 95% CI 1.79 to 2.18) was higher than for eight trials with community-based recruitment (RR 1.53, 95% CI 1.33 to 1.76). Compared to the first version of the review, previous weak evidence of differences in other subgroup analyses has disappeared. We did not detect differences between subgroups defined by motivation to quit, treatment provider, number or duration of support sessions, or take-up of treatment. Interventions that combine pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. Updating this review with an additional 12 studies (5,000 participants) did not materially change the effect estimate. Although trials differed in the details of their populations and interventions, we did not detect any factors that modified treatment effects apart from the recruitment setting. We did not find evidence from indirect comparisons that offering more intensive behavioural support was associated with larger treatment effects.
We included six RCTs (708 women analysed) on ICI and IUI in donor sperm treatment. Two studies compared IUI and ICI in natural cycles, two studies compared IUI and ICI in gonadotrophin-stimulated cycles, and two studies compared timing of IUI and ICI. There was very low-quality evidence; the main limitations were risk of bias due to poor reporting of study methods, and serious imprecision. IUI versus ICI in natural cycles There was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in natural cycles (odds ratio (OR) 3.24, 95% confidence interval (CI) 0.12 to 87.13; 1 RCT, 26 women; very low-quality evidence). There was only one live birth in this study (in the IUI group). IUI resulted in higher clinical pregnancy rates (OR 6.18, 95% CI 1.91 to 20.03; 2 RCTs, 76 women; I² = 48%; very low-quality evidence). No multiple pregnancies or miscarriages occurred in this study. IUI versus ICI in gonadotrophin-stimulated cycles There was insufficient evidence to determine whether there was any clear difference in live birth rate between IUI and ICI in gonadotrophin-stimulated cycles (OR 2.55, 95% CI 0.72 to 8.96; 1 RCT, 43 women; very low-quality evidence). This suggested that if the chance of a live birth following ICI in gonadotrophin-stimulated cycles was assumed to be 30%, the chance following IUI in gonadotrophin-stimulated cycles would be between 24% and 80%. IUI may result in higher clinical pregnancy rates than ICI (OR 2.83, 95% CI 1.38 to 5.78; 2 RCTs, 131 women; I² = 0%; very low-quality evidence). IUI may be associated with higher multiple pregnancy rates than ICI (OR 2.77, 95% CI 1.00 to 7.69; 2 RCTs, 131 women; I² = 0%; very low-quality evidence). This suggested that if the risk of multiple pregnancy following ICI in gonadotrophin-stimulated cycles was assumed to be 10%, the risk following IUI would be between 10% and 46%. We found insufficient evidence to determine whether there was any clear difference between the groups in miscarriage rates in gonadotrophin-stimulated cycles (OR 1.97, 95% CI 0.43 to 9.04; 2 RCTs, overall 67 pregnancies; I² = 50%; very low-quality evidence). Timing of IUI and ICI We found no studies that reported on live birth rates. We found a higher clinical pregnancy rate when IUI was timed one day after a rise in blood levels of luteinising hormone (LH) compared to IUI two days after a rise in blood levels of LH (OR 2.00, 95% CI 1.14 to 3.53; 1 RCT, 351 women; low-quality evidence). We found insufficient evidence to determine whether there was any clear difference in clinical pregnancy rates between ICI timed after a rise in urinary levels of LH versus a rise in basal temperature plus cervical mucus scores (OR 1.31, 95% CI 0.42 to 4.11; 1 RCT, 56 women; very low-quality evidence). Neither of these studies reported multiple pregnancy or miscarriage rates as outcomes. There was insufficient evidence to determine whether there was a clear difference in live birth rates between IUI and ICI in natural or gonadotrophin-stimulated cycles in women who started with donor sperm treatment. There was insufficient evidence available for the effect of timing of IUI or ICI on live birth rates. Very low-quality data suggested that in gonadotrophin-stimulated cycles, IUI may be associated with a higher clinical pregnancy rate than ICI, but also with a higher risk of multiple pregnancy rate. We concluded that the current evidence was too limited to choose between IUI or ICI, in natural cycles or with ovarian stimulation, in donor sperm treatment.
We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens. CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.
We identified 14,488 unique records, and assessed 1030 in full text for eligibility. We found 58 studies meeting our inclusion criteria, including 22 RCTs, 3 NRCTs, 14 CBA studies, and 19 ITS studies, with a total of 1,180,096 participants. The median length of follow-up was 10 months. The studies included children, teenagers and adults, and were implemented in a variety of settings, including schools, retailing and food service establishments. We judged most studies to be at high or unclear risk of bias in at least one domain, and most studies used non-randomised designs. The studies examine a broad range of interventions, and we present results for these separately. Labelling interventions (8 studies): We found moderate-certainty evidence that traffic-light labelling is associated with decreasing sales of SSBs, and low-certainty evidence that nutritional rating score labelling is associated with decreasing sales of SSBs. For menu-board calorie labelling reported effects on SSB sales varied. Nutrition standards in public institutions (16 studies): We found low-certainty evidence that reduced availability of SSBs in schools is associated with decreased SSB consumption. We found very low-certainty evidence that improved availability of drinking water in schools and school fruit programmes are associated with decreased SSB consumption. Reported associations between improved availability of drinking water in schools and student body weight varied. Economic tools (7 studies): We found moderate-certainty evidence that price increases on SSBs are associated with decreasing SSB sales. For price discounts on low-calorie beverages reported effects on SSB sales varied. Whole food supply interventions (3 studies): Reported associations between voluntary industry initiatives to improve the whole food supply and SSB sales varied. Retail and food service interventions (7 studies): We found low-certainty evidence that healthier default beverages in children’s menus in chain restaurants are associated with decreasing SSB sales, and moderate-certainty evidence that in-store promotion of healthier beverages in supermarkets is associated with decreasing SSB sales. We found very low-certainty evidence that urban planning restrictions on new fast-food restaurants and restrictions on the number of stores selling SSBs in remote communities are associated with decreasing SSB sales. Reported associations between promotion of healthier beverages in vending machines and SSB intake or sales varied. Intersectoral approaches (8 studies): We found moderate-certainty evidence that government food benefit programmes with restrictions on purchasing SSBs are associated with decreased SSB intake. For unrestricted food benefit programmes reported effects varied. We found moderate-certainty evidence that multicomponent community campaigns focused on SSBs are associated with decreasing SSB sales. Reported associations between trade and investment liberalisation and SSB sales varied. Home-based interventions (7 studies): We found moderate-certainty evidence that improved availability of low-calorie beverages in the home environment is associated with decreased SSB intake, and high-certainty evidence that it is associated with decreased body weight among adolescents with overweight or obesity and a high baseline consumption of SSBs. Adverse outcomes reported by studies, which may occur in some circumstances, included negative effects on revenue, compensatory SSB consumption outside school when the availability of SSBs in schools is reduced, reduced milk intake, stakeholder discontent, and increased total energy content of grocery purchases with price discounts on low-calorie beverages, among others. The certainty of evidence on adverse outcomes was low to very low for most outcomes. We analysed interventions targeting sugar-sweetened milk separately, and found low- to moderate-certainty evidence that emoticon labelling and small prizes for the selection of healthier beverages in elementary school cafeterias are associated with decreased consumption of sugar-sweetened milk. We found low-certainty evidence that improved placement of plain milk in school cafeterias is not associated with decreasing sugar-sweetened milk consumption. The evidence included in this review indicates that effective, scalable interventions addressing SSB consumption at a population level exist. Implementation should be accompanied by high-quality evaluations using appropriate study designs, with a particular focus on the long-term effects of approaches suitable for large-scale implementation.
Four trials involving 649 participants were included in this review. Two of these trials (459 participants) were designed as randomised, double-blind, placebo-controlled trials with an adequate methodological description; the other two trials (190 participants) described an inadequate methodological design. All four trials with 649 participants were included in the meta-analysis. Significant differences were noted in rates of restenosis, recurrence angina pectoris, and serious cardiovascular adverse events between Xiongshao capsule plus conventional western medicine and the same conventional western medicine alone; RR values (95% CIs) were 0.41 (0.22 to 0.75), 0.47 (0.31 to 0.72), and 0.47 (0.25 to 0.90), respectively. Xiongshao capsule plus conventional western medicine showed more significant reductions in restenosis (RR 0.52, 95% CI 0.33 to 0.80), recurrence angina pectoris (RR 0.26, 95% CI 0.18 to 0.38), and serious cardiovascular adverse events (RR 0.45, 95% CI 0.28 to 0.70) than the same conventional western medicine plus placebo. Safety outcomes and adverse events of the Xiongshao capsule were reported in two trials, which reported no adverse events. The summary estimates indicate a protective effect of Xiongshao on restenosis and suggest that Xiongshao capsule may be used to prevent restenosis after a PCI procedure in CHD patients. However, this evidence is derived from small randomised trials, all conducted in China, and two of the included trials showed important methodological limitations that undermine the validity of the findings. Additional high-quality research trials with sufficient sample size are required.
We included three new RCTs in this update, which now comprises 10 studies with a total of 614 participants. We judged most trials as having uncertain risk of bias regarding randomization. Other than this, the overall risk of bias was low. Most included trials had small sample sizes. All of the trials assessed the primary outcome of conversion to general anaesthesia. Ten trials comparing anaesthesia performed with hyperbaric and isobaric bupivacaine failed to show any difference in need for conversion to general anaesthesia (RR 0.33, 95% CI 0.09 to 1.17, 614 participants, very low quality of evidence). Nine trials also failed to show a difference in the need for supplemental analgesics (RR 0.61, 95% CI 0.26 to 1.41, 554 participants, very low quality of evidence). Four trials comparing requirement for ephedrine did not show any difference (RR 0.89, 95% CI 0.57 to 1.38, 256 participants, very low quality of evidence). Seven trials did not provide convincing evidence of difference in nausea and vomiting (RR 0.99, 95% CI 0.57 to 1.72, 433 participants, low quality of evidence). Three trials failed to show a difference in headache (OR 1.82, 95% CI 0.47 to 6.99, 234 participants, low quality of evidence). Two trials showed that the time until sensory block to the thoracic 4th (T4) spinal level was shorter with hyperbaric bupivacaine (MD -1.06 minutes, 95% CI -1.80 to -0.31, 128 participants, moderate quality of evidence). Six trials showed no difference in the amount of ephedrine used (RR 0.23, 95% CI -1.65 to 2.12, 386 participants, moderate quality of evidence). Three trials failed to show any difference in high block (RR 0.88, 95% CI 0.16 to 4.90, 205 participants). Data are limited for some of the outcomes. Reporting of the included trials is less than optimal. For these reasons the overall quality of evidence is low or very low for most of the outcomes, based on the GRADE method of assessment. This review found that intrathecal hyperbaric bupivacaine had a more rapid onset of sensory blockade at the 4th thoracic vertebra (T4) level than isobaric bupivacaine. Hower, despite incorporating more data in the analysis, we found little evidence that the need for conversion to general anaesthesia and supplemental analgesia differed between the hyperbaric or isobaric bupivacaine groups. This is mainly due to the rarity of these outcomes, variability in the dose, use of adjuvant drugs and differences in the technique used for regional anaesthesia. There were no differences in the adverse effects studied. Any possible advantage of hyperbaric bupivacaine needs to be confirmed in larger randomized trials. In future research, criteria for conversion to general anaesthesia need to be defined objectively and applied uniformly.
We identified one randomised controlled trial including 541 participants that compared partial nephrectomy to radical nephrectomy. The median follow-up was 9.3 years. Based on low quality evidence, we found that time-to-death of any cause was decreased using partial nephrectomy (HR 1.50, 95% CI 1.03 to 2.18). This corresponds to 79 more deaths (5 more to 173 more) per 1000. Also based on low quality evidence, we found no difference in serious adverse events (RR 2.04, 95% CI 0.19 to 22.34). Findings are consistent with 4 more surgery-related deaths (3 fewer to 78 more) per 1000. Based on low quality evidence, we found no difference in time-to-recurrence (HR 1.37, 95% CI 0.58 to 3.24). This corresponds to 12 more recurrences (14 fewer to 70 more) per 1000. Due to the nature of reporting, we were unable to analyse overall rates for immediate and long-term adverse events. We found no evidence on haemodialysis or quality of life. Reasons for downgrading related to study limitations (lack of blinding, cross-over), imprecision and indirectness (a substantial proportion of patients were ultimately found not to have a malignant tumour). Based on the finding of a single trial, we were unable to conduct any subgroup or sensitivity analyses. Partial nephrectomy may be associated with a decreased time-to-death of any cause. With regards to surgery-related mortality, cancer-specific survival and time-to-recurrence, partial nephrectomy appears to result in little to no difference.
We included 19 RCTs in 6461 participants who were followed for one to eight years. Seven trials assessed the effects of supplemental GLA and 12 of LA, none DGLA or AA; the omega-6 fats usually displaced dietary saturated or monounsaturated fats. We assessed three RCTs as being at low summary risk of bias. Primary outcomes: we found low-quality evidence that increased intake of omega-6 fats may make little or no difference to all-cause mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.12, 740 deaths, 4506 randomised, 10 trials) or CVD events (RR 0.97, 95% CI 0.81 to 1.15, 1404 people experienced events of 4962 randomised, 7 trials). We are uncertain whether increasing omega-6 fats affects CVD mortality (RR 1.09, 95% CI 0.76 to 1.55, 472 deaths, 4019 randomised, 7 trials), coronary heart disease events (RR 0.88, 95% CI 0.66 to 1.17, 1059 people with events of 3997 randomised, 7 trials), major adverse cardiac and cerebrovascular events (RR 0.84, 95% CI 0.59 to 1.20, 817 events, 2879 participants, 2 trials) or stroke (RR 1.36, 95% CI 0.45 to 4.11, 54 events, 3730 participants, 4 trials), as we assessed the evidence as being of very low quality. We found no evidence of dose-response or duration effects for any primary outcome, but there was a suggestion of greater protection in participants with lower baseline omega-6 intake across outcomes. Additional key outcomes: we found increased intake of omega-6 fats may reduce myocardial infarction (MI) risk (RR 0.88, 95% CI 0.76 to 1.02, 609 events, 4606 participants, 7 trials, low-quality evidence). High-quality evidence suggests increasing omega-6 fats reduces total serum cholesterol a little in the long term (mean difference (MD) −0.33 mmol/L, 95% CI −0.50 to −0.16, I2 = 81%; heterogeneity partially explained by dose, 4280 participants, 10 trials). Increasing omega-6 fats probably has little or no effect on adiposity (body mass index (BMI) MD −0.20 kg/m2, 95% CI −0.56 to 0.16, 371 participants, 1 trial, moderate-quality evidence). It may make little or no difference to serum triglycerides (MD −0.01 mmol/L, 95% CI −0.23 to 0.21, 834 participants, 5 trials), HDL (MD −0.01 mmol/L, 95% CI −0.03 to 0.02, 1995 participants, 4 trials) or low-density lipoprotein (MD −0.04 mmol/L, 95% CI −0.21 to 0.14, 244 participants, 2 trials, low-quality evidence). This is the most extensive systematic assessment of effects of omega-6 fats on cardiovascular health, mortality, lipids and adiposity to date, using previously unpublished data. We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI, where 53 people may need to increase omega-6 fat intake to prevent 1 person from experiencing MI. Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity.
Sixteen trials (3689 participants) compared day hospitals with comprehensive care (five trials), domiciliary care (seven trials) or no comprehensive care (four trials). Overall there was low quality evidence from these trials for the following results. For the outcome of death, there was no strong evidence for or against day hospitals compared to other treatments overall (odds ratio (OR) 1.05; 95% CI 0.85 to 1.28; P = 0.66), or to comprehensive care (OR 1.26; 95% CI 0.87 to 1.82; P = 0.22), domiciliary care (OR 0.97; 95% CI 0.61 to 1.55; P = 0.89), or no comprehensive care (OR 0.88; 95% CI 0.63 to 1.22; P = 0.43). For the outcome of death or deterioration in activities of daily living (ADL), there was no strong evidence for day hospital attendance compared to other treatments (OR 1.07; 95% CI 0.76 to 1.49; P = 0.70), or to comprehensive care (OR 1.18; 95% CI 0.63 to 2.18; P = 0.61), domiciliary care (OR 1.41; 95% CI 0.82 to 2.42; P = 0.21) or no comprehensive care (OR 0.76; 95% CI 0.56 to 1.05; P = 0.09). For the outcome of death or poor outcome (institutional care, dependency, deterioration in physical function), there was no strong evidence for day hospitals compared to other treatments (OR 0.92; 95% CI 0.74 to 1.15; P = 0.49), or compared to comprehensive care (OR 1.05; 95% CI 0.79 to 1.40; P = 0.74) or domiciliary care (OR 1.08; 95% CI 0.67 to 1.74; P = 0.75). However, compared with no comprehensive care there was a difference in favour of day hospitals (OR 0.72; 95% CI 0.53 to 0.99; P = 0.04). For the outcome of death or institutional care, there was no strong evidence for day hospitals compared to other treatments overall (OR 0.85; 95% CI 0.63 to 1.14; P = 0.28), or to comprehensive care (OR 1.00; 95% CI 0.69 to 1.44; P = 0.99), domiciliary care (OR 1.05; 95% CI 0.57 to1.92; P = 0. 88) or no comprehensive care (OR 0.63; 95% CI 0.40 to 1.00; P = 0.05). For the outcome of deterioration in ADL, there was no strong evidence that day hospital attendance had a different effect than other treatments overall (OR 1.11; 95% CI 0.68 to 1.80; P = 0.67) or compared with comprehensive care (OR 1.21; 0.58 to 2.52; P = 0.61), or domiciliary care (OR 1.59; 95% CI 0.87 to 2.90; P = 0.13). However, day hospital patients showed a reduced odds of deterioration compared with those receiving no comprehensive care (OR 0.61; 95% CI 0.38 to 0.97; P = 0.04) and significant subgroup differences (P = 0.04). For the outcome of requiring institutional care, there was no strong evidence for day hospitals compared to other treatments (OR 0.84; 95% CI 0.58 to 1.21; P = 0.35), or to comprehensive care (OR 0.91; 95% CI 0.70 to 1.19; P = 0.49), domiciliary care (OR 1.49; 95% CI 0.53 to 4.25; P = 0.45), or no comprehensive care (OR 0.58; 95% CI 0.28 to 1.20; P = 0.14). There is low quality evidence that medical day hospitals appear effective compared to no comprehensive care for the combined outcome of death or poor outcome, and for deterioration in ADL. There is no clear evidence for other outcomes, or an advantage over other medical care provision.
Nine studies (3345 women) were included. Oral oestrogens did not reduce UTI compared to placebo (4 studies, 2798 women: RR 1.08, 95% CI 0.88 to 1.33). Vaginal oestrogens versus placebo reduced the number of women with UTIs in two small studies using different application methods. The RR for one was 0.25 (95% CI 0.13 to 0.50) and 0.64 (95% CI 0.47 to 0.86) in the second. Two studies compared oral antibiotics versus vaginal oestrogens (cream (1), pessaries (1)). There was very significant heterogeneity and the results could not be pooled. Vaginal cream reduced the proportion of UTIs compared to antibiotics in one study and in the second study antibiotics were superior to vaginal pessaries. Adverse events for vaginal oestrogens were breast tenderness, vaginal bleeding or spotting, nonphysiologic discharge, vaginal irritation, burning and itching. Based on only two studies comparing vaginal oestrogens to placebo, vaginal oestrogens reduced the number of UTIs in postmenopausal women with RUTI, however this varied according to the type of oestrogen used and the treatment duration.
We included 72 trials (52,678 women). Oral or sublingual misoprostol compared with placebo is effective in reducing severe PPH (oral: seven trials, 6225 women, not totalled due to significant heterogeneity; sublingual: risk ratio (RR) 0.66; 95% confidence interval (CI) 0.45 to 0.98; one trial, 661 women) and blood transfusion (oral: RR 0.31; 95% CI 0.10 to 0.94; four trials, 3519 women). Compared with conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH (RR 1.33; 95% CI 1.16 to 1.52; 17 trials, 29,797 women) and use of additional uterotonics, but with a trend to fewer blood transfusions (RR 0.84; 95% CI 0.66 to 1.06; 15 trials; 28,213 women). Additional uterotonic data were not totalled due to heterogeneity. Misoprostol use is associated with significant increases in shivering and a temperature of 38º Celsius compared with both placebo and other uterotonics. Oral or sublingual misoprostol shows promising results when compared with placebo in reducing blood loss after delivery. The margin of benefit may be affected by whether other components of the management of the third stage of labour are used or not. As side-effects are dose-related, research should be directed towards establishing the lowest effective dose for routine use, and the optimal route of administration. Neither intramuscular prostaglandins nor misoprostol are preferable to conventional injectable uterotonics as part of the management of the third stage of labour especially for low-risk women; however, evidence has been building for the use of oral misoprostol to be effective and safe in areas with low access to facilities and skilled healthcare providers and future research on misoprostol use in the community should focus on implementation issues.
Four small studies (224 participants) were included in the review. Little information was provided about the process of allocating participants to groups. None of the studies used independent outcome assessors, and evidence suggested researcher allegiance towards the active treatments. The four studies examined a diversity of third wave CBT approaches (extended behavioural activation, acceptance and commitment therapy and competitive memory training) and control conditions. None of the studies conducted follow-up assessments. The results showed a significant difference in clinical response rates in favour of third wave CBT when compared with treatment as usual (TAU) conditions (three studies, 170 participants, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.27 to 0.95; very low quality). No significant difference in treatment acceptability based on dropout rates was found between third wave CBT approaches and TAU (four studies, 224 participants, RR 1.01, 95% CI 0.08 to 12.30; very low quality). Both analyses showed substantial statistical heterogeneity. Very low quality evidence suggests that third wave CBT approaches appear to be more effective than treatment as usual in the treatment of acute depression. The very small number of available studies and the diverse types of interventions and control comparators, together with methodological limitations, limit the ability to draw any conclusions on their effect in the short term or over a longer term. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies of third wave CBT approaches in the treatment of acute depression, on a short- and long-term basis, to provide evidence of their effectiveness to policy-makers, clinicians and users of services.
We identified seven studies including 1774 participants. We judged three studies to be at high risk of bias and four to be at unclear risk. Each study provided face-to-face behavioural support delivered by pharmacy staff, and required pharmacy personnel training. Typically such programmes comprised support starting before quit day and continuing with weekly appointments for several weeks afterwards. Comparators were either minimal or less intensive behavioural support for smoking cessation, typically comprising a few minutes of one-off advice on how to quit. Participants in both intervention and control arms received equivalent smoking cessation pharmacotherapy in all but one study. All studies took place in high-income countries, and recruited participants visiting pharmacies. We pooled six studies of 1614 participants and detected a benefit of more intensive behavioural smoking cessation interventions delivered by community pharmacy personnel compared with less intensive cessation interventions at longest follow-up (RR 2.30, 95% CI 1.33 to 3.97; I2 = 54%; low-certainty evidence). Community pharmacists can provide effective behavioural support to people trying to stop smoking. However, this conclusion is based on low-certainty evidence, limited by risk of bias and imprecision. Further research could change this conclusion.
Three randomised controlled trials (633 participants) were included in this updated review. No significant differences in hospital mortality were noted between the study group (with omentoplasty) and the control group (without omentoplasty) (RR 1.28, 95% CI 0.49 to 3.39). None of the included studies reported differences in long-term survival between the two groups. The incidence of postoperative anastomotic leakage was significantly less among study participants treated with omentoplasty than among those treated without (RR 0.25, 95% CI 0.11 to 0.55), but the additional benefit was seen in the subgroup analysis only for participants undergoing a transhiatal oesophagogastrectomy (THE) procedure (RR 0.23, 95% CI 0.07 to 0.79); transthoracic oesophagogastrectomy (TTE) (RR 0.19, 95% CI 0.03 to 1.03); or three-field oesophagectomy (RR 0.33, 95% CI 0.09 to 1.19 ). Omentoplasty did not significantly improve other surgery-related complications, such as anastomotic stricture (RR 0.91, 95% CI 0.33 to 2.57). However, participants treated with omentoplasty could reduce the duration of hospitalisation compared with that seen in the control group (MD -2.13, 95% CI -3.57 to -0.69). Omentoplasty may provide additional benefit in decreasing the incidence of anastomotic leakage after oesophagectomy and oesophagogastrostomy for patients with oesophageal cancer without increasing or decreasing other complications, especially among those treated with THE. It also has the potential to reduce the duration of hospital stay after operation. Further randomised controlled trials are needed to investigate the influences of omentoplasty on the incidence of anastomotic leakage and anastomotic stricture, long-term survival, duration of hospital stay and quality of life after oesophagectomy and oesophagogastrostomy when different surgical approaches are used.
Seven randomized controlled trials (1249 participants) which met our inclusion criteria compared acyclovir to placebo or no treatment (five trials) and valacyclovir to placebo (two trials). The effect of antepartum antiviral prophylaxis on neonatal herpes could not be estimated. There were no cases of symptomatic neonatal herpes in the included studies in either the treatment or placebo groups. Women who received antiviral prophylaxis were significantly less likely to have a recurrence of genital herpes at delivery (relative risk (RR) 0.28, 95% confidence interval (CI) 0.18 to 0.43, I2 = 0%). Women who received antiviral prophylaxis were also significantly less likely to have a cesarean delivery for genital herpes (RR 0.30, 95% CI 0.20 to 0.45, I2 = 27.3%). Women who received antiviral prophylaxis were significantly less likely to have HSV detected at delivery (RR 0.14, 95% CI 0.05 to 0.39, I2 = 0%). Women with recurrent genital herpes simplex virus should be informed that the risk of neonatal herpes is low. There is insufficient evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes. Antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery and reduces the need for cesarean delivery for genital herpes. Limited information exists regarding the neonatal safety of prophylaxis. The risks, benefits, and alternatives to antenatal prophylaxis should be discussed with women who have a history and prophylaxis initiated for women who desire intervention.
We included 12 studies (in 13 publications) in this review, but interpretability and generalizability of these studies is difficult and the study designs used were at high risk of bias. The additional yield (calculated by dividing the additional 'unique' yield identified by checking reference lists by the total number of studies found to be eligible within the study) of relevant studies identified through checking reference lists ranged from 2.5% to 42.7%. Only two studies reported yield information by publication type (dissertations and systematic reviews). No cost data were reported although one study commented that it was impossible to isolate the time spent on reference tracking since this was done in parallel with the critical appraisal of each paper, and for that particular study costs were not specifically estimated. There is some evidence to support the use of checking reference lists for locating studies in systematic reviews. However, this evidence is derived from weak study designs. In situations where the identification of all relevant studies through handsearching and database searching is difficult, it would seem prudent that authors of reviews check reference lists to supplement their searching. The challenge, therefore, is for review authors to recognize those situations.
We found nine trials with 855 participants that randomised participants to fewer-than-four-ports laparoscopic cholecystectomy (n = 427) versus four-port laparoscopic cholecystectomy (n = 428). Most trials included low anaesthetic risk participants undergoing elective laparoscopic cholecystectomy. Seven of the nine trials used a single port laparoscopic cholecystectomy and the remaining two trials used three-port laparoscopic cholecystectomy as the experimental intervention. Only one trial including 70 participants had low risk of bias. Fewer-than-four-ports laparoscopic cholecystectomy could be completed successfully in more than 90% of participants in most trials. The remaining participants were mostly converted to four-port laparoscopic cholecystectomy but some participants had to undergo open cholecystectomy. There was no mortality in either group in the seven trials that reported mortality (318 participants in fewer-than-four-ports laparoscopic cholecystectomy group and 316 participants in four-port laparoscopic cholecystectomy group). The proportion of participants with serious adverse events was low in both treatment groups and the estimated RR was compatible with a reduction and substantial increased risk with the fewer-than-four-ports group (6/318 (1.9%)) and four-port laparoscopic cholecystectomy group (0/316 (0%)) (RR 3.93; 95% CI 0.86 to 18.04; 7 trials; 634 participants; very low quality evidence). The estimated difference in the quality of life (measured between 10 and 30 days) was imprecise (standardised mean difference (SMD) 0.18; 95% CI -0.05 to 0.42; 4 trials; 510 participants; very low quality evidence), as was the proportion of participants in whom the laparoscopic cholecystectomy had to be converted to open cholecystectomy between the groups (fewer-than-four ports 3/289 (adjusted proportion 1.2%) versus four port: 5/292 (1.7%); RR 0.68; 95% CI 0.19 to 2.35; 5 trials; 581 participants; very low quality evidence). The fewer-than-four-ports laparoscopic cholecystectomy took 14 minutes longer to complete (MD 14.44 minutes; 95% CI 5.95 to 22.93; 9 trials; 855 participants; very low quality evidence). There was no clear difference in hospital stay between the groups (MD -0.01 days; 95% CI -0.28 to 0.26; 6 trials; 731 participants) or in the proportion of participants discharged as day surgery (RR 0.92; 95% CI 0.70 to 1.22; 1 trial; 50 participants; very low quality evidence) between the two groups. The times taken to return to normal activity and work were shorter by two days in the fewer-than-four-ports group compared with four-port laparoscopic cholecystectomy (return to normal activity: MD -1.20 days; 95% CI -1.58 to -0.81; 2 trials; 325 participants; very low quality evidence; return to work: MD -2.00 days; 95% CI -3.31 to -0.69; 1 trial; 150 participants; very low quality evidence). There was no significant difference in cosmesis scores at 6 to 12 months between the two groups (SMD 0.37; 95% CI -0.10 to 0.84; 2 trials; 317 participants; very low quality evidence). There is very low quality evidence that is insufficient to determine whether there is any significant clinical benefit in using fewer-than-four-ports laparoscopic cholecystectomy compared with four-port laparoscopic cholecystectomy. The safety profile of using fewer-than-four ports is yet to be established and fewer-than-four-ports laparoscopic cholecystectomy should be reserved for well-designed randomised clinical trials.
No RCTs of interventions were identified. Eleven observational studies were included - two medical records reviews, one matched pair study, one clinician interview study, two studies documenting clinicians' decisions and five postal surveys. Three measures of recruitment were used, invitation to participate, entry into RCT and reported entry to RCT. Five studies explored the effect of patient characteristics. The effect of age and prognosis varied between trials. Six studies considered the association between clinicians' views and recruitment. Clinicians who agreed to participate because they were acquainted with the researchers were less likely to participate than those otherwise motivated (1 study, 2-sided p = 0.04 Fisher's exact test) and (Odds Ratio [OR] 0.4, 95% Confidence Interval [CI] 0.2 to 0.9, 1 study). Clinicians who had recruited were more likely to report some difficulties including "trials involve extra work" (OR 92.94, 95% CI 4.54 - 1902.11; p ≤ 0.01, 1 study) and "inviting patients to participate is embarrassing" (chi-square 15.55, df = 1, p < 0.0001, 1 study). The effect of the need to discuss clinical uncertainty was unclear but concern that the doctor-patient relationship would be adversely affected by participation was a deterrent (chi-square = 7.25, df = 1, p = 0.007, 1 study). The impact of factors varied across studies. Researchers need to be aware that aspects of the design and conduct of trials can affect clinicians' willingness to invite patients to participate. Further research is needed.
Ten trials involving 11,795 women met the inclusion criteria. We found no trials of freestanding birth centres or Snoezelen rooms. Allocation to an alternative setting increased the likelihood of: no intrapartum analgesia/anesthesia (six trials, n = 8953; RR 1.18, 95% CI 1.05 to 1.33); spontaneous vaginal birth (eight trials; n = 11,202; RR 1.03, 95% CI 1.01 to 1.05); breastfeeding at six to eight weeks (one trial, n = 1147; RR 1.04, 95% CI 1.02 to 1.06); and very positive views of care (two trials, n = 1207; RR 1.96, 95% CI 1.78 to 2.15). Allocation to an alternative setting decreased the likelihood of epidural analgesia (eight trials, n = 10.931; RR 0.80, 95% CI 0.74 to 0.87); oxytocin augmentation of labour (eight trials, n = 11,131; RR 0.77, 95% CI 0.67 to 0.88); instrumental vaginal birth (eight trials, n = 11,202; RR 0.89, 95% CI 0.79 to 0.99), and episiotomy (eight trials, n = 11,055; RR 0.83, 95% CI 0.77 to 0.90). There was no apparent effect on other adverse maternal or neonatal outcomes. Care by the same or separate staff had no apparent effects. No conclusions could be drawn regarding the effects of continuity of caregiver or architectural characteristics. In several of the trials included in this review, the design features of the alternative setting were confounded by important differences in the organizational models for care (separate staff for the alternative setting, offering more continuity of caregiver), and thus it is difficult to draw inferences about the independent effects of the physical birth environment. Hospital birth centres are associated with lower rates of medical interventions during labour and birth and higher levels of satisfaction, without increasing risk to mothers or babies.
We identified 51 trials with 22,509 participants. Most recruited adults from the community using media or local advertising. People enrolled in the studies typically smoked an average of 23 cigarettes a day. We judged 18 of the studies to be at high risk of bias, but restricting the analysis only to the five studies at low or to the 28 studies at unclear risk of bias did not significantly alter results. We identified very low-certainty evidence, limited by risk of bias, inconsistency and imprecision, comparing the effect of reduction-to-quit interventions with no treatment on cessation rates (RR 1.74, 95% CI 0.90 to 3.38; I2 = 45%; 6 studies, 1599 participants). However, when comparing reduction-to-quit interventions with abrupt quitting (standard care) we found evidence that neither approach resulted in superior quit rates (RR 1. 01, 95% CI 0.87 to 1.17; I2 = 29%; 22 studies, 9219 participants). We judged this estimate to be of moderate certainty, due to imprecision. Subgroup analysis provided some evidence (P = 0.01, I2 = 77%) that reduction-to-quit interventions may result in more favourable quit rates than abrupt quitting if varenicline is used as a reduction aid. Our analysis comparing reduction using pharmacotherapy with reduction alone found low-certainty evidence, limited by inconsistency and imprecision, that reduction aided by pharmacotherapy resulted in higher quit rates (RR 1. 68, 95% CI 1.09 to 2.58; I2 = 78%; 11 studies, 8636 participants). However, a significant subgroup analysis (P < 0.001, I2 = 80% for subgroup differences) suggests that this may only be true when fast-acting NRT or varenicline are used (both moderate-certainty evidence) and not when nicotine patch, combination NRT or bupropion are used as an aid (all low- or very low-quality evidence). More evidence is likely to change the interpretation of the latter effects. Although there was some evidence from within-study comparisons that behavioural support for reduction to quit resulted in higher quit rates than self-help resources alone, the relative efficacy of various other characteristics of reduction-to-quit interventions investigated through within- and between-study comparisons did not provide any evidence that they enhanced the success of reduction-to-quit interventions. Pre-quit AEs, SAEs and nicotine withdrawal symptoms were measured variably and infrequently across studies. There was some evidence that AEs occurred more frequently in studies that compared reduction using pharmacotherapy versus no pharmacotherapy; however, the AEs reported were mild and usual symptoms associated with NRT use. There was no clear evidence that the number of people reporting SAEs, or changes in withdrawal symptoms, differed between trial arms. There is moderate-certainty evidence that neither reduction-to-quit nor abrupt quitting interventions result in superior long-term quit rates when compared with one another. Evidence comparing the efficacy of reduction-to-quit interventions with no treatment was inconclusive and of low certainty. There is also low-certainty evidence to suggest that reduction-to-quit interventions may be more effective when pharmacotherapy is used as an aid, particularly fast-acting NRT or varenicline (moderate-certainty evidence). Evidence for any adverse effects of reduction-to-quit interventions was sparse, but available data suggested no excess of pre-quit SAEs or withdrawal symptoms. We downgraded the evidence across comparisons due to risk of bias, inconsistency and imprecision. Future research should aim to match any additional components of multicomponent reduction-to-quit interventions across study arms, so that the effect of reduction can be isolated. In particular, well-conducted, adequately-powered studies should focus on investigating the most effective features of reduction-to-quit interventions to maximise cessation rates.
Nine RCTs (N = 341 participants, 301 included in analyses) investigated various types and intensities of non pharmacological interventions for treating spasticity in adults with MS. These interventions included: physical activity programmes (such as physiotherapy, structured exercise programme, sports climbing); transcranial magnetic stimulation (Intermittent Theta Burst Stimulation (iTBS), Repetitive Transcranial Magnetic Stimulation (rTMS)); electromagnetic therapy (pulsed electromagnetic therapy; magnetic pulsing device), Transcutaneous Electrical Nerve Stimulation (TENS); and Whole Body Vibration (WBV). All studies scored 'low' on the methodological quality assessment implying high risk of bias. There is 'low level' evidence for physical activity programmes used in isolation or in combination with other interventions (pharmacological or non pharmacological), and for repetitive magnetic stimulation (iTBS/rTMS) with or without adjuvant exercise therapy in improving spasticity in adults with MS. No evidence of benefit exists to support the use of TENS, sports climbing and vibration therapy for treating spasticity in this population. There is 'low level' evidence for non pharmacological interventions such as physical activities given in conjunction with other interventions, and for magnetic stimulation and electromagnetic therapies for beneficial effects on spasticity outcomes in people with MS. A wide range of non pharmacological interventions are used for the treatment of spasticity in MS, but more robust trials are needed to build evidence about these interventions.
We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC. Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence). There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL. IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data. In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.
We included 16 randomised controlled trials consisting of 2933 colonoscopies. Primary outcome measures were cecal intubation rate and adenoma detection; secondary outcomes were time needed to reach the cecum, pain experienced by participants during the procedure, completion of cecal intubation without sedation/analgesia, and adverse events. Completeness of colonoscopy, that is cecal intubation rate, was similar between water infusion and standard air insufflation (risk ratio 1.00, 95% confidence interval (CI) 0.97 to 1.03, P = 0.93). Adenoma detection rate, that is number of participants with at least one detected adenoma, was slightly improved with water infusion (risk ratio 1.16, 95% CI 1.04 to 1.30, P = 0.007). Assuming the fraction of patients undergoing screening colonoscopy who had one or more adenomas detected was 20 per 100 with standard colonoscopy, the use of water colonoscopy may increase the fraction to 23 per 100 individuals. From our findings, it is possible that up to 68,000 more of the 1.7 million outpatient screening colonoscopies performed annually in the United States, could detect adenomas if water infusion colonoscopy was used. In addition, with water infusion participants experienced significantly less pain (mean difference in pain score on a 0 to 10 scale: -1.57, 95% CI -2.00 to -1.14, P < 0.00001) and a significantly lower proportion of participants requested on-demand sedation or analgesia, or both (risk ratio 1.20, 95% CI 1.14 to 1.27, P < 0.00001). Qualitative analysis suggests that water infusion colonoscopy was not associated with a markedly increased rate of adverse events compared with the standard procedure. Completeness of colonoscopy, that is cecal intubation rate, was not improved by water infusion compared with standard air insufflation colonoscopy. However, adenoma detection, assessed with two different measures (that is adenoma detection rate and number of detected adenomas per procedure), was slightly augmented by the water infusion colonoscopy. Improved adenoma detection might be due to the cleansing effects of water infusions on the mucosa. Detection of premalignant lesions during standard colonoscopy is suboptimal, and so improvements in adenoma detection by water infusion colonoscopy, although small, may help to reduce the risk of interval colorectal carcinoma. The most obvious benefit of water infusion colonoscopy was reduction of procedure-related abdominal pain, which may enhance the acceptance of screening/surveillance colonoscopy.
Eleven studies (n = 927 participants) met our inclusion criteria. Eight studies compared CTA with IADSA (n = 526) and three studies compared MRA with IADSA (n = 401). Methodological quality varied considerably among studies, with partial verification bias in 7/11 (64%) and retrospective designs in 5/10 (50%). In studies of CTA, the pooled estimate of sensitivity was 0.95 (95% confidence interval (CI) 0.90 to 0.97) and specificity was 0.99 (95% CI 0.95 to 1.00). The results remained robust in a sensitivity analysis in which only studies evaluating adult patients (≥ 16 years of age) were included. In studies of MRA, the pooled estimate of sensitivity was 0.98 (95% CI 0.80 to 1.00) and specificity was 0.99 (95% CI 0.97 to 1.00). An indirect comparison of CTA and MRA using a bivariate model incorporating test type as one of the parameters failed to reveal a statistically significant difference in sensitivity or specificity between the two imaging modalities (P value = 0.6). CTA and MRA appear to have good sensitivity and specificity following ICH for the detection of intracranial vascular malformations, although several of the included studies had methodological shortcomings (retrospective designs and partial verification bias in particular) that may have increased apparent test accuracy.
In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low. We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia. We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E. One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months. We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate. From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13). Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38). We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.
We identified six eligible trials including 16,135 individuals. The mean age of trial populations varied across trials; between 47.3 and 62.3 years. Four trials included individuals with diabetes mellitus type 2 only. The mean treatment duration and follow-up of participants across trials was 4.8 years. We judged the risks of selection and performance bias to be low; risks of detection bias, attrition bias, and reporting bias were unclear. Reporting of adverse effects by included trials was very limited; that is why we used discontinuation of therapy due to adverse effects as a proxy for adverse effects. Patients treated with fibrates had a reduced risk for the combined primary outcome of CVD death, non-fatal myocardial infarction, or non-fatal stroke compared to patients on placebo (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74 to 0.96; participants = 16,135; studies = 6; moderate-quality of evidence). For secondary outcomes we found RRs for fibrate therapy compared with placebo of 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92; participants = 16,135; studies = 6; moderate-quality of evidence); 1.01 for overall mortality (95% CI 0.81 to 1.26; participants = 8471; studies = 5; low-quality of evidence); 1.01 for non-CVD mortality (95% CI 0.76 to 1.35; participants = 8471; studies = 5; low-quality of evidence); and 1.38 for discontinuation of therapy due to adverse effects (95% CI 0.71 to 2.68; participants = 4805; studies = 3; I2 = 74%; very low-quality of evidence). Data on quality of life were not available from any trial. Trials that evaluated fibrates in the background of statins (2 studies) showed no benefits in preventing cardiovascular events. Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects.
There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating. One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events. For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00). Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.
We included 16 trials (19 articles) that enrolled 2520 adults living with HIV. All the interventions were multifaceted and included a mix of psychotherapy, relaxation, group support, and education. The included trials were conducted in the USA (12 trials), Canada (one trial), Switzerland (one trial), Uganda (one trial), and South Africa (one trial), and published between 1996 and 2016. Ten trials recruited men and women, four trials recruited homosexual men, and two trials recruited women only. Interventions were conducted with groups of four to 15 people, for 90 to 135 minutes, every week for up to 12 weeks. All interventions were conducted face-to-face except two, which were delivered by telephone. All were delivered by graduate or postgraduate trained health, psychology, or social care professionals except one that used a lay community health worker and two that used trained mindfulness practitioners. Group-based psychosocial interventions based on cognitive behavioural therapy (CBT) may have a small effect on measures of depression, and this effect may last for up to 15 months after participation in the group sessions (SMD −0.26, 95% CI −0.42 to −0.10; 1139 participants, 10 trials, low certainty evidence). Most trials used the Beck Depression Inventory (BDI), which has a maximum score of 63, and the mean score in the intervention groups was around 1.4 points lower at the end of follow-up. This small benefit was consistent across five trials where participants had a mean depression score in the normal range at baseline, but trials where the mean score was in the depression range at baseline effects were less consistent. Fewer trials reported measures of anxiety, where there may be little or no effect (four trials, 471 participants, low certainty evidence), stress, where there may be little or no effect (five trials, 507 participants, low certainty evidence), and coping (five trials, 697 participants, low certainty evidence). Group-based interventions based on mindfulness have not demonstrated effects on measures of depression (SMD −0.23, 95% CI −0.49 to 0.03; 233 participants, 2 trials, very low certainty evidence), anxiety (SMD −0.16, 95% CI −0.47 to 0.15; 62 participants, 2 trials, very low certainty evidence), or stress (MD −2.02, 95% CI −4.23 to 0.19; 137 participants, 2 trials, very low certainty evidence). No mindfulness based interventions included in the studies had any valid measurements of coping. Group-based psychosocial interventions may have a small effect on measures of depression, but the clinical importance of this is unclear. More high quality evidence is needed to assess whether group psychosocial intervention improve psychological well-being in HIV positive adults.
We identified two randomised trials eligible for inclusion in the review. There was significant variability between the trials for interventions, methodology and outcome measures and therefore meta-analysis was not performed. One study suggested that the transantral approach and endoscopic transnasal technique had similar effects in reducing exophthalmos but that the endoscopic approach may be safer, relating to fewer complications. This study had short-term follow-up and lacked information on our primary outcome (success or failure of treatment). The second study provided evidence that intravenous steroids may be superior to primary surgical decompression in the management of compressive optic neuropathy requiring less secondary surgical procedures, although it relates more frequently to transient side effects. This study was weakened by a small sample size. Until more credible evidence is available recommendations as to best treatment cannot be reliably made. A single study showed that the transantral approach for orbital decompression was related to more complications than the endoscopic transnasal technique which is preferred by Ear, Nose and Throat (ENT) surgeons, usually as an adjunctive procedure. Intravenous steroids were reported in a single trial to be the most efficient intervention for dysthyroid optic neuropathy. The majority of published literature on orbital decompression for thyroid eye disease consists of retrospective, cohort, or case series studies. Although these provide useful descriptive information, clarification is required to show the relative effectiveness of each intervention for various indications. The two RCTs reviewed are not robust enough to provide credible evidence to our understanding of current decompressive surgery and to support recommendations for clinical practice. There is evidence from currently available uncontrolled studies that removal of the medial and lateral wall (balanced decompression) with or without fat removal may be the most effective surgical method related to only a few complications. There is a clear need for randomised studies evaluating the balanced two-wall, three-wall and orbital fat decompression techniques. Comparison with other surgical techniques for orbital decompression or with immunosuppression in cases of compressive optic neuropathy would also be important. These studies should primarily address the reduction of exophthalmos, disease severity, complication rates, quality of life and cost of the intervention.
Ten RCTs including 658 patients were finally included in this systematic review. Five trials compared nalbuphine with placebo. Data from one out of five studies for the outcome moderate/severe pain following nalbuphine compared to placebo gave a risk ratio (RR) 1 hour postoperatively (postop) of 0.1 (95% confidence interval (CI) 0.01 to 0.71; low quality evidence) and a RR 2 hours postop of 0.14 (95% CI 0.02 to 1.06; low quality evidence). The estimated RR based on data from a single study indicated that nalbuphine reduced the requirement for analgesia two hours postop (RR 0.47; 95% CI 0.27 to 0.84; low quality evidence). Two included trials compared nalbuphine with morphine and showed a nonsignificant lower or comparable RR for moderate/severe pain at 1 hour postop (RR 0.84; 95% CI 0.12 to 5.74; low quality evidence), and 2 hours postop (RR 1.09; 95% CI 0.59 to 2.01; low quality evidence) for nalbuphine versus morphine. Four trials compared nalbuphine with tramadol for postoperative pain; data from one trial (per outcome) revealed a lower but nonsignificant RR for the need of additional rescue analgesics in children receiving nalbuphine (RR 2 hours postop 0.75; 95% CI 0.39 to 1.43; low quality evidence) (RR 12 hours postop 0.33; 95% CI 0.04 to 2.77; low quality evidence). One out of three trials comparing nalbuphine with pethidine demonstrated that the RR was not significantly lower following nalbuphine administration compared to pethidine (RR 2 hours postop 1.07; 95% CI 0.52 to 2.23; low quality evidence) (RR 24 hours postop 1.13; 95% CI 0.52 to 2.44; very low quality evidence). The most common adverse event was postoperative nausea and vomiting (PONV). Only one included trial reported that the RR for PONV in the postoperative care unit (PACU) was not significantly higher following nalbuphine compared to placebo (RR 1.00; 95% CI 0.16 to 6.42; low quality evidence) nor to morphine (RR 1.33; 95% CI 0.64 to 2.77; low quality evidence). Because the overall quality of available evidence was low, this systematic review could not definitively show that the analgesic efficacy of nalbuphine is superior compared to placebo. Furthermore, due to the lack of significant results the comparison with other common opioids is also unclear. The same holds true for the evidence focusing on adverse events following nalbuphine compared to placebo or other opioid administration. The evidence is limited, because studies did not report conclusively all important postoperative pain outcomes (e.g. number of patients with the need for rescue analgesia, postoperative pain scores). Thus, a quantitative analysis was not possible for many major aspects (e.g. rescue analgesia, pain scores) and heterogeneity could not be further explored.
We identified 28 studies (21 published, 7 unpublished): 13 from North America, 5 from the UK, 4 from continental Europe, 5 from Australia and 1 from China, comprising 1817 incident HCV infections and 8806.95 person-years of follow-up. HCV incidence ranged from 0.09 cases to 42 cases per 100 person-years across the studies. We judged only two studies to be at moderate overall risk of bias, while 17 were at serious risk and 7 were at critical risk; for two unpublished datasets there was insufficient information to assess bias. As none of the intervention effects were generated from RCT evidence, we typically categorised quality as low. We found evidence that current OST reduces the risk of HCV acquisition by 50% (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63, I2 = 0%, 12 studies across all regions, N = 6361), but the quality of the evidence was low. The intervention effect remained significant in sensitivity analyses that excluded unpublished datasets and papers judged to be at critical risk of bias. We found evidence of differential impact by proportion of female participants in the sample, but not geographical region of study, the main drug used, or history of homelessness or imprisonment among study samples. Overall, we found very low-quality evidence that high NSP coverage did not reduce risk of HCV acquisition (RR 0.79, 95% CI 0.39 to 1.61) with high heterogeneity (I2 = 77%) based on five studies from North America and Europe involving 3530 participants. After stratification by region, high NSP coverage in Europe was associated with a 76% reduction in HCV acquisition risk (RR 0.24, 95% CI 0.09 to 0.62) with less heterogeneity (I2 =0%). We found low-quality evidence of the impact of combined high coverage of NSP and OST, from three studies involving 3241 participants, resulting in a 74% reduction in the risk of HCV acquisition (RR 0.26 95% CI 0.07 to 0.89). OST is associated with a reduction in the risk of HCV acquisition, which is strengthened in studies that assess the combination of OST and NSP. There was greater heterogeneity between studies and weaker evidence for the impact of NSP on HCV acquisition. High NSP coverage was associated with a reduction in the risk of HCV acquisition in studies in Europe.
We identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin. The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate. The evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.
Six trials were included and five trials contributed to this review with data. A total of 2904 participants were randomly assigned to IFNs (1704) and GA (1200). The treatment duration was three years for one study, two years for the other four RCTs while one study was stopped early (after one year). The IFNs analysed in comparison with GA were IFN-beta 1b 250 mcg (two trials, 933 participants), IFN-beta 1a 44 mcg (three trials, 466 participants) and IFN-beta 1a 30 mcg (two trials, 305 participants). Enrolled participants were affected by active RRMS. All studies were at high risk for attrition bias. Three trials are still ongoing, one of them completed. Both therapies showed similar clinical efficacy at 24 months, given the primary outcome variables (number of participants with relapse (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.87 to 1.24) or progression (RR 1.11, 95% CI 0.91 to 1.35). However at 36 months, evidence from a single study suggests that relapse rates were higher in the group given IFNs than in the GA group (RR 1.40, 95% CI 1.13 to 1.74, P value 0.002). Secondary magnetic resonance imaging (MRI) outcomes analysis showed that effects on new or enlarging T2- or new contrast-enhancing T1 lesions at 24 months were similar (mean difference (MD) −0.15, 95% CI −0.68 to 0.39, and MD −0.14, 95% CI −0.30 to 0.02, respectively). However, the reduction in T2- and T1-weighted lesion volume was significantly greater in the groups given IFNs than in the GA groups (MD −0.58, 95% CI −0.99 to −0.18, P value 0.004, and MD −0.20, 95% CI −0.33 to −0.07, P value 0.003, respectively). The number of participants who dropped out of the study because of adverse events was similar in the two groups (RR 0.95, 95% CI 0.64 to 1.40). The quality of evidence for primary outcomes was judged as moderate for clinical end points, but for safety and some MRI outcomes (number of active T2 lesions), quality was judged as low. The effects of IFNs-beta and GA in the treatment of people with RRMS, including clinical (e.g. people with relapse, risk to progression) and MRI (Gd-enhancing lesions) measures, seem to be similar or to show only small differences. When MRI lesion load accrual is considered, the effect of the two treatments differs, in that IFNs-beta were found to limit the increase in lesion burden as compared with GA. Evidence was insufficient for a comparison of the effects of the two treatments on patient-reported outcomes, such as quality-of-life measures.
We included seven new RCTs (536 participants) in the update. In total, we included 19 studies in the review (776 participants in the low tidal volume group and 772 in the high volume group). There are four studies awaiting classification and three are ongoing. All included studies were at some risk of bias. Participants were scheduled for abdominal surgery, heart surgery, pulmonary thromboendarterectomy, spinal surgery and knee surgery. Low tidal volumes used in the studies varied from 6 mL/kg to 8.1 mL/kg while high tidal volumes varied from 10 mL/kg to 12 mL/kg. Based on 12 studies including 1207 participants, the effects of low volume ventilation on 0- to 30-day mortality were uncertain (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.42 to 1.53; I2 = 0%; low-quality evidence). Based on seven studies including 778 participants, lower tidal volumes probably reduced postoperative pneumonia (RR 0.45, 95% CI 0.25 to 0.82; I2 = 0%; moderate-quality evidence; NNTB 24, 95% CI 16 to 160), and it probably reduced the need for non-invasive postoperative ventilatory support based on three studies including 506 participants (RR 0.31, 95% CI 0.15 to 0.64; moderate-quality evidence; NNTB 13, 95% CI 11 to 24). Based on 11 studies including 957 participants, low tidal volumes during surgery probably decreased the need for postoperative invasive ventilatory support (RR 0.33, 95% CI 0.14 to 0.77; I2 = 0%; NNTB 39, 95% CI 30 to 166; moderate-quality evidence). Based on five studies including 898 participants, there may be little or no difference in the intensive care unit length of stay (standardized mean difference (SMD) –0.06, 95% CI –0.22 to 0.10; I2 = 33%; low-quality evidence). Based on 14 studies including 1297 participants, low tidal volumes may have reduced hospital length of stay by about 0.8 days (SMD –0.15, 95% CI –0.29 to 0.00; I2 = 27%; low-quality evidence). Based on five studies including 708 participants, the effects of low volume ventilation on barotrauma (pneumothorax) were uncertain (RR 1.77, 95% CI 0.52 to 5.99; I2 = 0%; very low-quality evidence). We found moderate-quality evidence that low tidal volumes (defined as less than 10 mL/kg) decreases pneumonia and the need for postoperative ventilatory support (invasive and non-invasive). We found no difference in the risk of barotrauma (pneumothorax), but the number of participants included does not allow us to make definitive statement on this. The four studies in 'Studies awaiting classification' may alter the conclusions of the review once assessed.
We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants. Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI -9 to -6, low quality evidence) in those receiving paracetamol at six hours. For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid-induced adverse events. Meta-analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti-inflammatory drugs) were either not statistically significant, not clinically significant, or both. Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta-analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event. Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.
We included seven trials involving 1,020 participants. Mean time to cessation of vomiting in one study was 0.34 days less with dimenhydrinate suppository compared to placebo (P value = 0.036). Pooled data from three studies comparing oral ondansetron with placebo showed: a reduction in the immediate hospital admission rate (RR 0.40, NNT 17, 95% CI 10 to 100) but no difference between the hospitalization rates at 72 hours after discharge from the Emergency Department (ED); a reduction in IV rehydration rates both during the ED stay (RR 0.41, NNT 5, 95% CI 4 to 8), and in follow-up to 72 hours after discharge from the ED stay (worst-best scenario for ondansetron RR 0.57, NNT 6, 95% CI 4 to 13) and an increase in the proportion of patients with cessation of vomiting (RR 1.34, NNT 5, 95% CI 3 to 7)). No significant difference was noted in the revisit rates or adverse events, although diarrhea was reported as a side effect in four of the five ondansetron studies. In one study the proportion of patients with cessation of vomiting in 24 hours was (58%) with IV ondansetron, (17%) placebo and (33%) in the metoclopramide group (P value = 0.039). Oral ondansetron increased the proportion of patients who had ceased vomiting and reduced the number needing intravenous rehydration and immediate hospital admission. Intravenous ondansetron and metoclopramide reduced the number of episodes of vomiting and hospital admission, and dimenhydrinate as a suppository reduced the duration of vomiting.
Only one trial met the inclusion criteria for this review which was a small, open-label, unblinded, randomised trial of the safety and feasibility of switching from phenytoin to levetiracetam monotherapy or continuing phenytoin for glioma-related seizure control following craniotomy (Lim 2009). Levetiracetam (a non enzyme-inducing antiepileptic drug) appears to have been at least as well tolerated and as effective as phenytoin (an enzyme-inducing antiepileptic drug) for the treatment of seizures in people with brain tumours. Eighty-seven per cent of participants treated with levetiracetam were free of seizures at six months compared with 75% of participants treated with phenytoin.   There is one ongoing study of levetiracetam versus pregabalin for the treatment of seizures in adults undergoing chemotherapy, radiotherapy,or both for primary brain tumours. No data from this study were available at the time of preparing this review. There is a lack of robust, randomised, controlled evidence to support the choice of antiepileptic drug for the treatment of seizures in adults with brain tumours. While some authors support the use of non enzyme-inducing antiepileptic drugs, reliable, comparative evidence to provide clinical justification for this is limited. There is a need for further large, randomised, controlled trials in this area.
We included a total of 24 randomised controlled trials (reported in 39 published research articles or abstracts) in this review. The trials included 2352 participants with lumbar spinal stenosis with symptoms of neurogenic claudication. None of the included trials compared surgery with no treatment, placebo or sham surgery. Therefore, all included studies compared two or more surgical techniques. We judged all trials to be at high risk of bias for the blinding of care provider domain, and most of the trials failed to adequately conceal the randomisation process, blind the participants or use intention-to-treat analysis. Five trials compared the effects of fusion in addition to decompression surgery. Our results showed no significant differences in pain relief at long-term (mean difference (MD) -0.29, 95% confidence interval (CI) -7.32 to 6.74). Similarly, we found no between-group differences in disability reduction in the long-term (MD 3.26, 95% CI -6.12 to 12.63). Participants who received decompression alone had significantly less perioperative blood loss (MD -0.52 L, 95% CI -0.70 L to -0.34 L) and required shorter operations (MD -107.94 minutes, 95% CI -161.65 minutes to -54.23 minutes) compared with those treated with decompression plus fusion, though we found no difference in the number of reoperations (risk ratio (RR) 1.25, 95% CI 0.81 to 1.92). Another three trials investigated the effects of interspinous process spacer devices compared with conventional bony decompression. These spacer devices resulted in similar reductions in pain (MD -0.55, 95% CI -8.08 to 6.99) and disability (MD 1.25, 95% CI -4.48 to 6.98). The spacer devices required longer operation time (MD 39.11 minutes, 95% CI 19.43 minutes to 58.78 minutes) and were associated with higher risk of reoperation (RR 3.95, 95% CI 2.12 to 7.37), but we found no difference in perioperative blood loss (MD 144.00 mL, 95% CI -209.74 mL to 497.74 mL). Two trials compared interspinous spacer devices with decompression plus fusion. Although we found no difference in pain relief (MD 5.35, 95% CI -1.18 to 11.88), the spacer devices revealed a small but significant effect in disability reduction (MD 5.72, 95% CI 1.28 to 10.15). They were also superior to decompression plus fusion in terms of operation time (MD 78.91 minutes, 95% CI 30.16 minutes to 127.65 minutes) and perioperative blood loss (MD 238.90 mL, 95% CI 182.66 mL to 295.14 mL), however, there was no difference in rate of reoperation (RR 0.70, 95% CI 0.32 to 1.51). Overall there were no differences for the primary or secondary outcomes when different types of surgical decompression techniques were compared among each other. The quality of evidence varied from 'very low quality' to 'high quality'. The results of this Cochrane review show a paucity of evidence on the efficacy of surgery for lumbar spinal stenosis, as to date no trials have compared surgery with no treatment, placebo or sham surgery. Placebo-controlled trials in surgery are feasible and needed in the field of lumbar spinal stenosis. Our results demonstrate that at present, decompression plus fusion and interspinous process spacers have not been shown to be superior to conventional decompression alone. More methodologically rigorous studies are needed in this field to confirm our results.
Fifteen trials were included which tested two treatment regimes, 90 and 180 mg/day of nimodipine for 12, 24 weeks and 52 weeks. Two trials included only patients with Alzheimer's disease (AD), 10 trials included only patients with cerebrovascular dementia (CVD), and three trials included patients with AD, CVD and mixed disease. Available outcome data from nine trials (2492 patients) cover the domains of cognitive function, activities of daily living, global clinical state, safety and tolerability. By pooling available data from all trials, whatever the diagnosis of the patients included, this review found benefit associated with nimodipine (90 mg/day at 12 weeks) compared with placebo on the SCAG scale (WMD -7.59, 95% CI -9.87 to -5.31, P<0.00001), on clinical global impression (WMD -0.87, 95% CI -1.07 to -0.67, P<0.00001) and cognitive function (SMD 0.61, 95% CI 0.42 to 0.81, P<0.00001) but not on scales assessing activities of daily living. When the AD trials and the VD trials were pooled separately, similar significant results were found for the 90 mg/day dose of nimodipine at 12 weeks. Drop-out rates were low in the trials, affecting similar proportions of treatment and placebo groups. Nimodipine is well tolerated with a low rate of adverse effects similar to that associated with placebo. There were slightly more adverse cerebrovascular events, and adverse events due to blood problems, associated with placebo than with nimodipine, and adverse autonomic events were slightly more common with nimodipine than with placebo. Nimodipine can be of some benefit in the treatment of patients with features of dementia due to unclassified disease or to Alzheimer's disease, cerebrovascular disease, or mixed Alzheimer's and cerebrovascular disease. It appears to be well tolerated with few side effects. Data were not available from several trials, a total of more than 500 patients. A meta-analysis of individual patient data from all trials is desirable. Dementia is a chronic disorder and the short-term benefits of nimodipine demonstrated in the trials reviewed do not justify its use as a long-term anti-dementia drug. New research must focus on longer term outcomes.
Three studies (313 participants) met the inclusion criteria. One study compared INF versus intramuscular morphine (IMM); another study compared INF versus intravenous morphine (IVM); and another study compared standard concentration INF (SINF) versus high concentration INF (HINF). All three studies reported a reduction in pain score following INF administration. INF produced a greater reduction in pain score at 10 minutes post administration when compared with IMM (INF group pain score: 1/5 vs IMM group pain score: 2/5; P value 0.014). No other statistically significant differences in pain scores were reported at any other time point. When INF was compared with IVM and HINF, no statistically significant differences in pain scores were noted between treatment arms, before analgesia or at 5, 10, 20 and 30 minutes post analgesia. Specifically, when INF was compared with IVM, both agents were seen to produce a statistically significant reduction in pain score up to 20 minutes post analgesia. No further reduction in pain score was noted after this time. When SINF was compared with HINF, a statistically and clinically significant reduction in pain scores over study time was observed (median decrease for both groups 40 mm, P value 0.000). No adverse events (e.g. opiate toxicity, death) were reported in any study following INF administration. One study described better patient tolerance to INF compared with IMM, which achieved statistical significance. The other studies described reports of a “bad taste” and vomiting with INF. Overall the risk of bias in all studies was considered low. INF may be an effective analgesic for the treatment of patients with acute moderate to severe pain, and its administration appears to cause minimal distress to children. However, this review of published studies does not allow any definitive conclusions regarding whether INF is superior, non-inferior or equivalent to intramuscular or intravenous morphine. Limitations of this review include the following: few eligible studies for inclusion (three); no study examined the use of INF in children younger than three years of age; no study included children with pain from a "medical" cause (e.g. abdominal pain seen in appendicitis); and all eligible studies were conducted in Australia. Consequently, the findings may not be generalizable to other healthcare settings, to children younger than three years of age and to those with pain from a "medical" cause.
The review now includes 13 poorly reported randomised trials (total 478 people), all participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. There was no clear difference between vitamin E and placebo for the outcome of TD: not improved to a clinically important extent (6 RCTs, N = 264, RR 0.95, 95% CI 0.89 to 1.01, low-quality evidence). However, people allocated to placebo may show more deterioration of their symptoms compared with those given vitamin E (5 RCTs, N = 85, RR 0.23, 95% CI 0.07 to 0.76, low-quality evidence). There was no evidence of a difference in the incidence of any adverse effects (9 RCTs, N = 205, RR 1.21, 95% CI 0.35 to 4.15, very low-quality evidence), extrapyramidal adverse effects (1 RCT, N = 104, MD 1.10, 95% CI -1.02 to 3.22, very low-quality evidence), or acceptability of treatment (measured by participants leaving the study early) (medium term, 8 RCTs, N = 232, RR 1.07, 95% CI 0.64 to 1.80, very low-quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, outcomes designated important to patients. There is no trial-based information regarding the effect of vitamin E for those with early onset of TD. Small trials of limited quality suggest that vitamin E may protect against deterioration of TD. There is no evidence that vitamin E improves symptoms of this problematic and disfiguring condition once established. New and better trials are indicated in this under-researched area, and, of the many adjunctive treatments that have been given for TD, vitamin E would be a good choice for further evaluation.
This is an update of a Cochrane review from 2011, which included five trials. This update includes seven studies on treadmill intervention in 175 children: 104 were allocated to treadmill groups, and 71 were controls. The studies varied in population (children with Down syndrome, cerebral palsy, developmental delay or at moderate risk for neuromotor delay); comparison type (treadmill versus no treadmill; treadmill with versus without orthoses; high- versus low-intensity training); study duration, and assessed outcomes. Due to the diversity of the studies, only data from five studies were used in meta-analyses for five outcomes: age of independent walking onset, overall gross motor function, gross motor function related to standing and walking, and gait velocity. GRADE assessments of quality of the evidence ranged from high to very low. The effects of treadmill intervention on independent walking onset compared to no treadmill intervention was population dependent, but showed no overall effect (mean difference (MD) -2.08, 95% confidence intervals (CI) -5.38 to 1.22, 2 studies, 58 children; moderate-quality evidence): 30 children with Down syndrome benefited from treadmill training (MD -4.00, 95% CI -6.96 to -1.04), but 28 children at moderate risk of developmental delay did not (MD -0.60, 95% CI -2.34 to 1.14). We found no evidence regarding walking onset in two studies that compared treadmill intervention with and without orthotics in 17 children (MD 0.10, 95% CI -5.96 to 6.16), and high- versus low-intensity treadmill interventions in 30 children with Down syndrome (MD -2.13, 95% -4.96 to 0.70). Treadmill intervention did not improve overall gross motor function (MD 0.88, 95% CI -4.54 to 6.30, 2 studies, 36 children; moderate-quality evidence) or gross motor skills related to standing (MD 5.41, 95% CI -1.64 to 12.43, 2 studies, 32 children; low-quality evidence), and had a negligible improvement in gross motor skills related to walking (MD 4.51, 95% CI 0.29 to 8.73, 2 studies, 32 children; low-quality evidence). It led to improved walking skills in 20 ambulatory children with developmental delay (MD 7.60, 95% CI 0.88 to 14.32, 1 study) and favourable gross motor skills in 12 children with cerebral palsy (MD 8.00, 95% CI 3.18 to 12.82). A study which compared treadmill intervention with and without orthotics in 17 children with Down syndrome suggested that adding orthotics might hinder overall gross motor progress (MD -8.40, 95% CI -14.55 to -2.25). Overall, treadmill intervention showed a very small increase in walking speed compared to no treadmill intervention (MD 0.23, 95% CI 0.08 to 0.37, 2 studies, 32 children; high-quality evidence). Treadmill intervention increased walking speed in 20 ambulatory children with developmental delay (MD 0.25, 95% CI 0.08 to 0.42), but not in 12 children with cerebral palsy (MD 0.18, 95% CI -0.09 to 0.45). This update of the review from 2011 provides additional evidence of the efficacy of treadmill intervention for certain groups of children up to six years of age, but power to find significant results still remains limited. The current findings indicate that treadmill intervention may accelerate the development of independent walking in children with Down syndrome and may accelerate motor skill attainment in children with cerebral palsy and general developmental delay. Future research should first confirm these findings with larger and better designed studies, especially for infants with cerebral palsy and developmental delay. Once efficacy is established, research should examine the optimal dosage of treadmill intervention in these populations.
We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs). Compared with placebo, PCSK9 inhibitors decreased LDL-C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison. Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).
One cluster-RCT (with 157,259 participants) and four RCTs of individuals (1917 participants) met the inclusion criteria. The cluster-RCT from the former USSR showed that, compared with no vaccine, a live-attenuated vaccine (called STI) protected against clinical anthrax whether given by a needleless device (RR 0.16; 102,737 participants, 154 clusters) or the scarification method (RR 0.25; 104,496 participants, 151 clusters). Confidence intervals were statistically significant in unadjusted calculations, but when a small amount of association within clusters was assumed, the differences were not statistically significant. The four RCTs (of individuals) of inactivated vaccines (anthrax vaccine absorbed and recombinant protective antigen) showed a dose response relationship for the anti-protective antigen IgG antibody titre. Intramuscular administration was associated with fewer injection site reactions than subcutaneous injection, and injection site reaction rates were lower when the dosage interval was longer. One cluster-RCT provides limited evidence that a live-attenuated vaccine is effective in preventing cutaneous anthrax. Vaccines based on anthrax antigens are immunogenic in most vaccinees with few adverse events or reactions. Ongoing randomized controlled trials are investigating the immunogenicity and safety of anthrax vaccines.
Apart from the five studies in the original review, this update included one additional RCT. In total, the analysis included 171 participants, all during treatment for childhood acute lymphoblastic leukaemia (ALL). The duration of the training sessions ranged from 15 to 60 minutes per session. Both the type of intervention and intervention period varied in all the included studies. However, the control group always received usual care. All studies had methodological limitations, such as small numbers of participants, unclear randomization methods, and single-blind study designs in case of one RCT and all results were of moderate to very low quality (GRADE). Cardiorespiratory fitness was evaluated by the 9-minute run-walk test, timed up-and-down stairs test, the timed up-and-go time test, and the 20-m shuttle run test. Data of the 9-minute run-walk test and the timed up-and-down stairs test could be pooled. The combined 9-minute run-walk test results showed significant differences between the intervention and the control groups, in favour of the intervention group (standardized mean difference (SMD) 0.69; 95% confidence interval (CI) 0.02 to 1.35). Pooled data from the timed up-and-down stairs test showed no significant differences in cardiorespiratory fitness (SMD -0.54; 95% CI -1.77 to 0.70). However, there was considerable heterogeneity (I2 = 84%) between the two studies on this outcome. The other two single-study outcomes, 20-m shuttle run test and the timed up-and-go test, also showed positive results for cardiorespiratory fitness in favour of the intervention group. Only one study assessed the effect of exercise on bone mineral density (total body), showing a statistically significant positive intervention effect (SMD 1.07; 95% CI 0.48 to 1.66). The pooled data on body mass index showed no statistically significant end-score difference between the intervention and control group (SMD 0.59; 95% CI -0.23 to 1.41). Three studies assessed flexibility. Two studies assessed ankle dorsiflexion. One study assessed active ankle dorsiflexion, while the other assessed passive ankle dorsiflexion. There were no statistically significant differences between the intervention and control group with the active ankle dorsiflexion test; however, in favour of the intervention group, they were found for passive ankle dorsiflexion (SMD 0.69; 95% CI 0.12 to 1.25). The third study assessed body flexibility using the sit-and-reach distance test, but identified no statistically significant difference between the intervention and control group. Three studies assessed muscle strength (knee, ankle, back and leg, and inspiratory muscle strength). Only the back and leg strength combination score showed statistically significant differences on the muscle strength end-score between the intervention and control group (SMD 1.41; 95% CI 0.71 to 2.11). Apart from one sub-scale of the cancer scale (Worries; P value = 0.03), none of the health-related quality of life scales showed a significant difference between both study groups on the end-score. For the other outcomes of fatigue, level of daily activity, and adverse events (all assessed in one study), there were no statistically significant differences between the intervention and control group. None of the included studies evaluated activity energy expenditure, time spent on exercise, anxiety and depression, or self efficacy as an outcome. The effects of physical exercise training interventions for childhood cancer participants are not yet convincing. Possible reasons are the small numbers of participants and insufficient study designs, but it can also be that this type of intervention is not as effective as in adult cancer patients. However, the first results show some positive effects on physical fitness in the intervention group compared to the control group. There were positive intervention effects for body composition, flexibility, cardiorespiratory fitness, muscle strength, and health-related quality of life (cancer-related items). These were measured by some assessment methods, but not all. However, the quality of the evidence was low and these positive effects were not found for the other assessed outcomes, such as fatigue, level of daily activity, and adverse events. There is a need for more studies with comparable aims and interventions, using a higher number of participants that also include diagnoses other than ALL.
We could only include five studies conducted between 1965 and 1980. Most of the included studies did not report details of randomisation, allocation concealment, details of blinding and we could not assess the impact of attrition due to poor reporting. For the primary outcome of Global state - not improved, the confidence interval was compatible with a small benefit and increased risk of not improving with pericyazine compared with typical antipsychotics (2 RCTs, n = 122, RR 1.24 CI 0.93 to 1.66, very low quality of evidence) or atypical antipsychotics (1 RCT, n = 93, RR 0.97 CI 0.67 to 1.42, very low quality of evidence). When compared with typical antipsychotics relapse was only experienced by one person taking pericyazine (1 RCT, n = 80, RR 2.59 CI 0.11 to 61.75, very low quality of evidence). Pericyazine was associated with more extrapyramidal side effects than typical antipsychotics (3 RCTs, n = 163, RR 0.52 CI 0.34 to 0.80, very low quality of evidence) and atypical antipsychotics (1 RCT, n = 93, RR 2.69 CI 1.35 to 5.36, very low quality of evidence). The estimated risk of leaving the study early for specific reasons was imprecise for the comparisons of pericyazine with typical antipsychotics (2 RCTs, n = 71, RR 0.46 CI 0.11 to 1.90, very low quality of evidence), and with atypical antipsychotics (1 RCT, n = 93, RR 0.13 CI 0.01 to 2.42, very low quality of evidence). On the basis of very low quality evidence we are unable to determine the effects of pericyazine in comparison with typical or atypical antipsychotics for the treatment of schizophrenia. However, there is some evidence that pericyazine may be associated with a higher incidence of extrapyramidal side effects than other antipsychotics, and again this was judged to be very low quality evidence. Large, robust studies are still needed before any firm conclusions can be drawn.
Thirty studies met our inclusion criteria. From 11 studies on osteoporosis, meta-analysis of five studies (high-certainty evidence) showed that a combination of a GP alerting system on a patient's increased risk of osteoporosis and a patient-directed intervention (including patient education and a reminder to see their GP) improves GP behaviour with regard to diagnostic bone mineral density (BMD) testing and osteoporosis medication prescribing (RR 4.44; (95% confidence interval (CI) 3.54 to 5.55; 3 studies; 3,386 participants)) for BMD and RR 1.71 (95% CI 1.50 to 1.94; 5 studies; 4,223 participants) for osteoporosis medication. Meta-analysis of two studies showed that GP alerting on its own also probably improves osteoporosis guideline-consistent GP behaviour (RR 4.75 (95% CI 3.62 to 6.24; 3,047 participants)) for BMD and RR 1.52 (95% CI 1.26 to 1.84; 3.047 participants) for osteoporosis medication) and that adding the patient-directed component probably does not lead to a greater effect (RR 0.94 (95% CI 0.81 to 1.09; 2,995 participants)) for BMD and RR 0.93 (95% CI 0.79 to 1.10; 2,995 participants) for osteoporosis medication. Of the 10 studies on low back pain, seven showed that guideline dissemination and educational opportunities for GPs may lead to little or no improvement with regard to guideline-consistent GP behaviour. Two studies showed that the combination of guidelines and GP feedback on the total number of investigations requested may have an effect on GP behaviour and result in a slight reduction in the number of tests, while one of these studies showed that the combination of guidelines and GP reminders attached to radiology reports may result in a small but sustained reduction in the number of investigation requests. Of the four studies on osteoarthritis, one study showed that using educationally influential physicians may result in improvement in guideline-consistent GP behaviour. Another study showed slight improvements in patient outcomes (pain control) after training GPs on pain management. Of three studies on shoulder pain, one study reported that there may be little or no improvement in patient outcomes (functional capacity) after GP education on shoulder pain and injection training. Of two studies on other musculoskeletal conditions, one study on pain management showed that there may be worse patient outcomes (pain control) after GP training on the use of validated assessment scales. The 12 remaining studies across all musculoskeletal conditions showed little or no improvement in GP behaviour and patient outcomes. The direction of the targeted behaviour (i.e. increasing or decreasing a behaviour) does not seem to affect the effectiveness of an intervention. The majority of the studies did not investigate the potential adverse effects of the interventions and only three studies included a cost-effectiveness analysis. Overall, there were important methodological limitations in the body of evidence, with just a third of the studies reporting adequate allocation concealment and blinded outcome assessments. While our confidence in the pooled effect estimate of interventions for improving diagnostic testing and medication prescribing in osteoporosis is high, our confidence in the reported effect estimates in the remaining studies is low. There is good-quality evidence that a GP alerting system with or without patient-directed education on osteoporosis improves guideline-consistent GP behaviour, resulting in better diagnosis and treatment rates. Interventions such as GP reminder messages and GP feedback on performance combined with guideline dissemination may lead to small improvements in guideline-consistent GP behaviour with regard to low back pain, while GP education on osteoarthritis pain and the use of educationally influential physicians may lead to slight improvement in patient outcomes and guideline-consistent behaviour respectively. However, further studies are needed to ascertain the effectiveness of such interventions in improving GP behaviour and patient outcomes.
Our search strategies led to 699 potentially relevant references. Of these, one RCT involving 79 patients was included. We judged the quality of the trial as moderate. The study was reported as a randomised open-label study and published as a full-text article. Even though PFS was statistically significantly improved for patients treated with HD-MTX plus cytarabine (HR 0.54; 95% CI 0.31 to 0.92; P = 0.01), this did not translate to a statistical significant OS benefit (HR 0.65; 95% CI 0.38 to 1.13; P = 0.07). AEs, especially infective complications, hepatotoxicity and haematological toxicities, were assessed more often in patients undergoing HD-MTX therapy combined with cytarabine. However, there were no statistically significant differences in terms of TRM (RR 3.08; 95% CI 0.33 to 28.32; P = 0.35). Owing to the small number of included trials and patients, the findings in this review remain uncertain. In summary, the presently available evidence (one small trial) showed a benefit in terms of PFS, ORR and CRR but no statistically significant difference regarding OS for patients with PCNSL treated with HD-MTX plus cytarabine compared to HD-MTX alone. However, the risk of severe infections and toxicity was significantly higher in patients treated with combined chemotherapy. More RCTs with additional chemotherapy to HD-MTX therapy with higher numbers of patients and longer follow-up periods are needed to confirm the results of this review and determine whether the PFS benefit will translate into an OS advantage. At least the one included study shows that RCTs of moderate quality and with valuable outcomes for this malignant disease are feasible.
Six randomised controlled trials met the inclusion criteria for this review. Four studies compared LED and halogen light sources. Two studies compared LED and compact fluorescent light sources. The duration of phototherapy (six studies, 630 neonates) was comparable in LED and non-LED phototherapy groups (mean difference (hours) -0.43, 95% CI -1.91 to 1.05). The rate of decline of serum total bilirubin (STB) (four studies, 511 neonates) was also similar in the two groups (mean difference (mg/dL/hour) 0.01, 95% CI -0.02 to 0.04). Treatment failure, defined as the need of additional phototherapy or exchange blood transfusion (1 study, 272 neonates), was comparable (RR 1.83, 95% CI 0.47 to 7.17). Side effects of phototherapy such as hypothermia (RR 6.41, 95% CI 0.33 to 122.97), hyperthermia (RR 0.61, 95% CI 0.18 to 2.11) and skin rash (RR 1.83, 95% CI 0.17 to 19.96) were rare and occurred with similar frequency in the two groups. LED light source phototherapy is efficacious in bringing down levels of serum total bilirubin at rates that are similar to phototherapy with conventional (compact fluorescent lamp (CFL) or halogen) light sources. Further studies are warranted for evaluating efficacy of LED phototherapy in neonates with haemolytic jaundice or in the presence of severe hyperbilirubinaemia (STB ≥ 20 mg/dL).
Twenty studies (1150 women) were included. Women who had caesarean section performed under regional analgesia and had wound infiltration had a decrease in morphine consumption at 24 hours (SMD -1.70mg; 95% confidence interval (CI) -2.75 to -0.94) compared to placebo. In women under general anaesthesia, with caesarean section wound infiltration and peritoneal spraying with local anaesthetic (one study, 100 participants), the need for opioid rescue was reduced (risk ratio (RR) 0.51; 95% CI 0.38 to 0.69). The numerical pain score (0 to10) within the first hour was also reduced (mean difference (MD) -1.46; 95% CI -2.60 to -0.32). Women with regional analgesia who had local anaesthetic and non-steriodal anti-inflammatory cocktail wound infiltration consumed less morphine (one study, 60 participants; MD -7.40 mg; 95% CI -9.58 to -5.22) compared to local anaesthetic control. Women who had regional analgesia with abdominal nerves blocked had decreased opioid consumption (four studies, 175 participants; MD -25.80 mg; 95% CI -50.39 to -5.37). For the outcome of visual analogue scale 0 to 10 over 24 hours, no advantage was demonstrated in the single study of 50 participants who had wound infiltrated with a mixture of local analgesia and narcotics versus local analgesia. Addition of ketamine to the local analgesia in women who had regional analgesia does not confer any advantage. Local analgesia infiltration and abdominal nerve blocks as adjuncts to regional analgesia and general anaesthesia are of benefit in caesarean section by reducing opioid consumption. Nonsteroidal anti-inflammatory drugs as an adjuvant may confer additional pain relief.
We identified 16 eligible trials. Four trials are ongoing and two have been completed but the results have not yet been published (trial completion dates: April 2012 to February 2017). Therefore, the review included 10 trials in eight references with 554 participants. Six trials (336 participants) only included participants with acute myeloid leukaemia undergoing intensive chemotherapy, two trials (38 participants) included participants with lymphoma undergoing intensive chemotherapy and two trials (180 participants) reported participants undergoing allogeneic stem cell transplantation. Men and women were equally well represented in the trials. The age range of participants included in the trials was from 16 years to 81 years. All trials took place in high-income countries. The manufacturers of the agent sponsored eight trials that were under investigation, and two trials did not report their source of funding. No trials assessed artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin. Nine trials compared a TPO mimetic to placebo or standard care; seven of these used pegylated recombinant human megakaryocyte growth and differentiation factor (PEG-rHuMGDF) and two used recombinant human thrombopoietin (rhTPO). One trial compared platelet-poor plasma to platelet transfusion. We considered that all the trials included in this review were at high risk of bias and meta-analysis was not possible in seven trials due to problems with the way data were reported. We are very uncertain whether TPO mimetics reduce the number of participants with any bleeding episode (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.10 to 1.62, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce the risk of a life-threatening bleed after 30 days (OR 1.46, 95% CI 0.06 to 33.14, three trials, 209 participants, very low quality evidence); or after 90 days (OR 1.00, 95% CI 0.06 to 16.37, one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce platelet transfusion requirements after 30 days (mean difference -3.00 units, 95% CI -5.39 to -0.61, one trial, 120 participants, very low quality evidence). No deaths occurred in either group after 30 days (one trial, 120 participants, very low quality evidence). We are very uncertain whether TPO mimetics reduce all-cause mortality at 90 days (OR 1.00, 95% CI 0.24 to 4.20, one trial, 120 participants, very low quality evidence). No thromboembolic events occurred for participants treated with TPO mimetics or control at 30 days (two trials, 209 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed or quality of life. One trial with 18 participants compared platelet-poor plasma transfusion with platelet transfusion. We are very uncertain whether platelet-poor plasma reduces the number of participants with any bleeding episode (OR 16.00, 95% CI 1.32 to 194.62, one trial, 18 participants, very low quality evidence). We are very uncertain whether platelet-poor plasma reduces the number of participants with severe or life-threatening bleeding (OR 4.00, 95% CI 0.56 to 28.40, one trial, 18 participants, very low quality evidence). We found no trials that looked at: number of days on which bleeding occurred, time from randomisation to first bleed, number of platelet transfusions, all-cause mortality, thromboembolic events or quality of life. There is insufficient evidence to determine if platelet-poor plasma or TPO mimetics reduce bleeding for participants with haematological malignancies undergoing intensive chemotherapy or stem cell transplantation. To detect a decrease in the proportion of participants with clinically significant bleeding from 12 in 100 to 6 in 100 would require a trial containing at least 708 participants (80% power, 5% significance). The six ongoing trials will provide additional information about the TPO mimetic comparison (424 participants) but this will still be underpowered to demonstrate this level of reduction in bleeding. None of the included or ongoing trials include children. There are no completed or ongoing trials assessing artificial platelet substitutes, fibrinogen concentrate, recombinant activated factor VII or desmopressin in people undergoing intensive chemotherapy or stem cell transplantation for haematological malignancies.
We included eight RCTs that fulfilled our criteria, with a total of 3680 participants. The quality of evidence, according GRADE, varied by outcome and ranged from low to moderate. We found an incidence of DVT ranging from 4.3% to 40% in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least one week, and who received no prophylaxis, or placebo. This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization, with event rates ranging from 0% to 37% (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33 to 0.61; with minimal evidence of heterogeneity: I² = 26%, P = 0.23; seven studies; 1676 participants, moderate-quality evidence). Comparable results were seen in the following groups of participants: patients with below-knee casts, conservatively treated patients (non-operated patients), operated patients, patients with fractures, patients with soft-tissue injuries, and patients with distal or proximal thrombosis. No clear differences were found between the LMWH and control groups for pulmonary embolism (OR 0.50, 95% CI 0.17 to 1.47; with no evidence of heterogeneity: I² = 0%, P = 0.56; five studies, 2517 participants; low-quality evidence). The studies also showed less symptomatic VTE in the LMWH groups compared with the control groups (OR 0.40, 95% CI 0.21 to 0.76; with minimal evidence of heterogeneity: I² = 16%, P = 0.31; six studies; 2924 participants; low-quality evidence). One death was reported in the included studies, but no deaths due to pulmonary embolism were reported. Complications of major adverse events were rare, with minor bleeding the main adverse events reported. Moderate-quality evidence showed that the use of LMWH in outpatients reduced DVT when immobilization of the lower limb was required, when compared with no prophylaxis or placebo. The quality of the evidence was reduced to moderate because of risk of selection and attrition bias in the included studies. Low-quality evidence showed no clear differences in PE between the LMWH and control groups, but less symptomatic VTE in the LMWH groups. The quality of the evidence was downgraded due to risk of bias and imprecision.
A total of 10 RCTs and four quasi-randomised trials with 6466 participants met the inclusion criteria. Six studies involved minor procedures conducted in an outpatient or emergency department setting; eight studies involved major surgery conducted in theatre. Nine different topical antibiotics were included. We included two three-arm trials, two four-arm trials and 10 two-arm trials. The control groups comprised; an alternative topical antibiotic (two studies), topical antiseptic (six studies) and no topical antibiotic (10 studies), which comprised inert ointment (five studies) no treatment (four studies) and one study with one arm of each. The risk of bias of the 14 studies varied. Seven studies were at high risk of bias, five at unclear risk of bias and two at low risk of bias. Most risk of bias concerned risk of selection bias. Twelve of the studies (6259 participants) reported infection rates, although we could not extract the data for this outcome from one study. Four studies (3334 participants) measured allergic contact dermatitis as an outcome. Four studies measured positive wound swabs for patterns of antimicrobial resistance, for which there were no outcomes reported. No episodes of anaphylaxis were reported. Topical antibiotic versus no topical antibiotic We pooled the results of eight trials (5427 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with no topical antibiotic (RR 0.61, 95% CI 0.42 to 0.87; moderate-quality evidence downgraded once for risk of bias). This equates to 20 fewer SSIs per 1000 patients treated with topical antibiotics (95% CI 7 to 29) and a number needed to treat for one additional beneficial outcome (NNTB) (i.e. prevention of one SSI) of 50. We pooled the results of three trials (3012 participants) for the outcome of allergic contact dermatitis, however this comparison was underpowered, and it is unclear whether topical antibiotics affect the risk of allergic contact dermatitis (RR 3.94, 95% CI 0.46 to 34.00; very low-quality evidence, downgraded twice for risk of bias, once for imprecision). Topical antibiotic versus antiseptic We pooled the results of five trials (1299 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with using topical antiseptics (RR 0.49, 95% CI 0.30 to 0.80; moderate-quality evidence downgraded once for risk of bias). This equates to 43 fewer SSIs per 1000 patients treated with topical antibiotics instead of antiseptics (95% CI 17 to 59) and an NNTB of 24. We pooled the results of two trials (541 participants) for the outcome of allergic contact dermatitis; there was no clear difference in the risk of dermatitis between topical antibiotics and antiseptics, however this comparison was underpowered and a difference cannot be ruled out (RR 0.97, 95% CI 0.52 to 1.82; very low-quality evidence, downgraded twice for risk of bias and once for imprecision). Topical antibiotic versus topical antibiotic One study (99 participants) compared mupirocin ointment with a combination ointment of neomycin/polymyxin B/bacitracin zinc for the outcome of SSI. There was no clear difference in the risk of SSI, however this comparison was underpowered (very low-quality evidence downgraded twice for risk of bias, once for imprecision). A four-arm trial involved two antibiotic arms (neomycin sulfate/bacitracin zinc/polymyxin B sulphate combination ointment versus bacitracin zinc, 219 participants). There was no clear difference in risk of SSI between the combination ointment and the bacitracin zinc ointment. The quality of evidence for this outcome was low, downgraded once for risk of bias, and once for imprecision. Topical antibiotics applied to surgical wounds healing by primary intention probably reduce the risk of SSI relative to no antibiotic, and relative to topical antiseptics (moderate quality evidence). We are unable to draw conclusions regarding the effects of topical antibiotics on adverse outcomes such as allergic contact dermatitis due to lack of statistical power (small sample sizes). We are also unable to draw conclusions regarding the impact of increasing topical antibiotic use on antibiotic resistance. The relative effects of different topical antibiotics are unclear.
Thirteen studies (1403 enrolled patients) were identified. Risks of bias attributes were frequently poorly performed. Low risk of bias was reported in six studies (50%) for sequence generation (selection bias) and in seven (58%) for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and of outcome assessment (detection bias) was at low risk of bias in three studies. Five studies reported complete outcome data (attrition bias) while eight studies reported expected outcomes so were at low risk of reporting bias. Eight studies evaluated therapy to prevent persistent kidney disease in HSP. There was no significant difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32), or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of HSP compared with placebo or supportive treatment. There were no significant differences in the risk of persistent kidney disease with antiplatelet therapy in children with or without kidney disease at entry. Heparin significantly reduced the risk of persistent kidney disease by three months compared with placebo (1 study, 228 children: RR 0.27, 95% CI 0.14 to 0.55); no significant bleeding occurred. Four studies examined the treatment of severe HSP-associated kidney disease. Two studies (one involving 56 children and the other involving 54 adults) compared cyclophosphamide with placebo or supportive treatment and found no significant benefit of cyclophosphamide. There were no significant differences in adverse effects. In one study comparing cyclosporin with methylprednisolone (15 children) there was no significant difference in remission at final follow-up at a mean of 6.3 years (RR 1.37, 95% CI 0.74 to 2.54). In one study (17 children) comparing mycophenolate mofetil with azathioprine, there was no significant difference in the remission of proteinuria at one year (RR 1.32, 95% CI 0.86 to 2.03). No studies were identified which evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of HSP. There are no substantial changes in conclusions from this update compared with the initial review. From generally low quality evidence, we found no evidence of benefit from RCTs for the use of prednisone or antiplatelet agents to prevent persistent kidney disease in children with HSP. Though heparin appeared effective, this potentially dangerous therapy is not justified to prevent serious kidney disease when fewer than 2% of children with HSP develop severe kidney disease. No evidence of benefit has been found for cyclophosphamide treatment in children or adults with HSP and severe kidney disease. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin and mycophenolate mofetil have any roles in the treatment of children with HSP and severe kidney disease.
The searches identified 22 trials (34 references). Four trials (200 participants) are included: one short-term single-center trial (n = 7) comparing insulin with oral repaglinide and no medication in people with cystic fibrosis-related diabetes and normal fasting glucose; one long-term multicenter trial (n = 100, 74 of whom had cystic fibrosis-related diabetes) comparing insulin with oral repaglinide and placebo; one long-term multicenter trial (n = 73) comparing insulin with oral repaglinide; and one 12-week single-center trial (n = 20) comparing the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin. Two trials with data for the comparison of insulin to placebo did not report any significant differences between groups for the primary outcomes of blood glucose levels, lung function and nutritional status. This was also true for the single trial with data for the comparison of repaglinide to placebo. Two trials (one lasting one year and one lasting two years) contributed data for the comparison of insulin versus repaglinide. There were no significant differences for the primary outcomes at any time point, except at one year (in the two-year trial) when the insulin group had significant improvement in z score for body mass index compared to the repaglinide group. The single trial comparing glargine to neutral protamine Hagedorn insulin also did not report any significant differences in the review's primary outcomes. A few cases of hypoglycemia were seen in three out of the four trials (none in the longest trial), but these events resolved without further treatment. There was an unclear risk of bias from randomization and allocation concealment in two of the four included trials as the authors did not report any details; in the remaining two studies details for randomization led to a low risk of bias, but only one had sufficient details on allocation concealment to allow a low risk judgement, the second was unclear. There was a high risk from blinding for all trials (except for the comparison of oral repaglinide versus placebo) due to the nature of the interventions. Complete data for all outcomes were not available from any trial leading to a high risk of reporting bias. The amounts of insulin and repaglinide administered were not comparable and this may lead to bias in the results. None of the included trials were powered to show a significant improvement in lung function. This review has not found any significant conclusive evidence that long-acting insulins, short-acting insulins or oral hypoglycemic agents have a distinct advantage over one another in controlling hyperglycemia or clinical outcomes associated with cystic fibrosis-related diabetes. While some cystic fibrosis centers use oral medications to help control diabetes, the Cystic Fibrosis Foundation (USA) clinical practice guidelines support the use of insulin therapy and this remains the most widely-used treatment method. Randomized controlled trials specifically related to controlling diabetes with this impact on the course of pulmonary disease process in cystic fibrosis continue to be a high priority. There is no demonstrated advantage yet established for using oral hypoglycemic agents over insulin, and further trials need to be evaluated to establish whether there is clear benefit for using hypoglycemic agents. Agents that potentiate insulin action, especially agents with additional anti-inflammatory potential should be further investigated to see if there may be a clinical advantage to adding these medications to insulin as adjuvant therapy.
Two effectiveness trials (9823 infants) and one safety trial (48 mothers) were included. The main outcomes were measured on infants born to a subset of those randomised women who became pregnant during the course of the studies. For our primary outcomes, there was no high-quality evidence according to GRADE assessments. One study (1182 infants) assessed the effectiveness of tetanus toxoid in comparison with influenza vaccine in preventing neonatal tetanus deaths. A single dose did not provide significant protection against neonatal tetanus deaths, (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.26 to 1.24; 494 infants; GRADE: low-quality evidence). However, a two- or three-dose course did provide protection against neonatal deaths, (RR 0.02, 95% CI 0.00 to 0.30; 688 infants; GRADE: moderate-quality evidence). Administration of a two- or three-dose course resulted in significant protection when all causes of death are considered as an outcome (RR 0.31, 95% CI 0.17 to 0.55; 688 infants; GRADE: moderate-quality evidence). No effect was detected on causes of death other than tetanus. Cases of neonatal tetanus after at least one dose of tetanus toxoid were reduced in the tetanus toxoid group, (RR 0.20, 95% CI 0.10 to 0.40; 1182 infants; GRADE: moderate-quality evidence). Another study, involving 8641 children, assessed the effectiveness of tetanus-diphtheria toxoid in comparison with cholera toxoid in preventing neonatal mortality after one or two doses. Neonatal mortality was reduced in the tetanus-diphtheria toxoid group (RR 0.68, 95% CI 0.56 to 0.82). In preventing deaths at four to 14 days, neonatal mortality was reduced again in the tetanus-diphtheria toxoid group (RR 0.38, 95% CI 0.27 to 0.55). The quality of evidence as assessed using GRADE was found to be low. The third small trial assessed that pain at injection site was reported more frequently among pregnant women who received tetanus diphtheria acellular pertussis than placebo (RR 5.68, 95% CI 1.54 to 20.94; GRADE: moderate-quality evidence). Available evidence supports the implementation of immunisation practices on women of reproductive age or pregnant women in communities with similar, or higher, levels of risk of neonatal tetanus, to the two study sites.
We included six trials involving 418 patients for this review. The sample size in the trials varied from 30 to 131 patients. Only one trial involving 131 patients was of low risk of bias for mortality. This trial was at high risk of bias for other outcomes. Four trials excluded patients who underwent liver transplantation for acute liver failure. All the trials included livers obtained from cadaveric donors. The remaining five trials were of high risk of bias for all outcomes. Liver transplantation was performed by the conventional method (caval replacement) in two trials and piggy-back method (caval preservation) in one trial. The method of liver transplantation was not available in the remaining three trials. The comparisons performed included an initial hepatic artery flush versus initial portal vein flush; blood venting via inferior vena cava in addition to venting of storage fluid versus no blood venting; initial hepatic artery reperfusion versus initial portal vein reperfusion; simultaneous hepatic artery and portal vein reperfusion versus initial portal vein reperfusion; and retrograde inferior vena cava reperfusion versus simultaneous hepatic artery and portal vein reperfusion. Only one or two trials could be included under each comparison. There was no significant difference in mortality, graft survival, or severe morbidity rates in any of the comparisons. Quality of life was not reported in any of the trials. There is currently no evidence to support or refute the use of any specific technique of flushing or reperfusion during liver transplantation. Due to the paucity of data, absence of evidence should not be confused with evidence of absence of any differences. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.
A total of 2061 patients from seven RCTs were included for final analysis, with 1226 patients in the TOR group and 835 patients in the TAM group. The ORR for the TOR group was 25.8% (316/1226) whereas, the ORR for the TAM group was 26.9% (225/835). The pooled risk ratio (RR) suggested that the ORRs were not statistically different between the two groups (RR 1.02, 95% confidence interval (CI) 0.88 to 1.18, P = 0.83). The median TTP was 6.1 months for the TOR group and 5.8 months for the TAM group. The median OS was 27.8 months for the TOR group and 27.6 months for the TAM group. There were no significant differences in TTP and OS between the two therapeutic groups (for TTP: HR 1.08, 95% CI 0.94 to 1.24; for OS: HR 1.02, 95% CI 0.86 to 1.20). The frequencies of most adverse events were also similar in the two groups, while headache seemed to occur less in the TOR group than in the TAM group (RR 0.14, 95% CI 0.03 to 0.74, P = 0.02). There was no significant heterogeneity between studies in most of the above meta-analyses. Sensitivity analysis did not alter the results. TOR and TAM are equally effective and the safety profile of the former is at least not worse than the latter in the first-line treatment of patients with advanced breast cancer. Thus, TOR may serve as a reasonable alternative to TAM when anti-oestrogens are applicable but TAM is not the preferred choice for some reason.
We found two trials with 132 participants that met our inclusion criteria. One of the included trials was a quasi-randomised trial. Adjunctive corticosteroids reduced the risk of death (typical RR 0.46, 95% confidence interval (CI) 0.24 to 0.88; typical RD -0.19, 95% CI -0.33 to -0.04; NNTB = 6; two studies, 132 participants, very low-quality evidence) but did not have a significant effect on the number of infants with sensorineural deafness at two years (RR 1.80, 95% CI 0.18 to 18.21; RD 0.04, 95% CI -0.12 to 0.21; one study, 38 participants, low-quality evidence). In one trial, dexamethasone reduced the likelihood of hearing loss at four to 10 weeks post discharge (RR 0.41, 95% CI 0.17 to 0.98; RD -0.25, 95% CI -0.48 to -0.01; one study, 59 participants, low-quality evidence). Data reported on the other outcomes of interest were insufficient. Very low-quality data from two randomised controlled trials suggest that some reduction in death and hearing loss may result from use of adjunctive steroids alongside standard antibiotic therapy for treatment of patients with neonatal meningitis. Benefit is not yet seen with regards to reduction in neurological sequelae. Researchers who wish to clarify these findings must conduct more robustly designed trials with greater numbers of participants, evaluating more relevant outcomes and providing adequate follow-up.
Nineteen longitudinal studies that followed up a total of over 29,000 baseline nonsmokers met inclusion criteria. The studies measured exposure or receptivity to advertising and promotion in a variety of ways, including having a favourite advertisement or an index of receptivity based on awareness of advertising and ownership of a promotional item. One study measured the number of tobacco advertisements in magazines read by participants. All studies assessed smoking behaviour change in participants who reported not smoking at baseline. In 18 of the 19 studies the nonsmoking adolescents who were more aware of tobacco advertising or receptive to it, were more likely to have experimented with cigarettes or become smokers at follow up. There was variation in the strength of association, and the degree to which potential confounders were controlled for. Longitudinal studies consistently suggest that exposure to tobacco advertising and promotion is associated with the likelihood that adolescents will start to smoke. Based on the strength and specificity of this association, evidence of a dose-response relationship, the consistency of findings across numerous observational studies, temporality of exposure and smoking behaviours observed, as well as the theoretical plausibility regarding the impact of advertising, we conclude that tobacco advertising and promotion increases the likelihood that adolescents will start to smoke.
We included three new RCTs for this update, for a total of six included RCTs involving 559 children aged from 29 days to 12 years with pneumonia who were treated as inpatients. Pneumonia severity was described as moderate in one trial, severe in two trials, and was not stated in three trials. The studies assessed five different interventions: effects of conventional chest physiotherapy (3 studies, 211 children), positive expiratory pressure (1 study, 72 children), continuous positive airway pressure (CPAP) (1 study, 94 children), bubble CPAP (bCPAP) (1 study, 225 children), and assisted autogenic drainage (1 studies, 29 children). The included studies were conducted in Bangladesh, Brazil, China, Egypt, and South Africa. The studies were overall at low risk of bias. Blinding of participants was not possible in most studies, but we considered that the outcomes were unlikely to be influenced by the lack of blinding. One study of bCPAP reported that three deaths occurred in children in the physiotherapy group (N = 79), and 20 deaths in the control group (N = 146) (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.08 to 0.90; 225 children; low-quality evidence). One study of assisted autogenic drainage (N = 29), and one study of conventional chest physiotherapy (N = 72) reported no deaths occurred. It is uncertain whether chest physiotherapy techniques (bCPAP, assisted autogenic drainage, and conventional chest physiotherapy) reduced hospital stay duration (days) (mean difference (MD) 0.10, 95% CI -0.56 to 0.76; 4 studies; low-quality evidence). There was variation among clinical parameters used to define clinical resolution. Two small studies found no difference in resolution of fever between children in the physiotherapy (conventional chest physiotherapy and assisted autogenic drainage) and control groups. Of five studies that considered peripheral oxygen saturation levels, only two reported that use of chest physiotherapy (CPAP and conventional chest physiotherapy) showed a greater improvement in peripheral oxygen saturation levels. However, it was unclear whether respiratory rate (breaths/min) improved after conventional chest physiotherapy (MD -2.25, 95% CI -5.17 to 0.68; 2 studies, 122 children; low-quality evidence). Two studies assessed adverse events (number of events), but only one study reported any events (RR 1.28, 95% CI 0.98 to 1.67; 2 studies, 254 children; low-quality evidence). We could draw no reliable conclusions concerning the use of chest physiotherapy for children with pneumonia due to the small number of included trials with differing study characteristics and statistical presentation of data. Future studies should consider the following key points: appropriate sample size with adequate power to detect expected differences, standardisation of chest physiotherapy techniques, appropriate outcomes (such as duration of leukocytosis, and airway clearance), and adverse effects.
Three trials met our predefined inclusion criteria and were included for analysis in the review (499 participants). All three trials compared a standard trigger (10 x 109/L) versus a higher trigger (20 x 109/L or 30 x 109/L). None of the trials compared a low trigger versus a standard trigger or an alternative platelet trigger. The trials were conducted between 1991 and 2001 and enrolled participants from fairly comparable patient populations. The original review contained four trials (658 participants); in the previous update of this review we excluded one trial (159 participants) because fewer than 80% of participants had a haematological disorder. We identified no new trials in this update of the review. Overall, the methodological quality of the studies was low across different outcomes according to GRADE methodology. None of the included studies were at low risk of bias in every domain, and all the included studies had some threats to validity. Three studies reported the number of participants with at least one clinically significant bleeding episode within 30 days from the start of the study. There was no evidence of a difference in the number of participants with a clinically significant bleeding episode between the standard and higher trigger groups (three studies; 499 participants; risk ratio (RR) 1.35, 95% confidence interval (CI) 0.95 to 1.90; low-quality evidence). One study reported the number of days with a clinically significant bleeding event (adjusted for repeated measures). There was no evidence of a difference in the number of days of bleeding per participant between the standard and higher trigger groups (one study; 255 participants; relative proportion of days with World Health Organization Grade 2 or worse bleeding (RR 1.71, 95% CI 0.84 to 3.48, P = 0.162; authors' own results; low-quality evidence). Two studies reported the number of participants with severe or life-threatening bleeding. There was no evidence of any difference in the number of participants with severe or life-threatening bleeding between a standard trigger level and a higher trigger level (two studies; 421 participants; RR 0.99, 95% CI 0.52 to 1.88; low-quality evidence). Only one study reported the time to first bleeding episode. There was no evidence of any difference in the time to the first bleeding episode between a standard trigger level and a higher trigger level (one study; 255 participants; hazard ratio 1.11, 95% CI 0.64 to 1.91; low-quality evidence). Only one study reported on all-cause mortality within 30 days from the start of the study. There was no evidence of any difference in all-cause mortality between standard and higher trigger groups (one study; 255 participants; RR 1.78, 95% CI 0.83 to 3.81; low-quality evidence). Three studies reported on the number of platelet transfusions per participant. Two studies reported on the mean number of platelet transfusions per participant. There was a significant reduction in the number of platelet transfusions per participant in the standard trigger group (two studies, mean difference -2.09, 95% CI -3.20 to -0.99; low-quality evidence). One study reported on the number of transfusion reactions. There was no evidence to demonstrate any difference in transfusion reactions between the standard and higher trigger groups (one study; 79 participants; RR 0.07, 95% CI 0.00 to 1.09). None of the studies reported on quality of life. In people with haematological disorders who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT, we found low-quality evidence that a standard trigger level (10 x 109/L) is associated with no increase in the risk of bleeding when compared to a higher trigger level (20 x 109/L or 30 x 109/L). There was low-quality evidence that a standard trigger level is associated with a decreased number of transfusion episodes when compared to a higher trigger level (20 x 109/L or 30 x 109/L). Findings from this review were based on three studies and 499 participants. Without further evidence, it is reasonable to continue with the current practice of administering prophylactic platelet transfusions using the standard trigger level (10 x 109/L) in the absence of other risk factors for bleeding.
Four trials (five articles) met the inclusion criteria of this review; three were RCTs and one was a quasi-RCT; and included a total of 280 participants treated in neonatal intensive care units in the UK. The trials were published between 1980 and 1990. The studies were sufficiently similar regarding the research question they asked and the interventions that we could combine the trials to assess the effect of the intervention. Meta-analysis showed that the intervention produced no significant difference when compared to conservative management for the outcomes of: placement of hydrocephalus shunt (typical risk ratio (RR) 0.96, 95% confidence interval (CI) 0.73 to 1.26; 3 trials, 233 infants; I² statistic = 0%; moderate quality evidence), death (RR 0.88, 95% CI 0.53 to 1.44; 4 trials, 280 infants; I² statistic = 0%; low quality evidence), major disability in survivors (RR 0.98, 95% CI 0.81 to 1.18; 2 trials, 141 infants; I² statistic = 11%; high quality evidence), multiple disability in survivors (RR 0.9, 95% CI 0.66 to 1.24; 2 trials, 141 infants; I² statistic = 0%; high quality evidence), death or disability (RR 0.99, 95% CI 0.86 to 1.14; 2 trials, 180 infants; I² statistic = 0%; high quality evidence), death or shunt (RR 0.91, 95% CI 0.75 to 1.11; 3 trials, 233 infants; I² statistic = 0%; moderate quality evidence), and infection of CSF presurgery (RR 1.73, 95% CI 0.53 to 5.67; 2 trials, 195 infants; low quality evidence). We assessed the quality of the evidence as high for the outcomes of major disability, multiple disability, and disability or death. We rated the evidence for the outcomes of shunt insertion, and death or shunt insertion as of moderate quality as one included trial used an alternation method of randomisation. For the outcomes of death and infection of CSF presurgery, the quality of the evidence was low as one trial used an alternation method, the number of participants was too low to assess the objectives with sufficient precision, and there was inconsistency regarding the findings in the included trials regarding the outcome of infection of CSF presurgery. There was no evidence that repeated removal of CSF via lumbar puncture, ventricular puncture or from a ventricular reservoir produces any benefit over conservative management in neonates with or at risk for developing PHH in terms of reduction of disability, death, or need for placement of a permanent shunt.
Three eligible trials involving 569 patients were identified. Due to methodological limitations in the included studies, there was considerable variation in the results of acute (risk range 38.67% to 96.51%) and chronic pain (risk range 7.83% to 40.47%) across the control groups. Therefore, meta-analysis was not performed but the results of the outcomes in the individual trials were compared. Two trials involving 322 patients reported less chronic pain after preperitoneal repair (relative risk (RR) 0.18, number needed to treat (NNT) 8; RR 0.51, NNT 5), whereas one trial, including 247 patients, described more chronic pain after this repair (RR 1.17, NNT 77). The same trials favoured the preperitoneal technique concerning acute pain (RR 0.17, NNT 3; RR 0.78, NNT 7), whereas in the third trial it was almost omnipresent and thus comparable in both intervention arms (RR 0.997, NNT 333). Early and late hernia recurrence rates were similar across the studies, whereas contrasting results were reported for other early outcomes as infection and hematoma. No late mesh infection occurred in the included trials.  Both techniques are valid as they result in similar low recurrence rates. Evaluation of pain results in the individual trials shows some evidence that preperitoneal repair causes less or comparable acute and chronic pain compared to the Lichtenstein procedure. We emphasize the need for homogeneous high quality randomized trials comparing elective preperitoneal inguinal hernia techniques and Lichtenstein repair in terms of chronic pain.
We revisited decisions made in the earlier version of this review and excluded five studies that were previously included. We identified one new study for this update. This review includes six studies with 388 participants. We did not identify any studies in children. The included studies differed so much in their methods and comparisons that no synthesis of results was feasible. Only one study (103 participants) specifically reported the number of participants with a given level of pain relief, in this case a reduction of at least 20% - similar in both the methadone and morphine groups. Using an outcome of 'no worse than mild pain', methadone was similar to morphine in effectiveness, and most participants who could tolerate methadone achieved 'no worse than mild pain'. Adverse event withdrawals with methadone were uncommon (12/202) and similar in other groups. Deaths were uncommon except in one study where the majority of participants died, irrespective of treatment group. For specific adverse events, somnolence was more common with methadone than with morphine, while dry mouth was more common with morphine than with methadone. None of the studies reported effects on appetite. We judged the quality of evidence to be low, downgraded due to risk of bias and sparse data. For specific adverse events, we considered the quality of evidence to be very low, downgraded due to risk of bias, sparse data, and indirectness, as surrogates for appetite, thirst and somnolence were used. There were no data on the use of methadone in children. Based on low-quality evidence, methadone is a drug that has similar analgesic benefits to morphine and has a role in the management of cancer pain in adults. Other opioids such as morphine and fentanyl are easier to manage but may be more expensive than methadone in many economies.
For this update, eight additional studies were included making a total of 13 included studies with a combined total of 3081 randomised patients. Three studies compared UGFS with surgery, eight compared EVLT with surgery and five compared RFA with surgery (two studies had two or more comparisons with surgery). Study quality, evaluated through the six domains of risk of bias, was generally moderate for all included studies, however no study blinded participants, researchers and clinicians or outcome assessors. Also, nearly all included studies had other sources of bias. The overall quality of the evidence was moderate due to the variations in the reporting of results, which limited meaningful meta-analyses for the majority of proposed outcome measures. For the comparison UGFS versus surgery, the findings may have indicated no difference in the rate of recurrences in the surgical group when measured by clinicians, and no difference between the groups for symptomatic recurrence (odds ratio (OR) 1.74, 95% confidence interval (CI) 0.97 to 3.12; P = 0.06 and OR 1.28, 95% CI 0.66 to 2.49, respectively). Recanalisation and neovascularisation were only evaluated in a single study. Recanalisation at < 4 months had an OR of 0.66 (95% CI 0.20 to 2.12), recanalisation > 4 months an OR of 5.05 (95% CI 1.67 to 15.28) and for neovascularisation an OR of 0.05 (95% CI 0.00 to 0.94). There was no difference in the rate of technical failure between the two groups (OR 0.44, 95% CI 0.12 to 1.57). For EVLT versus surgery, there were no differences between the treatment groups for either clinician noted or symptomatic recurrence (OR 0.72, 95% CI 0.43 to 1.22; P = 0.22 and OR 0.87, 95% CI 0.47 to 1.62; P = 0.67, respectively). Both early and late recanalisation were no different between the two treatment groups (OR 1.05, 95% CI 0.09 to 12.77; P = 0.97 and OR 4.14, 95% CI 0.76 to 22.65; P = 0.10). Neovascularisation and technical failure were both statistically reduced in the laser treatment group (OR 0.05, 95% CI 0.01 to 0.22; P < 0.0001 and OR 0.29, 95% CI 0.14 to 0.60; P = 0.0009, respectively). Long-term (five-year) outcomes were evaluated in one study so no association could be derived,but it appeared that EVLT and surgery maintained similar findings. Comparing RFA versus surgery, there were no differences in clinician noted recurrence (OR 0.82, 95% CI 0.49 to 1.39; P = 0.47); symptomatic noted recurrence was only evaluated in a single study. There were also no differences between the treatment groups for recanalisation (early or late) (OR 0.68, 95% CI 0.01 to 81.18; P = 0.87 and OR 1.09, 95% CI 0.39 to 3.04; P = 0.87, respectively), neovascularisation (OR 0.31, 95% CI 0.06 to 1.65; P = 0.17) or technical failure (OR 0.82, 95% CI 0.07 to 10.10; P = 0.88). QoL scores, operative complications and pain were not amenable to meta-analysis, however quality of life generally increased similarly in all treatment groups and complications were generally low, especially major complications. Pain reporting varied greatly between the studies but in general pain was similar between the treatment groups. Currently available clinical trial evidence suggests that UGFS, EVLT and RFA are at least as effective as surgery in the treatment of great saphenous varicose veins. Due to large incompatibilities between trials and different time point measurements for outcomes, the evidence is lacking in robustness. Further randomised trials are needed, which should aim to report and analyse results in a congruent manner to facilitate future meta-analysis.
We included two unique studies with 446 randomised participants with clinically localised prostate cancer. The mean age, prostate volume, and prostate-specific antigen (PSA) of the participants were 61.3 years, 49.78 mL, and 7.09 ng/mL, respectively. Primary outcomes  We found no study that addressed the outcome of prostate cancer-specific survival. Based on data from one trial, RARP likely results in little to no difference in urinary quality of life (MD -1.30, 95% CI -4.65 to 2.05) and sexual quality of life (MD 3.90, 95% CI -1.84 to 9.64). We rated the quality of evidence as moderate for both quality of life outcomes, downgrading for study limitations. Secondary outcomes  We found no study that addressed the outcomes of biochemical recurrence-free survival or overall survival. Based on one trial, RARP may result in little to no difference in overall surgical complications (RR 0.41, 95% CI 0.16 to 1.04) or serious postoperative complications (RR 0.16, 95% CI 0.02 to 1.32). We rated the quality of evidence as low for both surgical complications, downgrading for study limitations and imprecision. Based on two studies, LRP or RARP may result in a small, possibly unimportant improvement in postoperative pain at one day (MD -1.05, 95% CI -1.42 to -0.68 ) and up to one week (MD -0.78, 95% CI -1.40 to -0.17). We rated the quality of evidence for both time-points as low, downgrading for study limitations and imprecision. Based on one study, RARP likely results in little to no difference in postoperative pain at 12 weeks (MD 0.01, 95% CI -0.32 to 0.34). We rated the quality of evidence as moderate, downgrading for study limitations. Based on one study, RARP likely reduces the length of hospital stay (MD -1.72, 95% CI -2.19 to -1.25). We rated the quality of evidence as moderate, downgrading for study limitations. Based on two study, LRP or RARP may reduce the frequency of blood transfusions (RR 0.24, 95% CI 0.12 to 0.46). Assuming a baseline risk for a blood transfusion to be 8.9%, LRP or RARP would result in 68 fewer blood transfusions per 1000 men (95% CI 78 fewer to 48 fewer). We rated the quality of evidence as low, downgrading for study limitations and indirectness. We were unable to perform any of the prespecified secondary analyses based on the available evidence. All available outcome data were short-term and we were unable to account for surgeon volume or experience. There is no high-quality evidence to inform the comparative effectiveness of LRP or RARP compared to ORP for oncological outcomes. Urinary and sexual quality of life-related outcomes appear similar. Overall and serious postoperative complication rates appear similar. The difference in postoperative pain may be minimal. Men undergoing LRP or RARP may have a shorter hospital stay and receive fewer blood transfusions. All available outcome data were short-term, and this study was unable to account for surgeon volume or experience.
We included 51 studies with 9052 participants. Of these, 45 trials assessed treatment outcomes at five weeks or less after commencement of treatment, and six trials assessed outcomes over a longer time frame. We believe that 24 trials had some form of conflict of interest, such as funding by pharmaceutical companies. Among the included studies were 12 ketoconazole trials (N = 3253), 11 ciclopirox trials (N = 3029), two lithium trials (N = 141), two bifonazole trials (N = 136) and one clotrimazole trial (N = 126) that compared the effectiveness of these treatments versus placebo or vehicle. Nine ketoconazole trials (N = 632) and one miconazole trial (N = 47) compared these treatments versus steroids. Fourteen studies (N = 1541) compared one antifungal versus another or compared different doses or schedules of administration of the same agent versus one another. Ketoconazole Topical ketoconazole 2% treatment showed a 31% lower risk of failed clearance of rashes compared with placebo (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.59 to 0.81, eight studies, low-quality evidence) at four weeks of follow-up, but the effect on side effects was uncertain because evidence was of very low quality (RR 0.97, 95% CI 0.58 to 1.64, six studies); heterogeneity between studies was substantial (I² = 74%). The median proportion of those who did not have clearance in the placebo groups was 69%. Ketoconazole treatment resulted in a remission rate similar to that of steroids (RR 1.17, 95% CI 0.95 to 1.44, six studies, low-quality evidence), but occurrence of side effects was 44% lower in the ketoconazole group than in the steroid group (RR 0.56, 95% CI 0.32 to 0.96, eight studies, moderate-quality evidence). Ketoconozale yielded a similar remission failure rate as ciclopirox (RR 1.09, 95% CI 0.95 to 1.26, three studies, low-quality evidence). Most comparisons between ketoconazole and other antifungals were based on single studies that showed comparability of treatment effects. Ciclopirox Ciclopirox 1% led to a lower failed remission rate than placebo at four weeks of follow-up (RR 0.79, 95% CI 0.67 to 0.94, eight studies, moderate-quality evidence) with similar rates of side effects (RR 0.9, 95% CI 0.72 to 1.11, four studies, moderate-quality evidence). Other antifungals Clotrimazole and miconazole efficacies were comparable with those of steroids on short-term assessment in single studies. Treatment effects on individual symptoms were less clear and were inconsistent, possibly because of difficulties encountered in measuring these symptoms. Evidence was insufficient to conclude that dose or mode of delivery influenced treatment outcome. Only one study reported on treatment compliance. No study assessed quality of life. One study assessed the maximum rash-free period but provided insufficient data for analysis. One small study in patients with HIV compared the effect of lithium versus placebo on seborrhoeic dermatitis of the face, but treatment outcomes were similar. Ketoconazole and ciclopirox are more effective than placebo, but limited evidence suggests that either of these agents is more effective than any other agent within the same class. Very few studies have assessed symptom clearance for longer periods than four weeks. Ketoconazole produced findings similar to those of steroids, but side effects were fewer. Treatment effect on overall quality of life remains unknown. Better outcome measures, studies of better quality and better reporting are all needed to improve the evidence base for antifungals for seborrhoeic dermatitis.
In three RCTs, 171 women over the age of 18 years were randomised to receive celecoxib 400 mg daily for 14 to 18 weeks versus placebo (one study, 130 participants), celecoxib 200 mg twice daily by mouth for six months versus placebo (one study, 25 participants), or rofecoxib 25 mg once daily by mouth for three months versus placebo (one study, 16 participants). The study with rofecoxib was discontinued when the medicine was withdrawn from the market in 2004. The trials ran from June 2005 to April 2012, June 2002 to October 2003, and May to October 2004, respectively. We have chosen to include the data from the rofecoxib study as outcomes may be similar when other such NSAIDs are utilised. Partial or complete regression of CIN 2 or CIN 3 occurred in 31 out of 70 (44%) in the treatment arms and 19 of 62 (31%) in the placebo arms (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.93 to 2.27; P value 0.10), three studies, 132 participants; moderate-certainty evidence). Complete regression of CIN 2 or CIN 3 occurred in 15 of 62 (24%) of those receiving celecoxib versus 10 of 54 (19%) of those receiving placebo (RR 1.31, 95% CI 0.65 to 2.67; P value 0.45, two studies, 116 participants; moderate-certainty evidence). Partial regression of CIN 2 or CIN 3 occurred in 14 of 62 (23%) of those receiving celecoxib versus 8 of 54 (15%) of those receiving placebo (RR 1.56, 95% CI 0.72 to 3.4; P value 0.26), two studies, 116 participants; moderate-certainty evidence). Progression to a higher grade of CIN, but not to invasive cancer, occurred in one of 12 (8%) of those receiving celecoxib and two of 13 (15%) receiving placebo (RR 0.54, 95% CI 0.05 to 5.24; P value 0.60, one study, 25 participants; very low-certainty evidence). Two studies reported no cases of progression to invasive cancer within the timeframe of the study. No toxicity was reported in the two original articles. The trial added in this update had one Grade 3 gastrointestinal adverse effect in the treatment arm, but otherwise had similar Grade 1 to 2 side effects between treatment and placebo groups. Although the studies were well-conducted and randomised, some risk of bias was detected in all studies. Furthermore, the duration of the studies was short, which may mask identifying progression to cancer. The addition of the trial in this update quadrupled the number of patients in the original review and was a well-designed multicentre trial thus, increasing the overall certainty of evidence from very low to moderate for this review. There are currently no convincing data to support a benefit for NSAIDs in the treatment of CIN. With the addition of this new, larger randomised trial we would rate this as overall moderate-certainty evidence by the GRADE criteria.
We identified 14 randomised trials that involved over 13,000 premenopausal women with operable breast cancer, most of whom were ER+. The numbers of trials making the different comparisons were: (A) i. LHRH versus tamoxifen (three trials), ii. LHRH versus chemotherapy (four trials); (B) i. LHRH + tamoxifen versus tamoxifen (two trials), ii. LHRH + tamoxifen versus LHRH (three trials), iii. LHRH + tamoxifen versus chemotherapy (two trials), iv. LHRH + aromatase inhibitor versus LHRH + tamoxifen (one trial); (C) i. LHRH + chemotherapy versus LHRH (one trial), ii. LHRH + chemotherapy versus chemotherapy (five trials); (D) LHRH + tamoxifen + chemotherapy versus chemotherapy (three trials). The LHRH agonist in most of these trials was goserelin. For most of the treatment comparisons there are too few trials, too few randomised patients, or too little follow up to draw reliable estimates of the relative effects of different treatments. (A) LHRH monotherapy: results suggest that adjuvant LHRH agonist monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrence-free and overall survival in ER+ patients. There are insufficient data to compare LHRH agonist monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrence-free survival. (B) LHRH + anti-oestrogen therapy: there are insufficient data to compare the combination of an LHRH agonist plus tamoxifen to tamoxifen alone. Results suggest that the LHRH agonist plus tamoxifen combination may be superior to an LHRH agonist alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing LHRH agonists plus aromatase inhibitors to LHRH agonists plus tamoxifen are currently inconclusive. (C) LHRH + chemotherapy: there are insufficient data to compare the LHRH + chemotherapy combination to an LHRH agonist alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus chemotherapy combination in comparison to chemotherapy alone. (D) LHRH agonist + chemotherapy + tamoxifen: there is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus tamoxifen plus chemotherapy in comparison to chemotherapy alone. There are insufficient data to assess the effect of the addition of LHRH agonists to the current standard treatment of chemotherapy plus tamoxifen. Endocrine therapy with LHRH agonists appears to have fewer side-effects than the forms of chemotherapy assessed. The optimal duration of LHRH therapy in the adjuvant setting is unclear. Overall, the data from currently published clinical trials of LHRH agonists in the adjuvant setting for premenopausal women with endocrine-sensitive breast cancer are supportive of clinical benefit. Nonetheless, definitive comparisons against current clinical standards of care that include third generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. The authors conclude that the current data strongly support the continuation of current trials that definitively compare a variety of combinations of LHRH agonists and anti-oestrogenic strategies to the current standard of five years of tamoxifen.
Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis was performed including 11 comparisons based on 1975 patients. The median follow up was six years. The pooled hazard ratio of death was 0.82 (95% confidence interval (CI) 0.71 to 0.95; P = 0.006) corresponding to an absolute survival benefit of 6% at five years from chemotherapy (from 56% to 62%). The pooled hazard ratio of tumour failure or death was 0.76 (95% CI 0.67 to 0.86; P < 0.00001) corresponding to an absolute event-free survival benefit of 10% at five years from chemotherapy (from 42% to 52%). A significant interaction was observed between chemotherapy timings and overall survival (P = 0.005), explaining the heterogeneity observed in the treatment effect (P = 0.03) with the highest benefit from concomitant chemotherapy. Chemotherapy led to a small but significant benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with radiotherapy.
Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta-analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all-cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr). For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all-cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non-fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarction, while seven adults would avoid experiencing new-onset albuminuria and two would avoid worsening albuminuria. This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured.
Seven trials involving 1558 participants were included in this review; 457 were involved in four trials of antibiotic medication, and 1101 were involved in three trials of beta-blocker medication. Five of the studies were rated at a high risk of bias. Individually, all of the included trials reported non-significant differences in AAA expansion rates between their intervention and control groups. The two major drug groups were then analysed separately. For AAA expansion it was only possible to combine two of the antibiotic trials in a meta-analysis. This demonstrated that roxithromycin had a small but significant protective effect (MD -0.86 mm; 95% confidence interval (CI) -1.57 to -0.14). When referral to AAA surgery was compared (including all four antibiotic trials in the meta-analysis), non-significantly fewer patients were referred in the intervention groups (OR 0.96; 95% CI 0.59 to 1.57) than the control groups. When only the trials reporting actual elective surgery were included in a subgroup analysis, the result remained statistically non-significant (OR 1.17; 95% CI 0.57 to 2.42). For the beta-blocker trials, when all were combined in a meta-analysis, there was a very small, non-significant protective effect for propranolol on AAA expansion (MD -0.08 mm; 95% CI -0.25 to 0.10), and non-significantly fewer patients were referred to AAA surgery in the propranolol group (OR 0.74; 95% CI 0.52 to 1.05). Bronchospasm and shortness of breath were the main adverse effects from the beta-blockers. In one trial the adverse effects were reportedly so severe that the trial was stopped early after two years. There is some limited evidence that antibiotic medication may have a slight protective effect in retarding the expansion rates of small AAAs. The quality of the evidence makes it unclear whether this translates into fewer referrals to AAA surgery, owing mainly to the small sample sizes of the studies. Antibiotics were generally well tolerated with minimal adverse effects. Propranolol was poorly tolerated by patients in all of the beta-blocker trials and demonstrated only minimal and non-significant protective effects. Further research on beta-blockers for AAA needs to consider the use of drugs other than propranolol. In general, there is surprisingly little high quality evidence on medical treatment for small AAAs, especially in relation to the use of newer beta-blockers, ACE inhibitors and statins.
Two RCTs involving 2024 patients (1502 adults and 522 children) were included in this review. Both RCTs excluded patients with suspected severe disease. It was not possible to pool the results due to incomplete data. Both included trials concluded that the use of chest radiographs did not result in a better clinical outcome (duration of illness and of symptoms) for patients with acute LRTIs. In the study involving children in South Africa, the median time to recovery was seven days (95% confidence interval (CI) six to eight days (radiograph group) and six to nine days (control group)), P value = 0.50, log-rank test) and the hazard ratio for recovery was 1.08 (95% CI 0.85 to 1.34). In the study with adult participants in the USA, the average duration of illness was 16.9 days versus 17.0 days (P value > 0.05) in the radiograph and no radiograph groups respectively. This result was not statistically significant and there were no significant differences in patient outcomes between the groups with or without chest radiograph. The study in adults also reports that chest radiographs did not affect the frequencies with which clinicians ordered return visits or antibiotics. However, there was a benefit of chest radiographs in a subgroup of the adult participants with an infiltrate on their radiograph, with a reduction in length of illness (16.2 days in the group allocated to chest radiographs and 22.6 in the non-chest radiograph group, P < 0.05), duration of cough (14.2 versus 21.3 days, P < 0.05) and duration of sputum production (8.5 versus 17.8 days, P < 0.05). The authors mention that this difference in outcome between the intervention and control group in this particular subgroup only was probably a result of "the higher proportion of patients treated with antibiotics when the radiograph was used in patient care". Hospitalisation rates were only reported in the study involving children and it was found that a higher proportion of patients in the radiograph group (4.7%) required hospitalisation compared to the control group (2.3%) with the result not being statistically significant (P = 0.14). None of the trials report the effect on mortality, complications of infection or adverse events from chest radiographs. Overall, the included studies had a low or unclear risk for blinding, attrition bias and reporting bias, but a high risk of selection bias. Both trials had strict exclusion criteria which is important but may limit the clinical practicability of the results as participants may not reflect those presenting in clinical practice. Data from two trials suggest that routine chest radiography does not affect the clinical outcomes in adults and children presenting to a hospital with signs and symptoms suggestive of a LRTI. This conclusion may be weakened by the risk of bias of the studies and the lack of complete data available.
We included five studies involving 113 adults. Participants in four studies had mild to moderate asthma and the fifth study included participants independent of their asthma severity. There were substantial differences between the studies, including the training protocol, duration of training sessions (10 to 30 minutes) and duration of the intervention (3 to 25 weeks). Three clinical trials were produced by the same research group. Risk of bias in the included studies was difficult to ascertain accurately due to poor reporting of methods. The included studies showed a statistically significant increase in inspiratory muscle strength, measured by maximal inspiratory pressure (PImax) (mean difference (MD) 13.34 cmH2O, 95% CI 4.70 to 21.98, 4 studies, 84 participants, low quality evidence). Our other primary outcome, exacerbations requiring a course of oral or inhaled corticosteroids or emergency department visits, was not reported. For the secondary outcomes, results from one trial showed no statistically significant difference between the inspiratory muscle training group and the control group for maximal expiratory pressure, peak expiratory flow rate, forced expiratory volume in one second, forced vital capacity, sensation of dyspnoea and use of beta2-agonist. There were no studies describing inspiratory muscle endurance, hospital admissions or days off work or school. There is no conclusive evidence in this review to support or refute inspiratory muscle training for asthma. The evidence was limited by the small number of trials with few participants together with the risk of bias. More well conducted randomised controlled trials are needed. Future trials should investigate the following outcomes: lung function, exacerbation rate, asthma symptoms, hospital admissions, use of medications and days off work or school. Inspiratory muscle training should also be assessed in people with more severe asthma and conducted in children with asthma.
This review included eight studies (with a total of 590 participants). Seven studies investigated the effects of hearing aids, four combination hearing aids and three sound generators. Seven studies were parallel-group RCTs and one had a cross-over design. In general, risk of bias was unclear due to lack of detail about sequence generation and allocation concealment. There was also little or no use of blinding. No data for our outcomes were available for any of our three main comparisons (comparing hearing aids, sound generators and combination devices with a waiting list control group, placebo or education/information only). Data for our additional comparisons (comparing these devices with each other) were also few, with limited potential for data pooling. Hearing aid only versus sound generator device only One study compared patients fitted with sound generators versus those fitted with hearing aids and found no difference between them in their effects on our primary outcome, tinnitus symptom severity measured with the Tinnitus Handicap Inventory (THI) at 3, 6 or 12 months (low-quality evidence). The use of both types of device was associated with a clinically significant reduction in tinnitus symptom severity. Combination hearing aid versus hearing aid only Three studies compared combination hearing aids with hearing aids and measured tinnitus symptom severity using the THI or Tinnitus Functional Index. When we pooled the data we found no difference between them (standardised mean difference -0.15, 95% confidence interval -0.52 to 0.22; three studies; 114 participants) (low-quality evidence). The use of both types of device was again associated with a clinically significant reduction in tinnitus symptom severity. Adverse effects were not assessed in any of the included studies. None of the studies measured the secondary outcomes of depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health-related quality of life as measured by a validated instrument, nor the newly developed core outcomes tinnitus intrusiveness, ability to ignore, concentration, quality of sleep and sense of control. There is no evidence to support the superiority of sound therapy for tinnitus over waiting list control, placebo or education/information with no device. There is insufficient evidence to support the superiority or inferiority of any of the sound therapy options (hearing aid, sound generator or combination hearing aid) over each other. The quality of evidence for the reported outcomes, assessed using GRADE, was low. Using a combination device, hearing aid or sound generator might result in little or no difference in tinnitus symptom severity. Future research into the effectiveness of sound therapy in patients with tinnitus should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the use of validated, patient-centred outcome measures for research in the field of tinnitus.
Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality. Primary outcomes  There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were lower in comparison to those with LABA alone, from nine studies which randomised 9921 participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our confidence in this effect was limited by statistical heterogeneity between the results of the studies (I2 = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed as the number of people experiencing one or more exacerbations over the course of the study, FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6 studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation. Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this effect from high to moderate. There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to 1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency). There was no significant difference in mortality between people on combined inhalers and those on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95% CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were no significant differences between the results for either exacerbations or pneumonia from trials adding different doses or types of inhaled corticosteroid. Secondary outcomes  ICS/LABA was more effective than LABA alone in improving health-related quality of life measured by the St George's Respiratory Questionnaire (1.58 units lower with FPS; 2.69 units lower with BDF), dyspnoea (0.09 units lower with FPS), symptoms (0.07 units lower with BDF), rescue medication (0.38 puffs per day fewer with FPS, 0.33 puffs per day fewer with BDF), and forced expiratory volume in one second (FEV1) (70 mL higher with FPS, 50 mL higher with BDF). Candidiasis (OR 3.75) and upper respiratory infection (OR 1.32) occurred more frequently with FPS than SAL. We did not combine adverse event data relating to candidiasis for BDF studies as the results were very inconsistent. Concerns over the analysis and availability of data from the studies bring into question the superiority of ICS/LABA over LABA alone in preventing exacerbations. The effects on hospitalisations were inconsistent and require further exploration. There was moderate quality evidence of an increased risk of pneumonia with ICS/LABA. There was moderate quality evidence that treatments had similar effects on mortality. Quality of life, symptoms score, rescue medication use and FEV1 improved more on ICS/LABA than on LABA, but the average differences were probably not clinically significant for these outcomes. To an individual patient the increased risk of pneumonia needs to be balanced against the possible reduction in exacerbations. More information would be useful on the relative benefits and adverse event rates with combination inhalers using different doses of inhaled corticosteroids. Evidence from head-to-head comparisons is needed to assess the comparative risks and benefits of the different combination inhalers.
No new trials were identified in this 2014 update. We included four trials (three RCTs and one quazi-RCT), with 759 children in the rapid viral testing group and 829 in the control group. Three out of the four studies were comparable in terms of young age of participants, with one study increasing the age of inclusion up to five years of age. All studies included either fever or respiratory symptoms as inclusion criteria (two required both, one required fever or respiratory symptoms, and one required only fever). All studies were comparable in terms of exclusion criteria, intervention, and outcome data. In terms of risk of bias, one study failed to utilize a random sequence generator, one study did not comment on completeness of outcome data, and only one of four studies included allocation concealment as part of the study design. None of the studies definitively blinded participants. Rapid viral testing resulted in a trend toward decreased antibiotic use in the ED, but this was not statistically significant. We found lower rates of chest radiography (RR 0.77, 95% CI 0.65 to 0.91) in the rapid viral testing group, but no effect on length of ED visits, or blood or urine testing in the ED. No study made mention of any adverse effects related to viral testing. There is insufficient evidence to support routine rapid viral testing to reduce antibiotic use in pediatric EDs. Rapid viral testing may or may not reduce rates of antibiotic use, and other investigations (urine and blood testing); these studies do not provide enough power to resolve this question. However, rapid viral testing does reduce the rate of chest X-rays in the ED. An adequately powered trial with antibiotic use as an outcome is needed.
Seven studies were included, they were all parallel-group studies, two studies were assessed as at low risk of bias and three at high risk of bias; two were considered to have unclear bias in their methodology. A total of 2241 participants were enrolled in these trials. Ibuprofen was found to be a superior analgesic to paracetamol at several doses with high quality evidence suggesting that ibuprofen 400 mg is superior to 1000 mg paracetamol based on pain relief (estimated from TOTPAR data) and the use of rescue medication meta-analyses. The risk ratio for at least 50% pain relief (based on TOTPAR) at six hours was 1.47 (95% confidence interval (CI) 1.28 to 1.69; five trials) favouring 400 mg ibuprofen over 1000 mg paracetamol, and the risk ratio for not using rescue medication (also favouring ibuprofen) was 1.50 (95% CI 1.25 to 1.79; four trials). The combined drug showed promising results, with a risk ratio for at least 50% of the maximum pain relief over six hours of 1.77 (95% CI 1.32 to 2.39) (paracetamol 1000 mg and ibuprofen 400 mg) (one trial; moderate quality evidence), and risk ratio not using rescue medication 1.60 (95% CI 1.36 to 1.88) (two trials; moderate quality evidence). The information available regarding adverse events from the studies (including nausea, vomiting, headaches and dizziness) indicated that they were comparable between the treatment groups. However, we could not formally analyse the data as it was not possible to work out how many adverse events there were in total. There is high quality evidence that ibuprofen is superior to paracetamol at doses of 200 mg to 512 mg and 600 mg to 1000 mg respectively based on pain relief and use of rescue medication data collected at six hours postoperatively. The majority of this evidence (five out of six trials) compared ibuprofen 400 mg with paracetamol 1000 mg, these are the most frequently prescribed doses in clinical practice. The novel combination drug is showing encouraging results based on the outcomes from two trials when compared to the single drugs.
We found only one trial, which included 61 women, that met our inclusion criteria. This trial reported data on surgical versus clinical staging and an assessment of the two surgical staging techniques; laparoscopic (LAP) versus extraperitoneal (EXP) surgical staging. The clinical staging was either a contrast-enhanced computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the abdomen and pelvis to determine nodal status. In this trial, clinical staging appeared to significantly prolong overall and progression-free survival compared to surgical staging. There was no statistically significant difference in the number of women who experienced severe (grade 3 or 4) toxicity. There was no statistically significant difference in the risk of death, disease recurrence or progression, blood loss, severe toxicity and the duration of the operational procedure between LAP and EXP surgical staging techniques. The strength of the evidence is weak in this review as it is based on one small trial that was at moderate risk of bias. Since the last version of this review no new studies were found. From the one available RCT we found insufficient evidence that pre-treatment surgical para-aortic lymph node assessment for locally advanced cervical cancer is beneficial, and it may actually have an adverse effect on survival. However, this conclusion is based on analysis of a small single trial and therefore definitive guidance or recommendations for clinical practice cannot be made. Therefore, the decision to offer surgical pre-treatment assessment of para-aortic lymph nodes in locally advanced cervical cancer needs to be individualised. The uncertainty regarding any impact on survival from pre-treatment para-aortic lymph node assessment should be discussed openly with the women.
Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update. There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens. Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop-outs were accounted for in all but one study. All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta-analysis should be treated with caution. Meta-analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence. The meta-analysis showed no significant difference in 1-year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta-analysis of 1-year overall survival for patients with good performance status (WHO performance status 0-1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1-year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence). Radiotherapy for patients with incurable non-small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.
We identified two RCTs involving 978 women with cervical cancer stage IIB to IVA. As the trials were significantly different clinically, we did not perform meta-analyses. One industry-funded trial involving 515 women compared CCRT (cisplatin) versus CCRT (cisplatin and gemcitabine) plus ACT (two additional cycles). This trial reported significant improvement in progression-free survival (PFS) and overall survival (OS) in women who were given CCRT plus ACT compared with those treated with CCRT alone: Three-year PFS was 74.4% versus 65.0% (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.49 to 0.95, P value 0.027), and three-year OS was 80% versus 69% (HR 0.68, 95% CI 0.49 to 0.95, P value 0.022). However, as the CCRT chemotherapy differed between the two arms, we considered the findings to be at high risk of bias. The second trial was a four-arm study from which we extracted data on 463 women in two study arms receiving CCRT (intravenous mitomycin C and oral 5-fluorouracil (5-FU)) or CCRT plus ACT (oral 5-FU for three cycles). The HR for OS in women who received ACT after CCRT compared with the HR for OS in those who were given CCRT alone was 1.309 (95% CI 0.795 to 2.157), and the HR for disease-free survival (DFS) was 1.125 (95% CI 0.799 to 1.586). Haematological adverse events were more common in the ACT arms of both trials. Quality of life (QoL) was not reported in either trial. With limited data from only two trials, we found insufficient evidence to support the use of ACT after CCRT. Future large trials are required to demonstrate efficacy, toxicities and QoL.
We selected 23 studies for inclusion (22 journal articles and one conference abstract). We evaluated the following scales: Cincinnati Prehospital Stroke Scale (CPSS; 11 studies), Recognition of Stroke in the Emergency Room (ROSIER; eight studies), Face Arm Speech Time (FAST; five studies), Los Angeles Prehospital Stroke Scale (LAPSS; five studies), Melbourne Ambulance Stroke Scale (MASS; three studies), Ontario Prehospital Stroke Screening Tool (OPSST; one study), Medic Prehospital Assessment for Code Stroke (MedPACS; one study) and PreHospital Ambulance Stroke Test (PreHAST; one study). Nine studies compared the accuracy of two or more scales. We considered 12 studies at high risk of bias and one with applicability concerns in the patient selection domain; 14 at unclear risk of bias and one with applicability concerns in the reference standard domain; and the risk of bias in the flow and timing domain was high in one study and unclear in another 16. We pooled the results from five studies evaluating ROSIER in the ER and five studies evaluating LAPSS in a prehospital setting. The studies included in the meta-analysis of ROSIER were of relatively good methodologic quality and produced a summary sensitivity of 0.88 (95% CI 0.84 to 0.91), with the prediction interval ranging from approximately 0.75 to 0.95. This means that the test will miss on average 12% of people with stroke/TIA which, depending on the circumstances, could range from 5% to 25%. We could not obtain a reliable summary estimate of specificity due to extreme heterogeneity in study-level results. The summary sensitivity of LAPSS was 0.83 (95% CI 0.75 to 0.89) and summary specificity 0.93 (95% CI 0.88 to 0.96). However, we were uncertain in the validity of these results as four of the studies were at high and one at uncertain risk of bias. We did not report summary estimates for the rest of the scales, as the number of studies per test per setting was small, the risk of bias was high or uncertain, the results were highly heterogenous, or a combination of these. Studies comparing two or more scales in the same participants reported that ROSIER and FAST had similar accuracy when used in the ER. In the field, CPSS was more sensitive than MedPACS and LAPSS, but had similar sensitivity to that of MASS; and MASS was more sensitive than LAPSS. In contrast, MASS, ROSIER and MedPACS were more specific than CPSS; and the difference in the specificities of MASS and LAPSS was not statistically significant. In the field, CPSS had consistently the highest sensitivity and, therefore, should be preferred to other scales. Further evidence is needed to determine its absolute accuracy and whether alternatives scales, such as MASS and ROSIER, which might have comparable sensitivity but higher specificity, should be used instead, to achieve better overall accuracy. In the ER, ROSIER should be the test of choice, as it was evaluated in more studies than FAST and showed consistently high sensitivity. In a cohort of 100 people of whom 62 have stroke/TIA, the test will miss on average seven people with stroke/TIA (ranging from three to 16). We were unable to obtain an estimate of its summary specificity. Because of the small number of studies per test per setting, high risk of bias, substantial differences in study characteristics and large between-study heterogeneity, these findings should be treated as provisional hypotheses that need further verification in better-designed studies.
Two studies tested gabapentin to treat fibromyalgia pain. One was identified in previous versions of the review and is included here. We identified another study as a conference abstract, with insufficient detail to determine eligibility for inclusion; it is awaiting assessment. The one included study of 150 participants was a 12-week, multi-centre, randomised, double-blind, placebo-controlled, parallel-group study using last-observation-carried-forward imputation for withdrawals. The maximum dose was 2400 mg daily. The overall risk of bias was low, except for attrition bias. At the end of the trial, the outcome of 50% reduction in pain over baseline was not reported. The outcome of 30% or greater reduction in pain over baseline was achieved by 38/75 participants (49%) with gabapentin compared with 23/75 (31%) with placebo (very low quality). A patient global impression of change any category of "better" was achieved by 68/75 (91%) with gabapentin and 35/75 (47%) with placebo (very low quality). Nineteen participants discontinued the study because of adverse events: 12 in the gabapentin group (16%) and 7 in the placebo group (9%) (very low quality). The number of serious adverse events were not reported, and no deaths were reported (very low quality). We have only very low quality evidence and are very uncertain about estimates of benefit and harm because of a small amount of data from a single trial. There is insufficient evidence to support or refute the suggestion that gabapentin reduces pain in fibromyalgia.
We included five RCTs involving 201 carers assessing the effectiveness of MBSR. Controls used in included studies varied in structure and content. Mindfulness-based stress reduction programmes were compared with either active controls (those matched for time and attention with MBSR, i.e. education, social support, or progressive muscle relaxation), or inactive controls (those not matched for time and attention with MBSR, i.e. self help education or respite care). One trial used both active and inactive comparisons with MBSR. All studies were at high risk of bias in terms of blinding of outcome assessment. Most studies provided no information about selective reporting, incomplete outcome data, or allocation concealment. 1. Compared with active controls, MBSR may reduce depressive symptoms of carers at the end of the intervention (3 trials, 135 participants; standardised mean difference (SMD) -0.63, 95% confidence interval (CI) -0.98 to -0.28; P<0.001; low-quality evidence). We could not be certain of any effect on clinically significant depressive symptoms (very low-quality evidence). Mindfulness-based stress reduction compared with active control may decrease carer anxiety at the end of the intervention (1 trial, 78 participants; mean difference (MD) -7.50, 95% CI -13.11 to -1.89; P<0.001; low-quality evidence) and may slightly increase carer burden (3 trials, 135 participants; SMD 0.24, 95% CI -0.11 to 0.58; P=0.18; low-quality evidence), although both results were imprecise, and we could not exclude little or no effect. Due to the very low quality of the evidence, we could not be sure of any effect on carers' coping style, nor could we determine whether carers were more or less likely to drop out of treatment. 2. Compared with inactive controls, MBSR showed no clear evidence of any effect on depressive symptoms (2 trials, 50 participants; MD -1.97, 95% CI -6.89 to 2.95; P=0.43; low-quality evidence). We could not be certain of any effect on clinically significant depressive symptoms (very low-quality evidence). In this comparison, MBSR may also reduce carer anxiety at the end of the intervention (1 trial, 33 participants; MD -7.27, 95% CI -14.92 to 0.38; P=0.06; low-quality evidence), although we were unable to exclude little or no effect. Due to the very low quality of the evidence, we could not be certain of any effects of MBSR on carer burden, the use of positive coping strategies, or dropout rates. We found no studies that looked at quality of life of carers or care-recipients, or institutionalisation. Only one included study reported on adverse events, noting a single adverse event related to yoga practices at home After accounting for non-specific effects of the intervention (i.e. comparing it with an active control), low-quality evidence suggests that MBSR may reduce carers' depressive symptoms and anxiety, at least in the short term. There are significant limitations to the evidence base on MBSR in this population. Our GRADE assessment of the evidence was low to very low quality. We downgraded the quality of the evidence primarily because of high risk of detection or performance bias, and imprecision. In conclusion, MBSR has the potential to meet some important needs of the carer, but more high-quality studies in this field are needed to confirm its efficacy.
The review includes 15 studies (N = 2428). Risk of selection bias is unclear in most of the studies, especially concerning allocation concealment. Other areas of risk such as missing data and selective reporting also caused some concern, although not affected on the direction of effect of our primary outcome, as demonstrated by sensitivity analysis. Many of the included trials have industry sponsorship of involvement. Nonetheless, generally people in the risperidone group are more likely to achieve a significant clinical improvement in mental state (6 RCTs, N = 864, RR 0.64, CI 0.52 to 0.78, very low-quality evidence). The effect withstood, even when three studies with >50% attrition rate were removed from the analysis (3 RCTs, N = 589, RR 0.77, CI 0.67 to 0.88). Participants receiving placebo were less likely to have a clinically significant improvement on Clinical Global Impression scale (CGI) than those receiving risperidone (4 RCTs, N = 594, RR 0.69, CI 0.57 to 0.83, very low-quality evidence). Overall, the risperidone group was 31% less likely to leave early compared to placebo group (12 RCTs, N = 2261, RR 0.69, 95% CI 0.62 to 0.78, low-quality evidence), but Incidence of significant extrapyramidal side effect was more likely to occur in the risperidone group (7 RCTs, N = 1511, RR 1.56, 95% CI 1.13 to 2.15, very low-quality evidence). When risperidone and placebo were augmented with clozapine, there is no significant differences between groups for clinical response as defined by a less than 20% reduction in PANSS/BPRS scores (2 RCTs, N = 98, RR 1.15, 95% CI 0.93 to 1.42, low-quality evidence) and attrition (leaving the study early for any reason) (3 RCTs, N = 167, RR 1.13, 95% CI 0.53 to 2.42, low quality evidence). One study measured clinically significant responses using the CGI, no effect was evident (1 RCT, N = 68, RR 1.12 95% CI 0.87 to 1.44, low quality evidence). No data were available for extrapyramidal adverse effects. Based on low quality evidence, risperidone appears to be benefitial in improving mental state compared with placebo, but it also causes more adverse events. Eight out of the 15 included trials were funded by pharmaceutical companies. The currently available evidence isvery low to low quality.
Nineteen studies met the inclusion criteria (with 10,400 participants randomly assigned, lasting between 4 and 156 weeks, mean 42 weeks). Studies used three different combined preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol). The studies were generally at low risk of bias for blinding but at unclear or high risk for attrition bias because of participant dropouts. Compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations. Mometasone/formoterol reduced the number of participants experiencing one or more exacerbation. Pooled analysis of the combined therapies indicated that exacerbations were less frequent when compared with placebo (Rate Ratio 0.73; 95% CI 0.69 to 0.78, 7 studies, 7495 participants); the quality of this evidence when GRADE criteria were applied was rated as moderate. Participants included in these trials had on average one or two exacerbations per year, which means that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years in these individuals. An overall reduction in mortality was seen, but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Generally, deaths in the smaller, shorter studies were too few to contribute to the overall estimate. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. When a baseline risk of death of 15.2% from the placebo arm of TORCH was used, the three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was 42 (95% CI 24 to 775). All three combined treatments led to statistically significant improvement in health status measurements, although the mean differences observed are relatively small in relation to the minimum clinically important difference. Furthermore, symptoms and lung function assessments favoured combined treatments. An increase in the risk of pneumonia was noted with combined inhalers compared with placebo treatment (OR 1.62, 95% CI 1.36 to 1.94), and the quality of this evidence was rated as moderate, but no dose effect was seen. The three-year NNTH for one extra case of pneumonia was 17, based on a 12.3% risk of pneumonia in the placebo arm of TORCH. Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy. Combined inhaler therapy led to around a quarter fewer COPD exacerbations than were seen with placebo. A significant reduction in all-cause mortality was noted, but this outcome was dominated by one trial (TORCH), emphasising the need for further trials of longer duration. Furthermore, we note there has been some debate about the appropriateness of the analysis conducted in the TORCH trial (see Feeback). Increased risk of pneumonia is a concern; however, this did not translate into increased exacerbations, hospitalisations or deaths. Current evidence does not suggest any major differences between inhalers in terms of effects, but nor is the evidence strong enough to demonstrate that all are equivalent. Importantly, we cannot comment on the relative contribution of the individual components of combined therapy to the effects identified, as this review presents only the pair-wise comparison between combined therapy and placebo. To permit firmer conclusions about the effects of combined therapy, more data are needed, particularly in relation to the profile of adverse events and benefits in relation to different formulations and doses of inhaled ICS. Head-to-head comparisons are necessary to determine whether one combined inhaler is better than the others.
A statistically significant benefit was observed for auranofin when compared to placebo for tender joint scores, pain, patient and physician global assessments and ESR. The standardized weighted mean difference between treatment and placebo was -0.39 (95% CI -0.54, -0.25) for tender joint scores, -0.08 (95% CI -0.22, -0.07) for swollen joint scores, and the weighed mean difference was -4.68 (95% CI -6.59, -2.77) for pain scores. The WMD for ESR was -9.85mm (95% CI -16.46, -3.25). Withdrawals from adverse reactions were 1.5 times higher in the auranofin group OR = 1.52 (95% CI 0.94, 2.46) but this result was not statistically significant. Patients receiving placebo were four times more likely to discontinue treatment because of lack of efficacy than patients receiving auranofin OR=0.29 (95% CI: 0.19, 0.43). Auranofin appears to have a small clinically and statistically significant benefit on the disease activity of patients with RA. The beneficial effects appear to be modest compared to drugs such as methotrexate or parenteral gold. Its effects on long term health status and radiological progression are not clear at this time.
Eleven studies with a total of 3716 participants were included. A consistent and strong reduction in the risk of recurrent venous thromboembolic events was observed during prolonged treatment with VKA (risk ratio (RR) 0.20, 95% confidence interval (CI) 0.11 to 0.38) independent of the period elapsed since the index thrombotic event. A statistically significant "rebound" phenomenon (ie, an excess of recurrences shortly after cessation of prolonged treatment) was not found (RR 1.28, 95% CI 0.97 to 1.70). In addition, a substantial increase in bleeding complications was observed for patients receiving prolonged treatment during the entire period after randomization (RR 2.60, 95% CI 1.51 to 4.49). No reduction in mortality was noted during the entire study period (RR 0.89, 95% CI 0.66 to 1.21, P = 0.46). In conclusion, this review shows that treatment with VKA strongly reduces the risk of recurrent VTE for as long as they are used. However, the absolute risk of recurrent VTE declines over time, although the risk for major bleeding remains. Thus, the efficacy of VKA administration decreases over time since the index event.
We identified two studies for inclusion. Both studies were randomised cross-over trials performed in single centres. Both studies used the Premature Infant Pain Profile (PIPP) score as a measure of pain response. Different methods of evaluating PIPP scores are presented including the absolute PIPP score, a PIPP score > 10 or > 12 and an increase in PIPP ≥ 4 from the baseline value. There is a nonsignificant reduction in pain scores at one minute and a nonsignificant increase at five minutes post insertion of the speculum. PIPP score > 12 at one minute resulted in a statistically significant reduction in the number of patients who experienced pain (typical risk ratio (RR) 0.56, 95% CI 0.36 to 0.89; typical risk difference (RD) -0.23, 95% CI -0.39 to -0.86; number needed to treat to benefit (NNTB) 4). When pain was defined as an increase in PIPP > 4 there was a statistically significant reduction in the absolute number of patients who experienced pain at one minute (typical RR 0.70, 95% CI 0.52 to 0.94; typical RD -0.19, 95% CI -0.34 to -0.04; NNTB 5.3). The administration of topical proparacaine 30 seconds prior to the ophthalmological evaluation was associated with a reduction in pain scores especially at the time of speculum insertion. However, despite treatment, screening remains a painful procedure and the role of nonpharmacological and pharmacological intervention including different local anaesthetic agents should be ascertained in future randomised trials.
In this update we found four randomised controlled trials involving 317 participants in total. Three of them including 295 participants, 148 allocated to surgery and 147 to non-surgical treatment reported information on our primary outcome (improvement at three months of follow-up). The pooled estimate favoured surgery (RR 1.23, 95% CI 1.04 to 1.46). Two trials including 245 participants described outcome at six month follow-up, also favouring surgery (RR 1.19, 95% CI 1.02 to 1.39). Two trials reported clinical improvement at one year follow-up. They included 198 patients favouring surgery (RR 1.27, 95% CI 1.05 to 1.53). The only trial describing changes in neurophysiological parameters in both groups also favoured surgery (RR 1.44, 95% CI 1.05 to 1.97). Two trials described need for surgery during follow-up, including 198 patients. The pooled estimate for this outcome indicates that a significant proportion of people treated medically will require surgery while the risk of re-operation in surgically treated people is low (RR 0.04 favouring surgery, 95% CI 0.01 to 0.17). Complications of surgery and medical treatment were described by two trials with 226 participants. Although the incidence of complications was high in both groups, they were significantly more common in the surgical arm (RR 1.38, 95% CI 1.08 to 1.76). Surgical treatment of carpal tunnel syndrome relieves symptoms significantly better than splinting. Further research is needed to discover whether this conclusion applies to people with mild symptoms and whether surgical treatment is better than steroid injection.
Four studies met the inclusion criteria. They were three cluster-randomised controlled trials and one with a stepped-wedge design. Changing task characteristics One study with 961 teachers in eight schools compared a task-based organisational change intervention along with stress management training to no intervention. It found a small reduction at 12 months in 10 out of 14 of the subscales in the Occupational Stress Inventory, with a mean difference (MD) varying from -3.84 to 0.13, and a small increase in the Work Ability Index (MD 2.27; 95% confidence interval (CI) 1.64 to 2.90; 708 participants, low-quality evidence). Changing organisational characteristics Two studies compared teacher training combined with school-wide coaching support to no intervention. One study with 59 teachers in 43 schools found no significant effects on job-related anxiety (MD -0.25 95% CI -0.61 to 0.11, very low-quality evidence) or depression (MD -0.26 95% CI -0.57 to 0.05, very low-quality evidence) after 24 months. The other study with 77 teachers in 18 schools found no significant effects on the Maslach Burnout Inventory subscales (e.g. emotional exhaustion subscale: MD -0.05 95% CI -0.52 to 0.42, low-quality evidence) or the Teacher Perceived Emotional Ability subscales (e.g. regulating emotions subscale: MD 0.11 95% CI -0.11 to 0.33, low-quality evidence) after six months. Multi-component intervention One study with 1102 teachers in 34 schools compared a multi-component intervention containing performance bonus, job promotion opportunities and mentoring support to a matched-comparison group consisting of 300 schools. It found moderately higher teacher retention rates (MD 11.50 95% CI 3.25 to 19.75 at 36 months follow-up, very low-quality evidence). However, the authors reported results only from one cohort out of four (eight schools), demonstrating a high risk of reporting bias. We found low-quality evidence that organisational interventions lead to improvements in teacher wellbeing and retention rates. We need further evaluation of the effects of organisational interventions for teacher wellbeing. These studies should follow a complex-interventions framework, use a cluster-randomised design and have large sample sizes.
We included 25 studies of which 4 are awaiting assessment. The 21 studies that could be analysed were 1 RCT, 14 cRCTs and 6 CBAs with a total of at least 3479 employees in intervention and control groups. We judged 12 studies to have an unclear risk of bias and the remaining nine studies to have a high risk of bias. Sixteen studies focused on improving supervisor-employee interaction, whereas five studies aimed at improving the design of working environments by means of supervisor training. Training versus no intervention We found very low-quality evidence that supervisor training does not reduce employees' stress levels (6 studies) or absenteeism (1 study) when compared to no intervention, regardless of intervention type or follow-up. We found inconsistent, very low-quality evidence that supervisor training aimed at employee interaction may (2 studies) or may not (7 studies) improve employees' well-being when compared to no intervention. Effects from two studies were not estimable due to missing data. Training versus placebo We found moderate-quality evidence (2 studies) that supervisor training off the job aimed at employee interaction does not reduce employees' stress levels more than a placebo training at mid-term follow-up. We found low-quality evidence in one study that supervisor training on the job aimed at employee interaction does not reduce employees' absenteeism more than placebo training at long-term follow-up. Effects from one study were not estimable due to insufficient data. Training versus other training One study compared the effects of supervisor training off the job aimed at employee interaction on employees' stress levels to training off the job aimed at working conditions at long-term follow-up but due to insufficient data, effects were not estimable. Based on a small and heterogeneous sample of controlled intervention studies and in contrast to prevailing consensus that supervisor behaviour influences employees' health and well-being, we found inconsistent evidence that supervisor training may or may not improve employees' well-being when compared to no intervention. For all other types of interventions and outcomes, there was no evidence of a considerable effect. However, due to the very low- to moderate-quality of the evidence base, clear conclusions are currently unwarranted. Well-designed studies are needed to clarify effects of supervisor training on employees' stress, absenteeism, and well-being.
We included nine randomised clinical trials (involving 861 women). The trials compared Chinese herbal medicines (various formulations) either alone (one trial), or in combination with other pharmaceuticals (seven trials) versus other pharmaceuticals alone. One study compared Chinese herbal medicines and other pharmaceuticals versus psychotherapy. We did not identify any trials comparing Chinese herbal medicines with placebo or no treatment, including bed rest. Various Chinese herbal medicines were used in the different trials (and some of the classical the formulations were modified in the trials). The Western pharmaceutical medicines included tocolytic drugs such as salbutamol and magnesium sulphate; hormonal supplementation with human chorionic gonadotrophin (HCG), progesterone or dydrogesterone; and supportive supplements such as vitamin E, vitamin K and folic acid. Overall, the methodological quality of the included studies was poor with unclear risk of bias for nearly all the 'Risk of bias' domains assessed. Chinese herbal medicines alone versus other pharmaceuticals alone - the live birth rate was no different between the two groups (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.67 to 1.65; one trial, 80 women). No data were available for the outcome of pregnancy rate (continuation of pregnancy after 20 weeks of gestation). In contrast, the continuing pregnancy rate (RR 1.27 95% CI 1.10 to 1.48, two trials, 189 women) and live birth rate (average RR 1.55; 95% CI 1.14 to 2.10; six trials, 601 women, Tau² = 0.10; I² = 73%) were higher among the group of women who received a combination of Chinese herbal medicines and other pharmaceuticals when compared with women who received other pharmaceuticals alone. For Chinese herbal medicines and psychotherapy versus psychotherapy alone (one study) - there was a higher live birth rate (RR 1.32; 95% CI 1.07 to 1.64; one trial, 90 women) in the group of women who received a combination of Chinese herbal medicines and psychotherapy compared to those women who received psychotherapy alone. No data were available on the continuing pregnancy rate for this comparison. Other primary outcomes (maternal adverse effect and toxicity rate and the perinatal adverse effect and toxicity rate) were not reported in most of the included studies. Two trials (341 women) reported that no maternal adverse effects were found (one trial compared (combined) medicines with other pharmaceuticals, and one trial compared combined Chinese herbal medicine alone versus other pharmaceuticals). One trial (Chinese herbal medicine alone versus other pharmaceuticals alone) reported that there were no abnormal fetuses (ultrasound) or after delivery. There were no data reported for any of this review's secondary outcomes. We found limited evidence (from nine studies with small sample sizes and unclear risk of bias) to assess the effectiveness of Chinese herbal medicines for treating unexplained recurrent miscarriage; no data were available to assess the safety of the intervention for the mother or her baby. There were no data relating to any of this review's secondary outcomes. From the limited data we found, a combination of Chinese herbal medicines and other pharmaceuticals (mainly Western medicines) may be more effective than Western medicines alone in terms of the rate of continuing pregnancy and the rate of live births. However, the methodological quality of the included studies was generally poor. A comparison of Chinese herbal medicines alone versus placebo or no treatment (including bed rest) was not possible as no relevant trials were identified. More high-quality studies are needed to further evaluate the effectiveness and safety of Chinese herbal medicines for unexplained recurrent miscarriage. In addition to assessing the effect of Chinese herbal medicines on pregnancy rate and the rate of live births, future studies should also consider safety issues (adverse effects and toxicity for the mother and her baby) as well as the secondary outcomes listed in this review. This review would provide more valuable information if the included studies could overcome the problems in their designs, such as lacking of qualified placebo-controlled trials, applying adequate randomisation methods and avoiding potential bias.
One study met our inclusion criteria (26 children with minimal change nephrotic syndrome) and 11 were excluded (nine cross-over studies, one where albumin was not used for nephrotic syndrome and one where authors did not state whether the children had oedema). Risk of bias for the included study was unclear for selection bias, high for performance and detection bias, low for attrition bias, and high for selective reporting. The included study compared albumin plus furosemide with an equal volume of dextrose. Of our prespecified outcomes, the authors reported clinical improvement as weight change, serum sodium and adverse outcomes (blood pressure). The authors reported a greater weight loss in the albumin treated group initially but no difference overall at 10 days. However, the data in the text and the figures were inconsistent so we could not confirm the authors statements (very low certainty evidence). It is uncertain whether albumin infusion improves serum sodium when compared with an equal volume of dextrose (MD 2.00 mEq/L, 95% CI -0.09 to 4.09), systolic blood pressure (MD 2.00 mmHg, 95% CI -3.52 to 7.52) or diastolic blood pressure (MD 2.00 mmHg, 95%CI -4.29 to 8.29). Death, quality of life, and kidney function were not reported. We identified only one small study that was relevant to our review, therefore we are unable to draw any conclusions regarding the use of human albumin with or without diuretics in nephrotic syndrome. More RCTs are needed.
Seven trials involving 570 participants met the inclusion criteria. Two small trials compared DFO with placebo (plus standard antimalarial drugs in both groups). No evidence of benefit or harm was shown in relation to death, but the trials were small (435 participants). The risk of experiencing persistent seizures was lower with DFO compared with placebo (RR 0.80, 95% CI 0.67 to 0.95; 334 participants, 1 trial), but adverse effects were more common with DFO. One small trial involving 45 adults and children compared deferiprone with placebo (plus standard antimalarial drugs in both groups). Participants in the deferiprone group had significantly faster coma recovery (MD -27 h, 95% CI -34.20 to -19.80) and parasite clearance (MD -24 h, 95% CI -35.27 to -12.73). No adverse effects were reported for this trial. There are insufficient data to draw any conclusions for DFO and deferiprone. There are nonsignificant trends towards fewer seizures but overall harm (death) with DFO, and results from one small trial of deferiprone suggest shorter coma recovery and parasite clearance. 2008: We do not plan to update this review given the paucity of recent trials in this area and other priorities in malaria treatment research.
One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with SCD. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children). Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/L and values below 5 µg/L (low-quality evidence). In the folic acid group, values above 18 µg/L were observed in 33 of 41 (81%) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/L, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year (low-quality evidence). It is important to note that none of the raw data for the outcomes listed above were available for analysis. The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio (RR) 0.99 (95% confidence interval (CI) 0.85 to 1.15) (low-quality evidence); major infections, RR 0.89 (95% CI 0.47 to 1.66) (low-quality evidence); dactylitis, RR 0.67 (95% CI 0.35 to 1.27) (low-quality evidence); acute splenic sequestration, RR 1.07 (95% CI 0.44 to 2.57) (low-quality evidence); or episodes of pain, RR 1.16 (95% CI 0.70 to 1.92) (low-quality evidence). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05). Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups. The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low. There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet). One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with SCD was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear. If further trials were conducted, these may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to SCD-related morbidity. Such trials should include people with SCD of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow-up, than the trial currently included in this review. However, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.
We included 34 studies, which includes one that was a follow-up study and 20 that were rated as being at high risk of bias. We conducted 14 meta-analyses assessing physical outcomes post-intervention. Nine meta-analyses showed significant findings favouring the intervention group for weight (MD -965.25 g; 95% CI -1360.52 to -569.98), length (MD -1.30 cm; 95% CI -1.60 to -1.00), head circumference (MD -0.81 cm; 95% CI -1.18 to -0.45), arm circumference (MD -0.47 cm; 95% CI -0.80 to -0.13), leg circumference (MD -0.31 cm; 95% CI -0.49 to -0.13), 24-hour sleep duration (MD -0.91 hr; 95% CI -1.51 to -0.30), time spent crying/fussing (MD -0.36; 95% CI -0.52 to -0.19), deceased levels of blood bilirubin (MD -38.11 mmol/L; 95% CI -50.61 to -25.61), and there were fewer cases of diarrhoea, RR 0.39; 95% CI 0.20 to 0.76). Non-significant results were obtained for cortisol levels, mean increase in duration of night sleep, mean increase in 24-hour sleep and for number of cases of upper respiratory tract disease and anaemia. Sensitivity analyses were conducted for weight, length and head circumference, and only the finding for length remained significant following removal of studies judged to be at high risk of bias. These three outcomes were the only ones that could also be meta-analysed at follow-up; although both weight and head circumference continued to be significant at 6-month follow-up, these findings were obtained from studies conducted in Eastern countries only. No sensitivity analyses were possible. We conducted 18 meta-analyses measuring aspects of mental health and development. A significant effect favouring the intervention group was found for gross motor skills (SMD -0.44; 95% CI -0.70 to -0.18), fine motor skills (SMD -0.61; 95% CI -0.87 to -0.35), personal and social behaviour (SMD -0.90; 95% CI -1.61 to -0.18) and psychomotor development (SMD -0.35; 95% CI -0.54 to -0.15); although the first three findings were obtained from only two studies, one of which was rated as being at high risk of bias, and the finding for psychomotor development was not maintained following following removal of studies judged to be at high risk of bias in a sensitivity analysis. No significant differences were found for a range of aspects of infant temperament, parent-infant interaction and mental development. Only parent-infant interaction could be meta-analysed at follow-up, and the result was again not significant. These findings do not currently support the use of infant massage with low-risk groups of parents and infants. Available evidence is of poor quality, and many studies do not address the biological plausibility of the outcomes being measured, or the mechanisms by which change might be achieved. Future research should focus on the impact of infant massage in higher-risk groups (for example, demographically and socially deprived parent-infant dyads), where there may be more potential for change.
Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants). The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating. In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this. One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%). There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.
Twenty studies met our inclusion criteria. Five investigated performance-based reward, where groups of smokers competed against each other to win a prize (N = 915). The remaining 15 used performance-based eligibility, where cessation resulted in entry into a prize draw (N = 10,580). Five of these used Quit & Win contests (N = 4282), of which three were population-level interventions. Fourteen studies were RCTs, and the remainder quasi-randomized or controlled trials. Six had suitable abstinence data for a meta-analysis, which did not show evidence of effectiveness of performance-based eligibility interventions (risk ratio (RR) 1.16, 95% confidence interval (CI) 0.77 to 1.74, N = 3201, I2 = 57%). No trials that used performance-based rewards found a beneficial effect of the intervention on long-term quit rates. The three population-level Quit & Win studies found higher smoking cessation rates in the intervention group (4% to 16.9%) than the control group at long-term follow-up, but none were RCTs and all had important between-group differences in baseline characteristics. These studies suggested that fewer than one in 500 smokers would quit because of the contest. Reported unintended consequences in all sets of studies generally related to discrepancies between self-reported smoking status and biochemically-verified smoking status. More serious adverse events were not attributed to the competition intervention. Using the GRADE system we rated the overall quality of the evidence for smoking cessation as ‘very low', because of the high and unclear risk of bias associated with the included studies, substantial clinical and methodological heterogeneity, and the limited population investigated. At present, it is impossible to draw any firm conclusions about the effectiveness, or a lack of it, of smoking cessation competitions. This is due to a lack of well-designed comparative studies. Smoking cessation competitions have not been shown to enhance long-term cessation rates. The limited evidence suggesting that population-based Quit & Win contests at local and regional level might deliver quit rates above baseline community rates has not been tested adequately using rigorous study designs. It is also unclear whether the value or frequency of possible cash reward schedules influence the success of competitions. Future studies should be designed to compensate for the substantial biases in the current evidence base.
Two studies met the inclusion criteria, involving a total of 22,106 participants. One study tested low height beds and the other tested bed exit alarms. Both studies used standard care for their control group and both studies were conducted in hospitals. No study investigating bed rails met the inclusion criteria. Due to the clinical heterogeneity of the interventions in the included studies pooling of data and meta-analysis was inappropriate, and so the results of the studies are described. A single cluster randomised trial of low height beds in 18 hospital wards, including 22,036 participants, found no significant reduction in the frequency of patient injuries due to their beds (there were no injuries in either group), patient falls in the bedroom (rate ratio 0.69, 95% CI 0.35 to 1.34), all falls (rate ratio 1.26, 95% CI 0.83 to 1.90) or patient injuries due to all falls (rate ratio 1.35, 95% CI 0.68 to 2.68). One randomised controlled trial of bed exit alarms in one hospital geriatric ward, involving 70 participants, found no significant reduction in the frequency of patient injuries due to their beds (there were no injuries in either group), patient falls out of bed (rate ratio 0.25, 95% CI 0.03 to 2.24), all falls (rate ratio 0.42, 95% CI 0.15 to 1.18) or patient injuries due to all falls (no injuries in either group). The effectiveness of interventions designed to prevent patient injuries from their beds (including bed rails, low height beds and bed exit alarms) remains uncertain. The available evidence shows no significant increase or decrease in the rate of injuries with the use of low height beds and bed exit alarms. Limitations of the two included studies include lack of blinding and insufficient power. No randomised controlled trials of bed rails were identified. Future reports should fully describe the standard care received by the control group.
Studies enrolled 37724 North American youth; participants were ethnically diverse. Programs took place in schools (10), community facilities (24), both schools and community facilities (2), healthcare facilities (2), and family homes (1). Median final follow-up occurred 12 months after baseline. Results showed no evidence that abstinence-plus programs can affect self-reported sexually transmitted infection (STI) incidence, and limited evidence that programs can reduce self-reported pregnancy incidence. Results for behavioral outcomes were promising; 23 of 39 evaluations found a significantly protective intervention effect for at least one behavioral outcome. Consistently favorable program effects were found for HIV knowledge. No adverse effects were observed. Several evaluations found that one version of an abstinence-plus program was more effective than another, suggesting that more research into intervention mechanisms is warranted. Methodological strengths included large samples and statistical controls for baseline values. Weaknesses included under-utilization of relevant outcomes, self-report bias, and analyses neglecting attrition and clustered randomization. Many abstinence-plus programs appear to reduce short-term and long-term HIV risk behavior among youth in high-income countries. Evidence for program effects on biological measures is limited. Evaluations consistently show no adverse program effects for any outcomes, including the incidence and frequency of sexual activity. Trials comparing abstinence-only, abstinence-plus, and safer-sex interventions are needed.
Four studies (606 patients) were included. All of the studies were rated as having a low risk of bias. Pooled analyses revealed that vedolizumab was significantly superior to placebo for induction of remission, clinical response, and endoscopic remission and prevention of relapse. After 4 to 6 weeks of therapy 77% (293/382) of vedolizumab patients failed to enter clinical remission compared to 92% (205/224) of placebo patients (RR 0.86, 95% CI 0.80 to 0.91; 4 studies 606 patients). After 6 weeks of therapy 48% of vedolizumab patients failed to have a clinical response compared to 72% of placebo patients (RR 0.68, 95% CI 0.59 to 0.78; 3 studies 601 patients). After 4 to 6 weeks of therapy 68% of vedolizumab patients failed to enter endoscopic remission compared to 81% of placebo patients (RR 0.82, 95% CI 0.75 to 0.91; 3 studies, b583 patients). After 52 weeks of therapy, 54% of vedolizumab patients had a clinical relapse compared to 84% of placebo patients (RR 0.67, 95% CI 0.59 to 0.77; 1 study, 373 patients). One small study (28 patients) found no statistically significant difference in endoscopic response (RR 1.00, 95% CI 0.62 to 1.61). GRADE analyses indicated that the overall quality of the evidence for the primary outcomes was high for induction of remission and moderate for relapse (due to sparse data 246 events). There was no statistically significant difference between vedolizumab and placebo in terms of the risk of any adverse event (RR 0.99, 95% CI 0.93 to 1.07), or serious adverse events (RR 1.01, 95% CI 0.72 to 1.42). There was a statistically significant difference in withdrawals due to adverse events. Six per cent of vedolizumab patients withdrew due to an adverse event compared to 11% of placebo patients (RR 0.55, 95% CI 0.35 to 0.87; 2 studies, 941 patients). Adverse events commonly reported across the studies included: worsening ulcerative colitis, headache, nasopharyngitis, upper respiratory tract infection, nausea, and abdominal pain. Moderate to high quality data from four studies shows that vedolizumab is superior to placebo for induction of clinical remission and response and endoscopic remission in patients with moderate to severely active ulcerative colitis and prevention of relapse in patients with quiescent ulcerative colitis. Moderate quality data from one study suggests that vedolizumab is superior to placebo for prevention of relapse in patients with quiescent ulcerative colitis. Adverse events appear to be similar to placebo. Future trials are needed to define the optimal dose, frequency of administration and long-term efficacy and safety of vedolizumab used for induction and maintenance therapy of ulcerative colitis. Vedolizumab should be compared to other currently approved therapies for ulcerative colitis in these trials.
Thirty-seven studies met the inclusion criteria and included a total of 5080 participants (range 50 to 1732). Enteric fever prevalence rates in the study populations ranged from 1% to 75% (median prevalence 24%, interquartile range (IQR) 11% to 46%). The included studies evaluated 16 different RDTs, and 16 studies compared two or more different RDTs. Only three studies used the Grade 1 reference standard, and only 11 studies recruited unselected febrile patients. Most included studies were from Asia, with five studies from sub-Saharan Africa. All of the RDTs were designed to detect S.Typhi infection only. Most studies evaluated three RDTs and their variants: TUBEX in 14 studies; Typhidot (Typhidot, Typhidot-M, and TyphiRapid-Tr02) in 22 studies; and the Test-It Typhoid immunochromatographic lateral flow assay, and its earlier prototypes (dipstick, latex agglutination) developed by the Royal Tropical Institute, Amsterdam (KIT) in nine studies. Meta-analyses showed an average sensitivity of 78% (95% confidence interval (CI) 71% to 85%) and specificity of 87% (95% CI 82% to 91%) for TUBEX; and an average sensitivity of 69% (95% CI 59% to 78%) and specificity of 90% (95% CI 78% to 93%) for all Test-It Typhoid and prototype tests (KIT). Across all forms of the Typhidot test, the average sensitivity was 84% (95% CI 73% to 91%) and specificity was 79% (95% CI 70% to 87%). When we based the analysis on the 13 studies of the Typhidot test that either reported indeterminate test results or where the test format means there are no indeterminate results, the average sensitivity was 78% (95% CI 65% to 87%) and specificity was 77% (95% CI 66% to 86%). We did not identify any difference in either sensitivity or specificity between TUBEX, Typhidot, and Test-it Typhoid tests when based on comparison to the 13 Typhidot studies where indeterminate results are either reported or not applicable. If TUBEX and Test-it Typhoid are compared to all Typhidot studies, the sensitivity of Typhidot was higher than Test-it Typhoid (15% (95% CI 2% to 28%), but other comparisons did not show a difference at the 95% level of CIs. In a hypothetical cohort of 1000 patients presenting with fever where 30% (300 patients) have enteric fever, on average Typhidot tests reporting indeterminate results or where tests do not produce indeterminate results will miss the diagnosis in 66 patients with enteric fever, TUBEX will miss 66, and Test-It Typhoid and prototype (KIT) tests will miss 93. In the 700 people without enteric fever, the number of people incorrectly diagnosed with enteric fever would be 161 with Typhidot tests, 91 with TUBEX, and 70 with Test-It Typhoid and prototype (KIT) tests. The CIs around these estimates were wide, with no difference in false positive results shown between tests. The quality of the data for each study was evaluated using a standardized checklist called QUADAS-2. Overall, the certainty of the evidence in the studies that evaluated enteric fever RDTs was low. In 37 studies that evaluated the diagnostic accuracy of RDTs for enteric fever, few studies were at a low risk of bias. The three main RDT tests and variants had moderate diagnostic accuracy. There was no evidence of a difference between the average sensitivity and specificity of the three main RDT tests. More robust evaluations of alternative RDTs for enteric fever are needed.
Two studies (154 participants) were included. There is low quality evidence from one randomised controlled study that exercises as an adjunctive to other conservative treatments increase the efficacy of these treatments (thoracic curve reduced: mean difference (MD) 9.00, (95% confidence interval (CI) 5.47 to 12.53); lumbar curve reduced:MD 8.00, (95% CI 5.08 to 10.92)). There is very low quality evidence from a prospective controlled cohort study that scoliosis-specific exercises structured within an exercise programme can reduce brace prescription (risk ratio (RR) 0.24, (95% CI 0.06 to1.04) as compared to usual physiotherapy (many different kinds of general exercises according to the preferences of the single therapists within different facilities). There is a lack of high quality evidence to recommend the use of SSE for AIS. One very low quality study suggested that these exercises may be more effective than electrostimulation, traction and postural training to avoid scoliosis progression, but better quality research needs to be conducted before the use of SSE can be recommended in clinical practice.
We included six trials, four of which took place in the USA. Four trials employed randomised controlled trial (RCT) designs. Trials were conducted in workplaces from the manufacturing, industrial and services-based sectors. The sample sizes of workplaces ranged from 12 to 114. Workplace policies and practices targeted included: healthy catering policies; point-of-purchase nutrition labelling; environmental supports for healthy eating and physical activity; tobacco control policies; weight management programmes; and adherence to guidelines for staff health promotion. All implementation interventions utilised multiple implementation strategies, the most common of which were educational meetings, tailored interventions and local consensus processes. Four trials compared an implementation strategy intervention with a no intervention control, one trial compared different implementation interventions, and one three-arm trial compared two implementation strategies with each other and a control. Four trials reported a single implementation outcome, whilst the other two reported multiple outcomes. Investigators assessed outcomes using surveys, audits and environmental observations. We judged most trials to be at high risk of performance and detection bias and at unclear risk of reporting and attrition bias. Of the five trials comparing implementation strategies with a no intervention control, pooled analysis was possible for three RCTs reporting continuous score-based measures of implementation outcomes. The meta-analysis found no difference in standardised effects (standardised mean difference (SMD) −0.01, 95% CI −0.32 to 0.30; 164 participants; 3 studies; low certainty evidence), suggesting no benefit of implementation support in improving policy or practice implementation, relative to control. Findings for other continuous or dichotomous implementation outcomes reported across these five trials were mixed. For the two non-randomised trials examining comparative effectiveness, both reported improvements in implementation, favouring the more intensive implementation group (very low certainty evidence). Three trials examined the impact of implementation strategies on employee health behaviours, reporting mixed effects for diet and weight status (very low certainty evidence) and no effect for physical activity (very low certainty evidence) or tobacco use (low certainty evidence). One trial reported an increase in absolute workplace costs for health promotion in the implementation group (low certainty evidence). None of the included trials assessed adverse consequences. Limitations of the review included the small number of trials identified and the lack of consistent terminology applied in the implementation science field, which may have resulted in us overlooking potentially relevant trials in the search. Available evidence regarding the effectiveness of implementation strategies for improving implementation of health-promoting policies and practices in the workplace setting is sparse and inconsistent. Low certainty evidence suggests that such strategies may make little or no difference on measures of implementation fidelity or different employee health behaviour outcomes. It is also unclear if such strategies are cost-effective or have potential unintended adverse consequences. The limited number of trials identified suggests implementation research in the workplace setting is in its infancy, warranting further research to guide evidence translation in this setting.
Nine randomized controlled trials involving the prophylactic use of antibiotics in patients having urodynamic studies were identified and these included 973 patients in total; one study was an abstract. Two further trials were excluded from the review. The methods of the included trials were poorly described. The primary outcome in all trials was the rate of developing significant bacteriuria, defined as the presence of more than 100,000 bacteria per millilitre of a mid-stream urine sample on culture and sensitivity testing. The other outcomes included pyrexia, haematuria, dysuria and adverse reactions to antibiotics. The administration of prophylactic antibiotics when compared to a placebo reduced the risk of significant bacteriuria (4% with antibiotics versus 12% without, risk ratio (RR) 0.35, 95% CI 0.22 to 0.56) in both men and women. The administration of prophylactic antibiotics also reduced the risk of haematuria (RR 0.46, 95% CI 0.23 to 0.91). However, there was no statistically significant difference in the primary outcome, risk of symptomatic urinary tract infection (40/201, 20% versus 59/214, 28%; RR 0.73, 95% CI 0.52 to 1.03); or in the risk of fever (RR 5.16, 95% CI 0.94 to 28.16) or dysuria (RR 0.83, 95% CI 0.5 to 1.36). Only two of 135 people had an adverse reaction to the antibiotics. The number of patients needed to treat with antibiotics to prevent bacteriuria was 12.3. Amongst women, the number needed to treat to prevent bacteriuria was 13.4; while amongst men it was 9.1 (number needed to treat = 1/ absolute risk reduction). Prophylactic antibiotics did reduce the risk of bacteriuria after urodynamic studies but there was not enough evidence to suggest that this effect reduced symptomatic urinary tract infections. There was no statistically significant difference in the risk of fever, dysuria or adverse reactions. Potential benefits have to be weighed against clinical and financial implications, and the risk of adverse effects.
This review included 16 studies with a total of 1024 participants aged between five and 18 years, all of whom were recruited from paediatric outpatient clinics. Studies were conducted in seven countries: seven in the USA, four in Iran, and one each in the UK, Switzerland, Turkey, Sri Lanka, and India. Follow-up ranged from two weeks to four months. The studies examined the following interventions to treat RAP: tricyclic antidepressants, antibiotics, 5-HT4 receptor agonists, antispasmodics, antihistamines, H2 receptor antagonists, serotonin antagonists, selective serotonin re-uptake inhibitors, a dopamine receptor antagonist, and a hormone. Although some single studies reported that treatments were effective, all of these studies were either small or had key methodological weaknesses with a substantial risk of bias. None of these 'positive' results have been reproduced in subsequent studies. We judged the evidence of effectiveness to be of low quality. No adverse effects were reported in these studies. There is currently no convincing evidence to support the use of drugs to treat RAP in children. Well-conducted clinical trials are needed to evaluate any possible benefits and risks of pharmacological interventions. In practice, if a clinician chooses to use a drug as a 'therapeutic trial', they and the patient need to be aware that RAP is a fluctuating condition and any 'response' may reflect the natural history of the condition or a placebo effect, rather than drug efficacy.
Six studies (involving 2105 women) are included. Overall, the included studies were not of high quality, and only two had both adequate randomisation sequence generation and allocation concealment. All studies that were able to be included enrolled only women at increased risk of complications. Comparison of traditional CTG versus no CTG showed no significant difference identified in perinatal mortality (risk ratio (RR) 2.05, 95% confidence interval (CI) 0.95 to 4.42, 2.3% versus 1.1%, four studies, N = 1627, low quality evidence) or potentially preventable deaths (RR 2.46, 95% CI 0.96 to 6.30, four studies, N = 1627), though the meta-analysis was underpowered to assess this outcome. Similarly, there was no significant difference identified in caesarean sections (RR 1.06, 95% CI 0.88 to 1.28, 19.7% versus 18.5%, three trials, N = 1279, low quality evidence). There was also no significant difference identified for secondary outcomes related to Apgar scores less than seven at five minutes (RR 0.83, 95% CI 0.37 to 1.88, one trial, N = 396, very low quality evidence); or admission to neonatal special care units or neonatal intensive care units (RR 1.08, 95% CI 0.84 to 1.39, two trials, N = 883, low quality evidence), nor in the other secondary outcomes that were assessed. There were no eligible studies that compared computerised CTG with no CTG. Comparison of computerised CTG versus traditional CTG showed a significant reduction in perinatal mortality with computerised CTG (RR 0.20, 95% CI 0.04 to 0.88, two studies, 0.9% versus 4.2%, 469 women, moderate quality evidence). However, there was no significant difference identified in potentially preventable deaths (RR 0.23, 95% CI 0.04 to 1.29, two studies, N = 469), though the meta-analysis was underpowered to assess this outcome. There was no significant difference identified in caesarean sections (RR 0.87, 95% CI 0.61 to 1.24, 63% versus 72%, one study, N = 59, low quality evidence), Apgar scores less than seven at five minutes (RR 1.31, 95% CI 0.30 to 5.74, two studies, N = 469, very low quality evidence) or in secondary outcomes. There is no clear evidence that antenatal CTG improves perinatal outcome, but further studies focusing on the use of computerised CTG in specific populations of women with increased risk of complications are warranted.
Seventeen studies with a total of 3898 participants were analysed. One studied fibrin sealant, and the other 16 studied HA. No evidence was found of a treatment effect of fibrin sealant as an adherence compound. For HA, evidence of a positive treatment effect was identified in the six trials that reported live birth rates (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.17 to 1.69; six RCTs, N = 1950, I2 = 0%, moderate-quality evidence). Furthermore, the 14 trials reporting clinical pregnancy rates showed evidence of treatment benefit when embryos were transferred in media containing functional concentrations of HA (OR 1.39, 95% CI 1.21 to 1.60; 14 RCTs, N = 3452, I2 = 46%, moderate-quality evidence) as compared with low or no use of HA. The multiple pregnancy rate (OR 1.86, 95% CI 1.49 to 2.31; five RCTs, N = 1951, I2 = 0%, moderate-quality evidence) was significantly increased in the high HA group, but no significant differences in adverse event rates were found (OR 0.74, 95% CI 0.49 to 1.12; four RCTs, N = 1525, I2 = 0%, moderate-quality evidence). Evidence suggests improved clinical pregnancy and live birth rates with the use of functional concentrations of HA as an adherence compound in ART cycles. However, the evidence obtained is of moderate quality. The increase in multiple pregnancy rate may be the result of use of a combination of an adherence compound and a policy of transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.
We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing. We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups. We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.
Fourteen clinical trials, involving 721 participants, met the criteria for inclusion in the review. Thirteen studies compared a pharmaceutical treatment with placebo (or a low dose of the intervention), in heterogenous groups of degenerative cerebellar ataxias. Three compounds were studied in two trials each: a levorotatory form of 5-hydroxytryptophan (L-5HT), idebenone and thyrotropin-releasing hormone tartrate (TRH-T); each of the other compounds (riluzole, varenicline, buspirone, betamethasone, coenzyme Q10 with vitamin E, α-tocopheryl quinone and erythropoietin) were studied in one trial. The 14th trial, involving a mixed group of participants with spinocerebellar ataxia, compared the effectiveness of nonspecific physiotherapy and occupational therapy within an inpatient hospital setting to no treatment. No studies utilised traditional speech therapies. We defined the primary outcome measure in this review as the percentage change (improvement) in overall speech production immediately following completion of the intervention or later, measured by any validated speech assessment tool. None of the trials included speech as a primary outcome or examined speech using any validated speech assessment tool. Eleven studies reported speech outcomes derived from a subscale embedded within disease rating scales. The remaining three studies used alternative assessments to measure speech, including mean time to produce a standard sentence, a subjective rating of speech on a 14-point analogue scale, patient-reported assessment of the impact of dysarthria on activities of daily living and acoustic measures of syllable length. One study measured speech both subjectively as part of a disease rating scale and with further measures of speech timing. Three studies utilised the Short Form-36 Health Survey (SF-36) and one used the Child Health Questionnaire as measures of general quality of life. A further study utilised the Functional Independence Measure to assess functional health. Five studies reported statistically significant improvement on an overall disease rating scale in which a speech subscale was included. Only three of those studies provided specific data on speech performance; all were comparisons with placebo. Improvements in overall disease severity were observed with α-tocopheryl quinone; however, no significant changes were found on the speech subscale in a group of individuals with Friedreich ataxia. A statistically significant improvement in speech according to a speech disorders subscale was observed with betamethasone. Riluzole was found to have a statistically significant effect on speech in a group of participants with mixed hereditary, sporadic and unknown origin ataxias. No significant differences were observed between treatment and placebo in any other pharmaceutical study. A statistically significant improvement in functional independence occurred at the end of the treatment period in the rehabilitation study compared to the delayed treatment group but these effects were not present 12 to 24 weeks after treatment. Of the four studies that assessed quality of life, none found a significant effect. A variety of minor adverse events were reported for the 13 pharmaceutical therapies, including gastrointestinal side effects and nausea. Serious adverse effects were reported in two participants in one of the L-5HT trials (participants discontinued due to gastrointestinal effects), and in four participants (three taking idebenone, one taking placebo) in the idebenone studies. Serious adverse events with idebenone were gastrointestinal side effects and, in people with a previous history of these events, chest pain and idiopathic thrombocytopenic purpura. The rehabilitation study did not report any adverse events. We considered six studies to be at high risk of bias in some respect. We suspected inadequate blinding of participants or assessors in four studies and poor randomisation in a further two studies. There was a high risk of reporting bias in two studies and attrition bias in four studies. Only one study had a low risk of bias across all criteria. Taken together with other limitations of the studies relating to the validity of the measurement scales used, we downgraded the quality of the evidence for many of the outcomes to low or very low. There is insufficient and low or very low quality evidence from either RCTs or observational studies to determine the effectiveness of any treatment for speech disorder in any of the hereditary ataxia syndromes.
We found only one study that met our inclusion criteria. This was a randomised double blind, placebo-controlled multicentre study conducted to evaluate the effectiveness of a single dose of intravenous tranexamic acid (15 mg/kg body weight) versus placebo, given immediately before surgery for reducing blood loss and the need for red blood cell transfusion. The mean total estimated blood loss was 668.34 mL and 916.93 mL for participants assigned to tranexamic acid and placebo groups, respectively. The mean difference (MD) of total estimated blood loss between the groups did not show a clinically important effect (MD − 248.59 mL; 95% confidence interval (CI) − 550.9 to 53.79; one study, 100 participants; moderate quality evidence). The mean number of transfused units of blood components was not different between the two groups (low quality evidence). There were no noted differences in the incidence of reoperation, readmission or thromboembolic events (very low quality evidence). We considered the methodology of the included study to be at low risk of selection, detection, and reporting biases. However, we were concerned about an imbalance of some baseline characteristics between the groups, and as there was no protocol for blood transfusion, the rate of blood transfusion may vary depending on the practice of each participating hospital. Currently, there is insufficient evidence to recommend the routine use of tranexamic acid for reducing blood loss in women undergoing cytoreductive surgery for advanced EOC, as only limited data are available from a single, low quality RCT at low overall risk of bias.
No trials comparing different systolic BP targets were found. Seven trials (22,089 subjects) comparing different diastolic BP targets were included. Despite a -4/-3 mmHg greater achieved reduction in systolic/diastolic BP, p< 0.001, attempting to achieve "lower targets" instead of "standard targets" did not change total mortality (RR 0.92, 95% CI 0.86-1.15), myocardial infarction (RR 0.90, 95% CI 0.74-1.09), stroke (RR 0.99, 95% CI 0.79-1.25) , congestive heart failure (RR 0.88, 95% CI 0.59-1.32), major cardiovascular events (RR 0.94, 95% CI 0.83-1.07), or end-stage renal disease (RR 1.01, 95% CI 0.81-1.27). The net health effect of lower targets cannot be fully assessed due to lack of information regarding all total serious adverse events and withdrawals due to adverse effects in 6 of 7 trials. A sensitivity analysis in diabetic patients and in patients with chronic renal disease also did not show a reduction in any of the mortality and morbidity outcomes with lower targets as compared to standard targets. Treating patients to lower than standard BP targets, ≤140-160/90-100 mmHg, does not reduce mortality or morbidity. Because guidelines are recommending even lower targets for diabetes mellitus and chronic renal disease, we are currently conducting systematic reviews in those groups of patients.
We found 10 trials (23 reports) of education and support for breastfeeding that included women with twins or higher order multiples. The quality of evidence was mixed, and the risk of bias was mostly high or unclear. It is difficult to blind women or staff to group allocation for this intervention, so in all studies there was high risk of performance and high or unclear risk of detection bias. Trials recruited 5787 women (this included 512 women interviewed as part of a cluster randomised trial); of these, data were available from two studies for 42 women with twins or higher order multiples. None of the interventions were specifically designed for women with more than one infant, and the outcomes for multiples were not reported separately for each infant. Due to the scarcity of evidence and the format in which data were reported, a narrative description of the data is presented, no analyses are presented in this review, and we were unable to GRADE the evidence. The two trials with data for women with multiple births compared home nurse visits versus usual care (15 women), and telephone peer counselling versus usual care (27 women). The number of women who initiated breastfeeding was reported (all 15 women in one study, 25 out of 27 women in one study). Stopping any breastfeeding before four to six weeks postpartum, stopping exclusive breastfeeding before four to six weeks postpartum, stopping any breastfeeding before six months postpartum andstopping exclusive breastfeeding before six months postpartum were not explicitly reported, and there were insufficient data to draw any meaningful conclusions from survival data. Stopping breast milk expression before four to six weeks postpartum, andstopping breast milk expression before six months postpartum were not reported. Measures ofmaternal satisfaction were reported in one study of 15 women, but there were insufficient data to draw any conclusions; no other secondary outcomes were reported for women with multiple births in either study. No adverse events were reported. We found no evidence from randomised controlled trials about the effectiveness of breastfeeding education and support for women with twins or higher order multiples, or the most effective way to provide education and support . There was no evidence about the best way to deliver the intervention, the timing of care, or the best person to deliver the care. There is a need for well-designed, adequately powered studies of interventions designed for women with twins or higher order multiples to find out what types of education and support are effective in helping these mothers to breastfeed their babies.
We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week). Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence). Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population.
We included nine studies reporting on 10 psychological interventions and one combined intervention. The studies included 1546 participants. No RCTs were found of pharmacological interventions, exercise programmes or employee assistance programmes. We assessed seven studies as having low risk of bias and the studies that were pooled together were comparable. For those who received no treatment, compared with CBT, the assumed time to partial and full RTW was 88 and 252 days respectively. Based on two studies with a total of 159 participants, moderate-quality evidence showed that CBT had similar results for time (measured in days) until partial RTW compared to no treatment at one-year follow-up (mean difference (MD) -8.78, 95% confidence interval (CI) -23.26 to 5.71). We found low-quality evidence of similar results for CBT and no treatment on the reduction of days until full RTW at one-year follow-up (MD -35.73, 95% CI -113.15 to 41.69) (one study with 105 participants included in the analysis). Based on moderate-quality evidence, problem solving therapy (PST) significantly reduced time until partial RTW at one-year follow-up compared to non-guideline based care (MD -17.00, 95% CI -26.48 to -7.52) (one study with 192 participants clustered among 33 treatment providers included in the analysis), but we found moderate-quality evidence of no significant effect on reducing days until full RTW at one-year follow-up (MD -17.73, 95% CI -37.35 to 1.90) (two studies with 342 participants included in the analysis). We found moderate-quality evidence that CBT did not significantly reduce time until partial RTW and low-quality evidence that it did not significantly reduce time to full RTW compared with no treatment. Moderate-quality evidence showed that PST significantly enhanced partial RTW at one-year follow-up compared to non-guideline based care but did not significantly enhance time to full RTW at one-year follow-up. An important limitation was the small number of studies included in the meta-analyses and the small number of participants, which lowered the power of the analyses.
The review currently includes nine studies with an average 60 participants per study. All of these studies are now over 60 years old, conducted between 1955 and 1962. When chlorpromazine was compared with reserpine for people with schizophrenia, improvement in global state was better at short term for those receiving chlorpromazine (n = 781, 6 RCTs, RR 'not improved' 0.75 95% CI 0.62 to 0.92, low-quality evidence). Short-term improvement in paranoid distortion was measured using the Multidimensional Scale for Rating Psychiatric Patients (MSRPP). Data showed no clear difference between treatment groups (n = 19, 1 RCT, RR 1.33 95% CI 0.62 to 2.89, very low-quality evidence). There was no difference in functioning: occupational adjustment, medium term (n = 40, 1 RCT, RR 0.83 95% CI 0.47 to 1.47, moderate-quality evidence) and general behaviour (n = 98, 1 RCT, RR 0.79 CI 0.41 to 1.53, moderate-quality evidence). Adverse events were poorly reported. For 'toxic reaction' there was, again, no obvious difference between the two compounds (n = 210, 3 RCTs, RR 1.68 95% CI 0.43 to 6.54, moderate-quality evidence), and this also applied to leaving the study early (n = 229, 4 RCTs, RR 1.16 95% CI 0.94 to 1.42, moderate-quality evidence). Judged by standards of today, the evidence is largely of limited quality. However, some of these 1950s studies are remarkable in their foresight and clarity. Reserpine did have some effect on global state - but chlorpromazine did seem to perform better. Important issues regarding adverse effects were not really addressed by these trials. Chlorpromazine remains on the WHO list of essential drugs. Reserpine is now almost obsolete, although, probably as a result of evidence other than that reported in the pioneering trials used in this review.
Only one study, funded by Pfizer, met the inclusion criteria for the review. A total of 64 participants (with chronic pain due to chronic pancreatitis) were randomly assigned to receive escalating doses of pregabalin (150 mg per day to 600 mg per day; 34 participants) or matching placebo (30 participants). Participants received pregabalin or placebo for three weeks on an outpatient basis; the outcomes were measured at the end of the treatment (i.e. three weeks from commencement of treatment). Potential participants taking concomitant analgesic medication and expected to stay on a stable regime during the trial were allowed to enter the study. This trial was at low risk of bias. The overall quality of evidence was low or moderate. Only the short-term outcomes were available in this trial. The medium and long-term outcomes, number of work days lost, and length of hospital stay due to admissions for pain control were not available. This trial found that the changes in opiate use (MD -26.00 mg; 95% CI -47.36 to -4.64; participants = 64; moderate-quality evidence), and pain score percentage changes from baseline (MD -12.00; 95% CI -21.82 to -2.18; participants = 64; moderate-quality evidence) were better in participants taking pregabalin compared to those taking placebo. This trial also found that there were more adverse events in participants taking pregabalin compared to those taking placebo (RR 1.71; 95% CI 1.20 to 2.43; participants = 64). The differences between pregabalin and placebo were imprecise for short-term health-related quality of life measured with the EORTC CLQ-30 questionnaire (MD 11.40; 95% CI -3.28 to 26.08; participants = 64; moderate-quality evidence), proportion of people with serious adverse events (RR 1.76; 95% CI 0.35 to 8.96; participants = 64; low-quality evidence), and proportion of people requiring hospital admissions (RR 0.44; 95% CI 0.04 to 4.62; participants = 64; low quality evidence). Based on low- to moderate-quality evidence, short-term use of pregabalin decreases short-term opiate use, and short-term pain scores, but increases the adverse events compared to placebo, in people with chronic pain due to chronic pancreatitis. The clinical implication of the decreases in short-term opiate use and short-term pain scores is not known. Future trials assessing the role of pregabalin in decreasing chronic pain in chronic pancreatitis should assess the medium- or long-term effects of pregabalin and should include outcomes such as, quality of life, treatment-related adverse events, number of work days lost, number of hospital admissions, and the length of hospital stay, in addition to pain scores, to assess the clinical and socioeconomic impact.
Eleven papers describing 10 unique trials met the inclusion criteria. The 10 trials reported results for nine antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate. Six of the eight drugs investigated in placebo-controlled trials were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). One prospective, randomised, double-blind, single cross-over trial of 48 patients demonstrated a significant superiority of carbamazepine over placebo in the proportion of responders (OR 11.77; 95% confidence interval (CI) 3.92 to 35.32). The NNT was 2 (95% CI 2 to 3). In a small prospective, randomised, double-blind, parallel-group trial, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency per 28-day period during treatment (MD -2.40; 95% CI -4.52 to -0.28; 26 patients), as well as in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients). The NNT was 2 (95% CI 1 to 4). The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate in headache frequency per 28-day period during treatment (MD 1.40; 95% CI 0.14 to 2.66; 28 patients). There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients). Finally, one trial with 75 participants examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment. Adverse events for active treatment versus placebo were available for all investigated drugs except levetiracetam, vigabatrin, and zonisamide. A high prevalence of adverse events was noted for carbamazepine, with a NNH of only 2 (95% CI 2 to 4). Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. Acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not more effective than placebo in reducing headache frequency. In one trial each, carbamazepine and levetiracetam were significantly superior to placebo in reducing headache frequency, and there was no significant difference in proportion of responders between zonisamide and active comparator. These three positive studies suffer from considerable methodological limitations.
We included five RCTs with 414 participants. The comparisons in the included trials were as follows: CHM versus clomiphene, CHM plus clomiphene versus clomiphene (with or without ethinyloestradiol cyproterone acetate (CEA)), CHM plus follicle aspiration plus ovulation induction versus follicle aspiration plus ovulation induction alone, and CHM plus laparoscopic ovarian drilling (LOD) versus LOD alone. The overall quality of the evidence for most comparisons was very low. None of the included studies reported live birth rate, and only one study reported data on adverse events. When CHM was compared with clomiphene (with or without LOD in both arms), there was no evidence of a difference between the groups in pregnancy rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 0.78 to 5.06; two studies, 90 participants, I² statistic = 0%, very low quality evidence). No study reported data on adverse events. When CHM plus clomiphene was compared with clomiphene (with or without CEA), there was low quality evidence of a higher pregnancy rate in the CHM plus clomiphene group (OR 2.62, 95% CI 1.65 to 4.14; three RCTs, 300 women, I² statistic = 0%,low quality evidence). No data were reported on adverse events. When CHM with follicle aspiration and ovulation induction was compared with follicle aspiration and ovulation induction alone, there was no evidence of a difference between the groups in pregnancy rates (OR 1.60, 95% CI 0.46 to 5.52; one study, 44 women, very low quality evidence), severe luteinized unruptured follicle syndrome (LUFS) (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence), ovarian hyperstimulation syndrome (OHSS) (OR 0.16, 95% CI 0.00 to 8.19; one study, 44 women, very low quality evidence) or multiple pregnancy (OR 0.60, 95% CI 0.06 to 6.14; one study, 44 women, very low quality evidence). When CHM with LOD was compared with LOD alone, there was no evidence of a difference between the groups in rates of pregnancy (OR 3.50, 95% CI 0.72 to 17.09; one study, 30 women, very low quality evidence), No data were reported on adverse events. There was no evidence of a difference between any of the comparison groups for any other outcomes. The quality of the evidence for all other comparisons and outcomes was very low. The main limitations in the evidence were failure to report live birth or adverse events, failure to describe study methods in adequate detail and imprecision due to very low event rates and wide CIs. There is insufficient evidence to support the use of CHM for women with PCOS and subfertility. No data are available on live birth, and there is no consistent evidence to indicate that CHM influences fertility outcomes. However there is very limited low quality evidence to suggest that the addition of CHM to clomiphene may improve pregnancy rates. There is insufficient evidence on adverse effects to indicate whether CHM is safe.
We identified five clinical trials that involved 3405 children for inclusion. For this 2016 update, we identified one new trial for inclusion. This trial was systematically reviewed but due to several sources of heterogeneity, was not included in the meta-analysis. The remaining four trials were of adequate methodological quality. In three RCTs that involved a total of 1826 healthy Finnish children attending daycare, there is moderate quality evidence that xylitol (in any form) can reduce the risk of AOM from 30% to around 22% compared with the control group (RR 0.75, 95% CI 0.65 to 0.88). Among the reasons for dropouts, there were no significant differences in abdominal discomfort and rash between the xylitol and the control groups. Xylitol was not effective in reducing AOM among healthy children during a respiratory infection (RR 1.13, 95% CI 0.83 to 1.53; moderate quality evidence) or among otitis-prone healthy children (RR 0.90, 95% CI 0.67 to 1.21; low-quality evidence). There is moderate quality evidence showing that the prophylactic administration of xylitol among healthy children attending daycare centres can reduce the occurrence of AOM. There is inconclusive evidence with regard to the efficacy of xylitol in preventing AOM among children with respiratory infection, or among otitis-prone children. The meta-analysis was limited because data came from a small number of studies, and most were from the same research group.
Our searches found no RCTs or Q-RCTs that met the eligibility criteria for this review. We are unable to reach any conclusion about the effectiveness of environmental or behavioural interventions for reducing physical activity limitation in community-dwelling visually impaired older people, as no eligible studies were found. However a number of studies reviewed included only the secondary outcome measures of this review. Although behavioural interventions delivered by occupational therapists have been shown to reduce the rate of falls, we are unable to conclude if this is due to reduced activity restriction (increased mobility) or reduced activity (lessening exposure to risk). There are inconclusive and conflicting results from trials evaluating the effectiveness of behavioural and environmental interventions aimed at improving quality of life. Further research is necessary (such as ongoing Dutch and UK trials considering the effectiveness of orientation and mobility training on activity restriction, physical activity, falls, fear of falling and quality of life in older adults with low vision, and the effect of an occupational therapist delivering home safety modification, coping strategies and exercise with older people with low vision) before any conclusions can be reached.
We included three studies, two of which evaluated the progression from MCI to ADD, and one evaluated the progression from MCI to any form of dementia. Progression from MCI to ADD was evaluated in 448 participants. The studies reported data on 401 participants with 1.6 years of follow-up and in 47 participants with three years of follow-up. Sixty-one (15.2%) participants converted at 1.6 years follow-up; nine (19.1%) participants converted at three years of follow-up. Progression from MCI to any form of dementia was evaluated in five participants with 1.5 years of follow-up, with three (60%) participants converting to any form of dementia. There were concerns regarding applicability in the reference standard in all three studies. Regarding the domain of flow and timing, two studies were considered at high risk of bias. MCI to ADD; Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment (n = 47, 1 study). Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment by the standardised uptake value ratio (SUVR)(n = 401, 1 study). MCI to any form of dementia; Progression from MCI to any form of dementia in those with a follow-up between one to less than two years had a sensitivity of 67% (95% CI 9 to 99) and a specificity of 50% (95% CI 1 to 99) by visual assessment (n = 5, 1 study). MCI to any other forms of dementia (non-ADD); There was no information regarding the progression from MCI to any other form of dementia (non-ADD). Although sensitivity was good in one included study, considering the poor specificity and the limited data available in the literature, we cannot recommend routine use of 18F-florbetapir PET in clinical practice to predict the progression from MCI to ADD. Because of the poor sensitivity and specificity, limited number of included participants, and the limited data available in the literature, we cannot recommend its routine use in clinical practice to predict the progression from MCI to any form of dementia. Because of the high financial costs of 18F-florbetapir, clearly demonstrating the DTA and standardising the process of this modality are important prior to its wider use.
Of the 16 identified trials, four (112 participants) were eligible for inclusion. Two trials evaluated 59 people with haemophilia A and B undergoing 63 dental extractions. Trials compared the use of a different type (tranexamic acid or epsilon-aminocaproic acid) and regimen of antifibrinolytic agents as haemostatic support to the initial replacement treatment. Neither trial specifically addressed mortality (one of this review's primary outcomes); however, in the frame of safety assessments, no fatal adverse events were reported. The second primary outcome of blood loss was assessed after surgery and these trials showed the reduction of blood loss and requirement of post-operative replacement treatment in people receiving antifibrinolytic agents compared with placebo. The remaining primary outcome of need for re-intervention was not reported by either trial. Two trials reported on 53 people with haemophilia A and B with inhibitors treated with different regimens of recombinant activated factor VII (rFVIIa) for haemostatic coverage of 33 major and 20 minor surgical interventions. Neither of the included trials specifically addressed any of the review's primary outcomes (mortality, blood loss and need for re-intervention). In one trial a high-dose rFVIIa regimen (90 μg/kg) was compared with a low-dose regimen (35 μg/kg); the higher dose showed increased haemostatic efficacy, in particular in major surgery, with shorter duration of treatment, similar total dose of rFVIIa administered and similar safety levels. In the second trial, bolus infusion and continuous infusion of rFVIIa were compared, showing similar haemostatic efficacy, duration of treatment and safety. There is insufficient evidence from randomised controlled trials to assess the most effective and safe haemostatic treatment to prevent bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgical procedures. Ideally large, adequately powered, and well-designed randomised controlled trials would be needed, in particular to address the cost-effectiveness of such demanding treatments in the light of the increasing present economic constraints, and to explore the new challenge of ageing patients with haemophilia or other congenital bleeding disorders. However, performing such trials is always a complex task in this setting and presently does not appear to be a clinical and research priority. Indeed, major and minor surgeries are effectively and safely performed in these individuals in clinical practice, with the numerous national and international recommendations and guidelines providing regimens for treatment in this setting mainly based on data from observational, uncontrolled studies.
We included eight studies (358 participants), five assessing TAP blocks, three assessing rectus sheath blocks; with moderate risk of bias overall. All studies had a background of general anaesthesia in both arms in most cases. Compared with no TAP block or saline placebo, TAP block resulted in significantly less postoperative requirement for morphine at 24 hours (mean difference (MD) -21.95 mg, 95% confidence interval (CI) -37.91 to 5.96; five studies, 236 participants) and 48 hours (MD -28.50, 95% CI -38.92 to -18.08; one study of 50 participants) but not at two hours (all random-effects analyses). Pain at rest was significantly reduced in two studies, but not a third. Only one of three included studies of rectus sheath blocks found a reduction in postoperative analgesic requirements in participants receiving blocks. One study, assessing number of participants who were pain-free after their surgery, found more participants who received a rectus sheath block to be pain-free for up to 10 hours postoperatively. As with TAP blocks, rectus sheath blocks made no apparent impact on nausea and vomiting or sedation scores. No studies have compared TAP block with other analgesics such as epidural analgesia or local anaesthetic infiltration into the abdominal wound. There is only limited evidence to suggest use of perioperative TAP block reduces opioid consumption and pain scores after abdominal surgery when compared with no intervention or placebo. There is no apparent reduction in postoperative nausea and vomiting or sedation from the small numbers of studies to date. Many relevant studies are currently underway or awaiting publication.
For this update we identified one new study (43 participants), but it did not contribute any data for analysis. The review included 13 studies using sumatriptan 85 mg or 50 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity. Twelve studies contributed data for analyses: 3663 participants received combination treatment, 3682 placebo, 964 sumatriptan, and 982 naproxen. We judged only one small study to be at high risk of bias for any of the criteria evaluated; it did not contribute to any analyses. Overall, the combination was better than placebo for the primary outcomes of pain-free and headache relief at two hours. The NNT for pain-free at two hours was 3.1 (95% confidence interval 2.9 to 3.5) when the baseline pain was mild (50% response with sumatriptan plus naproxen compared with 18% with placebo), and 4.9 (4.3 to 5.7) when baseline pain was moderate or severe (28% with sumatriptan plus naproxen compared with 8% with placebo) (high quality evidence). Using 50 mg of sumatriptan, rather than 85 mg, in the combination did not significantly change the result. Treating early, when pain was still mild, was significantly better than treating once pain was moderate or severe for pain-free responses at two hours and during the 24 hours post dose. Adverse events were mostly mild or moderate in severity and rarely led to withdrawal; they were more common with the combination than with placebo (moderate quality evidence). Where the data allowed direct comparison, combination treatment was superior to either monotherapy, but adverse events were less frequent with naproxen than with sumatriptan (moderate quality evidence). The conclusions of this review were not changed. Combination treatment was effective in the acute treatment of migraine headaches. The effect was greater than for the same dose of either sumatriptan or naproxen alone, but additional benefits over sumatriptan alone were not large. More participants achieved good relief when medication was taken early in the attack, when pain was still mild. Adverse events were more common with the combination and sumatriptan alone than with placebo or naproxen alone.
A total of three studies involving 144 eligible participants were included in the review. Two of the studies (56 participants) compared an early version of acceptance and commitment therapy (ACT) with CBT, and one study (88 eligible participants) compared extended behavioural activation with CBT. No other studies of third wave CBT were identified. The two ACT studies were assessed as being at high risk of performance bias and researcher allegiance. Post-treatment results, which were based on dropout rates, showed no evidence of any difference between third wave CBT and other psychological therapies for the primary outcomes of efficacy (risk ratio (RR) of clinical response 1.14, 95% confidence interval (CI) 0.79 to 1.64; very low quality) and acceptability. Results at two-month follow-up showed no evidence of any difference between third wave CBT and other psychological therapies for clinical response (2 studies, 56 participants, RR 0.22, 95% CI 0.04 to 1.15). Moderate statistical heterogeneity was indicated in the acceptability analyses (I2 = 41%). Very low quality evidence suggests that third wave CBT and CBT approaches are equally effective and acceptable in the treatment of acute depression. Evidence is limited in quantity, quality and breadth of available studies, precluding us from drawing any conclusions as to their short- or longer-term equivalence. The increasing popularity of third wave CBT approaches in clinical practice underscores the importance of completing further studies to compare various third wave CBT approaches with other psychological therapy approaches to inform clinicians and policymakers on the most effective forms of psychological therapy in treating depression.
Seven trials were included (362 participants randomized, data from 264 participants available for analysis); six of parallel design and one a partial cross-over design. One multicenter trial was conducted in Canada; the remaining six were single centre undertaken in the UK, USA, Iran and in the Netherlands. All trials had a high risk of bias for participant blinding and use of patient-reported outcomes. Evidence was retrieved on four interventions: psycho-education (DVD plus information booklet versus information booklet alone; computerised learning versus no intervention); cognitive therapy (auto-hypnosis (self-hypnosis) versus control); and behavioural therapy (relaxation (progressive or self control) versus no treatment). We also aimed to assess psychodynamic therapy and systemic therapy, but no trials were identified. Heterogeneity of the outcome measures and measurements precluded meta-analyses. No trial reported the cost of the psychological intervention and family adjustment. DVD plus information booklet compared to information booklet alone One trial (108 participants) showed coping strategies may lower pre-contemplation scores and negative thoughts, mean difference (MD) -0.24 (95%CI -0.48 - 0.00, low-certainty evidence), however, other measures of coping strategies in the same trial suggest little or no difference between groups, e.g. contemplation, MD (-0.09, 95%CI -0.32 – 0.14, low-certainty evidence). The same trial measured QoL and showed little or no difference between treatment groups for the physical domain, MD 0.59 (95% CI -3.66 to 4.84, low-certainty evidence), but may improve scores in the mental health domain for those receiving the booklet plus DVD compared to booklet alone, MD (4.70, 95% CI 0.33 to 9.07, low-certainty evidence). Mood or personal well-being were not reported. Computerised learning compared to no intervention Two trials (57 participants) reported on interventions aimed at children and adolescents and their impact on promoting a sense of self-efficacy (primary outcome 'Mood and personal well-being'), but only one showed an increase, MD 7.46 (95%CI 3.21 to 11.71, 17 participants, very low-certainty evidence); the second did not report control group data. One trial (30 participants) showed the intervention did not improve self-efficacy in adults, but appropriate data could not be extracted. Two trials (47 participants) reported coping strategies; one only reported within-group differences from baseline, the second showed an increase from baseline in coping strategies in the Internet program group compared to the no intervention group (disease-specific knowledge, MD 2.45 (95% CI 0.89 to 4.01); self-management ability and transition readiness, MD 19.90 (95% CI 3.61 to 36.19; low-certainty evidence). One trial reported QoL but with insufficient information to calculate changes from baseline; no difference in post-treatment scores was seen between groups, MD -8.65, 95% CI -18.30 to 1.00, very low-certainty evidence). Auto-hypnosis (self-hypnosis) compared to control There were two older trials that reported on this intervention (50 participants) focusing mainly on the secondary outcome 'physical health'; only one trial reported the primary outcome ‘mood and personal well-being’ (only within-group differences in the treatment group). Coping strategies and QoL were not assessed in the trials. Relaxation (progressive or self control) compared to no treatment Only one trial (seven participants) from 1985, was included which focused on 'physical health' and did not report on any of our primary outcomes. Not all of the seven included trials analysed the effects of the interventions on our primary outcomes (mood and personal well-being, coping strategies and QoL). Three trials were conducted in the 1970s and 1980s using techniques of auto-hypnosis or relaxation and, in accordance with the needs and therapeutic possibilities of the time, they focused on secondary outcomes, e.g. frequency of bleeding (physical health) and adherence to the intervention. The four newer trials assessed psycho-educational interventions all mediated by the use of technologies (DVD or computer) and often created according to age needs of the target group. In these cases, attention was shifted to our pre-defined primary outcomes. This review has identified low- and very low-certainty evidence, prompting caution in its interpretation. The major problem we encountered was the heterogeneity of trial designs, of interventions and of outcome measures used across the trials. We strongly suggest that researchers consider developing a core outcome set to streamline future research; randomization was proven to be safe and acceptable, and blinding should be considered for those assessing patient-reported outcomes.
Of 785 identified citations, 20 trials from 1990 to 2011 enrolling 1652 participants fulfilled the inclusion criteria. We judged most of the trials to be at low or unclear risk of bias across the six domains, and we judged four studies to have elements of high risk of bias; we did not classify any studies at overall low risk of bias. The quality of evidence was low for five of the seven outcomes (very low N = 1, moderate N = 1) and there was heterogeneity among the studies. There was a variety of adult participants and the procedures were performed by a wide range of differently experienced operators in different situations. There was no evidence of a difference in the rate of the primary outcomes: mortality directly related to the procedure (Peto odds ratio (POR) 0.52, 95% confidence interval (CI) 0.10 to 2.60, I² = 44%, P = 0.42, 4 studies, 257 participants, low quality evidence); and serious, life-threatening adverse events - intraoperatively: risk ratio (RR) 0.93, 95% CI 0.57 to 1.53, I² = 27%, P = 0.78, 12 studies, 1211 participants, low quality evidence,and direct postoperatively: RR 0.72, 95% CI 0.41 to 1.25, I² = 24%, P = 0.24, 10 studies, 984 participants, low quality evidence. PTs significantly reduce the rate of the secondary outcome, wound infection/stomatitis by 76% (RR 0.24, 95% CI 0.15 to 0.37, I² = 0%, P < 0.00001, 12 studies, 936 participants, moderate quality evidence) and the rate of unfavourable scarring by 75% (RR 0.25, 95% CI 0.07 to 0.91, I² = 86%, P = 0.04, 6 studies, 789 participants, low quality evidence). There was no evidence of a difference in the rate of the secondary outcomes, major bleeding (RR 0.70, 95% CI 0.45 to 1.09, I² = 47%, P = 0.12, 10 studies, 984 participants, very low quality evidence) and tracheostomy tube occlusion/obstruction, accidental decannulation, difficult tube change (RR 1.36, 95% CI 0.65 to 2.82, I² = 22%, P = 0.42, 6 studies, 538 participants, low quality evidence). When compared to STs, PTs significantly reduce the rate of wound infection/stomatitis (moderate quality evidence) and the rate of unfavourable scarring (low quality evidence due to imprecision and heterogeneity). In terms of mortality and the rate of serious adverse events, there was low quality evidence that non-significant positive effects exist for PTs. In terms of the rate of major bleeding, there was very low quality evidence that non-significant positive effects exist for PTs. However, because several groups of participants were excluded from the included studies, the number of participants in the included studies was limited, long-term outcomes were not evaluated, and data on participant-relevant outcomes were either sparse or not available for each study, the results of this meta-analysis are limited and cannot be applied to all critically ill adults.
We included 18 RCTs (739 participants) that tested the effectiveness of a broad range of physiotherapy-based interventions. Overall, there was a paucity of high quality evidence concerning physiotherapy treatment for pain and disability in people with CRPS I. Most included trials were at 'high' risk of bias (15 trials) and the remainder were at 'unclear' risk of bias (three trials). The quality of the evidence was very low or low for all comparisons, according to the GRADE approach. We found very low quality evidence that graded motor imagery (GMI; two trials, 49 participants) may be useful for improving pain (0 to 100 VAS) (mean difference (MD) −21.00, 95% CI −31.17 to −10.83) and functional disability (11-point numerical rating scale) (MD 2.30, 95% CI 1.12 to 3.48), at long-term (six months) follow-up, in people with CRPS I compared to usual care plus physiotherapy; very low quality evidence that multimodal physiotherapy (one trial, 135 participants) may be useful for improving 'impairment' at long-term (12 month) follow-up compared to a minimal 'social work' intervention; and very low quality evidence that mirror therapy (two trials, 72 participants) provides clinically meaningful improvements in pain (0 to 10 VAS) (MD 3.4, 95% CI −4.71 to −2.09) and function (0 to 5 functional ability subscale of the Wolf Motor Function Test) (MD −2.3, 95% CI −2.88 to −1.72) at long-term (six month) follow-up in people with CRPS I post stroke compared to placebo (covered mirror). There was low to very low quality evidence that tactile discrimination training, stellate ganglion block via ultrasound and pulsed electromagnetic field therapy compared to placebo, and manual lymphatic drainage combined with and compared to either anti-inflammatories and physical therapy or exercise are not effective for treating pain in the short-term in people with CRPS I. Laser therapy may provide small clinically insignificant, short-term, improvements in pain compared to interferential current therapy in people with CRPS I. Adverse events were only rarely reported in the included trials. No trials including participants with CRPS II met the inclusion criteria of this review. The best available data show that GMI and mirror therapy may provide clinically meaningful improvements in pain and function in people with CRPS I although the quality of the supporting evidence is very low. Evidence of the effectiveness of multimodal physiotherapy, electrotherapy and manual lymphatic drainage for treating people with CRPS types I and II is generally absent or unclear. Large scale, high quality RCTs are required to test the effectiveness of physiotherapy-based interventions for treating pain and disability of people with CRPS I and II. Implications for clinical practice and future research are considered.
We included 13 RCTs, although we could only extract data to meta-analyse 12 trials, which involved 3720 participants including children, adults (aged around 40 years) and older people. We found that probiotics were better than placebo when measuring the number of participants experiencing episodes of acute URTI (at least one episode: odds ratio (OR) 0.53; 95% confidence interval (CI) 0.37 to 0.76, P value < 0.001, low quality evidence; at least three episodes: OR 0.53; 95% CI 0.36 to 0.80, P value = 0.002, low quality evidence); the mean duration of an episode of acute URTI (mean difference (MD) -1.89; 95% CI -2.03 to -1.75, P value < 0.001, low quality evidence); reduced antibiotic prescription rates for acute URTIs (OR 0.65; 95% CI 0.45 to 0.94, moderate quality evidence) and cold-related school absence (OR 0.10; 95% CI 0.02 to 0.47, very low quality evidence). Probiotics and placebo were similar when measuring the rate ratio of episodes of acute URTI (rate ratio 0.83; 95% CI 0.66 to 1.05, P value = 0.12, very low quality evidence) and adverse events (OR 0.88; 95% CI 0.65 to 1.19, P value = 0.40, low quality evidence). Side effects of probiotics were minor and gastrointestinal symptoms were the most common. We found that some subgroups had a high level of heterogeneity when we conducted pooled analyses and the evidence level was low or very low quality. Probiotics were better than placebo in reducing the number of participants experiencing episodes of acute URTI, the mean duration of an episode of acute URTI, antibiotic use and cold-related school absence. This indicates that probiotics may be more beneficial than placebo for preventing acute URTIs. However, the quality of the evidence was low or very low.
Four trials fulfilled the selection criteria: one of azathioprine (27 participants), two of IFN beta-1a (77 participants in total) and one of methotrexate (60 participants). The risk of bias was considered low in the trials of IFN beta-1a and methotrexate but high in the trial of azathioprine. None of the trials showed significant benefit in any of the outcomes selected by their authors. The results of the outcomes which approximated most closely to the primary outcome for this review were as follows. In the azathioprine trial there was a median improvement in the Neuropathy Impairment Scale (scale range 0 to 280) after nine months of 29 points (range 49 points worse to 84 points better) in the azathioprine and prednisone treated participants compared with 30 points worse (range 20 points worse to 104 points better) in the prednisone alone group. There were no reports of adverse events. In a cross-over trial of IFN beta-1a with 20 participants, the treatment periods were 12 weeks. The median improvement in the Guy's Neurological Disability Scale (range 1 to 10) was 0.5 grades (interquartile range (IQR) 1.8 grades better to zero grade change) in the IFN beta-1a treatment period and 0.5 grades (IQR 1.8 grades better to 1.0 grade worse) in the placebo treatment period. There were no serious adverse events in either treatment period. In a parallel group trial of IFN beta-1a with 67 participants, none of the outcomes for this review was available. The trial design involved withdrawal from ongoing IVIg treatment. The primary outcome used by the trial authors was total IVIg dose administered from week 16 to week 32 in the placebo group compared with the IFN beta-1a groups. This was slightly but not significantly lower in the combined IFN beta-1a groups (1.20 g/kg) compared with the placebo group (1.34 g/kg, P = 0.75). There were four participants in the IFN beta-1a group and none in the placebo group with one or more serious adverse events, risk ratio (RR) 4.50 (95% confidence interval (CI) 0.25 to 80.05). The methotrexate trial had a similar design involving withdrawal from ongoing corticosteroid or IVIg treatment. At the end of the trial (approximately 40 weeks) there was no significant difference in the change in the Overall Neuropathy Limitations Scale, a disability scale (scale range 0 to 12), the median change being 0 (IQR −1 to 0) in the methotrexate group and 0 (IQR −0.75 to 0) in the placebo group. These changes in disability might have been confounded by the reduction in corticosteroid or IVIg dose required by the protocol. There were three participants in the methotrexate group and one in the placebo with one or more serious adverse events, RR 3.56 (95% CI 0.39 to 32.23). Low-quality evidence from randomised trials does not show significant benefit from azathioprine or interferon beta-1a and moderate-quality evidence from one randomised trial does not show significant benefit from a relatively low dose of methotrexate for the treatment of CIDP. None of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures relevant to people with CIDP, and longer treatment durations.
Only two studies, with a total of 65 participants, were eligible for inclusion in the review. Overall the quality of the two studies was low, with small study populations and significant sources of bias, so we were not able to use all the data in our comparisons. . The studies were old from 1968 and 1972, and would be unlikely to pass modern peer review standard. We were only able to find short-term data and only trials randomising zuclopenthixol dihydrochloride. We also hoped to identify data for zuclopenthixol acetate versus placebo and zuclopenthixol decanoate versus placebo comparisons. We were unable to identify any studies that included data on these two fairly widely used drugs. For our primary outcome of interest, clinically significant improvement, we found one study that provided useable data. Global state measured by clinical global impression scale (CGI) improvement showed different ratings when assessed by a psychiatrist or a nurse.The psychiatrist scores failed to achieve statistical significance, however when assessed by nursing staff, the difference favouring zuclopenthixol did reach statistical significance (1 RCT n = 29, RR 2.57 95% CI 1.06 to 6.20, very low quality data). There was also evidence of increased sedation with those treated with zuclopenthixol when compared with placebo (1 RCT n = 29, RR 4.67 95% CI 1.23 to 17.68, very low quality data). 'Leaving the study early' data were equivocal. No useable data were available for outcomes such as relapse, mental state, death, quality of life, service use or economic costs. For people with schizophrenia this review shows that zuclopenthixol dihydrochloride may help with the symptoms of schizophrenia. The review provides some trial evidence that, if taking zuclopenthixol dihydrochloride, people may experience some adverse effects and sedation compared with placebo. However this evidence is of very low quality and with some significant sources of bias. There are no data for zuclopenthixol decanoate or zuclopenthixol acetate. For clinicians, the available trial data on the absolute effectiveness of zuclopenthixol dihydrochloride do support its use but the limited nature of the data and significant sources of bias make conclusions hard to draw. Zuclopenthixol in all three forms is a commonly used antipsychotic and it is disappointing that there are so few data regarding its use.
We included 16 studies (involving 13,123 participants) in this systematic review, two of which were of high quality. These two studies showed that nicotine sublingual tablet and varenicline increased the quit rate over placebo (risk ratio (RR) 2.60 (95% confidence interval (CI) 1.29 to 5.24) and RR 3.34 (95% CI 1.88 to 5.92)). Pooled results of two studies also showed a positive effect of bupropion compared with placebo (RR 2.03 (95% CI 1.26 to 3.28)). When pooling these four studies, we found high-quality evidence for the effectiveness of pharmacotherapy plus high-intensity behavioural treatment compared with placebo plus high-intensity behavioural treatment (RR 2.53 (95% CI 1.83 to 3.50)). Furthermore, we found some evidence that high-intensity behavioural treatment increased abstinence rates when compared with usual care (RR 25.38 (95% CI 8.03 to 80.22)) or low-intensity behavioural treatment (RR 2.18 (95% CI 1.05 to 4.49)). Finally, the results showed effectiveness of various combinations of psychosocial and pharmacological interventions. We found high-quality evidence in a meta-analysis including four (1,540 participants) of the 16 included studies that a combination of behavioural treatment and pharmacotherapy is effective in helping smokers with COPD to quit smoking. Furthermore, we conclude that there is no convincing evidence for preferring any particular form of behavioural or pharmacological treatment.
We included five studies, involving 756 participants. Three studies assessed the effect of brief psychological therapies, one assessed the impact of a self-help booklet, and one the effect of collaborative care. The disparate nature of the trials covering different patient populations, interventions and outcomes meant that it was not possible to pool data meaningfully across studies. There was no evidence of a protective effect of brief psychological therapy or educational booklets on preventing disability. There was evidence from one trial of a reduction in both post-traumatic stress disorder (PTSD) and depressive symptoms one month after injury in those who received a collaborative care intervention combined with a brief psycho-educational intervention, however this was not retained at follow up. Overall mental health status was the only disability outcome affected by any intervention. In three trials the psychosocial intervention had a detrimental effect on the mental health status of patients. This review provides no convincing evidence of the effectiveness of psychosocial interventions for the prevention of disability following traumatic physical injury. Taken together, our findings cannot be considered as supporting the provision of psychosocial interventions to prevent aspects of disability arising from physical injury. However, these conclusions are based on a small number of disparate trials with small to moderate sample sizes and are therefore necessarily cautious. More research, using larger sample sizes, and similar interventions and patient populations to enable pooling of results, is needed before these findings can be confirmed.
There were a total of 2276 subjects across the 34 included studies; 1264 subjects were assigned to exercise interventions. The 34 studies comprised 47 interventions that included exercise. Effects of several disparate interventions on global well-being, selected FM signs and symptoms, and physical function in individuals with FM were summarized using standardized mean differences (SMD). There is moderate quality evidence that aerobic-only exercise training at recommended intensity levels has positive effects global well-being (SMD 0.49, 95% CI: 0.23 to 0.75) and physical function (SMD 0.66, 95% CI: 0.41 to 0.92) and possibly on pain (SMD 0.65, 95% CI: -0.09 to 1.39) and tender points (SMD 0.23, 95% CI: -0.18 to 0.65). Strength and flexibility remain under-evaluated. There is 'gold' level evidence (www.cochranemsk.org) that supervised aerobic exercise training has beneficial effects on physical capacity and FM symptoms. Strength training may also have benefits on some FM symptoms. Further studies on muscle strengthening and flexibility are needed. Research on the long-term benefit of exercise for FM is needed.
Five studies are included (2187 women). It was not possible for the intervention to be blinded, and it is not clear what impact lack of blinding would have on the outcomes reported. For other 'Risk of bias' domains studies were either at low or unclear risk of bias. One study reported on ECV that was undertaken and completed before 37 weeks' gestation compared with no ECV. No difference was found in the rate of non-cephalic presentation at birth (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.64 to 1.69; participants = 102). One study reported on a policy of ECV that was initiated before term (33 weeks) and up until 40 weeks' gestation and which could be repeated up until delivery compared with no ECV. This study showed a decrease in the rate of non-cephalic presentation at birth (RR 0.59, 95% CI 0.45 to 0.77; participants = 179). Three studies reported on ECV started at between 34 to 35 weeks' gestation compared with beginning at 37 to 38 weeks' gestation. Pooled results suggested that early ECV reduced the risk of non-cephalic presentation at birth (RR 0.81, 95% CI 0.74 to 0.90; participants = 1906; studies = three; I² = 0%, evidence graded high quality), failure to achieve vaginal cephalic birth (RR 0.90, 95% CI 0.83 to 0.97; participants = 1888; studies = three; I² = 0%, evidence graded high quality), and vaginal breech delivery (RR 0.44, 95% CI 0.25 to 0.78; participants = 1888; studies = three; I² = 0%, evidence graded high quality). The difference between groups for risk of caesarean was not statistically significant (RR 0.92, 95% CI 0.85 to 1.00; participants = 1888; studies = three; I² = 0%, evidence graded high quality). There was evidence that risk of preterm labour was increased with early ECV compared with ECV after 37 weeks (6.6% in the ECV group and 4.3% for controls) (RR 1.51, 95% CI 1.03 to 2.21; participants = 1888; studies = three; I² = 0%, evidence graded high quality). There was no clear difference between groups for low infant Apgar score at five minutes or perinatal death (stillbirth plus neonatal mortality up to seven days) (evidence graded as low quality for both outcomes). Compared with no ECV attempt, ECV commenced before term reduces non-cephalic presentation at birth. Compared with ECV at term, beginning ECV at between 34 to 35 weeks may have some benefit in terms of decreasing the rate of non-cephalic presentation, and risk of vaginal breech birth. However, early ECV may increase risk of late preterm birth, and it is important that any future research reports infant morbidity outcomes. Results of the review suggest that there is a need for careful discussion with women about the timing of the ECV procedure so that they can make informed decisions.
Thirty-two studies were included in this review. However, only 22 studies, involving 2658 women, provided data for analysis. All the women in the included studies had a caesarean section under general anaesthesia. The studies covered a number of comparisons, but were mostly small and of unclear or poor quality. When compared with no treatment or placebo, there was a significant reduction in the risk of intragastric pH < 2.5 with antacids (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.09 to 0.32, two studies, 108 women), H2 antagonists (RR 0.09, 95% CI 0.05 to 0.18, two studies, 170 women) and proton pump antagonists (RR 0.26, 95% CI 0.14 to 0.46, one study 80 women). H2 antagonists were associated with a reduced the risk of intragastric pH < 2.5 at intubation when compared with proton pump antagonists (RR 0.39, 95% CI 0.16 to 0.97, one study, 120 women), but compared with antacids the findings were unclear. The combined use of 'antacids plus H2 antagonists' was associated with a significant reduction in the risk of intragastric pH < 2.5 at intubation when compared with placebo (RR 0.02, 95% CI 0.00 to 0.15, one study, 89 women) or compared with antacids alone (RR 0.12, 95% CI 0.02 to 0.92, one study, 119 women). The quality of the evidence was poor, but the findings suggest that the combination of antacids plus H2 antagonists was more effective than no intervention, and superior to antacids alone in preventing low gastric pH. However, none of the studies assessed potential adverse effects or substantive clinical outcomes. These findings are relevant for all women undergoing caesarean section under general anaesthesia.
Twenty-two studies (reported in 25 publications) involving 228,615 pregnancies (including 1067 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high risk pregnancies. Ten studies made direct comparisons between tests. Thirty-two different test combinations were evaluated formed from combinations of eight different tests and maternal age; first trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free βhCG, Inhibin A, PAPP-A and ADAM 12. We looked at tests combining first and second trimester markers with or without ultrasound as complete tests, and we also examined stepwise and contingent strategies. Meta-analysis of the six most frequently evaluated test combinations showed that a test strategy involving maternal age and a combination of first trimester NT and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A significantly outperformed other test combinations that involved only one serum marker or NT in the first trimester, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate. However, the evidence was limited in terms of the number of studies evaluating this strategy, and we therefore cannot recommend one single screening strategy. Tests involving first trimester ultrasound with first and second trimester serum markers in combination with maternal age are significantly better than those without ultrasound, or those evaluating first trimester ultrasound in combination with second trimester serum markers, without first trimester serum markers. We cannot make recommendations about a specific strategy on the basis of the small number of studies available.
Two trials including a total of 81 participants fulfilled the inclusion criteria for this review. All participants in both studies had a history of postnatal depression and were not taking antidepressant medication at baseline. Both trials were conducted by the same research group. Risk of bias was low or unclear in most domains for both studies. We were unable to perform a meta-analysis due to the small number of studies. One study compared nortriptyline with placebo and did not find any evidence that nortriptyline was effective in preventing postnatal depression. In this study, 23% (6/26) of women who took nortriptyline and 24% (6/25) of women who took placebo experienced postnatal depression (RR 0.96, 95% CI 0.36 to 2.59, very low quality evidence) in the first 17 weeks postpartum. One woman taking nortriptyline developed mania; and one side effect, constipation, was more common among women taking nortriptyline than those taking placebo. The second study compared sertraline with placebo. In this study, 7% (1/14) of women who took sertraline developed postnatal depression in the first 17 weeks postpartum compared with 50% (4/8) of women who took placebo. It is uncertain whether sertraline reduces the risk of postnatal depression (RR 0.14, 95% CI 0.02 to 1.07, very low quality evidence). One woman taking sertraline had a hypomanic episode. Two side effects (dizziness and drowsiness) were more common among women taking sertraline than women taking placebo. Conclusions are limited by the small number of studies, small sample sizes and incomplete outcome data due to study drop-out which may have led to bias in the results. We have assessed the certainty of the evidence as very low, based on the GRADE system. No data were available on secondary outcomes of interest including child development, the mother‒infant relationship, breastfeeding, maternal daily functioning, family relationships or maternal satisfaction. Due to the limitations of the current evidence base, such as the low statistical power of the included studies, it is not possible to draw any clear conclusions about the effectiveness of antidepressants for the prevention of postnatal depression. It is striking that no new eligible trials have been completed in the period of over a decade since the last published version of this review. Larger trials are needed which include comparisons of antidepressant drugs with other prophylactic treatments (e.g. psychological interventions), and examine adverse effects for the fetus or infant. Future reviews in this area may benefit from broadening their focus to examine the effectiveness of antidepressants for the prevention of perinatal (i.e. antenatal or postnatal) depression, which could include studies comparing antidepressant discontinuation with continuation for the prevention of relapse of depression during pregnancy and the postnatal period.
Four studies (634 participants) met the inclusion criteria. Two of the included studies included only patients with AHFS following acute myocardial infarction (AMI); one study excluded patients with overt AMI; and one study included participants with AHFS with and without acute coronary syndromes. Based on a single study, there was no significant difference in the rapidity of symptom relief between intravenous nitroglycerin/N-acetylcysteine and intravenous frusemide/morphine after 30 minutes (fixed-effect MD -0.30, 95% CI -0.65 to 0.05), 60 minutes (fixed-effect MD -0.20, 95% CI -0.65 to 0.25), three hours (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-effect MD 0.00, 95% CI -0.31 to 0.31). There is no evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following outcome measures: requirement for mechanical ventilation, systolic blood pressure (SBP) change after three hours and 24 hours, diastolic blood pressure (DBP) change after 30, 60 and 90 minutes, heart rate change at 30 minutes, 60 minutes, three hours and 24 hours, pulmonary artery occlusion pressure (PAOP) change after three hours and 18 hours, cardiac output (CO) change at 90 minutes and three hours and progression to myocardial infarction. There is a significantly higher incidence of adverse events after three hours with nitroglycerin compared with placebo (odds ratio 2.29, 95% CI 1.26 to 4.16) based on a single study. There was no consistent evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following secondary outcome measures: SBP change after 30 and 60 minutes, heart rate change after 90 minutes, and PAOP change after 90 minutes. None of the included studies reported healthcare costs as an outcome measure. There were no data reported by any of the studies relating to the acceptability of the treatment to the patients (patient satisfaction scores). Overall there was a paucity of relevant quality data in the included studies. Assessment of overall risk of bias in these studies was limited as three of the studies did not give sufficient detail to allow assessment of potential risk of bias. There appears to be no significant difference between nitrate vasodilator therapy and alternative interventions in the treatment of AHFS, with regard to symptom relief and haemodynamic variables. Nitrates may be associated with a lower incidence of adverse effects after three hours compared with placebo. However, there is a lack of data to draw any firm conclusions concerning the use of nitrates in AHFS because current evidence is based on few low-quality studies.
We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life. The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials). There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group). The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects. BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem. Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review.
We identified one study (290 randomised participants) that investigated the effectiveness of decision aids compared to standard information in the informed consent process for clinical trials. This study reported two separate decision aid randomised controlled trials (RCTs). The decision aid trials were nested within two different parent trials focusing on breast cancer in postmenopausal women. One trial focused on informed consent for treatment in women who had previously had surgery for ductal carcinoma in situ (DCIS), the other on informed consent for prevention in women at high risk for breast cancer. Two different decision aids were used in these RCTs, and were compared with standard information. The pooled findings highlight the uncertainty surrounding most reported outcomes, including knowledge, decisional conflict, anxiety, trial participation and attrition. There was very low quality evidence that decision aids lower levels of decisional regret to a small degree (MD -5.53, 95% CI -10.29 to -0.76). No data were identified on several prespecified primary outcomes, including accurate risk perception, values-based decision, or whether potential participants recognised that a decision needed to be made, were able to identify features of options that matter most to individuals, or were involved in the decision. There was insufficient evidence to determine whether decision aids to support the informed consent process for clinical trials are more effective than standard information. Additional well designed, adequately powered clinical trials in more diverse clinical and social populations are needed to strengthen the results of this review. More generally, future research on which outcomes are most relevant for assessment in this context would be helpful.
A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk. Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.
Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.
We included 56 trials with 4826 participants randomized to an exercise (n = 2286) or comparison (n = 1985) group. Cancer diagnoses in trial participants included breast, prostate, gynecologic, hematologic, and other. Thirty-six trials were conducted among participants who were currently undergoing active treatment for their cancer, 10 trials were conducted among participants both during and post active cancer treatment, and the remaining 10 trials were conducted among participants scheduled for active cancer treatment. Mode of exercise intervention differed across trials and included walking by itself or in combination with cycling, resistance training, or strength training; resistance training; strength training; cycling; yoga; or Qigong. HRQoL and its domains were assessed using a wide range of measures. The results suggest that exercise interventions compared with control interventions have a positive impact on overall HRQoL and certain HRQoL domains. Exercise interventions resulted in improvements in: HRQoL from baseline to 12 weeks' follow-up (SMD 0.33; 95% CI 0.12 to 0.55) or when comparing difference in follow-up scores at 12 weeks (SMD 0.47; 95% CI 0.16 to 0.79); physical functioning from baseline to 12 weeks' follow-up (SMD 0.69; 95% CI 0.16 to 1.22) or 6 months (SMD 0.28; 95% CI 0.00 to 0.55); or when comparing differences in follow-up scores at 12 weeks (SMD 0.28; 95% CI 0.11 to 0.45) or 6 months (SMD 0.29; 95% CI 0.07 to 0.50); role function from baseline to 12 weeks' follow-up (SMD 0.48; 95% CI 0.07 to 0.90) or when comparing differences in follow-up scores at 12 weeks (SMD 0.17; 95% CI 0.00 to 0.34) or 6 months (SMD 0.32; 95% CI 0.03 to 0.61); and, in social functioning at 12 weeks' follow-up (SMD 0.54; 95% CI 0.03 to 1.05) or when comparing differences in follow-up scores at both 12 weeks (SMD 0.16; 95% CI 0.04 to 0.27) and 6 months (SMD 0.24; 95% CI 0.03 to 0.44). Further, exercise interventions resulted in a decrease in fatigue from baseline to 12 weeks' follow-up (SMD -0.38; 95% CI -0.57 to -0.18) or when comparing difference in follow-up scores at follow-up of 12 weeks (SMD -0.73; 95% CI -1.14 to -0.31). Since there is consistency of findings on both types of measures (change scores and difference in follow-up scores) there is greater confidence in the robustness of these findings. When examining exercise effects by subgroups, exercise interventions had significantly greater reduction in anxiety for survivors with breast cancer than those with other types of cancer. Further, there was greater reduction in depression, fatigue, and sleep disturbances, and improvement in HRQoL, emotional wellbeing (EWB), physical functioning, and role function for cancer survivors diagnosed with cancers other than breast cancer but not for breast cancer. There were also greater improvements in HRQoL and physical functioning, and reduction in anxiety, fatigue, and sleep disturbances when prescribed a moderate or vigorous versus a mild exercise program. Results of the review need to be interpreted cautiously owing to the risk of bias. All the trials reviewed were at high risk for performance bias. In addition, the majority of trials were at high risk for detection, attrition, and selection bias. This systematic review indicates that exercise may have beneficial effects at varying follow-up periods on HRQoL and certain HRQoL domains including physical functioning, role function, social functioning, and fatigue. Positive effects of exercise interventions are more pronounced with moderate- or vigorous-intensity versus mild-intensity exercise programs. The positive results must be interpreted cautiously because of the heterogeneity of exercise programs tested and measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials. Further research is required to investigate how to sustain positive effects of exercise over time and to determine essential attributes of exercise (mode, intensity, frequency, duration, timing) by cancer type and cancer treatment for optimal effects on HRQoL and its domains.
We included six studies (373 workers), four parallel RCTs, one cross-over RCT, and one combined parallel plus cross-over RCT. At least 295 of the employees were female and at least 39 male; for the remaining 39 employees, the sex was not specified in the study trial. The studies investigated different work-break frequencies (five studies) and different work-break types (two studies). None of the studies investigated different work-break durations. We judged all studies to have a high risk of bias. The quality of the evidence for the primary outcomes of self-reported musculoskeletal pain, discomfort and fatigue was low; the quality of the evidence for the primary outcomes of productivity and work performance was very low. The studies were executed in Europe or Northern America, with none from low- to middle-income countries. One study could not be included in the data analyses, because no detailed results have been reported. Changes in the frequency of work breaks There is low-quality evidence that additional work breaks may not have a considerable effect on musculoskeletal pain, discomfort or fatigue, when compared with no additional work breaks (standardised mean difference (SMD) -0.08; 95% CI -0.35 to 0.18; three studies; 225 participants). Additional breaks may not have a positive effect on productivity or work performance, when compared with no additional work breaks (SMD -0.07; 95% CI -0.33 to 0.19; three studies; 225 participants; very low-quality evidence). We found low-quality evidence that additional work breaks may not have a considerable effect on participant-reported musculoskeletal pain, discomfort or fatigue (MD 1.80 on a 100-mm VAS scale; 95% CI -41.07 to 64.37; one study; 15 participants), when compared to work breaks as needed (i.e. microbreaks taken at own discretion). There is very low-quality evidence that additional work breaks may have a positive effect on productivity or work performance, when compared to work breaks as needed (MD 542.5 number of words typed per 3-hour recording session; 95% CI 177.22 to 907.78; one study; 15 participants). Additional higher frequency work breaks may not have a considerable effect on participant-reported musculoskeletal pain, discomfort or fatigue (MD 11.65 on a 100-mm VAS scale; 95% CI -41.07 to 64.37; one study; 10 participants; low-quality evidence), when compared to additional lower frequency work breaks. We found very low-quality evidence that additional higher frequency work breaks may not have a considerable effect on productivity or work performance (MD -83.00 number of words typed per 3-hour recording session; 95% CI -305.27 to 139.27; one study; 10 participants), when compared to additional lower frequency work breaks. Changes in the duration of work breaks No trials were identified that assessed the effect of different durations of work breaks. Changes in the type of work break We found low-quality evidence that active breaks may not have a considerable positive effect on participant-reported musculoskeletal pain, discomfort and fatigue (MD -0.17 on a 1-7 NRS scale; 95% CI -0.71 to 0.37; one study; 153 participants), when compared to passive work breaks. Relaxation work breaks may not have a considerable effect on participant-reported musculoskeletal pain, discomfort or fatigue, when compared to physical work breaks (MD 0.20 on a 1-7 NRS scale; 95% CI -0.43 to 0.82; one study; 97 participants; low-quality evidence). We found low-quality evidence that different work-break frequencies may have no effect on participant-reported musculoskeletal pain, discomfort and fatigue. For productivity and work performance, evidence was of very low-quality that different work-break frequencies may have a positive effect. For different types of break, there may be no effect on participant-reported musculoskeletal pain, discomfort and fatigue according to low-quality evidence. Further high-quality studies are needed to determine the effectiveness of frequency, duration and type of work-break interventions among workers, if possible, with much higher sample sizes than the studies included in the current review. Furthermore, work-break interventions should be reconsidered, taking into account worker populations other than office workers, and taking into account the possibility of combining work-break intervention with other interventions such as ergonomic training or counselling, which may may possibly have an effect on musculoskeletal outcomes and work performance.
Only two small trials comparing continuous vs. bolus indomethacin were eligible. Analysis of these studies showed that there were no statistically significant differences in PDA closure at day 2 (RR 1.57, 95% CI 0.54, 4.60) and at day 5 (RR 2.77, 95% CI 0.33, 23.14). There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage and necrotizing enterocolitis. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia, retinopathy of prematurity, neurodevelopmental outcome and isolated intestinal perforation. The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hours. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine. The available data is insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion vs. bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration in premature infants cannot be made based on the current findings of this review.
Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD -3.38 kg CI -4.2 to -2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD - 1.16 kg CI -1.9 to -0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD -1.69 kg CI -2.8 to -0.6) compared with standard care. Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size, short study duration and by variability of the interventions themselves, their intensity and duration. Future studies adequately powered, with longer treatment duration and rigorous methodology will be needed in further evaluating the efficacy and safety of weight loss interventions for moderating weight gain. At this stage, there is insufficient evidence to support the general use of pharmacological interventions for weight management in people with schizophrenia.
Fifteen studies were included in the previous version of the review, and we included two new studies in this update, although we were unable to pool new data. Overall, the quality of the studies was moderate; concealment of allocation was assessed as clearly adequate in only seven (45%) of the trials. There was significant clinical heterogeneity between studies as the doses of aminophylline and other medications and the severity of the acute asthma varied between studies. There was no statistically significant advantage when adding intravenous aminophylline with respect to hospital admissions (OR 0.58; 95% CI 0.30 to 1.12; 6 studies; n = 315). In 2000 it was found that there was no statistically significant effect of aminophylline on airflow outcomes at any time period; the addition of two trials in 2012 has not challenged this conclusion. People treated with aminophylline and beta2-agonists had similar peak expiratory flow (PEF) values compared to those treated with beta2-agonists alone at 12 h (MD 8.30 L/min; 95% CI -20.69 to 37.29 L/min) or (MD -1.21% predicted; 95% CI -14.21% to 11.78% predicted) and 24 h (MD 22.20 L/min; 95% CI -56.65 to 101.05 L/min). Two subgroup analyses were performed by grouping studies according to mean baseline airflow limitation (11 studies) and the use of any corticosteroids (nine studies). There was no relationship between baseline airflow limitation or the use of corticosteroids on the effect of aminophylline. Aminophylline-treated patients reported more palpitations/arrhythmias (OR 3.02; 95% CI 1.15 to 7.90; 6 studies; n = 249) and vomiting (OR 4.21; 95% CI 2.20 to 8.07; 7 studies; n = 321); however, no significant difference was found in tremor (OR 2.60; 95% CI 0.62 to 11.02; 5 studies; n = 249). The use of intravenous aminophylline did not result in significant additional bronchodilation compared to standard care with inhaled beta2-agonists in patients experiencing an asthma exacerbation in the ED setting, or in a significant reduction in the risk of hospital admission. For every 100 people treated with aminophylline an additional 20 people had vomiting and 15 people arrhythmias or palpitations. No subgroups in which aminophylline might be more effective were identified. Our update in 2012 is consistent with the original conclusions that the risk-benefit balance of intravenous aminophylline is unfavourable.
Twenty-five trials were included. Only two studies reported live births. The odds ratios (OR) for pregnancy following ovulation suppression versus placebo or no treatment was 0.97 (95% confidence interval (CI) 0.68 to 1.34, P = 0.8) for all women randomised, and 1.02 (95% CI 0.70 to 1.52, P = 0.82) for subfertile couples only despite the use of a variety of suppression agents. There was no evidence of benefit from the treatment. The common OR for pregnancy following all agents versus danazol was 1.38 (95% CI 1.05 to 1.82, P = 0.02) for all women randomised, and 1.37 (95% CI 0.94 to 1.99, P = 0.10) for subfertile couples only. When GnRHa and danazol were directly compared, the OR was 1.45 (95% CI 1.08 to 1.95, P = 0.01) for all women randomised, and 1.63 (95% CI 1.12 to 2.37, P = 0.01) for subfertile couples only, in favour of GnRHa. No effect was observed for GnRHa compared with oral contraception (OR 0.93, 95% CI 0.41 to 2.12, P = 0.86 for all women randomised; OR 0.83, 95% CI 0.34 to 2.05, P = 0.69 for subfertile couples only). There is no evidence of benefit in the use of ovulation suppression in subfertile women with endometriosis who wish to conceive.
Twenty-five trials met the inclusion criteria. Twelve included rapid smoking and nine used other aversion methods. Ten trials included two or more conditions allowing assessment of a dose-response to aversive stimulation. The odds ratio (OR) for abstinence following rapid smoking compared to control was 2.01 (95% confidence intervals (CI): 1.36 to 2.95). Several factors suggest that this finding should be interpreted cautiously. A funnel plot of included studies was asymmetric, due to the relative absence of small studies with negative results. Most trials had a number of serious methodological problems likely to lead to spurious positive results. The only trial using biochemical validation of all self reported cessation gave a non-significant result. Other aversion methods were not shown to be effective (OR 1.15, 95% CI 0.73 to 1.82). There was a borderline dose-response to the level of aversive stimulation (OR 1.67, 95% CI 0.99 to 2.81). The existing studies provide insufficient evidence to determine the efficacy of rapid smoking, or whether there is a dose-response to aversive stimulation. Milder versions of aversive smoking seem to lack specific efficacy. Rapid smoking is an unproven method with sufficient indications of promise to warrant evaluation using modern rigorous methodology.
Nine studies (484 patients) met the pre-specified inclusion criteria (Kappa 1.00). Six studies were rated as low risk of bias. Three studies were rated as high risk of bias due to blinding (two open label and one single-blind). The total daily dose of rectal 5-ASA ranged from 0.5 g to 4 g, and dose frequency ranged from once to three times daily. 5-ASA was delivered as liquid enema in five studies or as a suppository in four studies. Follow-up ranged from 6 to 24 months. Rectal 5-ASA was significantly superior to placebo for maintenance of symptomatic remission over a period of 12 months.Sixty-two per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 30% of patients in the placebo group (4 studies; 301 patients; RR 2.22, 95% CI 1.26 to 3.90; I2 = 67%; P < 0.01). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 144 events) and inconsistency (i.e. unexplained heterogeneity). Rectal 5-ASA was significantly superior to placebo for maintenance of endoscopic remission over a 12 month period. Seventy-five per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 15% of patients in the placebo group (1 study; 25 patients; RR 4.88, 95% CI 1.31 to 18.18; P < 0.05). There was no statistically significant difference in the proportion of patients who experienced at least one adverse event. Sixteen per cent of patients in the rectal 5-ASA group experienced at least one adverse compared to 12% of placebo patients (2 studies; 160 patients; RR 1.35, 95% CI 0.63 to 2.89; I2 = 0%; P = 0.44). The most commonly reported adverse events were anal irritation and abdominal pain. No statistically significant differences between rectal and oral 5-ASA were identified for either symptomatic or endoscopic remission over a period of six months. Eighty per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 65% of patients in the oral 5-ASA group (2 studies; 69 patients; RR 1.24, 95% CI 0.92 to 1.66; I2 = 0%; P = 0.15). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 50 events) and high risk of bias (i.e. both studies in the pooled analysis were open label). Eighty per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 70% of patients in the oral 5-ASA group (2 studies; 91 patients; RR 1.14, 95% CI 0.90 to 1.45; I2 = 0%; P = 0.26). In two small trials, one comparing 2 g/day 5-ASA enemas to 4 g/day 5-ASA enemas and the other comparing 0.5 g/day 5-ASA suppositories to 1 g/day 5-ASA suppositories no dose response relationship was observed. The limited data available suggest that rectal 5-ASA is effective and safe for maintenance of remission of mild to moderately active distal UC. Well designed randomized trials are needed to establish the optimal dosing regimen for rectal 5-ASA, to compare rectal 5-ASA with rectal corticosteroids and to identify subgroups of patients who are more or less responsive to specific rectal 5-ASA regimens. The combination of oral and rectal 5-ASA appears to be more effective than either oral or rectal monotherapy for induction of remission. The efficacy of combination therapy for maintenance of remission has not been assessed and could be evaluated in future trials.
We included 66 studies with 7840 participants in the review, though most analyses were based on data from fewer participants. In total there are 17 studies awaiting classification. No studies were at a low risk of bias. We noted substantial statistical and clinical heterogeneity between trials. Most of the studies reported the primary outcome pain as assessed by verbal response from participants in an awake state but some trials reported withdrawal of the injected limb as a proxy for pain after induction of anaesthesia in response to rocuronium administration. Few studies reported adverse events and no study reported heart rate and blood pressure changes after administration of rocuronium. Lidocaine was the most commonly studied intervention drug, used in 29 trials with 2256 participants. The risk ratio (RR) of pain on injection if given lidocaine compared to placebo was 0.23 (95% confidence interval (CI) 0.17 to 0.31; I² = 65%, low quality of evidence). The RR of pain on injection if fentanyl and remifentanil were given compared to placebo was 0.42 (95% CI 0.26 to 0.70; I² = 79%, low quality of evidence) and (RR 0.10, 95% CI 0.04 to 0.26; I² = 74%, low quality of evidence), respectively. Pain on injection of intervention drugs was reported with the use of lidocaine and acetaminophen in one study. Cough was reported with the use of fentanyl (one study), remifentanil (five studies, low quality evidence) and alfentanil (one study). Breath holding and chest tightness were reported with the use of remifentanil in two studies (very low quality evidence) and one study (very low quality evidence), respectively. The overall rate of complications was low. The evidence to suggest that the most commonly investigated pharmacological interventions reduce pain on injection of rocuronium is of low quality due to risk of bias and inconsistency. There is low or very low quality evidence for adverse events, due to risk of bias, inconsistency and imprecision of effect. We did not compare the various interventions with one another and so cannot comment on the superiority of one intervention over another. Complications were reported more often with use of opioids.
We included 13 studies, involving 1622 women. All were comparisons of single-dose treatment with short-course (four- to seven-day) treatments. The risk of bias of trials included in this review was largely unclear, and most trials were at high risk of performance bias. The quality of the evidence was assessed using the GRADE approach. When the any antibiotic agent was used, the 'no cure' rate for asymptomatic bacteriuria in pregnant women was slightly lower for the short-course treatment over the single-dose treatment, although there was evidence of statistical heterogeneity (average risk ratio (RR) 1.28, 95% confidence interval (CI) 0.87 to 1.88; women = 1502, studies = 13; I² = 56%; very low quality evidence). Data from only good quality trials also showed better cure rates with short (four- to seven-day) regimens of the same microbial agent (average RR 1.72, 95% CI 1.27 to 2.33; women = 803, studies = two; I² = 0%; high quality evidence). There was no clear difference in the recurrence of asymptomatic bacteriuria rate between treatment and control groups, whether the same or different microbial agents were used (RR 1.13, 95% CI 0.77 to 1.66; 445 women studies = eight; I² = 0%; very low quality evidence). Differences were detected for low birthweight babies, favoring a short course (four- to seven-day treatment) of the same microbial agent, although the data come from a single trial (RR 1.65, 95% CI 1.06 to 2.57; 714 women; high quality evidence), but no differences were observed for preterm delivery (RR 1.17, 95% CI 0.77 to 1.78; women = 804; studies = three; I² = 23%; moderate quality) or pyelonephritis (RR 3.09, 95% CI 0.54 to 17.55; women = 102; studies = two; I² = 0%; very low quality evidence). Finally, single-dose treatment of any microbial agent was associated with a decrease in reports of 'any side effects' (RR 0.70, 95% CI 0.56 to 0.88; 1460 women, studies = 12; I² = 9%; low quality evidence). Evidence was downgraded for risk of bias concerns in trials contributing data and for imprecise effect estimates (wide confidence intervals crossing the line of no effect, and in some cases, small studies with few events). A single-dose regimen of antibiotics may be less effective than a short-course (four- to seven-day) regimen, but more evidence is needed from large trials measuring important outcomes, such as cure rate. Women with asymptomatic bacteriuria in pregnancy should be treated by the standard regimen of antibiotics until more data become available testing seven-day treatment compared with shorter courses of three- or five-day regimens.
We included eight RCTs with 1157 patient participants and 943 carer participants. We found no quasi-RCTs. We identified seven studies that await classification, and three ongoing studies. Three studies designed an intervention targeted at patients, four at carers, and one at both patients and carers. Studies included varied information: standardised or tailored, presented once or several times, and that included verbal or written information, audio recordings, multimedia information, and interactive information packs. Five studies reported robust methods of randomisation and allocation concealment. We noted high attrition rates in five studies. It was not feasible to blind participants, and we rated all studies as at high risk of performance bias, and at unclear risk of detection bias because most outcomes required self reporting. We attempted to pool data statistically, however this was not always possible due to high levels of heterogeneity. We calculated mean differences (MDs) using data reported from individual study authors where possible, and narratively synthesised the results. We reported the following two comparisons. Information or education intervention versus no information or education intervention (4 studies) For patient anxiety, we did not pool data from three studies (332 participants) owing to unexplained substantial statistical heterogeneity and possible clinical or methodological differences between studies. One study reported less anxiety when an intervention was used (MD -3.20, 95% confidence interval (CI) -3.38 to -3.02), and two studies reported little or no difference between groups (MD -0.40, 95% CI -4.75 to 3.95; MD -1.00, 95% CI -2.94 to 0.94). Similarly, for patient depression, we did not pool data from two studies (160 patient participants). These studies reported less depression when an information or education intervention was used (MD -2.90, 95% CI -4.00 to -1.80; MD -1.27, 95% CI -1.47 to -1.07). However, it is uncertain whether information or education interventions reduce patient anxiety or depression due to very low-certainty evidence. It is uncertain whether information or education interventions improve health-related quality of life due to very low-certainty evidence from one study reporting little or no difference between intervention groups (MD -1.30, 95% CI -4.99 to 2.39; 143 patient participants). No study reported adverse effects, knowledge acquisition, PTSD severity, or patient or carer satisfaction. We used the GRADE approach and downgraded certainty of the evidence owing to study limitations, inconsistencies between results, and limited data from few small studies. Information or education intervention as part of a complex intervention versus a complex intervention without information or education (4 studies) One study (three comparison groups; 38 participants) reported little or no difference between groups in patient anxiety (tailored information pack versus control: MD 0.09, 95% CI -3.29 to 3.47; standardised general ICU information versus control: MD -0.25, 95% CI -4.34 to 3.84), and little or no difference in patient depression (tailored information pack versus control: MD -1.26, 95% CI -4.48 to 1.96; standardised general ICU information versus control: MD -1.47, 95% CI -6.37 to 3.43). It is uncertain whether information or education interventions as part of a complex intervention reduce patient anxiety and depression due to very low-certainty evidence. One study (175 carer participants) reported fewer carer participants with poor comprehension among those given information (risk ratio 0.28, 95% CI 0.15 to 0.53), but again this finding is uncertain due to very low-certainty evidence. Two studies (487 carer participants) reported little or no difference in carer satisfaction; it is uncertain whether information or education interventions as part of a complex intervention increase carer satisfaction due to very low-certainty evidence. Adverse effects were reported in only one study: one participant withdrew because of deterioration in mental health on completion of anxiety and depression questionnaires, but the study authors did not report whether this participant was from the intervention or comparison group. We downgraded certainty of the evidence owing to study limitations, and limited data from few small studies. No studies reported severity of PTSD, or health-related quality of life. We are uncertain of the effects of information or education interventions given to adult ICU patients and their carers, as the evidence in all cases was of very low certainty, and our confidence in the evidence was limited. Ongoing studies may contribute more data and introduce more certainty when incorporated into future updates of the review.
Four RCTs enrolling 2177 participants met our inclusion criteria. Of these, three compared ACEi with placebo and one compared ACEi with ARB. Two studies had an overall low risk of bias, and the other two were considered to be at moderate to high risk of bias. Low to moderate quality of evidence (from two studies representing 1906 patients) suggested that ACEi had no impact on all-cause mortality (RR 1.80, 95% CI 0.17 to 19.27, P = 0.63) or cardiovascular events (RR 0.87, 95% CI 0.66 to 1.14, P = 0.31) in people with stage 3 CKD. For all-cause mortality, there was substantial heterogeneity in the results. One study (quality assessment: low risk of bias) reported no difference in the risk of end-stage kidney disease in those with an eGFR > 45 mL/min/1.74 m² treated with ACEi versus placebo (RR 1.00, 95% CI 0.09 to 1.11, P = 0.99). The (high risk of bias) study that compared ACEi with ARB reported little difference in effect between the treatments when urinary protein, blood pressure or creatinine clearance were compared. No published studies comparing ARB with placebo or ACEi and ARB with placebo were identified. Our review demonstrated that there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 CKD who do not have diabetes mellitus. We have identified an area of significant uncertainty for a group of patients who account for most of those labelled as having CKD.
Seventeen trials were included. These involved 1433 people, mostly young physically active adults. All included trials had methodological weaknesses and were at risk of bias, notably selection bias from inadequate or lack of allocation concealment. Data for pooling individual outcomes were available for a maximum of nine trials and 54% of participants. There were no statistically or clinically significant differences between double-bundle and single-bundle reconstruction in the subjective functional knee scores (subjective IKDC score, Tegner activity score, Lysholm score) in the intermediate (six months up to two years since surgery) or long term (two to five years from surgery). For example, the long term results for the Lysholm score (0 to 100: best score) were: mean difference (MD) 0.12, 95% confidence interval (CI) -1.50 to 1.75; 5 trials, 263 participants). The only trial reporting on long term knee pain found no statistically significant differences between the two groups. There were no significant differences between the two groups in adverse effects and complications (e.g. infection reported by nine trials (7/285 versus 7/393; risk ratio (RR) 1.14, 95% CI 0.46 to 2.81); graft failure reported by six trials (1/169 versus 4/185; RR 0.45; 95% CI 0.07 to 2.90). Limited data from five trials found a better return to pre-injury level of activity after double-bundle reconstruction (147/162 versus 208/255; RR 1.15, 95% CI 1.07 to 1.25). At long term follow-up, there were statistically significant differences in favour of double-bundle reconstruction for IKDC knee examination (normal or nearly normal categories: 325/344 versus 386/429; RR 1.05, 95% CI 1.01 to 1.08; 9 trials), knee stability measured with KT-1000 arthrometer (MD -0.74 mm, 95% CI -1.10 to -0.37; 5 trials, 363 participants) and rotational knee stability tested by the pivot-shift test (normal or nearly normal categories: 293/298 versus 382/415; RR 1.06, 95% CI 1.02 to 1.09; 9 trials). There were also statistically significant differences in favour of double-bundle reconstruction for newly occurring meniscal injury (9/240 versus 24/358; RR 0.46, 95% CI 0.23 to 0.92; 6 trials) and traumatic ACL rupture (1/120 versus 8/149; RR 0.17, 95% CI 0.03 to 0.96; 3 trials). There were no statistically significant differences found between the two groups in range of motion (flexion and extension) deficits. There is insufficient evidence to determine the relative effectiveness of double-bundle and single-bundle reconstruction for anterior cruciate ligament rupture in adults, although there is limited evidence that double-bundle ACL reconstruction has some superior results in objective measurements of knee stability and protection against repeat ACL rupture or a new meniscal injury. High quality, large and appropriately reported randomised controlled trials of double-bundle versus single-bundle reconstruction for anterior cruciate ligament rupture in adults appear justified.
One single trial was eligible for inclusion. This non-randomised, unblinded, controlled trial undertaken in Bangladesh involved 117 tetanus patients. Vitamin C at a dosage of 1 g/day was administered intravenously alongside conventional treatment. At recruitment, the participants were stratified into two age groups and the results were reported by age. There was a significant difference in the vitamin C effect between the two age groups (P = 0.01). In the tetanus patients aged 1 to 12 years (n = 62), vitamin C treatment was associated with a 100% reduction in case fatality rate (95% CI from -100% to -94%). In patients aged 13 to 30 years (n = 55), vitamin C treatment was associated with a 45% reduction in case fatality rate (95% CI from -69% to -5%). A single, non-randomised, poorly reported trial of vitamin C as a treatment for tetanus suggests a considerable reduction in mortality. However, concerns about trial quality mean that this result must be interpreted with caution and vitamin C cannot be recommended as a treatment for tetanus on the basis of this evidence. New trials should be carried out to examine the effect of vitamin C on tetanus treatment.
We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures. We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis. We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality. We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary neurocysticercosis (identified on computed tomography (CT) scan) presenting with seizures. In total, 466 people were enrolled. These studies compared various AED treatment durations, six, 12 and 24 months. The risk of seizure recurrence with six months treatment compared with 12 to 24 months treatment was not statistically significant (odds ratio (OR) 1.34 (95% confidence interval (CI) 0.73 to 2.47; three studies, 360 participants; low-certainty evidence)). The risk of seizure recurrence with six to 12 months compared with 24 months treatment was not statistically significant (OR 1.36 (95% CI 0.72 to 2.57; three studies, 385 participants; low-certainty evidence)). Two studies co-related seizure recurrence with CT findings and suggested that persistent and calcified lesions had a higher recurrence risk and suggest longer duration of treatment with AEDs. One study reported no side effects, while the rest did not comment on side effects of drugs. None of the studies addressed the quality of life of the participants.These studies had certain methodological deficiencies such as a small sample size and a possibility of bias due to lack of blinding, which affect the results of this review. Despite neurocysticercosis being the most common cause of epilepsy worldwide, there is currently no evidence available regarding the use of AEDs as seizure prophylaxis among people presenting with symptoms other than seizures. For those presenting with seizures, there is no reliable evidence regarding the duration of treatment required. There is therefore a need for large scale randomised controlled trials to address these questions.
Two eligible studies of a total of 273 infants were included. Both studies were randomized controlled trials. One study treated 63 infants with vidarabine or placebo (Whitley 1980) and the other study treated 210 infants with aciclovir or vidarabine (Whitley 1991). In the study comparing vidarabine with placebo (Whitley 1980), infants with all forms of neonatal HSV disease were included [disseminated disease, central nervous system (CNS) disease alone, and skin, eye and mouth (SEM) disease].There was no significant reduction in the risk of mortality when analyzed as an entire group; however, mortality was significantly reduced when data from infants with CNS disease or disseminated disease were combined. There was no difference in the rate of neurological abnormalities in survivors at one year when analyzed as an entire group or by disease category. There was no difference between aciclovir and vidarabine (Whitley 1991) in preventing mortality from neonatal HSV disease, in preventing disease progression, in reducing the incidence of neurological abnormality at one year, or in the incidence of drug-induced renal or bone marrow toxicity. In infants with SEM disease, there was no significant difference in neurological outcome with aciclovir compared vidarabine treatment. Both drugs were well tolerated in the newborn period. There is insufficient trial evidence to evaluate the effects of antiviral agents with controls or with each other. The rarity of the condition makes effectively powered clinical trials difficult to perform. The efficacy of newer antiviral agents with better bioavailability (e.g. valaciclovir, valganciclovir) for the treatment of neonatal disease needs to be evaluated in randomised trials. The efficacy of oral formulations need to be evaluated as they may be useful for infants with skin, eye or mouth HSV disease or in the treatment of infants with recurrences after the neonatal period.
Nine RCTs, one with two reports, (N = 531 participants, 469 included in analyses) investigated a variety of telerehabilitation interventions in adults with MS. The mean age of participants varied from 41 to 52 years (mean 46.5 years) and mean years since diagnosis from 7.7 to 19.0 years (mean 12.3 years). The majority of the participants were women (proportion ranging from 56% to 87%, mean 74%) and with a relapsing-remitting course of MS. These interventions were complex, with more than one rehabilitation component and included physical activity, educational, behavioural and symptom management programmes. All studies scored 'low' on the methodological quality assessment. Overall, the review found 'low-level' evidence for telerehabilitation interventions in reducing short-term disability and symptoms such as fatigue. There was also 'low-level' evidence supporting telerehabilitation in the longer term for improved functional activities, impairments (such as fatigue, pain, insomnia); and participation measured by quality of life and psychological outcomes. There were limited data on process evaluation (participants'/therapists' satisfaction) and no data available for cost effectiveness. There were no adverse events reported as a result of telerehabilitation interventions. There is currently limited evidence on the efficacy of telerehabilitation in improving functional activities, fatigue and quality of life in adults with MS. A range of telerehabilitation interventions might be an alternative method of delivering services in MS populations. There is insufficient evidence to support on what types of telerehabilitation interventions are effective, and in which setting. More robust trials are needed to build evidence for the clinical and cost effectiveness of these interventions.
We included two RCTs that randomised 20 participants to NPPV and 20 participants to control. We assessed both studies as having high risk of bias; both trials assessed effects of bilateral positive airway pressure (BiPAP). Neither trial used continuous positive airway pressure (CPAP). Controls received standard care. Investigators reported no deaths and no serious adverse events (Grades of Recommendation, Assessment, Development and Evaluation (GRADE): very low quality of evidence due to serious risk of bias and serious imprecision of results). Both trials showed a statistically significant reduction in symptom score. One trial did not report a standard deviation (SD), but by using an estimated SD, we found a statistically significantly reduced asthma symptom score (mean difference (MD) ‐2.50, 95% confidence interval (CI) ‐4.70 to ‐0.30, P = 0.03, 19 participants, GRADE: very low quality of evidence). In the other trial, NPPV was associated with a lower total symptom score (5.6 vs 1.9, 16 participants, very low quality of evidence) before cross‐over, but investigators did not report an SD, nor could it be estimated from the first phase of the trial, before the cross‐over. These gains could be clinically relevant, as a reduction of three or more points in symptom score is considered a clinically meaningful change. Researchers documented five dropouts (12.5%), four of which were due to intolerance to NPPV, and one to respiratory failure requiring intubation. Owing to insufficient reporting in the latter trial and use of different scoring systems, it was not possible to conduct a meta‐analysis nor a Trial Sequential Analysis. Current evidence does not permit confirmation or rejection of the effects of NPPV for acute asthma in children. Large RCTs with low risk of bias are warranted.
We identified 10 trials, which included 375 women having six different types of needle suspension procedures and 489 who received comparison interventions. Needle suspensions were more likely to fail than open abdominal retropubic suspension. There was a higher subjective failure rate after the first year (91/313 (29%) failed versus 47/297 (16%) failed after open abdominal retropubic suspension). The risk ratio (RR) was 2.00 (95% confidence interval (CI) 1.47 to 2.72), although the difference in peri-operative complications was not significant (17/75 (23%) versus 12/77 (16%); RR 1.44, 95% CI 0.73 to 2.83). There were no significant differences for the other outcome measures. This effect was seen in both women with primary incontinence and women with recurrent incontinence after failed primary operations. Needle suspensions may be as effective as anterior vaginal repair (50/156 (32%) failed after needle suspension versus 64/181 (35%) after anterior repair; RR 0.86, 95% CI 0.64 to 1.16), but there was little information about morbidity. Data for comparison with suburethral slings were inconclusive because they came from a small and atypical population. No trials compared needle suspensions with conservative management, peri-urethral injections, or sham or laparoscopic surgery. Bladder neck needle suspension surgery is probably not as good as open abdominal retropubic suspension for the treatment of primary and secondary urodynamic stress incontinence because the cure rates were lower in the trials reviewed. However, the reliability of the evidence was limited by poor quality and small trials. There was not enough information to comment on comparisons with suburethral sling operations. Although cure rates were similar after needle suspension compared with after anterior vaginal repair, the data were insufficient to be reliable and inadequate to compare morbidity. A Brief Economic Commentary (BEC) identified no cost-effectiveness studies comparing bladder neck needle suspension with other surgeries.
We included four trials of good methodological quality involving 656 women in the review. The four included trials evaluated five different interventions including glycerine pads, lanolin with breast shells, lanolin alone, expressed breast milk, and an all-purpose nipple ointment. All studies included education to position the infant at the breast correctly as part of routine postpartum care to both treatment and control groups. Pooled data existed only for the comparison of lanolin versus usual care. We did not pool data for other outcomes due to either heterogeneity in outcome measures or differing interventions. There was no evidence that glycerine gel dressings or breast shells with lanolin significantly improved nipple pain. One trial found no clear differences in nipple pain (at one to three days, four to five days, or six to seven days' post-treatment) between women who applied lanolin or nothing to their nipples. In contrast, the same trial found that women who applied expressed breast milk had significantly lower perceptions of nipple pain following four to five days of treatment than women who applied lanolin. However, this beneficial effect was not maintained after six to seven days of treatment. There were no group differences in nipple pain perceptions at any assessment between women who applied expressed breast milk and women who applied nothing. Women who applied an "all-purpose nipple ointment", in comparison to women who applied lanolin, had no improvement in nipple pain after seven days of treatment. There was insufficient evidence that glycerine gel dressings, lanolin with breast shells, lanolin alone, expressed breast milk, or all-purpose nipple ointment improved maternal perceptions of nipple pain. Overall, there was insufficient evidence to recommend any intervention for the treatment of nipple pain. However, one important finding was that regardless of the treatment used, for most women nipple pain reduced to mild levels after approximately seven to 10 days' postpartum. The provision of anticipatory guidance regarding usual time to pain reduction may be a useful strategy in assisting women to continue to breastfeed and to do so exclusively. The overall quality of the evidence for the primary outcome of nipple pain as assessed using GRADE was of low quality, mainly because single studies with few participants contributed data for analysis. There was insufficient evidence that glycerine gel dressings, breast shells with lanolin, lanolin alone, or the all-purpose nipple ointment significantly improved maternal perceptions of nipple pain. The results from these four trials of good methodological quality suggested that applying nothing or just expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin. The quality of the evidence for this review did not lead to robust conclusions regarding the objectives assessed. We included only four trials, incorporating 656 women, in the review and all four trials compared varying interventions, participants, study outcome measures, and standards of usual care. The methodological quality of the included studies was good but the overall quality of the evidence for the primary outcome of nipple pain was of low quality, mainly because single studies with few participants contributed data for analysis.
One new trial was included in this update. In all, 11 trials (six were randomised and five were quasi-randomised), involving a total of 1654 predominantly elderly patients with hip fractures, are included in the review. Most trials were at risk of bias, particularly that resulting from inadequate allocation concealment, lack of assessor blinding and incomplete outcome assessment. Only very limited data pooling was possible. Ten trials compared predominantly skin traction with no traction. The available data provided no evidence of benefit from traction either in the relief of pain (pain soon after immobilisation (visual analogue score 0: none to 10: worst pain): mean difference 0.11, 95% CI -0.27 to 0.50; 3 trials), ease of fracture reduction or quality of fracture reduction at time of surgery. There were inconclusive data for pressures sores and other complications, including fracture fixation failure. Three minor adverse effects (sensory disturbance and skin blisters) related to skin traction were reported. One of the above trials included both skin and skeletal traction groups. This trial and one other compared skeletal traction with skin traction and found no important differences between these two methods, although the initial application of skeletal traction was noted as being more painful and more costly. From the evidence available, the routine use of traction (either skin or skeletal) prior to surgery for a hip fracture does not appear to have any benefit. However, the evidence is also insufficient to rule out the potential advantages for traction, in particular for specific fracture types, or to confirm additional complications due to traction use. Given the increasing lack of evidence for the use of pre-operative traction, the onus should now be on clinicians who persist in using pre-operative traction to either stop using it or to use it only in the context of a well-designed randomised controlled trial.
Five RCTs with a total of 341,342 participants were included in this review. All involved prostate-specific antigen (PSA) testing, with or without digital rectal examination (DRE), though the interval and threshold for further evaluation varied across trials. The age of participants ranged from 45 to 80 years and duration of follow-up from 7 to 20 years. Our meta-analysis of the five included studies indicated no statistically significant difference in prostate cancer-specific mortality between men randomised to the screening and control groups (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.86 to 1.17). The methodological quality of three of the studies was assessed as posing a high risk of bias. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial were assessed as posing a low risk of bias, but provided contradicting results. The ERSPC study reported a significant reduction in prostate cancer-specific mortality (RR 0.84, 95% CI 0.73 to 0.95), whilst the PLCO study concluded no significant benefit (RR 1.15, 95% CI 0.86 to 1.54). The ERSPC was the only study of the five included in this review that reported a significant reduction in prostate cancer-specific mortality, in a pre-specified subgroup of men aged 55 to 69 years of age. Sensitivity analysis for overall risk of bias indicated no significant difference in prostate cancer-specific mortality when referring to the meta analysis of only the ERSPC and PLCO trial data (RR 0.96, 95% CI 0.70 to 1.30). Subgroup analyses indicated that prostate cancer-specific mortality was not affected by the age at which participants were screened. Meta-analysis of four studies investigating all-cause mortality did not determine any significant differences between men randomised to screening or control (RR 1.00, 95% CI 0.96 to 1.03). A diagnosis of prostate cancer was significantly greater in men randomised to screening compared to those randomised to control (RR 1.30, 95% CI 1.02 to 1.65). Localised prostate cancer was more commonly diagnosed in men randomised to screening (RR 1.79, 95% CI 1.19 to 2.70), whilst the proportion of men diagnosed with advanced prostate cancer was significantly lower in the screening group compared to the men serving as controls (RR 0.80, 95% CI 0.73 to 0.87). Screening resulted in a range of harms that can be considered minor to major in severity and duration. Common minor harms from screening include bleeding, bruising and short-term anxiety. Common major harms include overdiagnosis and overtreatment, including infection, blood loss requiring transfusion, pneumonia, erectile dysfunction, and incontinence. Harms of screening included false-positive results for the PSA test and overdiagnosis (up to 50% in the ERSPC study). Adverse events associated with transrectal ultrasound (TRUS)-guided biopsies included infection, bleeding and pain. No deaths were attributed to any biopsy procedure. None of the studies provided detailed assessment of the effect of screening on quality of life or provided a comprehensive assessment of resource utilization associated with screening (although preliminary analyses were reported). Prostate cancer screening did not significantly decrease prostate cancer-specific mortality in a combined meta-analysis of five RCTs. Only one study (ERSPC) reported a 21% significant reduction of prostate cancer-specific mortality in a pre-specified subgroup of men aged 55 to 69 years. Pooled data currently demonstrates no significant reduction in prostate cancer-specific and overall mortality. Harms associated with PSA-based screening and subsequent diagnostic evaluations are frequent, and moderate in severity. Overdiagnosis and overtreatment are common and are associated with treatment-related harms. Men should be informed of this and the demonstrated adverse effects when they are deciding whether or not to undertake screening for prostate cancer. Any reduction in prostate cancer-specific mortality may take up to 10 years to accrue; therefore, men who have a life expectancy less than 10 to 15 years should be informed that screening for prostate cancer is unlikely to be beneficial. No studies examined the independent role of screening by DRE.
A total of 12 studies including 1020 participants were incorporated into the review. These studies had low to moderate risk of bias, mainly because allocation concealment or methods of sequence generation were not adequately reported. In addition, it was not clear whether follow-up was similar for the treatment groups. The index test was incorporated as a reference standard in the laparoscopy group, and differential verification or partial verification bias may have occurred in most RCTs. Overall the quality of the evidence was low to moderate for most outcomes, as per the GRADE approach. Laparoscopy was compared with open appendicectomy in eight RCTs. Laparoscopy was associated with an increased rate of specific diagnoses (seven RCTs, 561 participants; odds ratio (OR) 4.10, 95% confidence interval (CI) 2.50 to 6.71; I2 = 18%), but no evidence was found of reduced rates for any adverse events (eight RCTs, 623 participants; OR 0.46, 95% CI 0.19 to 1.10; I2 = 0%). A meta-analysis of seven studies found a significant difference favouring the laparoscopic procedure in the rate of removal of normal appendix (seven RCTs, 475 participants; OR 0.13, 95% CI 0.07 to 0.24; I2 = 0%). Laparoscopic diagnosis versus a 'wait and see' strategy was investigated in four RCTs. A significant difference favoured laparoscopy in terms of rate of specific diagnoses (four RCTs, 395 participants; OR 6.07, 95% CI 1.85 to 29.88; I2 = 79%), but no evidence suggested a difference in rates of adverse events (OR 0.87, 95% CI 0.45 to 1.67; I2 = 0%). We found that laparoscopy in women with acute lower abdominal pain, non-specific lower abdominal pain or suspected appendicitis led to a higher rate of specific diagnoses being made and a lower rate of removal of normal appendices compared with open appendicectomy only. Hospital stays were shorter. No evidence showed an increase in adverse events when any of these strategies were used.
Thirteen studies, most including adult patients, met the eligibility criteria. We found no clear evidence of an effect of leukoreduced PRBC versus non-leukoreduced PRBC in patients that were randomised to receive transfusion for the following outcomes: TRALI: RR 0.96, 95% CI 0.67 to 1.36, P = 0.80 from one trial reporting data on 1864 trauma patients. The accrued information of 1864 participants constituted only 28.5% of the diversity-adjusted required information size (DARIS) of 6548 participants. The quality of evidence was low. Death from any cause: RR 0.81, 95% CI 0.58 to 1.12, I² statistic = 63%, P = 0.20 from nine trials reporting data on 6485 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6485 participants constituted only 55.3% of the DARIS of 11,735 participants. The quality of evidence was very low. Infection from any cause: RR 0.80, 95% CI 0.62 to 1.03, I² statistic = 84%, P = 0.08 from 10 trials reporting data on 6709 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6709 participants constituted only 60.6% of the DARIS of 11,062 participants. The quality of evidence was very low. Adverse events: The only adverse event reported as an adverse event was fever (RR 0.81, 95% CI 0.64 to 1.02; I² statistic= 0%, P = 0.07). Fever was reported in two trials on 634 cardiovascular surgical and gastro-oncology surgical patients. The accrued information of 634 participants constituted only 84.4% of the DARIS of 751 participants. The quality of evidence was low. Incidence of other non-infectious complications: This outcome was not assessed in any included trial. There is no clear evidence for supporting or rejecting the routine use of leukoreduction in all patients requiring PRBC transfusion for preventing TRALI, death, infection, non-infectious complications and other adverse events. As the quality of evidence is very low to low, more evidence is needed before a definitive conclusion can be drawn.
We included 62 trials (6428 women). Twenty-two trials did not contribute data to the meta-analyses. The trials were generally small and of limited quality. Three trials (107 women) indicated that bromocriptine significantly reduced the proportion of women lactating compared with no treatment at or within seven days postpartum (three trials, 107 women; risk ratio (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.54). Seven trials involving oestrogen preparations (diethylstilbestrol, quinestrol, chlorotrianisene, hexestrol) suggested that they significantly reduced the proportion of lactating women compared with no treatment at or within seven days postpartum (RR 0.40, 95% CI 0.29 to 0.56). We found no trials comparing non-pharmacologic methods with no treatment. Trials comparing bromocriptine with other pharmacologic agents such as methergoline, prostaglandins, pyridoxine, carbegoline, diethylstilbestrol and cyclofenil suggested similarity in their effectiveness. Side effects were poorly reported in the trials and no case of thromboembolism was recorded in the four trials that reported it as an outcome. There is weak evidence that some pharmacologic treatments (most of which are currently unavailable to the public) are better than no treatment for suppressing lactation symptoms in the first postpartum week. No evidence currently exists to indicate whether non-pharmacologic approaches are more effective than no treatment. Presently, there is insufficient evidence to address the side effects of methods employed for suppressing lactation. When women desire treatment, bromocriptine may be considered where it is registered for lactation suppression in those without predisposition to its major side effects of public concerns. Many trials did not contribute data that could be included in analyses. Large randomised trials are needed to compare the effectiveness of pharmacologic (especially bromocriptine) and non-pharmacologic methods with no treatment. Such trials should consider the acceptability of the intervention and lactation symptoms of concern to women and be large enough to detect clinically important differences in major side effects between comparison groups.
We included 35 studies (including seven from the previous version of the review), which included 2565 participants in total. All studies used a parallel RCT design, and 33 studies (94%) only targeted T2DM patients. There was variation between studies with regards to included age groups (ages 18 to 80), duration of follow-up (3 to 12 months), use of antidiabetic therapy, and included participants' baseline HbA1c levels (from 5.5% to 13.1%). We assessed 29 studies (83%) as being at high risk of bias, two studies (6%) as being at low risk of bias, and four studies (11%) as unclear. Thirty-four of the studies provided data suitable for analysis under one or both of the two comparisons. Comparison 1: low quality evidence from 14 studies (1499 participants) comparing periodontal therapy with no active intervention/usual care demonstrated that mean HbA1c was 0.29% lower (95% confidence interval (CI) 0.48% to 0.10% lower) 3 to 4 months post-treatment, and 0.02% lower after 6 months (five studies, 826 participants; 95% CI 0.20% lower to 0.16% higher). Comparison 2: 21 studies (920 participants) compared different periodontal therapies with each other. There was only very low quality evidence for the multiple head-to-head comparisons, the majority of which were unsuitable to be pooled, and provided no clear evidence of a benefit for one periodontal intervention over another. We were able to pool the specific comparison between scaling and root planing (SRP) plus antimicrobial versus SRP and there was no consistent evidence that the addition of antimicrobials to SRP was of any benefit to delivering SRP alone (mean HbA1c 0.00% lower: 12 studies, 450 participants; 95% CI 0.22% lower to 0.22% higher) at 3-4 months post-treatment, or after 6 months (mean HbA1c 0.04% lower: five studies, 206 patients; 95% CI 0.41% lower to 0.32% higher). Less than half of the studies measured adverse effects. The evidence was insufficient to conclude whether any of the treatments were associated with harm. No other patient-reported outcomes (e.g. quality of life) were measured by the included studies, and neither were cost implications or diabetic complications. Studies showed varying degrees of success with regards to achieving periodontal health, with some showing high levels of residual inflammation following treatment. Statistically significant improvements were shown for all periodontal indices (BOP, CAL, GI, PI and PPD) at 3-4 and 6 months in comparison 1; however, this was less clear for individual comparisons within the broad category of comparison 2. There is low quality evidence that the treatment of periodontal disease by SRP does improve glycaemic control in people with diabetes, with a mean percentage reduction in HbA1c of 0.29% at 3-4 months; however, there is insufficient evidence to demonstrate that this is maintained after 4 months. There was no evidence to support that one periodontal therapy was more effective than another in improving glycaemic control in people with diabetes mellitus. In clinical practice, ongoing professional periodontal treatment will be required to maintain clinical improvements beyond 6 months. Further research is required to determine whether adjunctive drug therapies should be used with periodontal treatment. Future RCTs should evaluate this, provide longer follow-up periods, and consider the inclusion of a third 'no treatment' control arm. Larger, well conducted and clearly reported studies are needed in order to understand the potential of periodontal treatment to improve glycaemic control among people with diabetes mellitus. In addition, it will be important in future studies that the intervention is effective in reducing periodontal inflammation and maintaining it at lowered levels throughout the period of observation.
Two studies, involving a total of 122 participants who had experienced adductor-related groin pain for at least two months, were included in this review. All but one of the participants were male athletes aged between 18 and 50 years old. Both studies were assessed as 'high risk of bias' for at least one source of bias domain. The 'successful treatment' outcome reported in both studies was based primarily on pain measures. One study, based on an intention-to-treat analysis, found a significant difference favouring exercise therapy (strengthening with an emphasis on the adductor and abdominal muscles and training muscular co-ordination) compared with 'conventional' physiotherapy (stretching exercises, electrotherapy and transverse friction massage) in successful treatment at 16-week follow-up (25/34 (74%) versus 10/34 (29%); risk ratio (RR) 2.50, 95% CI 1.43 to 4.37, P = 0.001). Similarly, of those followed-up significantly more athletes treated by exercise therapy returned to sport at the same level (23/29 (79%) versus 4/30 (13%); RR 5.95, 95% CI 2.34 to 15.09, P = 0.0002). Although still favouring the exercise group, the differences between the two groups in patients' subjective global assessment at 16 weeks and successful treatment at 8 to 12 years follow-up were not statistically significant. The second study (54 participants) found no significant differences at 16-week follow-up between a multi-modal treatment (heat, manual therapy and stretching) and exercise therapy (the same intervention as in the above study) for the outcomes of successful treatment (14/26 (54%) versus 12/22 (55%); RR 0.99, 95% CI 0.59 to 1.66, P = 0.96) and return to full sports participation (13/26 (50%) versus 12/22 (55%); RR 0.92, 95% CI 0.53 to 1.58, P = 0.75). Those returning to full sports participation returned on average 4.5 weeks earlier after receiving multi-modal therapy (mean difference -4.50 weeks, 95% CI -8.60 to -0.40, P = 0.03) than those in the exercise therapy group. This study reported that there were no complications or side effects found in either intervention group. The available evidence from the randomized trials is insufficient to advise on any specific conservative modality for treating exercise-related groin pain. While still low quality, the best evidence is from one trial which found that exercise therapy (strengthening of hip and abdominal muscles) in athletes improves short-term outcomes (based primarily on pain measures) and return to sports compared with physiotherapy consisting of passive modalities. Given the low quality of the available evidence from both included trials, further randomized trials are necessary to reinforce their findings.
We included six randomised controlled trials involving 899 children; we added three studies (331 children) in this update. We assessed two studies as at high risk of performance and detection bias; three studies as at unclear risk of attrition bias; and three studies as at unclear risk of other bias. Studies compared honey with dextromethorphan, diphenhydramine, salbutamol, bromelin (an enzyme from the Bromeliaceae (pineapple) family), no treatment, and placebo. Five studies used 7-point Likert scales to measure symptomatic relief of cough; one used an unclear 5-point scale. In all studies, low score indicated better cough symptom relief. Using a 7-point Likert scale, honey probably reduces cough frequency better than no treatment or placebo (no treatment: mean difference (MD) -1.05, 95% confidence interval (CI) -1.48 to -0.62; I² = 0%; 2 studies; 154 children; moderate-certainty evidence; placebo: MD -1.62, 95% CI -3.02 to -0.22; I² = 0%; 2 studies; 402 children; moderate-certainty evidence). Honey may have a similar effect as dextromethorphan in reducing cough frequency (MD -0.07, 95% CI -1.07 to 0.94; I² = 87%; 2 studies; 149 children; low-certainty evidence). Honey may be better than diphenhydramine in reducing cough frequency (MD -0.57, 95% CI -0.90 to -0.24; 1 study; 80 children; low-certainty evidence). Giving honey for up to three days is probably more effective in relieving cough symptoms compared with placebo or salbutamol. Beyond three days honey probably had no advantage over salbutamol or placebo in reducing cough severity, bothersome cough, and impact of cough on sleep for parents and children (moderate-certainty evidence). With a 5-point cough scale, there was probably little or no difference between the effects of honey and bromelin mixed with honey in reducing cough frequency and severity. Adverse events included nervousness, insomnia, and hyperactivity, experienced by seven children (9.3%) treated with honey and two children (2.7%) treated with dextromethorphan (risk ratio (RR) 2.94, 95% Cl 0.74 to 11.71; I² = 0%; 2 studies; 149 children; low-certainty evidence). Three children (7.5%) in the diphenhydramine group experienced somnolence (RR 0.14, 95% Cl 0.01 to 2.68; 1 study; 80 children; low-certainty evidence). When honey was compared with placebo, 34 children (12%) in the honey group and 13 (11%) in the placebo group complained of gastrointestinal symptoms (RR 1.91, 95% CI 1.12 to 3.24; I² = 0%; 2 studies; 402 children; moderate-certainty evidence). Four children who received salbutamol had rashes compared to one child in the honey group (RR 0.19, 95% CI 0.02 to 1.63; 1 study; 100 children; moderate-certainty evidence). No adverse events were reported in the no-treatment group. Honey probably relieves cough symptoms to a greater extent than no treatment, diphenhydramine, and placebo, but may make little or no difference compared to dextromethorphan. Honey probably reduces cough duration better than placebo and salbutamol. There was no strong evidence for or against using honey. Most of the children received treatment for one night, which is a limitation to the results of this review. There was no difference in occurrence of adverse events between the honey and control arms.
Five reviews, 114 studies, 7333 participants, satisfied criteria for inclusions. The outcomes considered were alcohol withdrawal seizures, adverse events and dropouts. Comparing the five treatments with placebo, benzodiazepines performed better for seizures, three studies, 324 participants, RR 0.16 (95% CI 0.04 to 0.69), moderate quality of evidence. Comparing each of the five treatments versus specific class of drugs, benzodiazepines performed better than antipsychotics for seizures, 4 studies, 633 participants, RR 0.24 (95% CI 0.07 to 0.88) high quality of the evidence. Comparing different benzodiazepines and anticonvulsants among themselves, 28 comparisons, results never reached statistical significance but chlordiazepoxide performed better.  The quality of evidence was high for 3% of the results, moderate for 28%, low for 48% and very low for 20%. Among the treatments considered, benzodiazepines showed a protective benefit against seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with antipsychotics. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines were possible, because of the heterogeneity of the trials both in interventions and in the assessment of outcomes. Data on potential harms are sparse and fragmented. Results do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS, but anticonvulsants seem to have limited side effects. There is also not enough evidence of effectiveness and safety of baclofen, because only one study consider this treatment and of GHB for which no strong differences were observed in the comparisons with placebo, benzodiazepines and anticonvulsants.
Ten studies fulfilled the inclusion criteria. Six CBA studies reported on interventions relating to temporal flexibility: self-scheduling of shift work (n = 4), flexitime (n = 1) and overtime (n = 1). The remaining four CBA studies evaluated a form of contractual flexibility: partial/gradual retirement (n = 2), involuntary part-time work (n = 1) and fixed-term contract (n = 1). The studies retrieved had a number of methodological limitations including short follow-up periods, risk of selection bias and reliance on largely self-reported outcome data. Four CBA studies on self-scheduling of shifts and one CBA study on gradual/partial retirement reported statistically significant improvements in either primary outcomes (including systolic blood pressure and heart rate; tiredness; mental health, sleep duration, sleep quality and alertness; self-rated health status) or secondary health outcomes (co-workers social support and sense of community) and no ill health effects were reported. Flexitime was shown not to have significant effects on self-reported physiological and psychological health outcomes. Similarly, when comparing individuals working overtime with those who did not the odds of ill health effects were not significantly higher in the intervention group at follow up. The effects of contractual flexibility on self-reported health (with the exception of gradual/partial retirement, which when controlled by employees improved health outcomes) were either equivocal or negative. No studies differentiated results by socio-economic status, although one study did compare findings by gender but found no differential effect on self-reported health outcomes. The findings of this review tentatively suggest that flexible working interventions that increase worker control and choice (such as self-scheduling or gradual/partial retirement) are likely to have a positive effect on health outcomes. In contrast, interventions that were motivated or dictated by organisational interests, such as fixed-term contract and involuntary part-time employment, found equivocal or negative health effects. Given the partial and methodologically limited evidence base these findings should be interpreted with caution. Moreover, there is a clear need for well-designed intervention studies to delineate the impact of flexible working conditions on health, wellbeing and health inequalities.
Of 720 records screened, we included eight trials that randomised 1048 participants with type 2 diabetes (387 SSI participants and 615 participants in comparator groups were available for final analysis). We included non-critically ill medical and surgical adults with the diagnosis of diabetes mellitus. The mean follow-up time was measured by the mean length of hospital stay and ranged between five and 24 days. The mean age of participants was 44.5 years to 71 years. Overall, we judged the risk of bias on the trial level as unclear for selection bias, high for outcome-related performance and detection bias with regard to hypoglycaemic episodes, other adverse events, and mean glucose levels, and low for all-cause mortality and length of hospital stay. Attrition bias was low for all outcome measures. Six trials compared SSI with a basal-bolus insulin scheme, three of which investigating 64% of all participants in this category also applying an SSI approach in the bolus comparator part. One trial had a basal insulin-only comparator arm, and the remaining trial used continuous insulin infusion as the comparator. For our main comparison of SSI versus basal-bolus insulin, the results were as follows. Four trials reported mortality data. One out of 268 participants in the SSI group (0.3%) compared with two out of 334 participants in the basal-bolus group (0.6%) died (low-certainty evidence). Severe hypoglycaemic episodes, defined as blood glucose levels below 40 mg/dL (2.2 mmol/L), showed a risk ratio (RR) of 0.22, 95% confidence interval (CI) 0.05 to 1.00; P = 0.05; 5 trials; 667 participants; very low-certainty evidence. The 95% prediction interval ranged between 0.02 and 2.57. All nine severe hypoglycaemic episodes were observed among the 369 participants on basal-bolus insulin (2.4%). The mean length of hospital stay was 0.5 days longer for the SSI group, 95% CI -0.5 to 1.4; P = 0.32; 6 trials; 717 participants; very low-certainty evidence. The 95% prediction interval ranged between -1.7 days and 2.7 days. Adverse events other than hypoglycaemic episodes, such as postoperative infections, showed a RR of 1.16, 95% CI 0.25 to 5.37; P = 0.85; 3 trials; 481 participants; very low-certainty evidence. The mean blood glucose levels ranged across basal-bolus groups from 156 mg/dL (8.7 mmol/L) to 221 mg/dL (12.3 mmol/L). The mean blood glucose level in the SSI groups was 14.8 mg/dL (0.8 mmol/L) higher (95% CI 7.8 (0.4) to 21.8 (1.2); P < 0.001; 6 trials; 717 participants; low-certainty evidence). The 95% prediction interval ranged between -3.6 mg/dL (-0.2 mmol/L) and 33.2 mg/dL (1.8 mmol/L). No trial reported on diabetes-related mortality or socioeconomic effects. We are uncertain which insulin strategy (SSI or basal-bolus insulin) is best for non-critically hospitalised adults with diabetes mellitus. A basal-bolus insulin strategy in these patients might result in better short-term glycaemic control but could increase the risk for severe hypoglycaemic episodes. The certainty of the body of evidence comparing SSI with basal-bolus insulin was low to very low and needs to be improved by adequately performed, well-powered RCTs in different hospital environments with well-educated medical staff using identical short-acting insulins in both intervention and comparator arms to compare the rigid SSI approach with flexible insulin application strategies.
We included four trials (three RCTs and one cross-over trial) involving 139 participants. Blinding of participants and physicians was well reported within all trials. We judged the overall risk of bias across trials as low. Only two trials (with 63 and 18 participants, respectively) provided sufficient information to be included in the meta-analysis. We found no clear effect of rPMS on activities of daily living at the end of treatment (mean difference (MD) -3.00, 95% confidence interval (CI) -16.35 to 10.35; P = 0.66; 1 trial; 63 participants; low-quality evidence) and at the end of follow-up (MD -2.00, 95% CI -14.86 to 10.86; P = 0.76; 1 trial; 63 participants; low-quality evidence) when comparing rPMS plus rehabilitation versus sham plus rehabilitation. We found no statistical difference in improvement of upper limb function at the end of treatment (MD 2.00, 95% CI -4.91 to 8.91; P = 0.57; 1 trial; 63 participants; low-quality evidence) and at the end of follow-up (MD 4.00, 95% CI -2.92 to 10.92; P = 0.26; 1 trial; 63 participants; low-quality evidence) when comparing rPMS plus rehabilitation versus sham plus rehabilitation. We observed a significant decrease in spasticity of the elbow at the end of follow-up (MD -0.48, 95% CI -0.93 to -0.03; P = 0.03; 1 trial; 63 participants; low-quality evidence) when comparing rPMS plus rehabilitation versus sham plus rehabilitation. In terms of muscle strength, rPMS treatment was not associated with improved muscle strength of the ankle dorsiflexors at the end of treatment (MD 3.00, 95% CI -2.44 to 8.44; P = 0.28; 1 trial; 18 participants; low-quality evidence) when compared with sham rPMS. No studies provided information on lower limb function or adverse events, including death. Based on the GRADE approach, we judged the quality of evidence related to the primary outcome as low, owing to the small sample size of the studies. Available trials provided insufficient evidence to permit any conclusions about routine use of rPMS for people after stroke. Additional trials with large sample sizes are needed to provide robust evidence for rPMS after stroke.
Nine small trials were identified. In total, 189 infants participated. Most participants were greater than 30 weeks gestational age at birth and were clinically stable. In eight of the studies, taurine was given enterally with formula milk. Only one small trial assessed parenteral taurine supplementation. Taurine supplementation increased intestinal fat absorption [weighted mean difference 4.0 (95% confidence interval 1.4, 6.6) percent of intake]. However, meta-analyses did not reveal any statistically significant effects on growth parameters assessed during the neonatal period or until three to four months chronological age [rate of weight gain: weighted mean difference -0.25 (95% confidence interval -1.16, 0.66) grams/kilogram/day; change in length: weighted mean difference 0.37 (95% confidence interval -0.23, 0.98) millimetres/week; change in head circumference: weighted mean difference 0.15 (95% confidence interval -0.19, 0.50) millimeters/week]. There are very limited data on the effect on neonatal mortality or morbidities, and no data on long-term growth or neurological outcomes. Despite that lack of evidence of benefit from randomised controlled trials, it is likely that taurine will continue to be added to formula milks and parenteral nutrition solutions used for feeding preterm and low birth weight infants given the putative association of taurine deficiency with various adverse outcomes. Further randomised controlled trials of taurine supplementation versus no supplementation in preterm or low birth weight infants are unlikely to be viewed as a research priority, but there may be issues related to dose or duration of supplementation in specific subgroups of infants that merit further research.
Seven randomised controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio [HR] for mortality 0.65; 95% confidence interval (CI) 0.54 to 0.78), overall response (relative risk of tumour response 1.21; 95% CI 1.16 to 1.27), and disease control (HR of disease event 0.62; 95% CI 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality 0.63; 95% CI 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality 0.60; 95% CI 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials (P 0.07), making the survival benefit less reliable. The systematic review demonstrated improved OS for patients with indolent lymphoma, particularly in the subgroups of follicular and in mantle cell lymphoma when treated with R-chemo compared to chemotherapy alone.
Fifteen RCTs were included, giving a total of 473 participants with ELP (study sizes ranged between 8-94). All studies involved oral sites only. Six studies included participants with non-erosive lichen planus but only the erosive subgroup was included for intended subgroup analysis. We were unable to pool data from any of the nine studies with only ELP participants or any of the six studies with the ELP subgroup, due to small numbers and the heterogeneity of the interventions, design methods, and outcome variables between studies. One study involving 50 participants found that 0.025% clobetasol propionate administered as liquid microspheres significantly reduced pain compared to ointment (Mean difference (MD) -18.30, 95% confidence interval (CI) -28.57 to -8.03), but outcome data was only available in 45 participants (high risk of performance bias for blinding of participants, low/unclear risk of bias overall). However, in another study, a significant difference in pain was seen in the small subgroup of 11 ELP participants, favouring ciclosporin solution over 0.1% triamcinolone acetonide in orabase (MD -1.40, 95% CI -1.86 to -0.94) (high risk of performance and detection bias due to likely lack of blinding, low/unclear risk of bias overall). Aloe vera gel was 6 times more likely to result in at least a 50% improvement in pain symptoms compared to placebo in a study involving 45 ELP participants (Risk ratio (RR) 6.16, 95% CI 2.35 to 16.13) (low risk of bias overall). No significant difference was seen in Physician Global Assessment in these three studies. In a small single study involving 20 ELP participants, 1% pimecrolimus cream was 7 times more likely to result in a strong improvement as rated by the Physician Global Assessment when compared to vehicle cream (RR 7.00, 95% CI 1.04 to 46.95) (low risk of bias overall). In a study involving a small subgroup of 8 ELP participants, a significant difference was seen for an improvement in the severity of the disease as rated by the Physician Global Assessment, in favour of the ciclosporin group when compared to the vehicle (MD -1.40, 95% CI -1.86 to -0.94) (unclear risk of selection bias for allocation concealment, overall risk of bias low). No statistically significant benefits were shown for topical tacrolimus or fluticasone spray in two separate studies of 29 and 44 participants respectively. There is no overwhelming evidence for the efficacy of a single treatment, including topical steroids, which are the widely accepted first-line therapy for ELP. Several side-effects were reported, but none were serious. With topical corticosteroids, the main side-effects were oral candidiasis and dyspepsia. This review suggests that there is only weak evidence for the effectiveness of any of the treatments for oral ELP, whilst no evidence was found for genital ELP. More RCTs on a larger scale are needed in the oral and genital ELP populations. We suggest that future studies should have standardised outcome variables that are clinically important to affected individuals. We recommend the measurement of a clinical severity score and a participant-rated symptom score using agreed and validated severity scoring tools. We also recommend the development of a validated combined severity scoring tool for both oral and genital populations.
We included 70 studies in the review; 66 studies with 17,067 participants were included in the quantitative analysis. An additional 18 studies are awaiting classification and 12 are ongoing. Fifteen of the 18 studies awaiting classification mainly correspond to congress summaries published before 2010, in which the available information does not allow the complete evaluation of all their risks of bias and characteristics. Our main outcome was prevention of PDPH, but we also assessed the onset of severe PDPH, headache in general and adverse events. The quality of evidence was moderate for most of the outcomes mainly due to risk of bias issues. For the analysis, we undertook three main comparisons: 1) traumatic needles versus atraumatic needles; 2) larger gauge traumatic needles versus smaller gauge traumatic needles; and 3) larger gauge atraumatic needles versus smaller gauge atraumatic needles. For each main comparison, if data were available, we performed a subgroup analysis evaluating lumbar puncture indication, age and posture. For the first comparison, the use of traumatic needles showed a higher risk of onset of PDPH compared to atraumatic needles (36 studies, 9378 participants, risk ratio (RR) 2.14, 95% confidence interval (CI) 1.72 to 2.67, I2 = 9%). In the second comparison of traumatic needles, studies comparing various sizes of large and small gauges showed no significant difference in effects in terms of risk of PDPH, with the exception of one study comparing 26 and 27 gauge needles (one study, 658 participants, RR 6.47, 95% CI 2.55 to 16.43). In the third comparison of atraumatic needles, studies comparing various sizes of large and small gauges showed no significant difference in effects in terms of risk of PDPH. We observed no significant difference in the risk of paraesthesia, backache, severe PDPH and any headache between traumatic and atraumatic needles. Sensitivity analyses of PDPH results between traumatic and atraumatic needles omitting high risk of bias studies showed similar results regarding the benefit of atraumatic needles in the prevention of PDPH (three studies, RR 2.78, 95% CI 1.26 to 6.15; I2 = 51%). There is moderate-quality evidence that atraumatic needles reduce the risk of post-dural puncture headache (PDPH) without increasing adverse events such as paraesthesia or backache. The studies did not report very clearly on aspects related to randomization, such as random sequence generation and allocation concealment, making it difficult to interpret the risk of bias in the included studies. The moderate quality of the evidence for traumatic versus atraumatic needles suggests that further research is likely to have an important impact on our confidence in the estimate of effect.
We included nine studies in this review. Eight studies involved 485 participants with CD. We assessed six of the studies to be at high risk of bias, and two to be at low risk of bias. We judged one study on RPD with 72 randomised participants to be at high risk of bias. Overall, the quality of the evidence for each comparison and outcome was either low or very low, therefore, results should be interpreted with caution, as future research is likely to change the findings. Complete dentures Two studies compared the same material and different techniques (one study contributed data to a secondary outcome only); two studies compared the same technique and different materials; and four studies compared different materials and techniques. One study (10 participants) evaluated two stage–two step, Biofunctional Prosthetic system (BPS) using additional silicone elastomer compared to conventional methods, and found no evidence of a clear difference for oral health-related quality of life, or quality of the dentures (denture satisfaction). The study reported that BPS required fewer adjustments. We assessed the quality of the evidence as very low. One study (27 participants) compared selective pressure final-impression technique using wax versus polysulfide elastomeric (rubber) material. The study did not measure quality of life or dentures, and found no evidence of a clear difference between interventions in the need for adjustments (RR 0.81, 95% CI 0.38 to 1.70). We assessed the quality of the evidence as very low. One study compared two stage–two step final impression with alginate versus silicone elastomer. Oral health-related quality of life measured by the OHIP-EDENT seemed to be better with silicone (MD 7.20, 95% CI 2.71 to 11.69; 144 participants). The study found no clear differences in participant-reported quality of the denture (comfort) after a two-week 'confirmation' period, but reported that silicone was better for stability and chewing efficiency. We assessed the quality of the evidence as low. Three studies compared single-stage impressions with alginate versus two stage-two step with elastomer (silicone, polysulfide, or polyether) impressions. There was no evidence of a clear difference in the OHIP-EDENT at one month (MD 0.05, 95% CI -2.37 to 2.47; two studies, 98 participants). There was no evidence of a clear difference in participant-rated general satisfaction with dentures at six months (MD 0.00, 95% CI -8.23 to 8.23; one study, 105 participants). We assessed the quality of the evidence as very low. One study compared single-stage alginate versus two stage-two step using zinc-oxide eugenol, and found no evidence of a clear difference in OHIP-EDENT (MD 0.50, 95% CI -2.67 to 3.67; 39 participants), or general satisfaction (RR 3.15, 95% CI 0.14 to 72.88; 39 participants) at six months. We assessed the quality of the evidence as very low. Removable partial dentures One study randomised 72 participants and compared altered-cast technique versus one-piece cast technique. The study did not measure quality of life, but reported that most participants were satisfied with the dentures and there was no evidence of any clear difference between groups for general satisfaction at one-year follow-up (low-quality evidence). There was no evidence of a clear difference in number of intaglio adjustments at one year (RR 1.43, 95% CI 0.61 to 3.34) (very low-quality evidence). We conclude that there is no clear evidence that one technique or material has a substantial advantage over another for making complete dentures and removable partial dentures. Available evidence for the relative benefits of different denture fabrication techniques and final-impression materials is limited and is of low or very low quality. More high-quality RCTs are required.
We include 70 studies involving a total of 4761 participants in the review. The first primary outcome for this review was reduction in the severity of PTSD symptoms, using a standardised measure rated by a clinician. For this outcome, individual TFCBT and EMDR were more effective than waitlist/usual care (standardised mean difference (SMD) -1.62; 95% CI -2.03 to -1.21; 28 studies; n = 1256 and SMD -1.17; 95% CI -2.04 to -0.30; 6 studies; n = 183 respectively). There was no statistically significant difference between individual TFCBT, EMDR and Stress Management (SM) immediately post-treatment although there was some evidence that individual TFCBT and EMDR were superior to non-TFCBT at follow-up, and that individual TFCBT, EMDR and non-TFCBT were more effective than other therapies. Non-TFCBT was more effective than waitlist/usual care and other therapies. Other therapies were superior to waitlist/usual care control as was group TFCBT. There was some evidence of greater drop-out (the second primary outcome for this review) in active treatment groups. Many of the studies were rated as being at 'high' or 'unclear' risk of bias in multiple domains, and there was considerable unexplained heterogeneity; in addition, we assessed the quality of the evidence for each comparison as very low. As such, the findings of this review should be interpreted with caution. The evidence for each of the comparisons made in this review was assessed as very low quality. This evidence showed that individual TFCBT and EMDR did better than waitlist/usual care in reducing clinician-assessed PTSD symptoms. There was evidence that individual TFCBT, EMDR and non-TFCBT are equally effective immediately post-treatment in the treatment of PTSD. There was some evidence that TFCBT and EMDR are superior to non-TFCBT between one to four months following treatment, and also that individual TFCBT, EMDR and non-TFCBT are more effective than other therapies. There was evidence of greater drop-out in active treatment groups. Although a substantial number of studies were included in the review, the conclusions are compromised by methodological issues evident in some. Sample sizes were small, and it is apparent that many of the studies were underpowered. There were limited follow-up data, which compromises conclusions regarding the long-term effects of psychological treatment.
We identified three RCTs including a total of 466 participants with a diagnosis of onchocerciasis. All trials compared doxycycline plus ivermectin versus ivermectin alone. One study investigated improvement in visual impairment at six-month follow-up; the other two studies measured microfilarial loads in skin snips to assess sustained effects of treatment at follow-up of 21 months or longer. The studies were conducted at various centers across three countries (Cameroon, Ghana, and Liberia). We judged all studies to be at overall high risk of bias because of inadequate randomization and lack of masking (one study), missing data (two studies), and selective outcome reporting (three studies). Only one study measured visual outcomes. This study reported uncertainty about the difference in the proportion of participants with improvement in visual impairment at six-month follow-up for doxycycline plus ivermectin compared with ivermectin alone (risk ratio (RR) 1.06, 95% confidence interval (95% CI) 0.80 to 1.39; 240 participants; very low-quality evidence). No participant in either group showed improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at six-month follow-up. More participants in the doxycycline plus ivermectin group than in the ivermectin alone group showed improvement in iridocyclitis (RR 1.24, 95% CI 0.69 to 2.22) and punctate keratitis (RR 1.43, 95% CI 1.02 to 2.00) at six-month follow-up; however, we graded these results as very low quality. Two studies reported that a six-week course of doxycycline may result in Wolbachia depletion and macrofilaricidal and sterilizing activities in female Onchocerca worms; however, no analysis was possible because data were missing and incomplete (graded evidence as very low quality). Adverse events were reported in 16 of 135 (12%) participants in one of these studies and included itching, headaches, body pains, and vertigo; no difference between treatment groups was reported for any adverse event. The second study reported that one (1.3%) participant in the doxycycline plus ivermectin group had bloody diarrhea after treatment was initiated. Available evidence on the effectiveness of doxycycline plus ivermectin compared with ivermectin alone in preventing and treating onchocerciasis is unclear. Limited evidence of very low quality from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, effects on vision-related outcomes are uncertain. Future studies should consider the effectiveness of treatments in preventing visual acuity and visual field loss and their effects on anterior and posterior segment lesions, particularly chorioretinitis. These studies should report outcomes in a uniform and consistent manner at follow-up of three years or longer to allow detection of meaningful changes in vision-related outcomes.
Twenty-three studies (2344 participants) were included in this update, including nine new studies. A broad variety of conservative interventions were evaluated. Two studies included patients with chronic symptoms (longer than three months), two included subacute (four to six weeks) symptoms, two had undefined duration of symptoms, and 17 studied patients with acute (less than three weeks) symptoms. Only eight studies (33.3%) satisfied one of our criteria of high quality, indicating overall, a poor methodological quality. Interventions were divided into passive (such as rest, immobilisation, ultrasound, etc) and active interventions (such as exercises, act as usual approach, etc.) and were compared with no treatment, a placebo or each other. Clinical and statistical heterogeneity and lack of data precluded pooling. Individual studies demonstrated effectiveness of one treatment over another, but the comparisons were varied and results inconsistent. Therefore, the evidence neither supports nor refutes the effectiveness of either passive or active treatments to relieve the symptoms of WAD, Grades 1 or 2. The current literature is of poor methodological quality and is insufficiently homogeneous to allow the pooling of results. Therefore, clearly effective treatments are not supported at this time for the treatment of acute, subacute or chronic symptoms of whiplash-associated disorders.
Thirteen studies were eligible for inclusion, but only 12 studies contributed data, with a total of 3446 CVCs assessed. The total number of participants enrolled was unclear as some studies did not provide such information. The participants were mainly adults admitted to intensive care units, haematology oncology units or general wards. Most studies assessed skin antisepsis prior to insertion and regularly thereafter during the in-dwelling period of the CVC, ranging from every 24 h to every 72 h. The methodological quality of the included studies was mixed due to wide variation in their risk of bias. Most trials did not adequately blind the participants or personnel, and four of the 12 studies had a high risk of bias for incomplete outcome data. Three studies compared different antisepsis regimens with no antisepsis. There was no clear evidence of a difference in all outcomes examined, including catheter-related BSI, septicaemia, catheter colonisation and number of patients who required systemic antibiotics for any of the three comparisons involving three different antisepsis regimens (aqueous povidone-iodine, aqueous chlorhexidine and alcohol compared with no skin antisepsis). However, there were great uncertainties in all estimates due to underpowered analyses and the overall very low quality of evidence presented.There were multiple head-to-head comparisons between different skin antiseptic agents, with different combinations of active substance and base solutions. The most frequent comparison was chlorhexidine solution versus povidone-iodine solution (any base). There was very low quality evidence (downgraded for risk of bias and imprecision) that chlorhexidine may reduce catheter-related BSI compared with povidone-iodine (RR of 0.64, 95% CI 0.41 to 0.99; ARR 2.30%, 95% CI 0.06 to 3.70%). This evidence came from four studies involving 1436 catheters. None of the individual subgroup comparisons of aqueous chlorhexidine versus aqueous povidone-iodine, alcoholic chlorhexidine versus aqueous povidone-iodine and alcoholic chlorhexidine versus alcoholic povidone-iodine showed clear differences for catheter-related BSI or mortality (and were generally underpowered). Mortality was only reported in a single study. There was very low quality evidence that skin antisepsis with chlorhexidine may also reduce catheter colonisation relative to povidone-iodine (RR of 0.68, 95% CI 0.56 to 0.84; ARR 8%, 95% CI 3% to 12%; ; five studies, 1533 catheters, downgraded for risk of bias, indirectness and inconsistency). Evaluations of other skin antiseptic agents were generally in single, small studies, many of which did not report the primary outcome of catheter-related BSI. Trials also poorly reported other outcomes, such as skin infections and adverse events. It is not clear whether cleaning the skin around CVC insertion sites with antiseptic reduces catheter related blood stream infection compared with no skin cleansing. Skin cleansing with chlorhexidine solution may reduce rates of CRBSI and catheter colonisation compared with cleaning with povidone iodine. These results are based on very low quality evidence, which means the true effects may be very different. Moreover these results may be influenced by the nature of the antiseptic solution (i.e. aqueous or alcohol-based). Further RCTs are needed to assess the effectiveness and safety of different skin antisepsis regimens in CVC care; these should measure and report critical clinical outcomes such as sepsis, catheter-related BSI and mortality.
We identified one trial, with 36 participants​ diagnosed ​with syphilis and HIV. The participants were mainly men, with a median age of 34 years. This trial, ​funded by a pharmaceutical company, compared ceftriaxone in 18 participants (2 g daily for 10 days), with penicillin G, also in 18 participants (4 million/Units (MU)/intravenous (IV) every 4 hours for 10 days). The trial reported incomplete and inconclusive results. Three of 18 (16%) participants receiving ceftriaxone versus 2 of 18 (11%) receiving penicillin G achieved serological cure (RR 1.50; 95% CI: 0.28 to 7.93; 1 trial, 36 participants very low-quality evidence); and 8 of 18 (44%) participants receiving ceftriaxone versus 2 of 18 (18%) participants receiving penicillin G achieved clinical cure (RR 4.00; 95% CI: 0.98 to 16.30; 1 trial, 36 participants very low-quality evidence). Although more participants who received ceftriaxone achieved serological and clinical cure compared to those who received penicillin G, the evidence from this trial was insufficient to determine whether there was a difference between treatment with ceftriaxone or penicillin G. In this trial, the authors reported what would usually be adverse events as symptoms and signs in the follow-up of participants. Furthermore, this trial did not evaluate recurrence of neurosyphilis, time to recovery nor quality of life. We judged risk of bias in this clinical trial to be unclear for random sequence generation, allocation, ​and blinding of participants, and high for incomplete outcome data, potential conflicts of interest (funding bias), and other bias, due to the lack of a sample size calculation. We rated the quality of evidence as very low. Due to low quality and insufficient evidence, it was not possible to determine whether there was a difference between treatment with ceftriaxone or Penicillin G. Also, the benefits to people without HIV and neurosyphilis are unknown, as is the ceftriaxone safety profile.Therefore, these results should be interpreted with caution. This conclusion does not mean that antibiotics should not be used for treating this clinical entity. This Cochrane Review has identified the need of adequately powered trials, which should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations, conducted and reported as recommended by the CONSORT statement. Furthermore, the outcomes should be based on patients' perspectives taking into account Patient-Centered Outcomes Research Institute (PCORI) recommendations.
We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the comparison of zotepine and risperidone, mental state scoring found no significant difference between the groups (vs 4 mg: n=40, 1 RCT, MD average endpoint score (BPRS total, high=poor) 1.40 CI -9.82 to 12.62; vs 8 mg: n=40, 1 RCT, MD -1.30 CI -12.95 to 10.35) and use of antiparkinson medication was equivocal (vs 4 mg: n=40, 1 RCT, MD 1.80 CI -0.64 to 4.24; vs 8 mg: n=40, 1 RCT, MD 2.50 CI -0.05 to 5.05). Finally, when zotepine was compared with remoxipride, again no effect was found for mental state (n=58, 1 RCT, MD average endpoint score (BPRS total, high=poor) 5.70 CI -4.13 to 15.53) and there was no significant difference between the two groups in terms of use of antiparkinson medication (n=49, 1 RCT, RR 0.97 CI 0.41 to 2.29). Data on important other outcomes such as other adverse events, service use or satisfaction with care, quality of life were not available. The evidence base around zotepine is insufficient to provide firm conclusions on its absolute or relative effects. This is despite it being in use in Austria, France, Germany, Japan and the UK.
We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was −5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) −6.7 to −4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were −22.4/h lower than in placebo (95% CI −27.8 to −16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD −5.3, 95% CI −8.4 to −2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably. The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.
We found one RCT and one retrospective study that met our inclusion criteria. The data from these studies were too sparse to adequately assess the effectiveness and safety of adjuvant chemotherapy in the treatment of malignant germ cell ovarian cancer. All comparisons were restricted to single study analyses and this review was only based on 32 women, so it was not adequately powered to detect differences in survival. Adverse effects of treatment and recurrence-free survival were incompletely documented and QoL was not reported in any of the studies. We did not find any studies that reported specifically on adults so there were problems in separating data on adults and children in many of the potentially relevant studies. We found only low quality evidence on the use of chemotherapy in malignant germ cell tumours of the ovaries. Therefore we are unable to reach definite conclusions about the relative benefits and harms of chemotherapy use in this disease regardless of disease stage. Due to the benefit of chemotherapy in germ cell cancer of the testis, a trial of chemotherapy versus best supportive care is unlikely to be feasible. Despite this, good quality randomised studies are warranted in this disease to define the role of chemotherapy (type of chemotherapy, duration of treatment, benefit, short and long term toxicities). Given the rarity of this disease, we feel a trans-global approach would be essential in order to perform such trials.
We included six trials with 560 patients. One trial involving 129 patients did not state the number of patients randomised to the two groups. In the remaining five trials 431 patients were randomised, 212 to the robot assistant group and 219 to the human assistant group. All the trials were at high risk of bias. Mortality and morbidity were reported in only one trial with 40 patients. There was no mortality or morbidity in either group. Mortality and morbidity were not reported in the remaining trials. Quality of life or the proportion of patients who were discharged as day-patient laparoscopic cholecystectomy patients were not reported in any trial. There was no significant difference in the proportion of patients who required conversion to open cholecystectomy (2 trials; 4/63 (weighted proportion 6.4%) in the robot assistant group versus 5/70 (7.1%) in the human assistant group; RR 0.90; 95% CI 0.25 to 3.20). There was no significant difference in the operating time between the two groups (4 trials; 324 patients; MD 5.00 minutes; 95% CI -0.55 to 10.54). In one trial, about one sixth of the laparoscopic cholecystectomies in which a robot assistant was used required temporary use of a human assistant. In another trial, there was no requirement for human assistants. One trial did not report this information. It appears that there was little or no requirement for human assistants in the other three trials. There were no randomised trials comparing one type of robot versus another type of robot. Robot assisted laparoscopic cholecystectomy does not seem to offer any significant advantages over human assisted laparoscopic cholecystectomy. However, all trials had a high risk of systematic errors or bias (that is, risk of overestimation of benefit and underestimation of harm). All trials were small, with few or no outcomes. Hence, the risk of random errors (that is, play of chance) is high. Further randomised trials with low risk of bias or random errors are needed.
We included 12 trials of varying sample sizes (N = 9 to 135), mainly from high-income countries, including a total of 578 participants. Ten trials recruited children (N = 448 participants). Two trials recruited adolescents and adults (N = 130 participants). We considered only three trials to be of high methodological quality (one trial each of diphenhydramine, pertussis immunoglobulin and montelukast). Included studies did not show a statistically significant benefit for any of the interventions. Only six trials, including a total of 196 participants, reported data in sufficient detail for analysis. Diphenhydramine did not change coughing episodes; the mean difference (MD) of coughing spells per 24 hours was 1.9; 95% confidence interval (CI) -4.7 to 8.5 (N = 49 participants from one trial). One trial on pertussis immunoglobulin reported a possible mean reduction of -3.1 whoops per 24 hours (95% CI -6.2 to 0.02, N = 47 participants) but no change in hospital stay (MD -0.7 days; 95% CI -3.8 to 2.4, N = 46 participants). Dexamethasone did not show a clear decrease in length of hospital stay (MD -3.5 days; 95% CI -15.3 to 8.4, N = 11 participants from one trial) and salbutamol showed no change in coughing paroxysms per day (MD -0.2; 95% CI -4.1 to 3.7, N = 42 participants from two trials). Only one trial comparing pertussis immunoglobulin versus placebo (N = 47 participants) reported data on adverse events: 4.3% in the treatment group (rash) versus 5.3% in the placebo group (loose stools, pain and swelling at injection site). There is insufficient evidence to draw conclusions about the effectiveness of interventions for the cough in whooping cough. More high-quality trials are needed to assess the effectiveness of potential antitussive treatments in patients with whooping cough.
Of the 27,865 records identified, 39 clinical trials and 14 observational studies, including a total of 945,240 participants, were eligible for inclusion. Five studies are awaiting classification. Overall, we found 114 adverse events in 33 studies (30 RCTs and three observational studies), and mortality was reported in 41 studies (32 RCTs and nine observational studies). Most studies were at low to moderate risk of bias for harms outcomes. However, overall harm assessment and reporting were of moderate to low quality in the RCTs, and of low quality in the observational studies. We downgraded the GRADE quality of evidence for venous thromboembolism and mortality to very low and low, respectively, because of risk of bias, high inconsistency, imprecision and limitations of study design. It is unclear whether there is an increase in the risk of any adverse events (Bayesian risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.21; 3099 participants; 9 studies; low-quality evidence) or venous thromboembolism (Bayesian RR 1.04, 95% CI 0.70 to 1.41; 18,917 participants; 18 studies; very low-quality evidence). There was a decreased risk of mortality with off-label use of ESAs in critically-ill people (Bayesian RR 0.76, 95% CI 0.61 to 0.92; 930,470 participants; 34 studies; low-quality evidence). Low quality of evidence suggests that off-label use of ESAs may reduce mortality in a critical care setting. There was a lack of high-quality evidence about the harm of ESAs in critically-ill people. The information for biosimilar ESAs is less conclusive. Most studies neither evaluated ESAs' harm as a primary outcome nor predefined adverse events. Any further studies of ESA should address the quality of evaluating, recording and reporting of adverse events.
We included 14 studies (909 participants) in this review. Surgical interventions, including laser therapy and cryotherapy, have never been studied by means of an RCT that included a no treatment or placebo arm. The included trials tested a range of medical and complementary treatments, in particular, vitamin A and retinoids (four studies); beta carotene or carotenoids (three studies); non-steroidal anti-inflammatory drugs (NSAIDs), specifically ketorolac and celecoxib (two studies); herbal extracts (four studies), including tea components, a Chinese herbal mixture and freeze-dried black raspberry gel; bleomycin (one study); and Bowman-Birk inhibitor (one study). We judged one study to be at low risk of bias, seven at unclear risk and six at high risk. In general, we judged the overall quality of the evidence to be low or very low, so findings are uncertain and further research is needed. Five studies recorded cancer incidence, only three of which provided useable data. None of the studies provided evidence that active treatment reduced the risk of oral cancer more than placebo: systemic vitamin A (RR 0.11, 95% CI 0.01 to 2.05; 85 participants, one study); systemic beta carotene (RR 0.71, 95% CI 0.24 to 2.09; 132 participants, two studies); and topical bleomycin (RR 3.00, 95% CI 0.32 to 27.83; 20 participants, one study). Follow-up ranged between two and seven years. Some individual studies suggested effectiveness of some proposed treatments, namely, systemic vitamin A, beta carotene and lycopene, for achieving clinical resolution of lesions more often than placebo. Similarly, single studies found that systemic retinoic acid and lycopene may provide some benefit in terms of improvement in histological features. Some studies also reported a high rate of relapse. Side effects of varying severity were often described; however, it seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups. Surgical treatment for oral leukoplakia has not been assessed in an RCT that included a no treatment or placebo comparison. Nor has cessation of risk factors such as smoking been assessed. The available evidence on medical and complementary interventions for treating people with leukoplakia is very limited. We do not currently have evidence of a treatment that is effective for preventing the development of oral cancer. Treatments such as vitamin A and beta carotene may be effective in healing oral lesions, but relapses and adverse effects are common. Larger trials of longer duration are required to properly evaluate the effects of leukoplakia treatments on the risk of developing oral cancer. High-quality research is particularly needed to assess surgical treatment and to assess the effects of risk factor cessation in people with leukoplakia.
Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required - as calculated by our information size calculation - to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta-analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate-quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI -0.07 to 1.34; 2 studies, 83 participants; low-quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low-quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low-quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low-quality evidence). Not all studies measured quality of life, short-term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well-designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.
We included eight studies involving 646 participants, most of which were of poor methodological quality. The urinary biomarkers were evaluated either in a specific phase of menstrual cycle or irrespective of the cycle phase. Five studies evaluated the diagnostic performance of four urinary biomarkers for endometriosis, including three biomarkers distinguishing women with and without endometriosis (enolase 1 (NNE); vitamin D binding protein (VDBP); and urinary peptide profiling); and one biomarker (cytokeratin 19 (CK 19)) showing no significant difference between the two groups. All of these biomarkers were assessed in small individual studies and could not be statistically evaluated in a meaningful way. None of the biomarkers met the criteria for a replacement test or a triage test. Three studies evaluated three biomarkers that did not differentiate women with endometriosis from disease-free controls. There was insufficient evidence to recommend any urinary biomarker for use as a replacement or triage test in clinical practice for the diagnosis of endometriosis. Several urinary biomarkers may have diagnostic potential, but require further evaluation before being introduced into routine clinical practice. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and diagnosis of endometriosis using urinary biomarkers should only be undertaken in a research setting.
29 RCTs, with eight weeks to five years follow-up, met our inclusion criteria; four were excluded from the primary meta-analysis because of inadequate outcome data. The remaining 25 trials assessed 1,198 participants, but adequate randomisation was confirmed in only seven trials and concealment of allocation in only one. Only one trial reported deaths, heart attacks and strokes (one of each). Meta-analysis indicated that relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mmHg, 95% CI: -8.2 to -2.8, I2 =72%) and DBP (mean difference: -3.5 mmHg, 95% CI: -5.3 to -1.6, I2 =75%) compared to control. The substantial heterogeneity between trials was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The nine trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mmHg, 95% CI: -7.7 to 1.4, I2 =69%) associated with relaxation. The 15 trials comparing relaxation with sham therapy likewise found a non-significant reduction in blood pressure (SBP mean difference: -3.5 mmHg, 95% CI: -7.1 to 0.2, I2 =63%). In view of the poor quality of included trials and unexplained variation between trials, the evidence in favour of causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.
The 2010 search strategy identified 1664 abstracts (and 827 duplicates) of which we obtained 23 studies in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria. The updated searches carried out in November 2013 identified 304 abstracts (261 excluding duplicates) of which we obtained 18 references in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria, therefore there were no included studies in this review. We found no registered trials of droperidol for the management of nausea or vomiting in palliative care. Since first publication of this review, no new studies were found. There is insufficient evidence to advise on the use of droperidol for the management of nausea and vomiting in palliative care. Studies of antiemetics in palliative care settings are needed to identify which agents are most effective, with minimum side effects.
Six randomized controlled clinical trials met selection criteria and were included in this review. In these studies of infants with signs and symptoms of RDS, intubation and early surfactant therapy followed by extubation to nasal CPAP (NCPAP) compared with later selective surfactant administration was associated with a lower incidence of mechanical ventilation [typical RR 0.67, 95% CI 0.57, 0.79], air leak syndromes [typical RR 0.52, 95% CI 0.28, 0.96] and BPD [typical RR 0.51, 95% CI 0.26, 0.99]. A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group [typical RR 1.62, 95% CI 1.41, 1.86]. The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group [WMD 0.57 doses per patient, 95% CI 0.44, 0.69]. In stratified analysis by FIO2 at study entry, a lower threshold for treatment (FIO2< 0.45) resulted in lower incidence of airleak [typical RR 0.46 and 95% CI 0.23, 0.93] and BPD [typical RR 0.43, 95% CI 0.20, 0.92]. A higher treatment threshold (FIO2 > 0.45) at study entry was associated with a higher incidence of patent ductus arteriosus requiring treatment [typical RR 2.15, 95% CI 1.09, 4.13]. Early surfactant replacement therapy with extubation to NCPAP compared with later selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support is associated with less need mechanical ventilation, lower incidence of BPD and fewer air leak syndromes. A lower treatment threshold (FIO2< 0.45) confers greater advantage in reducing the incidences of airleak syndromes and BPD; moreover a higher treatment threshold (FIO2 at study > 0.45) was associated with increased risk of PDA. These data suggest that treatment with surfactant by transient intubation using a low treatment threshold (FIO2< 0.45) is preferable to later, selective surfactant therapy by transient intubation using a higher threshold for study entry (FIO2 > 0.45) or at the time of respiratory failure and initiation of mechanical ventilation.
This review included three RCTs with a total of 228 eyes. The range of myopia of included patients was -6.0 D to -20.0 D of myopia with up to 4.0 D of myopic astigmatism. The percentage of eyes with uncorrected visual acuity (UCVA) of 20/20 or better at 12 months postoperative was not significantly different between the two groups. Phakic IOL surgery was safer than excimer laser surgical correction for moderate to high myopia as it results in significantly less loss of best spectacle corrected visual acuity (BSCVA) at 12 months postoperatively. However there is a low risk of developing early cataract with phakic IOLs. Phakic IOL surgery appears to result in better contrast sensitivity than excimer laser correction for moderate to high myopia. Phakic IOL surgery also scored more highly on patient satisfaction/preference questionnaires. The results of this review suggest that, at one year post surgery, phakic IOLs are safer than excimer laser surgical correction for moderate to high myopia in the range of -6.0 to -20.0 D and phakic IOLs are preferred by patients. While phakic IOLs might be accepted clinical practice for higher levels of myopia (greater than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism), it may be worth considering phakic IOL treatment over excimer laser correction for more moderate levels of myopia (less than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism). Further RCTs adequately powered for subgroup analysis are necessary to further elucidate the ideal range of myopia for phakic IOLs. This data should be considered alongside comparative data addressing long-term safety as it emerges.
We found and included three unblinded randomised trials in 8221 older adults (mean age 74.8 years), in which higher BP targets of less than 150/90 mmHg (two trials) and less than 160/90 mmHg (one trial) were compared to a lower target of less than 140/90 mmHg. Treatment to the two different BP targets over two to four years failed to produce a difference in any of our primary outcomes, including all-cause mortality (RR 1.24 95% CI 0.99 to 1.54), stroke (RR 1.25 95% CI 0.94 to 1.67) and total cardiovascular serious adverse events (RR 1.19 95% CI 0.98 to 1.45). However, the 95% confidence intervals of these outcomes suggest the lower BP target is probably not worse, and might offer a clinically important benefit. We judged all comparisons to be based on low-quality evidence. Data on adverse effects were not available from all trials and not different, including total serious adverse events, total minor adverse events, and withdrawals due to adverse effects. At the present time there is insufficient evidence to know whether a higher BP target (less than150 to 160/95 to 105 mmHg) or a lower BP target (less than 140/90 mmHg) is better for older adults with high BP. Additional good-quality trials assessing BP targets in this population are needed.
Eight RCTs were included, with 305 patients in the intervention groups and 288 in the control groups. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (IPV) (one trial). Seven trials had high and one trial had moderate risk of bias. VZV vaccine might reduce herpes zoster compared to no vaccine (RR 0.54, 95% CI 0.3 to 1.0, P=0.05), but not statistically significant. Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported severity score of zoster, which favored vaccination (MD 2.6, 95% CI 0.94 to 4.26, P=0.002). Two RCTs compared inactivated influenza vaccine with no vaccine and reported lower risk of lower respiratory infections (RR 0.39, 95% CI 0.19 to 0.78, P=0.008) and hospitalization (RR 0.17, 95% CI 0.09 to 0.31, P<0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without re-induction chemotherapy (one trial). The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplant (SCT) found no significant difference in seroconversion. Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. However, the quality of evidence is low. Local adverse effects occur frequently. Further high-quality RCTs are needed.
The five eligible trials reported on a total of 359 infants with RDS. Overall the risk of any reported mortality was less frequent in the MV group (summary RR 0.86, 95% CI 0.74, 1.00; RD -0.10, 95% CI -0.20, -0.01; NNT 10, 95% CI 5, 100). In infants with a birth weight of 1 to 2 kg, no significant difference in mortality was found (summary RR 0.86, 95% CI 0.70, 1.07). In infants with a birth weight of more than 2 kg there was a significant reduction in mortality with MV (summary RR 0.67, 95%CI 0.52, 0.87). Any IVH at autopsy was not significantly different between the groups in any study or overall in four studies reporting on 202 infants who had an autopsy. Pneumothorax was reported in two studies of 275 infants and there is a non-significant trend towards an increase in the mechanical ventilation group (summary RR 2.75, 95% CI 0.72, 10.45). When MV was introduced in the 1960s to treat infants with severe respiratory failure due to pulmonary disease, trials showed an overall reduction in mortality which was most marked in infants born with a birthweight of more than 2 kg. This review does not provide information to evaluate the relative benefits or harms of MV in the setting of modern perinatal care.
For efficacy we included three randomised trials of between five and eight weeks duration with a total of 204 participants. For adverse effects we included two randomised trials and three observational (non-randomised) studies of five to eight weeks duration with a total of 225 participants. Overall, the randomised trials had low-to-moderate risk of bias, and the observational studies had a high risk of bias (due to small size and high attrition). The participants in the studies all met DSM (Diagnostic and Statistics Manual of Mental Disorders) criteria for SAD. The average age was approximately 40 years and 70% of the participants were female. Results from one trial with 68 participants showed that fluoxetine was not significantly more effective than placebo in achieving clinical response (risk ratio (RR) 1.62, 95% confidence interval (CI) 0.92 to 2.83). The number of adverse effects were similar between the two groups. We located two trials that contained a total of 136 participants for the comparison fluoxetine versus light therapy. Our meta-analysis of the results of the two trials showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24), RR of remission 0.81 (95% CI 0.39 to 1.71). The number of adverse effects was similar in both groups. Two of the three randomised trials and three non-randomised studies contained adverse effect data on 225 participants who received fluoxetine, escitalopram, duloxetine, reboxetine, light therapy or placebo. We were only able to obtain crude rates of adverse effects, so any interpretation of this needs to be undertaken with caution. Between 22% and 100% of participants who received a SGA suffered an adverse effect and between 15% and 27% of participants withdrew from the studies because of adverse effects. Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo, which shows a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy, which suggest equivalence between the two interventions. The lack of available evidence precludes the ability to draw any overall conclusions on the use of SGAs for SAD. Further larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. Therefore the data we obtained on adverse effects is not robust and our confidence in the data is limited. Overall, up to 27% of participants treated with SGAs for SAD withdrew from the studies early due to adverse effects. The overall quality of evidence in this review is very low.
We included nine trials with 645 participants. Six trials assessed TACE versus control and three trials assessed TAE versus control. Seven trials had low risk of selection bias based on adequate generation of allocation sequence and concealment - but all these trials had other risks of bias. Three trials were stopped early due to interim inspections and one due to slow accrual. For all-cause mortality, statistical heterogeneity between trials was low to moderate (I2= 30%). Meta-analysis of trials with low risk of selection bias showed that TACE or TAE versus control does not significantly increase survival (HR 0.88; 95% CI 0.71 to 1.10). Two trials with low risk of selection bias, no early stopping, and no co-intervention did not establish any significant effect of TACE or TAE on overall survival (hazard ratio 1.22, 95% confidence interval 0.82 to 1.83; P = 0.33). Trial sequential analysis confirmed the absence of evidence for a beneficial effect of TACE or TAE on survival indicating the need for future randomisation of up to 383 additional participants. Substantial differences in criteria for assessing tumour response did not allow quantitative analyses. One trial investigated quality of life but did not detect any significant differences between the intervention groups. A range of adverse events including post-embolisation syndrome and serious complications were reported. There is no firm evidence to support or refute TACE or TAE for patients with unresectable HCC. More adequately powered and bias-protected trials are needed.
We included 25 trials in this version of the review (13 from the original 2010 review and 12 newly-included studies). Sixteen trials were of adolescents, eight trials of adults (seven of these in young adults aged up to 26 years) and one trial included three age groups: one adolescent, one young adult and one adult. Most investigated family-based therapy or variants. Reporting of trial conduct was generally inadequate, so that in a large number of studies we rated the risk of bias as unclear for many of the domains. Selective reporting bias was particularly problematic, with 68% of studies rated at high risk of bias in this area, followed by incomplete outcome data, with 44% of studies rated at high risk of bias in this area. For the main outcome measure of remission there was some low-quality evidence (from only two studies, 81 participants) suggesting that family therapy approaches might offer some advantage over treatment as usual on rates of remission, post intervention (risk ratio (RR) 3.50, 95% confidence interval (CI) 1.49 to 8.23; I2 = 0%). However, at follow-up, low-quality evidence from only one study suggested this effect was not maintained. There was very low-quality evidence from only one trial, which means it is difficult to determine whether family therapy approaches offer any advantage over educational interventions for remission (RR 9.00, 95% CI 0.53 to 153.79; 1 study, N = 30). Similarly, there was very low-quality evidence from only five trials for remission post-intervention, again meaning that it is difficult to determine whether there is any advantage of family therapy approaches over psychological interventions (RR 1.22, 95% CI 0.89 to 1.67; participants = 252; studies = 5; I2 = 37%) and at long-term follow-up (RR 1.08, 95% CI 0.91 to 1.28; participants = 200; studies = 4 with 1 of these contributing 3 pairwise comparisons for different age groups; I2 = 0%). There was no indication that the age group had any impact on the overall treatment effect; however, it should be noted that there were very few trials undertaken in adults, with the age range of adult studies included in this analysis from 20 to 27. There was some evidence of a small effect favouring family based therapy compared with other psychological interventions in terms of weight gain post-intervention (standardised mean difference (SMD) 0.32, 95% CI 0.01 to 0.63; participants = 210; studies = 4 with 1 of these contributing 3 pairwise comparisons for different age groups; I2 = 11%) . Overall, there was insufficient evidence to determine whether there were any differences between groups across all comparisons for most of the secondary outcomes (weight, eating disorder psychopathology, dropouts, relapse, or family functioning measures), either at post-intervention or at follow-up. There is a limited amount of low-quality evidence to suggest that family therapy approaches may be effective compared to treatment as usual in the short term. This finding is based on two trials that included only a small number of participants, and both had issues about potential bias. There is insufficient evidence to determine whether there is an advantage of family therapy approaches in people of any age compared to educational interventions (one study, very low quality) or other psychological therapies (five studies, very low quality). Most studies contributing to this finding were undertaken in adolescents and youth. There are clear potential impacts on how family therapy approaches might be delivered to different age groups and further work is required to understand what the resulting effects on treatment efficacy might be. There is insufficient evidence to determine whether one type of family therapy approach is more effective than another. The field would benefit from further large, well-conducted trials.
Three small randomised controlled trials, with a total of 109 participants with Orthopaedic Trauma Association/Arbeitsgemeinschaft für Osteosynthesefragen (OTA/AO) type C distal humeral fractures, were included. Overall, the quality of the available evidence is limited. As well as the small sample sizes and detection bias from the lack of blinding of subjective outcomes, the methods and results of all three trials were incompletely reported. One trial, involving 42 participants, compared open reduction-internal fixation (ORIF) with total elbow arthroplasty (TEA) in patients aged over 65 years. Of the 40 participants followed up for two years, five allocated ORIF underwent intraoperative conversion to TEA. These participants were crossed-over to the TEA group in the analyses. The reported Mayo Elbow Performance Score (MEPS) results were consistently better in the TEA group at follow-up after 6, 12, and 24 months, whereas the Disability of the Arm, Shoulder, Hand (DASH) scores showed short term (after 6 months), but not longer term (after 12 and 24 months), superiority in the TEA group. The reoperation rate, complication rate and elbow range of motion results showed no statistically significant differences between the two groups. While an intention-to-treat analysis of treatment failure, where the five cross-over participants are placed in their original allocated group, is in favour of TEA, the result did not reach statistical significance (9/21 versus 3/21; RR 3.00, 95% CI 0.94 to 9.55). The second trial, involving 38 patients but reporting results for 35, compared perpendicular versus parallel double plate fixation strategies. There was a consistent finding of a lack of significant differences between the two treatment groups in terms of MEPS, re-operation for complications (3/17 versus 3/18; RR 1.06, 95% CI 0.25 to 4.54), complications and elbow joint range of motion. The third trial, which included 29 patients with preoperative ulnar nerve compression symptoms, compared anterior subfascial transposition with in situ decompression of the ulnar nerve. Although results for complete recovery of ulnar nerve function (12/15 versus 8/14; RR 1.4, 95% CI 0.83 to 2.35) and grades based on the Bishop rating system tended to favour the transposition group, none of the differences were statistically significant. Overall, this review found there is either no or insufficient evidence from randomised or quasi-randomised controlled trials to determine whether surgery is, and which surgical interventions are, the most appropriate for the management of different types of distal humerus fractures. Well designed and reported large and multi-centre randomised controlled trials testing current interventions, such as pre-contoured and locking plating systems, are needed.
Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.
The search identified 102 potentially eligible studies. Judged from the information in the title and abstract six of these concerning the percutaneous block, involving 358 participants, fulfilled the inclusion criteria and were included in the review. All were RCTs in which the participants were followed for at least four weeks. We excluded studies published only as abstracts. We identified one RCT comparing EUS-guided or computed tomography (CT) -guided CPB but its aim was to assess efficacy in controlling chronic abdominal pain associated with chronic pancreatitis rather than pancreatic cancer, so it was excluded. For pain (VAS) at four weeks the mean difference was -0.42 in favour of CPB (95% confidence interval (CI) -0.70 to - 0.13, P = 0.004, fixed-effect model). At eight weeks the mean difference was -0.44 (95% CI -0.89 to - 0.01, random-effects model). At eight weeks there was significant heterogeneity (I2 = 89%). Opioid consumption was significantly lower in the CPB group than the control group (P < 0.00001). Although statistical evidence is minimal for the superiority of pain relief over analgesic therapy, the fact that CPB causes fewer adverse effects than opioids is important for patients. Further studies and RCTs are recommended to demonstrate the potential efficacy of a less invasive technique under EUS guidance.
Since 2000, one new trial has been published; the updated review now includes five RCTs involving 4023 women with breast cancer (clinical stage I, II or III). Two trials involving 2563 women compared follow-up based on clinical visits and mammography with a more intensive scheme including radiological and laboratory tests. After pooling the data, no significant differences in overall survival (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.84 to 1.15, two studies, 2563 participants, high-quality evidence), or disease-free survival (HR 0.84, 95% CI 0.71 to 1.00, two studies, 2563 participants, low-quality evidence) emerged. No differences in overall survival and disease-free survival emerged in subgroup analyses according to patient age, tumour size and lymph node status before primary treatment. In 1999, 10-year follow-up data became available for one trial of these trials, and no significant differences in overall survival were found. No difference was noted in quality of life measures (one study, 639 participants, high-quality evidence). The new included trial, together with a previously included trial involving 1264 women compared follow-up performed by a hospital-based specialist versus follow-up performed by general practitioners. No significant differences were noted in overall survival (HR 1.07, 95% CI 0.64 to 1.78, one study, 968 participants, moderate-quality evidence), time to detection of recurrence (HR 1.06, 95% CI 0.76 to 1.47, two studies, 1264 participants, moderate-quality evidence), and quality of life (one study, 356 participants, high-quality evidence). Patient satisfaction was greater among patients treated by general practitioners. One RCT involving 196 women compared regularly scheduled follow-up visits versus less frequent visits restricted to the time of mammography. No significant differences emerged in interim use of telephone and frequency of general practitioners's consultations. This updated review of RCTs conducted almost 20 years ago suggests that follow-up programs based on regular physical examinations and yearly mammography alone are as effective as more intensive approaches based on regular performance of laboratory and instrumental tests in terms of timeliness of recurrence detection, overall survival and quality of life. In two RCTs, follow-up care performed by trained and not trained general practitioners working in an organised practice setting had comparable effectiveness to that delivered by hospital-based specialists in terms of overall survival, recurrence detection, and quality of life.
We included three RCTs, with 328 participants, that compared six-month regimens with nine-month regimens to treat adults with intestinal and peritoneal TB. All trials were conducted in Asia, and excluded people with HIV, those with co-morbidities and those who had received ATT in the previous five years. Antituberculous regimens were based on isoniazid, rifampicin, pyrazinamide, and ethambutol, and these drugs were administered daily or thrice weekly under a directly observed therapy programme. The median duration of follow-up after completion of treatment was between 12 and 39 months. Relapse was uncommon, with two cases among 140 participants treated for six months, and no events among 129 participants treated for nine months. The small number of participants means we do not know whether or not there is a difference in risk of relapse between the two regimens (very low quality evidence). At the end of therapy, there was probably no difference in the proportion of participants that achieved clinical cure between six-month and nine-month regimens (RR 1.02, 95% CI 0.97 to 1.08; 294 participants, 3 trials, moderate quality evidence). For death, there were 2/150 (1.3%) in the six-month group and 4/144 (2.8%) in the nine-month group. All deaths occurred in the first four months of treatment, so was not linked to the duration of treatment in the included trials. Similarly, the number of participants that defaulted from treatment was small in both groups, and there may be no difference between them (RR 0.50, 95% CI 0.10 to 2.59; 294 participants, 3 trials, low quality evidence). Only one trial reported on adherence to treatment, with only one participant allocated to the nine-month regimen presenting poor adherence to treatment. We do not know whether six-month regimens are associated with fewer people experiencing adverse events that lead to treatment interruption (RR 0.53, 95% CI 0.18 to 1.55; 318 participants, 3 trials, very low quality evidence). We found no evidence to suggest that six-month treatment regimens are inadequate for treating people that have intestinal and peritoneal TB, but numbers are small. We did not find any incremental benefits of nine-month regimens regarding relapse at the end of follow-up, or clinical cure at the end of therapy, but our confidence in the relapse estimate is very low because of size of the trials. Further research is required to make confident conclusions regarding the safety of six-month treatment for people with abdominal TB. Larger studies that include HIV-positive people, with long follow-up for detecting relapse with reliability, would help improve our knowledge around this therapeutic question.
Thirty-nine RCTs met the inclusion criteria contributing a total of 4615 participants. Most trials enrolled a small number of patients and showed moderate to poor (reporting of) methodological quality, in particular regarding allocation concealment and intention-to-treat analysis. Fifteen systemic acting prokinetic drugs were investigated and ten comparisons could be summarized. Six RCTs support the effect of Alvimopan, a novel peripheral mu receptor antagonist. However, the trials do not meet reporting guidelines and the drug is still in an investigational stage. Erythromycin showed homogenous and consistent absence of effect across all included trials and outcomes. The evidence is insufficient to recommend the use of cholecystokinin-like drugs, cisapride, dopamine-antagonists, propranolol or vasopressin. Effects are either inconsistent across outcomes, or trials are too small and often of poor methodological quality. Cisapride has been withdrawn from the market due to adverse cardiac events in many countries. Intravenous lidocaine and neostigmine might show a potential effect, but more evidence on clinically relevant outcomes is needed. Heterogeneity among included trials was seen in 10 comparisons. No major adverse drug effects were evident. Alvimopan may prove to be beneficial but proper judgement needs adherence to reporting standards. Further trials are needed on intravenous lidocaine and neostigmine. The remaining drugs can not be recommended due to lack of evidence or absence of effect.
Eighteen RCTs out of 64 potentially eligible study reports met the inclusion criteria. They compared undertaking a sinus lift with not doing so, and the use of different sinus lift techniques. There were 650 patients providing data for the outcomes evaluated. Five studies were assessed as low risk of bias, 11 were assessed as high risk of bias, and in two the risk was unclear. Sinus lift versus no sinus lift  Four trials of moderate quality (three trials at low and one at high risk of bias) with 102 participants evaluated short implants (5 to 8.5 mm long) as an alternative to sinus lift in bone with residual height between 4 and 9 mm. One year after loading there was insufficient evidence to claim differences between the two procedures for prosthesis failure (OR (Peto) 0.37, 95% confidence interval (CI) 0.05 to 2.68; three trials) or implant failure (OR (Peto) 0.44, 95% CI 0.10 to 1.99; four trials). There was however an increase in complications at treated sites when undertaking the sinus lift (OR (Peto) 4.77, 95% CI 1.79 to 12.71, P value = 0.002; four trials). Different sinus lift techniques  Fourteen trials with 548 participants compared different sinus lift techniques. Only three comparisons included more than one trial (two trials for each). These were bone graft versus no bone graft, autogenous bone versus bone substitute, bone graft with or without platelet-rich plasma (PRP). There was insufficient evidence to claim a benefit for any of these techniques for the primary outcomes of prosthesis and implant failure. For the other reported outcomes, in a single study at high risk of bias, only bone gain was greater for the bone graft site than the site without a graft six months after augmentation, however this was not significant at 18 or 30 months. The other comparisons with single studies were rotary versus piezosurgery to open a lateral sinus window, two different bone substitutes, use or not of a membrane to seal the lateral window, one- versus two-stage lateral sinus lift, two-stage granular bone versus one-stage autogenous bone blocks, and crestal versus lateral sinus lift; two trials compared three different crestal sinus lifting techniques: rotatory versus hand malleting (patients preferred rotatory instruments over hand malleting) and hand versus electric malleting. There was no evidence of a benefit for any sinus lift procedure compared to any other for the primary outcomes prosthesis or implant failure. There is moderate quality evidence which is insufficient to determine whether sinus lift procedures in bone with residual height between 4 and 9 mm are more or less successful than placing short implants (5 to 8.5 mm) in reducing prosthesis or implant failure up to one year after loading. However, there are more complications at sites treated with sinus lift procedures. Many trials compared different sinus lift procedures and none of these indicated that one procedure reduced prosthetic or implant failures when compared to the other. Based on low quality evidence, patients may prefer rotary instruments over hand malleting for crestal sinus lift.
We identified six RCTs (707 women), eligible for inclusion in this updated review, however, three RCTs had mixed populations (that is, they included pregnant women with gestational diabetes) and did not report data separately for the relevant subset of women for this review. Therefore we have only included outcome data from three RCTs; data were available for 241 women and their infants. The three RCTs all compared an oral anti-diabetic agent (metformin) with insulin. The women in the RCTs that contributed data had type 2 diabetes diagnosed before or during their pregnancy. Overall, the RCTs were judged to be at varying risk of bias. We assessed the quality of the evidence for selected important outcomes using GRADE; the evidence was low- or very low-quality, due to downgrading because of design limitations (risk of bias) and imprecise effect estimates (for many outcomes only one or two RCTs contributed data). For our primary outcomes there was no clear difference between metformin and insulin groups for pre-eclampsia (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.33 to 1.20; RCTs = 2; participants = 227; very low-quality evidence) although in one RCT women receiving metformin were less likely to have pregnancy-induced hypertension (RR 0.58, 95% CI 0.37 to 0.91; RCTs = 1; participants = 206; low-quality evidence). Women receiving metformin were less likely to have a caesarean section compared with those receiving insulin (RR 0.73, 95% CI 0.61 to 0.88; RCTs = 3; participants = 241; low-quality evidence). In one RCT there was no clear difference between groups for large-for-gestational-age infants (RR 1.12, 95% CI 0.73 to 1.72; RCTs = 1; participants = 206; very low-quality evidence). There were no perinatal deaths in two RCTs (very low-quality evidence). Neonatal mortality or morbidity composite outcome and childhood/adulthood neurosensory disability were not reported. For other secondary outcomes we assessed using GRADE, there were no clear differences between metformin and insulin groups for induction of labour (RR 1.42, 95% CI 0.62 to 3.28; RCTs = 2; participants = 35; very low-quality evidence), though infant hypoglycaemia was reduced in the metformin group (RR 0.34, 95% CI 0.18 to 0.62; RCTs = 3; infants = 241; very low-quality evidence). Perineal trauma, maternal postnatal depression and postnatal weight retention, and childhood/adulthood adiposity and diabetes were not reported. There are insufficient RCT data to evaluate the use of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or in pregnant women with pre-existing diabetes. Low to very low-quality evidence suggests possible reductions in pregnancy-induced hypertension, caesarean section birth and neonatal hypoglycaemia with metformin compared with insulin for women with type 2 diabetes diagnosed before or during their pregnancy, and no clear differences in pre-eclampsia, induction of labour and babies that are large-for-gestational age. Further high-quality RCTs that compare any combination of oral anti-diabetic agent, insulin and dietary and lifestyle advice for these women are needed. Future RCTs could be powered to evaluate effects on short- and long-term clinical outcomes; such RCTs could attempt to collect and report on the standard outcomes suggested in this review. We have identified three ongoing studies and four are awaiting classification. We will consider these when this review is updated.
We included 16 trials, with a total of 2144 participants. Two studies included children only. The other 14 studies included predominantly young adults, of whom over 60% were male. Seven studies recruited people with ankle sprains only. Most studies were at low or unclear risk of bias; however, two were at high risk of selection bias, three were at high risk of bias from lack of blinding, one was at high risk of bias due to incomplete outcome data, and four were at high risk of selective outcome reporting bias. The evidence was usually either low quality or very low quality, reflecting study limitations, indirectness such from as suboptimal dosing of single comparators, imprecision, or one or more of these. Thus we are either uncertain or very uncertain of the estimates. Nine studies, involving 991 participants, compared NSAIDs with paracetamol. While tending to favour paracetamol, there was a lack of clinically important differences between the two groups in pain at less than 24 hours (377 participants, 4 studies; moderate-quality evidence), at days 1 to 3 (431 participants, 4 studies; low quality), and at day 7 or over (467 participants, 4 studies; low quality). A similar lack of difference between the two groups applied to swelling at day 3 (86 participants, 1 study; very low quality) and at day 7 or over (77 participants, 1 study; low quality). There was little difference between the two groups in return to function at day 7 or over (316 participants, 3 studies; very low quality): based on an assumed recovery of function of 804 per 1000 participants in the paracetamol group, 8 fewer per 1000 recovered in the NSAID group (95% confidence interval (CI) 80 fewer to 73 more). There was low-quality evidence of a lower risk of gastrointestinal adverse events in the paracetamol group: based on an assumed risk of gastrointestinal adverse events of 16 per 1000 participants in the paracetamol group, 13 more participants per 1000 had a gastrointestinal adverse event in the NSAID group (95% CI 0 to 35 more). Four studies, involving 958 participants, compared NSAIDs with opioids. Since a study of a selective COX-2 inhibitor NSAID (valdecoxib) that was subsequently withdrawn from the market dominates the evidence for this comparison (706 participants included in the analyses for pain, function and gastrointestinal adverse events), the applicability of these results is in doubt and we give only a brief summary. There was low quality evidence for a lack of clinically important differences between the two groups regarding pain at less than 24 hours, at days 4 to 6, and at day 7. Evidence from single studies showed a similar lack of difference between the two groups for swelling at day 3 (68 participants) and day 10 (84 participants). Return to function at day 7 or over favoured the NSAID group (low-quality), and there were fewer gastrointestinal adverse events in the selective COX-2 inhibitor NSAID group (very low quality). Four studies, involving 240 participants, compared NSAIDs with the combination of paracetamol and an opioid. The applicability of findings from these studies is partly in question because the dextropropoxyphene combination analgesic agents used are no longer in general use. While the point estimates favoured NSAID, the very low-quality evidence did not show a difference between the two interventions in the numbers with little or no pain at day 1 (51 participants, 1 study), day 3 (149 participants, 2 studies), or day 7 (138 participants, 2 studies). Very low-quality evidence showed a similar lack of difference between the two groups applied to swelling at day 3 (reported in two studies) and at day 7 (reported in two studies), in return to function at day 7 (89 participants, 1 study), and in gastrointestinal adverse events (141 participants, 3 studies). No studies compared NSAIDs with complementary and alternative medicines, and no study reported re-injury rates. There is generally low- or very low-quality but consistent evidence of no clinically important difference in analgesic efficacy between NSAIDs and other oral analgesics. There is low-quality evidence of more gastrointestinal adverse effects with non-selective NSAID compared with paracetamol. There is low- or very low-quality evidence of better function and fewer adverse events with NSAIDs compared with opioid-containing analgesics; however, one study dominated this evidence using a now unavailable COX-2 selective NSAID and is of uncertain applicability. Further research is required to determine whether there is any difference in return to function or adverse effects between both non-selective and COX-2 selective NSAIDs versus paracetamol.
We included 11 studies randomizing 4014 participants to molecular-targeted therapy plus conventional chemotherapy or chemotherapy alone. Five were at low risk of bias, and we considered the risk of bias in the other six studies to be high, mainly due to their open-label design. All identified studies reported data regarding survival. We found low-quality evidence that molecular-targeted may have a small effect on mortality (HR 0.92, 95% CI 0.80 to 1.05, 10 studies) compared with conventional chemotherapy alone. Similarly, it may have little effect on progression-free survival when compared with conventional chemotherapy alone (HR 0.90, 95% CI 0.78 to 1.04, 11 studies; low-quality evidence). We did not find evidence from subgroup analysis that survival outcomes differed by type of molecular-targeted agent (EGFR- or VEGF-targeting agents) or tumor type, meaning that we were unable to explain the variation in effect across the studies by the presence or absence of prognostic biomarkers or type of molecular-targeted agent. From 11 eligible trials, we were able to use data from 3723 participants with measurable tumors. We found low-quality evidence that molecular-targeted therapy may increase tumor response (OR 1.24, 95% CI 1.00 to 1.55, low-quality evidence). Data from one small trial were too limited to determine the effect of treatment on quality of life (very low-quality evidence). The addition of targeted therapy to chemotherapy probably increases the risk of adverse events (OR 2.23, 95% CI 1.27 to 3.92, 5 trials, 2290 participants, moderate-quality evidence) and severe adverse event (OR 1.19, 95% CI 1.03 to 1.37, 8 trials, 3800 participants), compared with receiving chemotherapy alone. There is uncertainty about the effect of adding targeted therapy to chemotherapy on survival outcomes in people with advanced gastric cancer, with very little information on its impact on quality of life. There is more certain evidence of increased risk of adverse events and serious adverse events. The main limitation of the evidence for survival outcomes was inconsistency of effects across the studies, which we could not explain by prespecified subgroups in terms of the type of therapy or tumor type. Ongoing studies in this area are small and unlikely to improve our understanding of the effects of targeted therapy, and larger studies are needed.
Twenty-five studies met our inclusion criteria (18 RCTs involving 64,852 participants and seven non-RCTs involving 62,294 participants). Meta-analysis of the RCTs found strong evidence of PPV efficacy against IPD with no statistical heterogeneity (OR 0.26, 95% CI 0.14 to 0.45; random-effects model, I2 statistic = 0%). There was efficacy against all-cause pneumonia in low-income (OR 0.54, 95% CI 0.43 to 0.67, I2 statistic = 19%) but not high-income countries in either the general population (OR 0.71, 95% CI 0.45 to 1.12, I2 statistic = 93%) or in adults with chronic illness (OR 0.93, 95% CI 0.73 to 1.19, I2 statistic = 10%). PPV was not associated with substantial reductions in all-cause mortality (OR 0.90, 95% CI 0.74 to 1.09; random-effects model, I2 statistic = 69%). Vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness. Non-RCTs provided evidence for protection against IPD in populations for whom the vaccine is currently utilised (OR 0.48, 95% CI 0.37 to 0.61; random-effects model, I2 statistic = 31%). This review did not consider adverse events as it was outside the scope of the review. This meta-analysis provides evidence supporting the recommendation for PPV to prevent IPD in adults. The evidence from RCTs is less clear with respect to adults with chronic illness. This might be because of lack of effect or lack of power in the studies. The meta-analysis does not provide evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality.
Three RCTs met our inclusion criteria. The trials randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to IM vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 38.6 to 72 years. The treatment frequency and daily dose of vitamin B12 in the oral and IM groups varied among trials. Only one trial had low or unclear risk of bias across all domains and outcome measures. Two trials reported data for serum vitamin B12 levels. The overall quality of evidence for this outcome was low due to serious imprecision (low number of trials and participants). In two trials employing 1000 μg/day oral vitamin B12, there was no clinically relevant difference in vitamin B12 levels when compared with IM vitamin B12. One trial used 2000 μg/day vitamin B12 and demonstrated a mean difference of 680 pg/mL (95% confidence interval 392.7 to 967.3) in favour of oral vitamin B12. Two trials reported data on adverse events (very low-quality evidence due to risk of performance bias, detection bias, and serious imprecision). One trial stated that no treatment-related adverse events were seen in both the oral and IM vitamin B12 groups. One trial reported that 2 of 30 participants (6.7%) in the oral vitamin B12 group left the trial early due to adverse events. Orally taken vitamin B12 showed lower treatment-associated costs than IM vitamin B12 in one trial (low-quality evidence due to serious imprecision). No trial reported on clinical signs and symptoms of vitamin B12 deficiency, health-related quality of life, or acceptability of the treatment scheme. Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less. We found very low-quality evidence that oral vitamin B12 appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12 deficiency, health related-quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting.
Twenty-one trials (2372 participants) met the inclusion criteria for quantitative synthesis. There were large variations in the exercise programme's content, mode of delivery, frequency and duration, participant's symptoms, duration of symptoms, outcomes measured, methodological quality and reporting. Comparator groups were varied and included normal care; education; and attention controls such as home visits, sham gel and wait list controls. Risk of bias was high in one and unclear risk in five studies regarding the randomisation process, high for 11 studies regarding allocation concealment, high for all 21 studies regarding blinding, and high for three studies and unclear for five studies regarding attrition. Studies did not provide information on adverse effects. There was moderate quality evidence that exercise reduced pain by an absolute percent reduction of 6% (95% confidence interval (CI) -9% to -4%, (9 studies, 1058 participants), equivalent to reducing (improving) pain by 1.25 points from 6.5 to 5.3 on a 0 to 20 scale and moderate quality evidence that exercise improved physical function by an absolute percent of 5.6% (95% CI -7.6% to 2.0%; standardised mean difference (SMD) -0.27, 95% CI -0.37 to -0.17, equivalent to reducing (improving) WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) function on a 0 to 100 scale from 49.9 to 44.3) (13 studies, 1599 participants)). Self-efficacy was increased by an absolute percent of 1.66% (95% CI 1.08% to 2.20%), although evidence was low quality (SMD 0.46, 95% CI 0.34 to 0.58, equivalent to improving the ExBeliefs score on a 17 to 85 scale from 64.3 to 65.4), with small benefits for depression from moderate quality evidence indicating an absolute percent reduction of 2.4% (95% CI -0.47% to 0.5%) (SMD -0.16, 95% CI -0.29 to -0.02, equivalent to improving depression measured using HADS (Hospital Anxiety and Depression Scale) on a 0 to 21 scale from 3.5 to 3.0) but no clinically or statistically significant effect on anxiety (SMD -0.11, 95% CI -0.26 to 0.05, 2% absolute improvement, 95% CI -5% to 1% equivalent to improving HADS anxiety on a 0 to 21 scale from 5.8 to 5.4; moderate quality evidence). Five studies measured the effect of exercise on health-related quality of life using the 36-item Short Form (SF-36) with statistically significant benefits for social function, increasing it by an absolute percent of 7.9% (95% CI 4.1% to 11.6%), equivalent to increasing SF-36 social function on a 0 to 100 scale from 73.6 to 81.5, although the evidence was low quality. Evidence was downgraded due to heterogeneity of measures, limitations with blinding and lack of detail regarding interventions. For 20/21 studies, there was a high risk of bias with blinding as participants self-reported and were not blinded to their participation in an exercise intervention. Twelve studies (with 6 to 29 participants) met inclusion criteria for qualitative synthesis. Their methodological rigour and quality was generally good. From the patients' perspectives, ways to improve the delivery of exercise interventions included: provide better information and advice about the safety and value of exercise; provide exercise tailored to individual's preferences, abilities and needs; challenge inappropriate health beliefs and provide better support. An integrative review, which compared the findings from quantitative trials with low risk of bias and the implications derived from the high-quality studies in the qualitative synthesis, confirmed the importance of these implications. Chronic hip and knee pain affects all domains of people's lives. People's beliefs about chronic pain shape their attitudes and behaviours about how to manage their pain. People are confused about the cause of their pain, and bewildered by its variability and randomness. Without adequate information and advice from healthcare professionals, people do not know what they should and should not do, and, as a consequence, avoid activity for fear of causing harm. Participation in exercise programmes may slightly improve physical function, depression and pain. It may slightly improve self-efficacy and social function, although there is probably little or no difference in anxiety. Providing reassurance and clear advice about the value of exercise in controlling symptoms, and opportunities to participate in exercise programmes that people regard as enjoyable and relevant, may encourage greater exercise participation, which brings a range of health benefits to a large population of people.
Three trials (723 participants) were included. Only one trial used adequate outcome measures of efficacy; therefore, the results pertaining to efficacy are based on a single trial, whereas the results pertaining to adverse events are based on all three included trials. There was no overall difference in time to treatment withdrawal between the two drugs (hazard ratio (HR) of oxcarbazepine (OXC) versus carbamazepine (CBZ): 1.04, 95% confidence interval (CI) 0.78 to 1.39). Further analyses showed no significant difference in treatment withdrawal for unacceptable side effects (HR of OXC versus CBZ: 0.85, 95% CI 0.59 to 1.24) and in treatment withdrawal for inadequate seizure control (HR of OXC versus CBZ: 1.33, 95% CI 0.82 to 2.15). Oxcarbazepine and carbamazepine appeared to be similarly effective and well tolerated although the confidence intervals around estimates were wide and do not rule out the possibility of important differences existing. Significantly fewer patients on carbamazepine treatment developed nausea or vomiting, or both (odds ratio of OXC versus CBZ: 3.15, 95% CI 1.39 to 7.14). Oxcarbazepine and carbamazepine appear to be similarly effective and well tolerated. However, the possibility of important differences existing between these drugs cannot be ruled out.
We included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide. Endothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.
We included one unpublished and seven published studies (total of 808 participants); four more studies and 478 more participants than the 2011 review. Six trials included young children aged one to four years receiving sucrose or candy lollypops for immunisation pain compared with water or no treatment. Usual care included topical anaesthetics, upright parental holding, and distraction. All studies were well designed blinded RCTs, however, five of the six studies had a high risk of bias based on small sample sizes. Two studies included school-aged children receiving sweet or unsweetened chewing gum before, or before and during, immunisation and blood collection. Both studies, conducted by the same author, had a high risk of bias based on small sample sizes. Results for the toddlers/pre-school children were conflicting. Duration of cry, using a random-effects model, was not significantly reduced by sweet taste (six trials, 520 children, WMD -15 seconds, 95% CI -54 to 24, I2 = 94%). Composite pain score at time of first needle was reported in four studies (n = 121 children). The scores were not significantly different between the sucrose and control group (SMD -0.26, 95% CI -1.27 to 0.75, I2 = 86%). A Children's Hospital of Eastern Ontario Pain Scale score > 4 was significantly less common in the sucrose group compared to the control group in one study (n = 472, RR 0.55, 95% CI 0.45 to 0.67; RD -0.29, 95% CI -0.37 to -0.20; NNTB 3, 95% CI 3 to 5; tests for heterogeneity not applicable. For school-aged children, chewing sweet gum before needle-related painful procedures (two studies, n = 111 children) or during the procedures (two studies, n = 103 children) did not significantly reduce pain scores. A comparison of the Faces Pain Scale scores in children chewing sweet gum before the procedures compared with scores of children chewing unsweetened gum revealed a WMD of -0.15 (95% CI -0.61 to 0.30). Similar results were found when comparing the chewing of sweet gum with unsweetened gum during the procedure (WMD 0.23, 95% CI -0.28 to 0.74). The Colored Analogue Scale for children chewing sweet gum compared to unsweetened gum before the procedure was not significantly different (WMD 0.24 (-0.69 to 1.18)) nor was it different when children chewed the gum during the procedure (WMD 0.86 (95% CI -0.12 to 1.83)). There was no heterogeneity for any of these analyses in school-aged children (I2 = 0%). Based on the eight studies included in this systematic review update, two of which were subgroups of small numbers of eligible toddlers from larger studies, and three of which were pilot RCTs with small numbers of participants, there is insufficient evidence of the analgesic effects of sweet tasting solutions or substances during acutely painful procedures in young children between one and four years of age. Further rigorously conducted, adequately powered RCTs are warranted in this population. Based on the two studies by the same author, there was no evidence of analgesic effects of sweet taste in school-aged children. As there are other effective evidence-based strategies available to use in this age group, further trials are not warranted. Despite the addition of four studies in this review, conclusions have not changed since the last version of the review.
Forty one trials (n=4935 women) were included. The evidence suggested that GnRHas were more effective at symptom relief than no treatment/placebo. There was no statistically significant difference between GnRHas and danazol for dysmenorrhoea RR 0.98 (95%CI 0.92 to 1.04; P = 0.53). This equates to 3 fewer women per 1000 (95%CI 12 to 6) with symptomatic pain relief in the GnRHa group. More adverse events were reported in the GnRHa group. There was a benefit in overall resolution for GnRHas RR1.10 (95%CI 1.01 to 1.21, P=0.03) compared with danazol. There was no statistically significant difference in overall pain between GnRHas and levonorgestrel SMD -0.25 (95%CI -0.60 to 0.10, P=0.46). Evidence was limited on optimal dosage or duration of treatment for GnRHas. No route of administration appeared superior to another. GnRHas appear to be more effective at relieving pain associated with endometriosis than no treatment/placebo. There was no evidence of a difference in pain relief between GnRHas and danazol although more adverse events reported in the GnRHa groups. There was no evidence of a difference in pain relief between GnRHas and levonorgestrel and no studies compared GnRHas with analgesics.
Five trials with a total of 924 participants met the inclusion criteria; 5% of participants were HIV positive. Only one small trial was methodologically adequate. The two largest trials (818 participants) had unclear allocation concealment and included < 90% of randomized participants in the analysis. There was no statistically significant difference in between the regimens for cure (RR 1.00, 95% CI 0.96 to 1.04; 553 participants, 2 trials) or relapse (RR 1.23, 95% CI 0.45 to 3.35; 448 participants, 2 trials). The number of adverse events was not significantly different (RR 1.42, 95% CI 0.88 to 2.31; 714 participants, 3 trials), though the RR increased with rifabutin dose: 150 mg (RR 0.98, 95% CI 0.45 to 2.12; 264 participants, 2 trials); and 300 mg (RR 1.78, 95% CI 0.94 to 3.34; 450 participants, 2 trials). However, lack of dose adjustment by weight in the relevant trials complicates interpretation of this relationship. The replacement of rifampicin by rifabutin for first-line treatment of tuberculosis is not supported by the current evidence. HIV-positive people with tuberculosis, the group most likely to benefit from the rifabutin use, are under-represented in trials to date, and further trials in this group would be useful.
The updated search retrieved 535 records; we included 13 parallel-designed RCTs comparing IMSI and ICSI (four studies were added since the previous version), comprising 2775 couples (IMSI = 1256; ICSI = 1519). We are uncertain if IMSI improves live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.89 to 1.39; 5 studies, 929 couples; I² = 1%), miscarriage rates per couple (RR 1.07, 95% CI 0.78 to 1.48; 10 studies, 2297 couples; I² = 0%, very-low quality evidence), and miscarriage rate per pregnancy (RR 0.90, 95% CI 0.68 to 1.20; 10 studies, 783 couples; I² = 0%, very-low quality evidence). We are uncertain if IMSI improves clinical pregnancy rates (RR 1.23, 95% CI 1.11 to 1.37; 13 studies, 2775 couples; I² = 47%, very-low quality evidence). None of the included studies reported congenital abnormalities. We judged the evidence for all outcomes to be of very low-quality. We downgraded the quality of the evidence due to limitations of the included studies (risk of bias), inconsistency of results, and a strong indication of publication bias. The current evidence from randomised controlled trials does not support or refute the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (IMSI). We are very uncertain of the chances of having a live birth and of the risk of having a miscarriage. We found very low-quality evidence that IMSI may increase chances of a clinical pregnancy, which means that we are still very uncertain about any real difference. We did not find any trials reporting on the risk of congenital abnormalities. Well-designed and sufficiently powered trials are still required.
Sixteen orlistat (n = 10,631), 10 sibutramine (n = 2623) and four rimonabant trials (n = 6365) met inclusion criteria. Attrition rates averaged 30% to 40%. Compared to placebo, orlistat reduced weight by 2.9 kg (95% confidence interval (CI) 2.5 to 3.2 kg), sibutramine by 4.2 kg (95% CI 3.6 to 4.7 kg), and rimonabant by 4.7 kg (95% CI 4.1 to 5.3 kg). Patients on active drug therapy were significantly more likely to achieve 5% and 10% weight loss thresholds. Placebo-controlled weight losses were consistently lower in patients with diabetes. Orlistat reduced diabetes incidence, improved total cholesterol, LDL-cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered HDL levels. Sibutramine improved HDL and triglyceride levels but raised blood pressure and pulse rate. Rimonabant improved HDL-cholesterol, triglyceride and blood pressure levels and glycaemic control in patients with diabetes but increased the risk of mood disorders. Orlistat, sibutramine and rimonabant have been studied in trials of one year or longer. Internal validity of studies was limited by high attrition rates. All three antiobesity agents are modestly effective in reducing weight and have differing effects on cardiovascular risk and adverse effects profiles. Longer and more methodologically rigorous studies of anti-obesity drugs that are powered to examine endpoints such as mortality and cardiovascular morbidity are required.
We included 15 studies from the earlier review and two new studies (17 studies, 1342 participants) in seven neuropathic pain conditions. Eight cross-over studies with 302 participants had a median of 36 participants, and nine parallel group studies with 1040 participants had a median of 84 participants. Study quality was modest, though most studies were at high risk of bias due to small size. There was no first-tier or second-tier evidence for amitriptyline in treating any neuropathic pain condition. Only third-tier evidence was available. For only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo (very low quality evidence). More participants experienced at least one adverse event; 55% of participants taking amitriptyline and 36% taking placebo. The risk ratio (RR) was 1.5 (95% confidence interval (CI) 1.3 to 1.8) and the number needed to treat for an additional harmful outcome was 5.2 (3.6 to 9.1) (low quality evidence). Serious adverse events were rare. Adverse event and all-cause withdrawals were not different, but were rarely reported (very low quality evidence). Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but only a minority of people will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.
Twenty-eight studies on 907 participants were included in the review. Study sample size was generally small (range 5 to 96 people) and overall quality was generally poor due to inadequate blinding and allocation procedures. Meta-analyses were limited by heterogeneity of outcome measurement and inadequate reporting of data. In people experiencing AECOPD, ACT use was associated with small but significant short-term reductions in the need for increased ventilatory assistance (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05 to 0.85; data from four studies on 171 people), the duration of ventilatory assistance (mean difference (MD) -2.05 days, 95% CI -2.60 to -1.51; mean duration for control groups seven days; data from two studies on 54 people) and hospital length of stay (MD -0.75 days, 95% CI -1.38 to -0.11; mean duration for control groups nine days; one study on 35 people). Data from a limited number of studies revealed no significant long-term benefits of ACTs on the number of exacerbations or hospitalisations, nor any short-term beneficial effect on health-related quality of life (HRQoL) as measured by the St. George's Respiratory Questionnaire (SGRQ) total score (MD -2.30, 95% CI -11.80 to 7.20; one study on 59 people). In people with stable COPD, data from single studies revealed no significant short-term benefit of ACTs on the number of people with exacerbations (OR 3.21, 95% CI 0.12 to 85.20; one study on 30 people), significant short-term improvements in HRQoL as measured by the SGRQ total score (MD -6.10, 95% CI -8.93 to -3.27; one study on 15 people) and a reduced long-term need for respiratory-related hospitalisation (OR 0.27, 95% CI 0.08 to 0.95; one study on 35 participants). The magnitude of effect of PEP-based ACTs on the need for increased ventilatory assistance and hospital length of stay was greater than for non-PEP ACTs, however we found no statistically significant subgroup differences. There was one report of vomiting during treatment with postural drainage and head-down tilt. Evidence from this review indicates that airway clearance techniques are safe for individuals with COPD and confer small beneficial effects on some clinical outcomes. Consideration may be given to the use of airway clearance techniques for patients with COPD in both acute and stable disease, however current studies suggest that the benefits achieved may be small.
We included eight studies in the review. All outcomes were short term (less than six months). There were clear differences in a number of outcomes in favour of the yoga group, although these were based on one study each, with the exception of leaving the study early. These included mental state (improvement in Positive and Negative Syndrome Scale, 1 RCT, n = 83, RR 0.70 CI 0.55 to 0.88, medium-quality evidence), social functioning (improvement in Social Occupational Functioning Scale, 1 RCT, n = 83, RR 0.88 CI 0.77 to 1, medium-quality evidence), quality of life (average change 36-Item Short Form Survey (SF-36) quality-of-life subscale, 1 RCT, n = 60, MD 15.50, 95% CI 4.27 to 26.73, low-quality evidence), and leaving the study early (8 RCTs, n = 457, RR 0.91 CI 0.6 to 1.37, medium-quality evidence). For the outcome of physical health, there was not a clear difference between groups (average change SF-36 physical-health subscale, 1 RCT, n = 60, MD 6.60, 95% CI -2.44 to 15.64, low-quality evidence). Only one study reported adverse effects, finding no incidence of adverse events in either treatment group. This review was subject to a considerable number of missing outcomes, which included global state, change in cognition, costs of care, effect on standard care, service intervention, disability, and activities of daily living. Even though we found some positive evidence in favour of yoga over standard-care control, this should be interpreted cautiously in view of outcomes largely based each on one study with limited sample sizes and short-term follow-up. Overall, many outcomes were not reported and evidence presented in this review is of low to moderate quality - -too weak to indicate that yoga is superior to standard-care control for the management of schizophrenia.
One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to propranolol (N = 32) or no treatment (N = 38) for an average duration of 9.3 years in the control group and 10.7 years in the treatment group. The initial dose of propranolol was 10 mg four times daily and the optimal dose was reached when the heart rate remained below 100 beats per minute during exercise or the systolic time interval increased by 30%. The mean (± standard error (SE)) optimal dose of propranolol was 212 ± 68 mg given in four divided doses daily. Beta-blocker therapy did not reduce the incidence of all-cause mortality (RR 0.24, 95% CI 0.01 to 4.75; participants = 70; low-quality evidence). Mortality attributed to Marfan syndrome was not reported. Non-fatal serious adverse events were also not reported. However, study authors report on pre-defined, non-fatal clinical endpoints, which include aortic dissection, aortic regurgitation, cardiovascular surgery and congestive heart failure. Their analysis showed no difference between the treatment and control groups in these outcomes (RR 0.79, 95% CI 0.37 to 1.69; participants = 70; low-quality evidence). Beta-blocker therapy did not reduce the incidence of aortic dissection (RR 0.59, 95% CI 0.12 to 3.03), aortic regurgitation (RR 1.19, 95% CI 0.18 to 7.96), congestive heart failure (RR 1.19, 95% CI 0.18 to 7.96) or cardiovascular surgery, (RR 0.59, 95% CI 0.12 to 3.03); participants = 70; low-quality evidence. The study reports a reduced rate of aortic dilatation measured by M-mode echocardiography in the treatment group (aortic ratio mean slope: 0.084 (control) vs 0.023 (treatment), P < 0.001). The change in systolic and diastolic blood pressure, total adverse events and withdrawal due to adverse events were not reported in the treatment or control group at study end point. We judged this study to be at high risk of selection (allocation concealment) bias, performance bias, detection bias, attrition bias and selective reporting bias. The overall quality of evidence was low. We do not know whether a statistically significant reduced rate of aortic dilatation translates into clinical benefit in terms of aortic dissection or mortality. Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfan syndrome, we could draw no definitive conclusions for clinical practice. High-quality, randomised trials are needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy.
We included 30 RCTs (6235 women) comparing different intra-vaginal oestrogenic preparations with each other and with placebo. The evidence was low to moderate quality; limitations were poor reporting of study methods and serious imprecision (effect estimates with wide confidence intervals) 1. Oestrogen ring versus other regimens Other regimens included oestrogen cream, oestrogen tablets and placebo. There was no evidence of a difference in improvement in symptoms (participant assessment) either between oestrogen ring and oestrogen cream (odds ratio (OR) 1.33, 95% CI 0.80 to 2.19, two RCTs, n = 341, I2 = 0%, low-quality evidence) or between oestrogen ring and oestrogen tablets (OR 0.78, 95% CI 0.53 to 1.15, three RCTs, n = 567, I2 = 0%, low-quality evidence). However, a higher proportion of women reported improvement in symptoms following treatment with oestrogen ring compared with placebo (OR 12.67, 95% CI 3.23 to 49.66, one RCT, n = 67). With respect to endometrial thickness, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring (OR 0.36, 95% CI 0.14 to 0.94, two RCTs, n = 273; I2 = 0%, low-quality evidence). This may have been due to the higher doses of cream used. 2. Oestrogen tablets versus other regimens Other regimens in this comparison included oestrogen cream, and placebo. There was no evidence of a difference in the proportions of women who reported improvement in symptoms between oestrogen tablets and oestrogen cream (OR 1.06, 95% CI 0.55 to 2.01, two RCTs, n = 208, I2 = 0% low-quality evidence). A higher proportion of women who were treated with oestrogen tablets reported improvement in symptoms compared to those who received placebo using a fixed-effect model (OR 12.47, 95% CI 9.81 to 15.84, two RCTs, n = 1638, I2 = 83%, low-quality evidence); however, using a random-effect model did not demonstrate any evidence of a difference in the proportions of women who reported improvement between the two treatment groups (OR 5.80, 95% CI 0.88 to 38.29). There was no evidence of a difference in the proportions of women with increase in endometrial thickness between oestrogen tablets and oestrogen cream (OR 0.31, 95% CI 0.06 to 1.60, two RCTs, n = 151, I2 = 0%, low-quality evidence). 3. Oestrogen cream versus other regimens Other regimens identified in this comparison included isoflavone gel and placebo. There was no evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and isoflavone gel (OR 2.08, 95% CI 0.08 to 53.76, one RCT, n = 50, low-quality evidence). However, there was evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and placebo with more women who received oestrogen cream reporting improvement in symptoms compared to those who were treated with placebo (OR 4.10, 95% CI 1.88 to 8.93, two RCTs, n = 198, I2 = 50%, low-quality evidence). None of the included studies in this comparison reported data on endometrial thickness. There was no evidence of a difference in efficacy between the various intravaginal oestrogenic preparations when compared with each other. However, there was low-quality evidence that intra-vaginal oestrogenic preparations improve the symptoms of vaginal atrophy in postmenopausal women when compared to placebo. There was low-quality evidence that oestrogen cream may be associated with an increase in endometrial thickness compared to oestrogen ring; this may have been due to the higher doses of cream used. However there was no evidence of a difference in the overall body of evidence in adverse events between the various oestrogenic preparations compared with each other or with placebo.
Eight RCTs (with 719 participants) were included in this update. The trials were small in size and methodological quality was poor. Viral detection was performed in 38% of participants, among whom 56% had positive results. Mortality between corticosteroids and control groups was non-significant (RR, 0.93, 95% CI 0.70 to 1.24). At 1 to 3 months follow-up, left ventricular ejection fraction (LVEF) was higher in the corticosteroids group compared to the control group (MD 7.36%, 95% CI 4.94 to 9.79), but there was substantial heterogeneity. Benefits were observed in LVEF in two trials with 200 children given corticosteroids (MD 9.00%, 95% CI 7.48 to 10.52). New York Heart Association (NYHA) class and left ventricular end-stage systole diameter (LVESD) were not affected. Creatine phosphokinase (CPK) (MD -104.00 U/L, 95% CI -115.18 to -92.82), Isoenzyme of creatine phosphate MB (CKMB) (MD 10.35 U/L, 95% CI 8.92 to 11.78), were reduced in the corticosteroids group compared to the control group, although the evidence is limited to small participant numbers. There were insufficient data on adverse events. For people diagnosed with viral myocarditis and low LVEF, corticosteroids do not reduce mortality. They may improve cardiac function but the trials were of low quality and small size so this finding must be regarded as uncertain. High-quality, large-scale RCTs should be careful designed to determine the role of corticosteroid treatment for viral myocarditis. Adverse events should also be carefully evaluated.
From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ß2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ß2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ß2-agonists. Dry mouth was increased by tiotropium. Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ß2-agonists and to assess its effectiveness in mild and very severe COPD.
We identified 6 randomised controlled trials and 1 quasi-randomised controlled trial for inclusion in the review; the total number of participants was 392. The trials had some risk of bias because five of the trials did not blind outcome assessors to treatment allocation. The interventions included ant, bee, and wasp immunotherapy in children or adults with previous systemic or large local reactions to a sting, using sublingual (one trial) or subcutaneous (six trials) VIT. We found that VIT is effective for preventing systemic allergic reaction to an insect sting, which was our primary outcome measure. This applies whether the sting occurs accidentally or is given intentionally as part of a trial procedure. In the trials, 3/113 (2.7%) participants treated with VIT had a subsequent systemic allergic reaction to a sting, compared with 37/93 (39.8%) untreated participants (risk ratio [RR] 0.10, 95% confidence interval [CI] 0.03 to 0.28). The efficacy of VIT was similar across studies; we were unable to identify a patient group or mode of treatment with different efficacy, although these analyses were limited by small numbers. We were unable to confirm whether VIT prevents fatal reactions to insect stings, because of the rarity of this outcome. Venom immunotherapy was also effective for preventing large local reactions to a sting (5 studies; 112 follow-up stings; RR 0.41, 95% CI 0.24 to 0.69) and for improving quality of life (mean difference [MD] in favour of VIT 1.21 points on a 7-point scale, 95% CI 0.75 to 1.67). We found a significant risk of systemic adverse reaction to VIT treatment: 6 trials reported this outcome, in which 14 of 150 (9.3%) participants treated with VIT and 1 of 135 (0.7%) participants treated with placebo or no treatment suffered a systemic reaction to treatment (RR 8.16, 95% CI 1.53 to 43.46; 2 studies contributed to the effect estimate). Our analysis of 11 observational studies found systemic adverse reactions occurred in 131/921 (14.2%) participants treated with bee venom VIT and 8/289 (2.8%) treated with wasp venom VIT. We found venom immunotherapy using extracted insect venom to be an effective therapy for preventing further allergic reactions to insect stings, which can improve quality of life. The treatment carries a small but significant risk of systemic adverse reaction.
Studies of prophylactic administration of protein free SS note a variable improvement in the respiratory status and a decrease in respiratory distress syndrome in infants who receive prophylactic protein free SS. The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.67, 95% CI 0.50, 0.90), pulmonary interstitial emphysema (typical relative risk 0.68, 95% CI 0.50, 0.93), and neonatal mortality (typical relative risk 0.70, 95% CI 0.58, 0.85). No differences were seen in the risk of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and cerebral palsy. The meta-analysis supports an increase in the risk of patent ductus arteriosus associated with prophylactic SS administration (typical relative risk 1.11, 95% CI 1.00, 1.22), and an increase in the risk of pulmonary hemorrhage (typical relative risk 3.28, 95% CI 1.50, 7.16). Prophylactic intratracheal administration of protein free synthetic surfactant to infants at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic protein free SS have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. Infants who receive prophylactic protein free SS have an increased risk of developing patent ductus arteriosus and pulmonary hemorrhage.
The searches identified 69 trials, of which 19 (2565 participants) met our inclusion criteria. Fifteen trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years. Dornase alfa compared to placebo or no treatment Dornase alfa improved forced expiratory volume at one second at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed no difference between groups for changes in quality of life. There was a decrease in pulmonary exacerbations with dornase alfa in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa: daily versus alternate day One cross-over trial (43 children) found no differences between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence). Dornase alfa compared to other medications that improve airway clearance Results for these comparisons were mixed. One trial (43 children) showed a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported no difference in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found a difference in quality of life favouring dornase alfa when compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence). When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash. There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.
We included ten studies involving data from 944 adults, all male. Five trials involved primarily cognitive behavioural interventions (CBT) (n = 664). Of these, four compared CBT with no treatment or wait list control, and one compared CBT with standard care. Only one study collected data on the primary outcome. The largest study (n = 484) involved the most complex intervention versus no treatment. Long-term outcome data are reported for groups in which the mean years 'at risk' in the community are similar (8.3 years for treatment (n = 259) compared to 8.4 in the control group (n = 225)). There was no difference between these groups in terms of the risk of reoffending as measured by reconviction for sexual offences (risk ratio (RR) 1.10; 95% CI 0.78 to 1.56). Four trials (n = 70) compared one behavioural programme with an alternative behavioural programme or with wait list control. No meta-analysis was possible for this comparison. For two studies (both cross-over, n = 29) no disaggregated data were available. The remaining two behavioural studies compared imaginal desensitisation with either covert sensitisation or as part of adjunctive drug therapy (n = 20 and 21, respectively). In these two studies, results for the primary outcome (being 'charged with anomalous behaviour') were encouraging, with only one new charge for the treated groups over one year in the former study, and in the latter study, only one new charge (in the drug-only group) over two years. One study compared psychodynamic intervention with probation. Results for this study (n = 231) indicate a slight trend in favour of the control group (probation) over the intervention (group therapy) in terms of sexual offending as measured by rearrest (RR 1.87; 95% CI 0.78 to 4.47) at 10-year follow-up. Data for adverse events, 'sexually anomalous urges' and for secondary outcomes thought to be 'dynamic' risk factors for reoffending, including anger and cognitive distortions, were limited. The inescapable conclusion of this review is the need for further randomised controlled trials. While we recognise that randomisation is considered by some to be unethical or politically unacceptable (both of which are based on the faulty premise that the experimental treatment is superior to the control – this being the point of the trial to begin with), without such evidence, the area will fail to progress. Not only could this result in the continued use of ineffective (and potentially harmful) interventions, but it also means that society is lured into a false sense of security in the belief that once the individual has been treated, their risk of reoffending is reduced. Current available evidence does not support this belief. Future trials should concentrate on minimising risk of bias, maximising quality of reporting and including follow-up for a minimum of five years 'at risk' in the community.
We included four trials, containing 2018 patients. The subjects were mostly white people (female: 26% to 56%), with a median age of 58 to 66 years. About half of them had histologically proven adenocarcinoma. Of the 2018 patients, 83% to 99% had their status measured using the Eastern Cooperative Oncology Group performance status, and had a score of 0 to 1 (which is usually considered as physically "fit"). All four studies provided data on overall survival, progression-free survival, one-year survival rate, objective response rate, and serious adverse events, with two studies (1901 patients) investigating the effect of cetuximab on quality of life as well. The risk of bias was low for the data on overall survival and one-year survival rate, and high for the data on all other outcomes, mainly due to lack of blinding. Compared with chemotherapy alone, chemotherapy plus cetuximab improved overall survival (10.5 months versus 8.9 months; HR 0.87, 95% CI 0.79 to 0.96), one-year survival rate (45% versus 40%; RR 1.13, 95% CI 1.02 to 1.25), and objective response rate (30% versus 23%; RR 1.31, 95% CI 1.14 to 1.51). The difference in progression-free survival was at the limit of the statistical significance (4.9 months versus 4.4 months; HR 0.91, 95% CI 0.83 to 1.00). No significant difference in quality of life between the two treatment arms was reported by the two relevant studies. Patients in the cetuximab group experienced more acneiform rash (11.2% versus 0.3%; RR 37.36, 95% CI 10.66 to 130.95), hypomagnesemia (5.3% versus 0.8%; RR 6.57, 95% CI 1.13 to 38.12), infusion reaction (3.9% versus 1.1%; RR 3.50, 95% CI 1.76 to 6.94), diarrhoea (4.8% versus 2.3%; RR 2.10, 95% CI 1.26 to 3.48), hypokalaemia (6.3% versus 3.6%; RR 1.74, 95% CI 1.02 to 2.99), febrile neutropenia (10.6% versus 7.6%; RR 1.40, 95% CI 1.10 to 1.77), and leukopenia (58.1% versus 42.7%; RR 1.36, 95% CI 1.17 to 1.58) than did those in the control group. The difference in other adverse events did not reach statistical significance. According to the reports of original studies, the adverse events were generally manageable. There were no cetuximab-related deaths. The quality of the evidence is high for overall survival and one-year survival rate, but low for most secondary outcomes. The combination of chemotherapy plus cetuximab is better than chemotherapy alone as the first-line treatment of advanced NSCLC in improving overall survival, while inducing higher rates of some reportedly manageable adverse events.
Twenty randomised trials met our inclusion criteria; 16 parallel trials (977 infants) and four cross-over trials (88 infants). No studies were blinded and the quality of evidence for outcomes assessed varied from moderate to low. We found no difference in the primary outcome, death before hospital discharge, between VTV modes versus PLV modes (typical RR 0.75, 95% CI 0.53 to 1.07; low quality evidence). However, there was moderate quality evidence that the use of VTV modes resulted in a reduction in the primary outcome, death or BPD at 36 weeks' gestation (typical RR 0.73, 95% CI 0.59 to 0.89; typical NNTB 8, 95% CI 5 to 20) and the following secondary outcomes: rates of pneumothorax (typical RR 0.52, 95% CI 0.31 to 0.87; typical NNTB 20, 95% CI 11 to 100), mean days of mechanical ventilation (MD -1.35 days, 95% CI -1.83 to -0.86), rates of hypocarbia (typical RR 0.49, 95% CI 0.33 to 0.72; typical NNTB 3, 95% CI 2 to 5), rates of grade 3 or 4 intraventricular haemorrhage (typical RR 0.53, 95% CI 0.37 to 0.77; typical NNTB 11, 95% CI 7 to 25) and the combined outcome of periventricular leukomalacia with or without grade 3 or 4 intraventricular haemorrhage (typical RR 0.47, 95% CI 0.27 to 0.80; typical NNTB 11, 95% CI 7 to 33). VTV modes were not associated with any increased adverse outcomes. Infants ventilated using VTV modes had reduced rates of death or BPD, pneumothoraces, hypocarbia, severe cranial ultrasound pathologies and duration of ventilation compared with infants ventilated using PLV modes. Further studies are needed to identify whether VTV modes improve neurodevelopmental outcomes and to compare and refine VTV strategies.
Eleven studies (672 participants) were included in the review. Four studies assessed the efficacy of single doses of various opioid and non-opioid analgesics; a pooled analysis of these studies was not performed but in each study opioids reduced pain more than placebo. There were no differences between analgesic drugs in these studies. Seven studies were between one and six weeks in duration and assessed six different oral opioids (dextropropoxyphene, codeine, tramadol, tilidine, pentazocine, morphine), either alone or combined with non-opioid analgesics. The only strong opioid investigated was controlled-release morphine sulphate, in a single study with 20 participants. Six studies compared an opioid to placebo. Opioids were superior to placebo in patient-reported global impression of change (3 studies, 324 participants: relative risk (RR) 1.44, 95% CI 1.03 to 2.03) but not for the number of withdrawals due to inadequate analgesia (4 studies, 345 participants: RR 0.82, 95% CI 0.34 to 2.0). Adverse events (most commonly nausea, vomiting, dizziness and constipation) were more frequent in patients receiving opioids compared to placebo (4 studies, 371 participants: odds ratio 3.90, 95% CI 2.31 to 6.56); the pooled risk ratio for withdrawal due to adverse events was 2.67 (3 studies, 331 participants: 95% CI 0.52 to 13.75). One study compared an opioid (codeine with paracetamol) to an NSAID (diclofenac) and found no difference in efficacy or safety between interventions. There is limited evidence that weak oral opioids may be effective analgesics for some patients with RA, but adverse effects are common and may offset the benefits of this class of medications. There is insufficient evidence to draw conclusions regarding the use of weak opioids for longer than six weeks, or the role of strong opioids.
We included 32 RCTs with 2844 adult participants. Twenty-six assessed upper-limb and six assessed lower-limb blocks. Seventeen compared ultrasound with peripheral nerve stimulation (PNS), and nine compared ultrasound combined with nerve stimulation (US + NS) against PNS alone. Two studies compared ultrasound with anatomical landmark technique, one with a transarterial approach, and three were three-arm designs that included US, US + PNS and PNS. There were variations in the quality of evidence, with a lack of detail in many of the studies to judge whether randomization, allocation concealment and blinding of outcome assessors was sufficient. It was not possible to blind practitioners and there was therefore a high risk of performance bias across all studies, leading us to downgrade the evidence for study limitations using GRADE. There was insufficient detail on the experience and expertise of practitioners and whether experience was equivalent between intervention and control. We performed meta-analysis for our main outcomes. We found that ultrasound guidance produces superior peripheral nerve block success rates, with more blocks being assessed as sufficient for surgery following sensory or motor testing (Mantel-Haenszel (M-H) odds ratio (OR), fixed-effect 2.94 (95% confidence interval (CI) 2.14 to 4.04); 1346 participants), and fewer blocks requiring supplementation or conversion to general anaesthetic (M-H OR, fixed-effect 0.28 (95% CI 0.20 to 0.39); 1807 participants) compared with the use of PNS, anatomical landmark techniques or a transarterial approach. We were not concerned by risks of indirectness, imprecision or inconsistency for these outcomes and used GRADE to assess these outcomes as being of moderate quality. Results were similarly advantageous for studies comparing US + PNS with NS alone for the above outcomes (M-H OR, fixed-effect 3.33 (95% CI 2.13 to 5.20); 719 participants, and M-H OR, fixed-effect 0.34 (95% CI 0.21 to 0.56); 712 participants respectively). There were lower incidences of paraesthesia in both the ultrasound comparison groups (M-H OR, fixed-effect 0.42 (95% CI 0.23 to 0.76); 471 participants, and M-H OR, fixed-effect 0.97 (95% CI 0.30 to 3.12); 178 participants respectively) and lower incidences of vascular puncture in both groups (M-H OR, fixed-effect 0.19 (95% CI 0.07 to 0.57); 387 participants, and M-H OR, fixed-effect 0.22 (95% CI 0.05 to 0.90); 143 participants). There were fewer studies for these outcomes and we therefore downgraded both for imprecision and paraesthesia for potential publication bias. This gave an overall GRADE assessment of very low and low for these two outcomes respectively. Our analysis showed that it took less time to perform nerve blocks in the ultrasound group (mean difference (MD), IV, fixed-effect -1.06 (95% CI -1.41 to -0.72); 690 participants) but more time to perform the block when ultrasound was combined with a PNS technique (MD, IV, fixed-effect 0.76 (95% CI 0.55 to 0.98); 587 participants). With high levels of unexplained statistical heterogeneity, we graded this outcome as very low quality. We did not combine data for other outcomes as study results had been reported using differing scales or with a combination of mean and median data, but our interpretation of individual study data favoured ultrasound for a reduction in other minor complications and reduction in onset time of block and number of attempts to perform block. There is evidence that peripheral nerve blocks performed by ultrasound guidance alone, or in combination with PNS, are superior in terms of improved sensory and motor block, reduced need for supplementation and fewer minor complications reported. Using ultrasound alone shortens performance time when compared with nerve stimulation, but when used in combination with PNS it increases performance time. We were unable to determine whether these findings reflect the use of ultrasound in experienced hands and it was beyond the scope of this review to consider the learning curve associated with peripheral nerve blocks by ultrasound technique compared with other methods.
We identified one eligible study that examined the effect of computerised cognitive training (CCT) in 6742 participants over 50 years of age, with training and follow-up duration of six months. We considered the study to be at high risk of attrition bias and the overall quality of the evidence to be low. Researchers provided no data on our primary outcome. Results indicate that there may be a small advantage for the CCT group for executive function (mean difference (MD) -1.57, 95% confidence interval (CI) -1.85 to -1.29; participants = 3994; low-quality evidence) and a very small advantage for the control group for working memory (MD 0.09, 95% CI 0.03 to 0.15; participants = 5831; low-quality evidence). The intervention may have had little or no effect on episodic memory (MD -0.03, 95% CI -0.10 to 0.04; participants = 3090; low-quality evidence). We found low-quality evidence from only one study. We are unable to determine whether computerised cognitive training is effective in maintaining global cognitive function among healthy adults in midlife. We strongly recommend that high-quality studies be undertaken to investigate the effectiveness and acceptability of cognitive training in midlife, using interventions that last long enough that they may have enduring effects on cognitive and brain reserve, and with investigators following up long enough to assess effects on clinically important outcomes in later life.
We included two studies with a total of 40 participants in the review. Exercise-based CR consisted of aerobic or resistance training or both three times per week for six to eight weeks. Exercise intensity was 50% of oxygen consumption (VO2) reserve, or ranged from 60% to 80% of heart rate reserve. Two serious adverse events were observed in one trial, in which participants did not complete the study due to infections. Furthermore, a total of four participants in each group required visits to the emergency department, although these participants did complete the study. Summary scores from the 36-item Short Form Health Survey (SF-36) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were measured as quality of life. One trial reported that the KCCQ summary score improved by 14.4 points in the exercise group compared with 0.5 points in the usual care group. The other trial reported that the SF-36 total score improved by 29.2 points in the exercise group compared with 16.3 points in the usual care group. A large difference in quality of life was observed between groups at the end of follow-up (standardised mean difference 0.88, 95% CI -0.12 to 1.88; 37 participants; 2 studies; very low-quality of evidence). However, there was no evidence for the effectiveness of exercise-based CR due to the young age of the participants, high risk of performance bias, very small sample size, and wide confidence intervals, which resulted in very low-quality evidence. Furthermore, we were not able to determine the effect of exercise-based CR on mortality, rehospitalisation, heart transplantation, and cost, as these outcomes were not reported. The evidence is currently inadequate to assess the safety and efficacy of exercise-based CR for people with implantable VADs compared with usual care. The amount of RCT evidence was very limited and of very low quality. In addition, the training duration was very short term, that is from six to eight weeks. Further high-quality and well-reported RCTs of exercise-based CR for people with implantable VADs are needed. Such trials need to collect data on events (mortality and rehospitalisation), patient-related outcomes (including quality of life), and cost-effectiveness.
Four randomised controlled studies met the inclusion criteria for this review, involving a total of 302 participants lasting from 29 days to 13 months; 14 studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis. One study only enrolled adult males, the remaining studies included both males and females aged 12 years and over. Risk of bias in the studies was moderate. Random sequence generation and allocation concealment was only described in the more recent study; the remaining three studies were judged to have an unclear risk of bias. All four studies documented double-blinding to the intervention, but there is some uncertainty with regards to participant blinding in one study. Some outcome data were missing from all four studies. There were no differences in either the number of respiratory exacerbations or the number of participants with an exacerbation between replacement therapy or placebo groups at any time point. Meta-analysis of most respiratory function tests showed no difference between treatment and placebo groups, but the smallest study (n = 16) reported forced vital capacity (litres) increased more in the placebo group at up to 24 hours. A further study reported a significant improvement in forced expiratory volume at one second (litres) at 30 days after participants had received their first dose of favouring the gene therapy agent, but this finding was not confirmed when combined with at second study in the meta-analysis. The more recent study (n = 140) demonstrated a small improvement in forced vital capacity (per cent predicted) at two and three months and again at 11 and 12 months for participants receiving CFTR gene replacement therapy compared to those receiving placebo. The same study reported a significant difference in the relative change in forced expiratory volume at one second (per cent predicted) at two months, three months and 12 months. One small study reported significant concerns with "influenza-like" symptoms in participants treated with CFTR gene replacement therapy; this was not reported on repeated use of the same agent in a larger recent study. There was no other evidence of positive impact on outcomes, in particular improved quality of life or reduced treatment burden. Two studies measured ion transport in the lower airways; one (n = 16) demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). The second study (n = 140) also reported significant changes toward normal values (P = 0.032); however, aggregate data were not available for analysis. In the most recent study, there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. One study of liposome-based CFTR gene transfer therapy demonstrated some improvements in respiratory function in people with CF, but this limited evidence of efficacy does not support this treatment as a routine therapy at present. There was no evidence of efficacy for viral-mediated gene delivery. Future studies need to investigate clinically important outcome measures.
Five studies met the review entry criteria (5537 adults). Study populations entered the studies having previously been treated with inhaled steroids and had moderate or mild airway obstruction (mean FEV1 predicted between 65% and 84% at baseline). Most of the studies assessed treatment over a period of six months. The studies were at a low risk of selection and performance/detection bias, although we could not determine whether missing data had an impact on the results. Availablility of outcome data was satisfactory. Primary outcomes The odds ratio for exacerbations requiring oral steroids was lower with fluticasone/salmeterol but did not reach statistical significance (OR 0.89, 95% confidence interval (CI) 0.74 to 1.07, four studies, N = 4949). With an assumed risk with budesonide/formoterol of 106/1000 participants requiring oral steroids, treatment with fluticasone/salmeterol would lead to between 25 fewer and seven more people per 1000 experiencing a course of oral steroids. Although the odds of hospital admission was higher with fluticasone/salmeterol, this did not reach statistical significance (OR 1.29, 95% CI 0.68 to 2.47, four studies, 4879 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between three fewer and nine more people per 1000 would be hospitalised on fluticasone/salmeterol. The odds of a serious adverse event related to asthma was higher with fluticasone/salmeterol but did not differ significantly between treatments (OR 1.47, 95% CI 0.75 to 2.86, three studies, 4054 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between two fewer and 13 more people per 1000 would experience a serious adverse event on fluticasone/salmeterol. Secondary outcomes Lung function outcomes, symptoms, rescue medication, composite of exacerbations leading to either emergency department visit or hospital admission, withdrawals and adverse events did not differ statistically between treatments. Assessment of quality of life was limited to two studies, both of which gave results that did not reach statistical significance. One study reported one death out of 1000 participants on fluticasone/salmeterol and no deaths in a similar number of participants treated with budesonide/formoterol. No deaths were reported in the other studies. Statistical imprecision in the effect estimates for exacerbations and serious adverse events do not enable us to conclude that either therapy is superior. The uncertainty around the effect estimates justify further trials to provide more definitive conclusions; the overall quality of evidence based on GRADE recommendations for the three primary outcomes and withdrawals due to serious adverse events was moderate. We rated the quality of evidence for mortality to be low. Results for lung function outcomes showed that the drugs were sufficiently similar that further research is unlikely to change the effects. No trials were identified in the under-12s and research in this population is a high priority. Evaluation of quality of life is a priority for future research.
Thirty-nine studies examined the effect of printed educational materials for physicians, audit and feedback, educational meetings, educational outreach visits, financial and healthcare system changes, physician reminders, patient-based interventions and multi-faceted interventions. These interventions addressed the overuse of antibiotics for viral infections, the choice of antibiotic for bacterial infections such as streptococcal pharyngitis and urinary tract infection, and the duration of use of antibiotics for conditions such as acute otitis media. Use of printed educational materials or audit and feedback alone resulted in no or only small changes in prescribing. The exception was a study documenting a sustained reduction in macrolide use in Finland following the publication of a warning against their use for group A streptococcal infections. Interactive educational meetings appeared to be more effective than didactic lectures. Educational outreach visits and physician reminders produced mixed results. Patient-based interventions, particularly the use of delayed prescriptions for infections for which antibiotics were not immediately indicated effectively reduced antibiotic use by patients and did not result in excess morbidity. Multi-faceted interventions combining physician, patient and public education in a variety of venues and formats were the most successful in reducing antibiotic prescribing for inappropriate indications. Only one of four studies demonstrated a sustained reduction in the incidence of antibiotic-resistant bacteria associated with the intervention. The effectiveness of an intervention on antibiotic prescribing depends to a large degree on the particular prescribing behaviour and the barriers to change in the particular community. No single intervention can be recommended for all behaviours in any setting. Multi-faceted interventions where educational interventions occur on many levels may be successfully applied to communities after addressing local barriers to change. These were the only interventions with effect sizes of sufficient magnitude to potentially reduce the incidence of antibiotic-resistant bacteria. Future research should focus on which elements of these interventions are the most effective. In addition, patient-based interventions and physician reminders show promise and innovative methods such as these deserve further study.
We identified 27 studies (1549 participants) that were eligible for inclusion. These studies provided no data relating to aldosterone antagonists in addition to ACEi or ARB (or both) on patient-level outcomes including major cardiovascular events and mortality and progression to end-stage kidney disease (ESKD) requiring dialysis or transplantation. Compared with ACEi or ARB (or both), non-selective aldosterone antagonists (spironolactone) combined with ACEi or ARB (or both) significantly reduced 24-hour protein excretion (11 studies, 596 participants): SMD -0.61, 95% CI -1.08 to -0.13). There was a significant reduction in both systolic and diastolic blood pressure (BP) at the end of treatment with additional non-selective aldosterone antagonist therapy (systolic BP (10 studies, 556 participants): MD -3.44 mm Hg, 95% CI -5.05 to -1.83) (diastolic BP (9 studies, 520 participants): MD -1.73 mm Hg, 95% CI -2.83 to -0.62). However, we found that aldosterone antagonist treatment had imprecise effects at the end of treatment on GFR (9 studies, 528 participants; MD -2.55 mL/min/1.73 m², 95% CI -5.67 to 0.51), doubled the risk of hyperkalaemia (11 studies, 632 patients): RR 2.00, 95% CI 1.25 to 3.20; number needed to treat for an additional harmful outcome (NNTH): 7.2, 95% CI 3.4 to ∞) and increased the risk of gynaecomastia compared to ACEi or ARB (or both) (4 studies, 281 patients): RR 5.14, 95% CI 1.14 to 23.23; NNTH: 14.1, 95% CI 8.7 to 37.3). Most studies enrolled few patients (range 12 to 268) and were powered to observe differences in surrogate end points rather than patient-focused outcomes. Nine studies had a cross-over design and the majority of studies did not adequately report study methods to assess methods and study quality. Aldosterone antagonists reduced proteinuria and blood pressure in adults who had mild to moderate CKD and were treated with ACEi or ARB (or both), but increase hyperkalaemia and gynaecomastia. Whether adding aldosterone antagonists to ACEi or ARB (or both) reduced the risk of major cardiovascular events or ESKD in this population is unknown.
Individual participant data were available for 480 out of a total of 517 participants (93%), from two out of three included trials. For remission outcomes, a HR of less than one indicated an advantage for phenytoin; and for first seizure and treatment failure outcomes, a HR of less than one indicated an advantage for oxcarbazepine. The results for time to treatment failure for any reason related to treatment showed a potential advantage of oxcarbazepine over phenytoin, but this was not statistically significant (pooled HR adjusted for epilepsy type: 0.78 95% CI 0.53 to 1.14, 476 participants, two trials, moderate-quality evidence). Our analysis showed that treatment failure due to adverse events occurred later on with oxcarbazepine than phenytoin (pooled HR for all participants: 0.22 (95% CI 0.10 to 0.51, 480 participants, two trials, high-quality evidence). Our analysis of time to treatment failure due to lack of efficacy showed no clear difference between the drugs (pooled HR for all participants: 1.17 (95% CI 0.31 to 4.35), 480 participants, two trials, moderate-quality evidence). We found no clear or statistically significant differences between drugs for any of the secondary outcomes of the review: time to first seizure post-randomisation (pooled HR adjusted for epilepsy type: 0.97 95% CI 0.75 to 1.26, 468 participants, two trials, moderate-quality evidence); time to 12-month remission (pooled HR adjusted for epilepsy type 1.04 95% CI 0.77 to 1.41, 468 participants, two trials, moderate-quality evidence) and time to six-month remission (pooled HR adjusted for epilepsy type: 1.06 95% CI 0.82 to 1.36, 468 participants, two trials, moderate-quality evidence). The most common adverse events reported in more than 10% of participants on either drug were somnolence (28% of total participants, with similar rates for both drugs), headache (15% of total participants, with similar rates for both drugs), dizziness (14.5% of total participants, reported by slightly more participants on phenytoin (18%) than oxcarbazepine (11%)) and gum hyperplasia (reported by substantially more participants on phenytoin (18%) than oxcarbazepine (2%)). The results of this review are applicable mainly to individuals with focal onset seizures; 70% of included individuals experienced seizures of this type at baseline. The two studies included in IPD meta-analysis were generally of good methodological quality but the design of the studies may have biased the results for the secondary outcomes (time to first seizure post-randomisation, time to six-month and 12-month remission) as seizure recurrence data were not collected following treatment failure or withdrawal from the study. In addition, misclassification of epilepsy type may have impacted on results, particularly for individuals with generalised onset seizures. High-quality evidence provided by this review indicates that treatment failure due to adverse events occurs significantly later with oxcarbazepine than phenytoin. For individuals with focal onset seizures, moderate-quality evidence suggests that oxcarbazepine may be superior to phenytoin in terms of treatment failure for any reason, seizure recurrence and seizure remission. Therefore, oxcarbazepine may be a preferable alternative treatment than phenytoin, particularly for individuals with focal onset seizures. The evidence in this review which relates to individuals with generalised onset seizures is of low quality and does not inform current treatment policy. We recommend that future trials should be designed to the highest quality possible with regards to choice of population, classification of seizure type, duration of follow-up (including continued follow-up after failure or withdrawal of randomised treatment), choice of outcomes and analysis, and presentation of results.
No trials comparing hydroxyurea with placebo or standard care were found. However, we included one randomised controlled trial (n = 61) comparing 20 mg/kg/day with 10 mg/kg/day of hydroxyurea for 24 weeks. Both haemoglobin and foetal haemoglobin levels were lower at 24 weeks in the 20 mg group compared with the 10 mg group, mean difference -2.39 (95% confidence interval - 2.8 to -1.98) and mean difference -1.5 (95% confidence interval -1.83 to -1.17), respectively. Major adverse effects were significantly more common in the 20 mg group, for neutropenia risk ratio 9.93 (95% confidence interval 1.34 to 73.97) and for thrombocytopenia risk ratio 3.68 (95% confidence interval 1.13 to 12.07). No difference was reported for minor adverse effects (gastrointestinal disturbances and raised liver enzymes). The effect of hydroxyurea on transfusion frequency was not reported. The overall quality for the outcomes reported was graded as very low mainly because the outcomes were derived from only one small study with an unclear method of allocation concealment. There is no evidence from randomised controlled trials to show whether hydroxyurea has any effect compared with controls on the need for blood transfusion. Administration of 10 mg/kg/day compared to 20 mg/kg/day of hydroxyurea resulted in higher haemoglobin levels and seems safer with fewer adverse effects. It has not been reported whether hydroxyurea is capable of reducing the need for blood transfusion. Large well-designed randomised controlled trials with sufficient duration of follow up are recommended.
While five studies addressed the interventions of interest, we did not include them in the review because the investigators of the studies did not report any information specific to people with cystic fibrosis. Our attempts to obtain this information have not yet been successful. We will include any provided data in future updates of the review. The lack of currently available evidence makes it impossible to draw conclusions about the comparative efficacy and safety of the various immunosuppressive drugs among people with cystic fibrosis after lung transplantation. A 2013 Cochrane Review comparing tacrolimus with cyclosporine in all lung transplant recipients (not restricted to those with cystic fibrosis) reported no significant difference in mortality and risk of acute rejection. However, tacrolimus use was associated with lower risk of broncholitis obliterans syndrome and arterial hypertension and higher risk of diabetes mellitus. It should be noted that this wider review contained only a small number of included studies (n = 3) with a high risk of bias. Additional randomised studies are required to provide evidence for the benefit and safety of the use of immunosuppressive therapy among people with cystic fibrosis after lung transplantation.
Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis decreased all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-quality evidence). Subgroup analyses revealed decrease in mortality in preterm infants, infants with confirmed sepsis, and infants with gram-negative sepsis (low-quality evidence, four studies). Pentoxifylline decreased length of hospital stay (MD -7.59 days, 95% CI -11.65 to -3.52; 2 studies, 148 participants, low-quality evidence). Pentoxifylline did not change the risk of development of NEC, chronic lung disease, severe intraventricular haemorrhage, retinopathy of prematurity, or periventricular leukomalacia in neonates with sepsis (one to two studies, very low-quality evidence). Pentoxifylline therapy compared to pentoxifylline and immunoglobulin M-enriched intravenous immunoglobulin or immunoglobulin M-enriched intravenous immunoglobulin alone did not change mortality or development of NEC in neonates with sepsis (one study, very low-quality evidence). We noted no adverse effects due to pentoxifylline. We identified no trials evaluating pentoxifylline treatment for NEC. Low-quality evidence from six small studies suggests that pentoxifylline therapy as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. We encourage researchers to undertake large, well-designed multicentre trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.
Twelve studies met the inclusion criteria recruiting 350 participants. Trial reporting was poor and trial quality was deemed inadequate to generalise findings. There was variation in the type of active and sham acupuncture, the outcomes measured and time-points presented. The points used in the sham arm of some studies are used for the treatment of asthma according to traditional Chinese medicine. Two studies used individualised treatment strategies and one study used a combination strategy of formula acupuncture with the addition of individualised points. No statistically significant or clinically relevant effects were found for acupuncture compared to sham acupuncture. Data from two small studies were pooled for lung function (post-treatment FEV1): Standardised Mean Difference 0.12, 95% confidence interval -0.31 to 0.55). There is not enough evidence to make recommendations about the value of acupuncture in asthma treatment. Further research needs to consider the complexities and different types of acupuncture.
Nine RCTs with a total of 320 participants were included. Four SSRIs were evaluated: fluoxetine (three studies), fluvoxamine (two studies), fenfluramine (two studies) and citalopram (two studies). Five studies included only children and four studies included only adults. Varying inclusion criteria were used with regard to diagnostic criteria and intelligence quotient of participants. Eighteen different outcome measures were reported. Although more than one study reported data for Clinical Global Impression (CGI) and obsessive-compulsive behaviour (OCB), different tool types or components of these outcomes were used in each study. As such, data were unsuitable for meta-analysis, except for one outcome (proportion improvement). One large, high-quality study in children showed no evidence of positive effect of citalopram. Three small studies in adults showed positive outcomes for CGI and OCB; one study showed improvements in aggression, and another in anxiety. There is no evidence of effect of SSRIs in children and emerging evidence of harm. There is limited evidence of the effectiveness of SSRIs in adults from small studies in which risk of bias is unclear.
A total of three studies including 242 participants met the inclusion criteria for this review. One study reported the diagnostic performance of CRP for two threshold levels (> 200 mg/L and > 279 mg/L) without stating the day on which the CRP was measured. One study reported the diagnostic performance of procalcitonin on day 1 (1 day after admission) using a threshold level of 0.5 ng/mL. One study reported the diagnostic performance of CRP on day 3 (3 days after admission) using a threshold level of 140 mg/L and LDH on day 5 (5 days after admission) using a threshold level of 290 U/L. The sensitivities and specificities varied: the point estimate of the sensitivities ranged from 0.72 to 0.88, while the point estimate of the specificities ranged from 0.75 to 1.00 for the different index tests on different days of hospital admission. However, the confidence intervals were wide: confidence intervals of sensitivities ranged from 0.51 to 0.97, while those of specificities ranged from 0.18 to 1.00 for the different tests on different days of hospital admission. Overall, none of the tests assessed in this review were sufficiently accurate to suggest that they could be useful in clinical practice. The paucity of data and methodological deficiencies in the studies meant that it was not possible to arrive at any conclusions regarding the diagnostic test accuracy of the index test because of the uncertainty of the results. Further well-designed diagnostic test accuracy studies with prespecified index test thresholds of CRP, procalcitonin, LDH; appropriate follow-up (for at least two weeks to ensure that the person does not have pancreatic necrosis, as early scans may not indicate pancreatic necrosis); and clearly defined reference standards (of surgical or radiological confirmation of pancreatic necrosis) are important to reliably determine the diagnostic accuracy of CRP, procalcitonin, and LDH.
Six trials (1078 women) were identified for inclusion in this updated review. All six trials provided data on OS (1071 women) and PFS (1027 women). Data on resection rates and pathological response were only available for five trials (908 to 940 women) and data on recurrence were only available for four trials (737 women). Both OS (HR 0.77, 95% confidence interval (CI) 0.62 to 0.96, P = 0.02) and PFS (HR 0.75, 95% CI 0.61 to 0.93, P = 0.008) were significantly improved with neoadjuvant chemotherapy. The estimate for local recurrence was in favour of neoadjuvant chemotherapy (OR 0.67, 95% CI 0.45 to 0.99, P = 0.04), although heterogeneity was observed. The result was no longer significant when the random-effects model was used (OR 0.60, 95% CI 0.32 to 1.12, P = 0.11). Whilst not significant, estimates for distant recurrence (OR 0.72, 95% CI 0.45 to 1.14, P = 0.16) and rates of resection (OR 1.55, 95% CI 0.96 to 2.50, P = 0.07) tended to favour neoadjuvant chemotherapy, although heterogeneity was observed. Exploratory analyses of pathological response showed a significant decrease in adverse pathological findings with neoadjuvant chemotherapy (OR 0.54, 95% CI 0.40 to 0.73, P = < 0.0001 for lymph node status; OR 0.58, 95% CI 0.41 to 0.82, P = 0.002 for parametrial infiltration) which, despite substantial heterogeneity, was still significant when the random-effects model was used. There were also no differences in the effect of neoadjuvant chemotherapy on survival according to total cisplatin dose, chemotherapy cycle length or by cervical cancer stage. Both OS and PFS were improved with neoadjuvant chemotherapy. Although the effects were less clear on all other pre-specified outcomes, they all tended to be in favour of neoadjuvant chemotherapy. Whilst these results appear to indicate that neoadjuvant chemotherapy may offer a benefit over surgery alone for women with early-stage or locally-advanced cervical cancer, the evidence is based on only a small number of trials, and further research may be warranted.
We included two interrupted time-series studies conducted in the USA. One study was conducted in five large US transportation companies (N = 115,019) that carried passengers and/or cargo. Monthly injury rates were available from 1983 to 1999. In the study company, two interventions of interest were evaluated: mandatory random drug testing and mandatory random and for-cause alcohol testing programmes. The third study focused only on mandatory random drug testing and was conducted on federal injury data that covered all truck drivers of interstate carriers. We recalculated the results from raw data provided by the study authors. Following reanalysis, we found that in one study mandatory random and for-cause alcohol testing was associated with a significant decrease in the level of injuries immediately following the intervention (-1.25 injuries/100 person years, 95% CI -2.29 to -0.21) but did not significantly affect the existing long-term downward trend (-0.28 injuries/100 person years/year, 95% CI -0.78 to 0.21). Mandatory random drug testing was significantly associated with an immediate change in injury level following the intervention (1.26 injuries/100 person years, 95% CI 0.36 to 2.16) in one study, and in the second study there was no significant effect (-1.36/injuries/100 person years, 95% CI -1.69 to 0.41). In the long term, random drug testing was associated with a significant increase in the downward trend (-0.19 injuries/100 person years/year, 95% CI -0.30 to -0.07) in one study, the other study was also associated with a significant improvement in the long-term downward trend (-0.83 fatal accidents/100 million vehicle miles/year, 95% CI -1.08 to -0.58). There is insufficient evidence to advise for or against the use of drug and alcohol testing of occupational drivers for preventing injuries as a sole, effective, long-term solution in the context of workplace culture, peer interaction and other local factors. Cluster-randomised trials are needed to better address the effects of interventions for injury prevention in this occupational setting.
Three cohort studies were eligible for analysis, including 3380 patients ; 96 children were diagnosed with CSI. One study evaluated the accuracy of the Canadian C-spine Rule and the NEXUS criteria, and two studies evaluated the accuracy of the NEXUS criteria. The studies were of moderate quality. Due to the small number of included studies and the diverse outcomes of those studies, we could not describe a pooled estimate for the diagnostic test accuracy. The sensitivity of the NEXUS criteria of the individual studies was 0.57 (95% confidence interval (CI) 0.18 to 0.90), 0.98 (95% CI 0.91 to 1.00) and 1.00 (95% CI 0.88 to 1.00). The specificity of the NEXUS criteria was 0.35 (95% CI 0.25 to 0.45), 0.54 (95% CI 0.45 to 0.62) and 0.2 (95% CI 0.18 to 0.21). For the Canadian C-spine Rule the sensitivity was 0.86 (95% CI 0.42 to 1.00) and specificity was 0.15 (95% CI 0.08 to 0.23). Since the quantity of the data was small we were not able to investigate heterogeneity. There are currently few studies assessing the diagnostic test accuracy of the NEXUS criteria and CCR in children. At the moment, there is not enough evidence to determine the accuracy of the Canadian C-spine Rule to detect CSI in pediatric trauma patients following blunt trauma. The confidence interval of the sensitivity of the NEXUS criteria between the individual studies showed a wide range, with a lower limit varying from 0.18 to 0.91 with a total of four false negative test results, meaning that if physicians use the NEXUS criteria in children, there is a chance of missing CSI. Since missing CSI could have severe consequences with the risk of significant morbidity, we consider that the NEXUS criteria are at best a guide to clinical assessment, with current evidence not supporting strict or protocolized adoption of the tool into pediatric trauma care. Moreover, we have to keep in mind that the sensitivity differs among several studies, and individual confidence intervals of these studies show a wide range. Our main conclusion is therefore that additional well-designed studies with large sample sizes are required to better evaluate the accuracy of the NEXUS criteria or the Canadian C-spine Rule, or both, in order to determine whether they are appropriate triage tools for the clearance of the cervical spine in children following blunt trauma.
We included seven trials, with a total of 5390 women. The quality of studies was mixed. The CS rate was slightly lower in the active management group compared with the group that received routine care, but this difference did not reach statistical significance (RR 0.88, 95% CI 0.77 to 1.01). However, in one study there was a large number of post-randomisation exclusions. On excluding this study, CS rates in the active management group were statistically significantly lower than in the routine care group (RR 0.77 95% CI 0.63 to 0.94). More women in the active management group had labours lasting less than 12 hours, but there was wide variation in length of labour within and between trials. There were no differences between groups in use of analgesia, rates of assisted vaginal deliveries or maternal or neonatal complications. Only one trial examined maternal satisfaction; the majority of women (over 75%) in both groups were very satisfied with care. Active management is associated with small reductions in the CS rate, but it is highly prescriptive and interventional. It is possible that some components of the active management package are more effective than others. Further work is required to determine the acceptability of active management to women in labour.
We included 18 RCTs, which were reported in 17 publications (one publication reports on two trials) with 4342 participants (of which 212 were children) suffering from the common cold, both naturally occurring and experimentally induced. The interventions consisted of an antihistamine as monotherapy compared with placebo. In adults there was a short-term beneficial effect of antihistamines on severity of overall symptoms: on day one or two of treatment 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.60 to 0.92). However, there was no difference between antihistamines and placebo in the mid term (three to four days) to long term (six to 10 days). When evaluating individual symptoms such as nasal congestion, rhinorrhoea and sneezing, there was some beneficial effect of the sedating antihistamines compared to placebo (e.g. rhinorrhoea on day three: mean difference (MD) -0.23, 95% CI -0.39 to -0.06 on a four- or five-point severity scale; sneezing on day three: MD -0.35, 95% CI -0.49 to -0.20 on a four-point severity scale), but this effect is clinically non-significant. Adverse events such as sedation were more commonly reported with sedating antihistamines although the differences were not statistically significant. Only two trials included children and the results were conflicting. The majority of the trials had a low risk of bias although some lacked sufficient trial quality information. Antihistamines have a limited short-term (days one and two of treatment) beneficial effect on severity of overall symptoms but not in the mid to long term. There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing. Although side effects are more common with sedating antihistamines, the difference is not statistically significant. There is no evidence of effectiveness of antihistamines in children.
There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data. The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life. Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy – Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data. In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.
We included data from 12 randomised trials with data for more than 11,000 women. The trials were carried out in countries across the world, and in both high- and low-resource settings. In low-resource settings women receiving usual care may have received no additional postnatal care after early hospital discharge. The interventions and control conditions varied considerably across studies with trials focusing on three broad types of comparisons: schedules involving more versus fewer postnatal home visits (five studies), schedules involving different models of care (three studies), and home versus hospital clinic postnatal check-ups (four studies). In all but two of the included studies, postnatal care at home was delivered by healthcare professionals. The aim of all interventions was broadly to assess the wellbeing of mothers and babies, and to provide education and support, although some interventions had more specific aims such as to encourage breastfeeding, or to provide practical support. For most of our outcomes only one or two studies provided data, and overall results were inconsistent. There was no evidence that home visits were associated with improvements in maternal and neonatal mortality, and no consistent evidence that more postnatal visits at home were associated with improvements in maternal health. More intensive schedules of home visits did not appear to improve maternal psychological health and results from two studies suggested that women receiving more visits had higher mean depression scores. The reason for this finding was not clear. In a cluster randomised trial comparing usual care with individualised care by midwives extended up to three months after the birth, the proportions of women with Edinburgh postnatal depression scale (EPDS) scores ≥ 13 at four months was reduced in the individualised care group (RR 0.68, 95% CI 0.53 to 0.86). There was some evidence that postnatal care at home may reduce infant health service utilisation in the weeks following the birth, and that more home visits may encourage more women to exclusively breastfeed their babies. There was some evidence that home visits are associated with increased maternal satisfaction with postnatal care. Increasing the number of postnatal home visits may promote infant health and maternal satisfaction and more individualised care may improve outcomes for women, although overall findings in different studies were not consistent. The frequency, timing, duration and intensity of such postnatal care visits should be based upon local and individual needs. Further well designed RCTs evaluating this complex intervention will be required to formulate the optimal package.
Nine randomised clinical trials were included in this review. Eight trials compared alpha blockers versus placebo (five trials tested alfuzosin and two trials tested tamsulosin, one trial tested both alfuzosin and tamsulosin, one trial tested silodosin) and one trial compared an alpha blocker (doxazosin) versus no treatment. Trial without catheter was performed after treatment with the drug for one to three days in seven trials and for eight and 32 days in two other trials respectively. There was moderate quality evidence to suggest that the rate of successful trial without catheter favoured alpha blockers over placebo ( 366/608, 60.2%, of men using an alpha blocker were able to void spontaneously after catheter removal compared with 185/486, 38.1%, using placebo, risk ratio (RR) 1.55, 95% confidence interval (CI) 1.36 to 1.76). The incidence of recurrent acute urinary retention was lower in groups treated with an alpha blocker (RR 0.69, 95% CI 0.60 to 0.79). This evidence was of moderate quality and was statistically significant for alfuzosin, tamsulosin and silodosin, though not for doxazosin. Of the trials mentioning adverse effects (for example, postural hypotension, dizziness), there was not enough information to detect statistically significant differences between the groups (RR 1.19, 95% CI 0.75 to 1.89) and the evidence was of low quality. Overall, adverse effect rates were low for both placebo and alpha blockers and, for example, vasodilatation-related adverse effects did not often result in discontinuation. However, the data in this review are limited due to the large amount of unpublished data that was not available to us. There was some evidence to suggest that alpha blockers increase the success rates of trial without catheter, and the incidence of adverse effects was low. There was some evidence of a decreased incidence of acute urinary retention. The need for further surgery, cost effectiveness and recommended duration of alpha blocker treatment after successful trial without catheter remain unknown as these were not reported by any trial. There is a lack of internationally agreed outcome measures for what constitutes successful trial without catheter. This makes meta-analysis difficult. Large, well-designed controlled trials, which use the recommendations set out in the CONSORT statement, and include clinically important outcome measures, are required.
Three RCTs met our inclusion criteria. The studies enrolled 151 participants with CAP or immunosuppressed patients with pulmonary infiltrates. Overall, we found that non-invasive ventilation can reduce the risk of death in the ICU, odd ratio (OR) 0.28, 95% confidence interval (CI) 0.09 to 0.88; endotracheal intubation, OR 0.26, 95% CI 0.11 to 0.61; complications, OR 0.23, 95% CI 0.08 to 0.70; and shorten ICU length of stay, mean duration (MD) -3.28, 95% CI -5.41 to -1.61. Non-invasive ventilation and standard oxygen supplementation via a Venturi mask were similar when measuring mortality in hospital, OR 0.54, 95% CI 0.11 to 2.68; two-month survival, OR 1.67, 95% CI 0.53 to 5.28; duration of hospital stay, MD -1.00, 95% CI -2.05 to 0.05; and duration of mechanical ventilation, standard MD -0.26, 95% CI -0.66 to 0.14. Some outcomes and complications of non-invasive ventilation were varied according to different participant populations. We also found that some subgroups had a high level of heterogeneity when conducting pooled analyses. Non-invasive ventilation can reduce the risk of death in the ICU, endotracheal intubation, shorten ICU stay and length of intubation. Some outcomes and complications of non-invasive ventilation were varied according to different participant populations. Other than the oxygen therapy, we must mention the importance of standard treatment by physicians. The evidence is weak and we did not include participants with pulmonary tuberculosis and cystic fibrosis. More RCTs are required to answer these clinical questions. However, the review indicates that non-invasive ventilation may be more beneficial than standard oxygen supplementation via a Venturi mask for pneumonia.
We included five studies involving 1140 women with asymptomatic bacteriuria. We did not perform meta-analysis; each trial examined different antibiotic regimens and so we were not able to pool results. In a study comparing a single dose of fosfomycin trometamol 3 g with a five-day course of cefuroxime, there was no significant difference in persistent infection (risk ratio (RR) 1.36, 95% confidence interval (CI) 0.24 to 7.75), shift to other antibiotics (RR 0.08, 95% CI 0.00 to 1.45), or in allergy or pruritus (RR 2.73, 95% CI 0.11 to 65.24). A comparison of seven-day courses of 400 mg pivmecillinam versus 500 mg ampicillin, both given four times daily, showed no significant difference in persistent infection at two weeks or recurrent infection, but there was an increase in vomiting (RR 4.57, 95% CI 1.40 to 14.90) and women were more likely to stop treatment early with pivmecillinam (RR 8.82, 95% CI 1.16 to 66.95). When cephalexin 1 g versus Miraxid® (pivmecillinam 200 mg and pivampicillin 250 mg) were given twice-daily for three days, there was no significant difference in persistent or recurrent infection. A one- versus seven-day course of nitrofurantoin resulted in more persistent infection with the shorter course (RR 1.76, 95% CI 1.29 to 2.40), but no significant difference in symptomatic infection at two weeks, nausea, or preterm birth. Comparing cycloserine with sulphadimidine, no significant differences in symptomatic, persistent, or recurrent infections were noted. We cannot draw any definite conclusion on the most effective and safest antibiotic regimen for the initial treatment of asymptomatic bacteriuria in pregnancy. One study showed advantages with a longer course of nitrofurantoin, and another showed better tolerability with ampicillin compared with pivmecillinam; otherwise, there was no significant difference demonstrated between groups treated with different antibiotics. Given this lack of conclusive evidence, it may be useful for clinicians to consider factors such as cost, local availability and side effects in the selection of the best treatment option.
Twenty-two trials with a total of 3529 patients are included (14 in the original review and a further eight in this update). For the majority of comparisons, only one trial was available so results were rarely combined in meta-analyses. Individual trials were generally small and risk of bias was often unclear due to limitations in reporting. Three trials reported on drug versus placebo/control; results were consistently available for a maximum follow-up of only six months. At six months post intervention, a statistically significant reduction in reocclusion was found for high-dose acetylsalicylic acid (ASA) combined with dipyridamole (DIP) (OR 0.40, 95% CI 0.19 to 0.84), but not for low-dose ASA combined with DIP (OR 0.69, 95% CI 0.44 to 1.10; P = 0.12) nor in major amputations for lipo-ecraprost (OR 0.89, 95% CI 0.44 to 1.80). The remaining trials compared different drugs; results were more consistently available for a longer period of 12 months. At 12 months post intervention, no statistically significant difference in reocclusion/restenosis was detected for any of the following comparisons: high-dose ASA versus low-dose ASA (OR 0.98, 95% CI 0.64 to 1.48; P = 0.91), ASA/DIP versus vitamin K antagonists (VKA) (OR 0.65, 95% CI 0.40 to 1.06; P = 0.08), clopidogrel and aspirin versus low molecular weight heparin (LMWH) plus warfarin (OR 0.31, 95% CI 0.06 to 1.68; P = 0.18), suloctidil versus VKA: reocclusion (OR 0.59, 95% CI 0.20 to 1.76; P = 0.34), restenosis (OR 1.87, 95% CI 0.66 to 5.31; P = 0.24) and ticlopidine versus VKA (OR 0.71, 95% CI 0.37 to 1.36; P = 0.30). Treatment with cilostazol resulted in statistically significantly fewer reocclusions than ticlopidine (OR 0.32, 95% CI 0.13 to 0.76; P = 0.01). Compared with aspirin alone, LMWH plus aspirin significantly decreased occlusion/restenosis (by up to 85%) in patients with critical limb ischaemia (OR 0.15, 95% CI 0.06 to 0.42; P = 0.0003) but not in patients with intermittent claudication (OR 1.73, 95% CI 0.97 to 3.08; P = 0.06) and batroxobin plus aspirin reduced restenosis in diabetic patients (OR 0.28, 95% CI 0.13 to 0.60). Data on bleeding and other potential gastrointestinal side effects were not consistently reported, although there was some evidence that high-dose ASA increased gastrointestinal side effects compared with low-dose ASA, that clopidogrel and aspirin resulted in fewer major bleeding episodes compared with LMWH plus warfarin, and that abciximab resulted in more severe bleeding episodes. There is limited evidence suggesting that restenosis/reocclusion at six months following peripheral endovascular treatment is reduced by use of antiplatelet drugs compared with placebo/control, but associated information on bleeding and gastrointestinal side effects is lacking. There is also some evidence of variation in effect according to different drugs with cilostazol reducing reocclusion/restenosis at 12 months compared with ticlopidine and both LMWH and batroxobin combined with aspirin appearing beneficial compared with aspirin alone. However, available trials are generally small and of variable quality and side effects of drugs are not consistently addressed. Further good quality, large-scale RCTs, stratified by severity of disease, are required.
No new trials were found for inclusion in this update. We included 24 studies; 19 including 2531 randomised participants and five including 4354 cluster-randomised participants. There were no cases of meningococcal disease during follow-up in the trials, thus effectiveness regarding prevention of future disease cannot be directly assessed. Mortality that was reported in one study was not related to meningococcal disease or treatment. Ciprofloxacin (RR 0.04; 95% CI 0.01 to 0.12), rifampin (rifampicin) (RR 0.17; 95% CI 0.13 to 0.24), minocycline (RR 0.28; 95% CI 0.21 to 0.37) and penicillin (RR 0.47; 95% CI 0.24 to 0.94) proved effective at eradicating N meningitidis one week after treatment when compared with placebo. Rifampin (RR 0.20; 95% CI 0.14 to 0.29), ciprofloxacin (RR 0.03; 95% CI 0.00 to 0.42) and penicillin (RR 0.63; 95% CI 0.51 to 0.79) still proved effective at one to two weeks. Rifampin was effective compared to placebo up to four weeks after treatment but resistant isolates were seen following prophylactic treatment. No trials evaluated ceftriaxone against placebo but rifampin was less effective than ceftriaxone after one to two weeks of follow-up (RR 5.93; 95% CI 1.22 to 28.68). Mild adverse events associated with treatment were observed. Using rifampin during an outbreak may lead to the circulation of resistant isolates. Use of ciprofloxacin, ceftriaxone or penicillin should be considered. All four agents were effective for up to two weeks follow-up, though more trials comparing the effectiveness of these agents for eradicating N. meningitidis would provide important insights.
One study (4155 women at less than 20 weeks' gestation) met the inclusion criteria. The intervention group (2058 women) received infection screening and treatment for bacterial vaginosis, trichomonas vaginalis and candidiasis; the control group (2097 women) also received screening, but the results of the screening program were not revealed and women received routine antenatal care. The rate of preterm birth before 37 weeks' gestation was significantly lower in the intervention group (3% versus 5% in the control group) with a risk ratio (RR) of 0.55 (95% confidence interval (CI) 0.41 to 0.75; the evidence for this outcome was graded as of moderate quality). The incidence of preterm birth for infants with a weight equal to or below 2500 g (low birthweight) and infants with a weight equal to or below 1500 g (very low birthweight) were significantly lower in the intervention group than in the control group (RR 0.48, 95% CI 0.34 to 0.66 and RR 0.34; 95% CI 0.15 to 0.75, respectively; both graded as moderate quality evidence). Based on a subset of costs for preterm births of < 1900 g, the authors reported that for each of those preterm births averted, EUR 60,262 would be saved. There is evidence from one trial that infection screening and treatment programs for pregnant women before 20 weeks' gestation reduce preterm birth and preterm low birthweight. Infection screening and treatment programs are associated with cost savings when used for the prevention of preterm birth. Future trials should evaluate the effects of different types of infection screening programs.
We found no randomised controlled trials for inclusion in this review. As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a fetal neuroprotective role for creatine when administered to the mother during pregnancy, no trials assessing creatine in pregnant women for fetal neuroprotection have been published to date. If creatine is established as safe for the mother and her fetus, research efforts should first be directed towards randomised trials comparing creatine with either no intervention (ideally using a placebo), or with alternative agents aimed at providing fetal neuroprotection (including magnesium sulphate for the very preterm infant). If appropriate, these trials should then be followed by studies comparing different creatine regimens (dosage and duration of exposure). Such trials should be high quality and adequately powered to evaluate maternal and infant short and longer-term outcomes (including neurodevelopmental disabilities such as cerebral palsy), and should consider utilisation/costs of health care.
Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials follow up was performed at 14 to 35 days after stroke. In all studies neurological outcome was assessed but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analysing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI) 1.79 to 3.94). One placebo-controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI -8.9 to 10.52). No deaths or major adverse events were reported during the follow-up period. There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomised controlled trials are needed to test its efficacy.
We identified 11 trials (800 participants) and two ongoing studies. Style and duration of yoga differed between trials. Half of the participants recruited to the studies were at high risk of CVD. Most of studies were at risk of performance bias, with inadequate details reported in many of them to judge the risk of selection bias. No study reported cardiovascular mortality, all-cause mortality or non-fatal events, and most studies were small and short-term. There was substantial heterogeneity between studies making it impossible to combine studies statistically for systolic blood pressure and total cholesterol. Yoga was found to produce reductions in diastolic blood pressure (mean difference (MD) -2.90 mmHg, 95% confidence interval (CI) -4.52 to -1.28), which was stable on sensitivity analysis, triglycerides (MD -0.27 mmol/l, 95% CI -0.44 to -0.11) and high-density lipoprotein (HDL) cholesterol (MD 0.08 mmol/l, 95% CI 0.02 to 0.14). However, the contributing studies were small, short-term and at unclear or high risk of bias. There was no clear evidence of a difference between groups for low-density lipoprotein (LDL) cholesterol (MD -0.09 mmol/l, 95% CI -0.48 to 0.30), although there was moderate statistical heterogeneity. Adverse events, occurrence of type 2 diabetes and costs were not reported in any of the included studies. Quality of life was measured in three trials but the results were inconclusive. The limited evidence comes from small, short-term, low-quality studies. There is some evidence that yoga has favourable effects on diastolic blood pressure, HDL cholesterol and triglycerides, and uncertain effects on LDL cholesterol. These results should be considered as exploratory and interpreted with caution.
We included 18 studies, although we were only able to extract participant data from 14 studies that included a total of 511 participants; 419 participants were managed by intralesional treatment and 92 underwent a wide resection. We were not able to extract participant data from four studies, including 270 participants, and so we included them as a narrative summary only. The evidence was at high risk of performance, detection and reporting bias. Meta-analysis of data from 238 participants across seven studies demonstrated little or no difference in recurrence-free survival after intralesional treatment versus wide resection for central LGCS in the long bones (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.92 to 1.04; very low-certainty evidence). MSTS scores were probably better after intralesional surgery (mean score 93%) versus resection (mean score 78%) with a mean difference of 12.69 (95% CI 2.82 to 22.55; P value < 0.001; 3 studies; 72 participants; low-certainty evidence). Major complications across six studies (203 participants) were lower in cases treated by intralesional treatment (5/125 cases) compared to those treated by wide resection (18/78 cases), with RR 0.23 (95% CI 0.10 to 0.55; low-certainty evidence). In four people (0.5% of total participants) a high-grade (grade 2 or dedifferentiated) tumour was found after a local recurrence. Two participants were treated with second surgery with no evidence of disease at their final follow-up and two participants (0.26% of total participants) died due to disease. Kaplan-Meier analysis of data from 115 individual participants across four studies demonstrated 96% recurrence-free survival after a maximum follow-up of 300 months after resection versus 94% recurrence-free survival after a maximum follow-up of 251 months after intralesional treatment (P value = 0.58; very low-certainty evidence). Local recurrence or metastases were not reported after 41 months in either treatment group. Only evidence of low- and very low-certainty was available for this review according to the GRADE system. Included studies were all retrospective in nature and at high risk of selection and attrition bias. Therefore, we could not determine whether wide resection is superior to intralesional treatment in terms of event-free survival and recurrence rates. However, functional outcome and complication rates are probably better after intralesional surgery compared to wide resection, although this is low-certainty evidence, considering the large effect size. Nevertheless, recurrence-free survival was excellent in both groups and a prospective RCT comparing intralesional treatment versus wide resection may be challenging for both practical and ethical reasons. Future research could instead focus on less invasive treatment strategies for these tumours by identifying predictors that help to stratify participants for surgical intervention or close observation.
In this update we identified 14 additional trials resulting in the inclusion of 18 small trials in 813 patients. Eleven trials used TENS, four interferential current stimulation, one both TENS and interferential current stimulation, and two pulsed electrostimulation. The methodological quality and the quality of reporting was poor and a high degree of heterogeneity among the trials (I2 = 80%) was revealed. The funnel plot for pain was asymmetrical (P < 0.001). The predicted SMD of pain intensity in trials as large as the largest trial was -0.07 (95% CI -0.46 to 0.32), corresponding to a difference in pain scores between electrostimulation and control of 0.2 cm on a 10 cm visual analogue scale. There was little evidence that SMDs differed on the type of electrostimulation (P = 0.94). The relative risk of being withdrawn or dropping out due to adverse events was 0.97 (95% CI 0.2 to 6.0). In this update, we could not confirm that transcutaneous electrostimulation is effective for pain relief. The current systematic review is inconclusive, hampered by the inclusion of only small trials of questionable quality. Appropriately designed trials of adequate power are warranted.
We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow-up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows. Non-pharmacological interventions (3 studies, 124 participants) All-cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low-quality evidence). Pharmacological interventions (11 trials, 375 participants) All-cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) −1.15, 95% CI −2.56 to 0.27; 2 studies, 25 participants; low-quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence). There is limited available evidence to determine the effects of non-pharmacological and pharmacological interventions in treating acute high altitude illness. Low-quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field. High-quality research in this field is needed, since most trials were poorly conducted and reported.
A total of 54 randomised controlled trials (n = 5122) were included. No strong evidence was found to indicate that fluvoxamine was either superior or inferior to other antidepressants regarding response, remission and tolerability. However, differing side effect profiles were evident, especially with regard to gastrointestinal side effects of fluvoxamine when compared to other antidepressants. For example, fluvoxamine was generally associated with a higher incidence of vomiting/nausea (versus imipramine, OR 2.23, CI 1.59 to 3.14; versus clomipramine, OR 2.13, CI 1.06 to 4.27; versus amitriptyline, OR 2.86, CI 1.31 to 2.63). We found no strong evidence that fluvoxamine was either superior or inferior to any other antidepressants in terms of efficacy and tolerability in the acute phase treatment of depression. However, differing side effect profiles were evident. Based on these findings, we conclude that clinicians should focus on practical or clinically relevant considerations, including these differences in side effect profiles.
We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively). Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.
A total of 26 trials involving 2997 people were included, with a follow-up ranging from 3 to 24 months. Studies were conducted in 11 different countries. The mean age of the included participants was 68 years, 68% were male and the mean forced expiratory volume in one second (FEV1)% predicted value was 44.3% (range 28% to 66%). Participants were treated in all types of healthcare settings: primary (n = 8), secondary (n = 12), tertiary care (n = 1), and in both primary and secondary care (n = 5). Overall, the studies were of high to moderate methodological quality. Compared with controls, IDM showed a statistically and clinically significant improvement in disease-specific QoL on all domains of the Chronic Respiratory Questionnaire after 12 months: dyspnea (mean difference (MD) 1.02; 95% confidence interval (CI) 0.67 to 1.36); fatigue (MD 0.82; 95% CI 0.46 to 1.17); emotional (MD 0.61; 95% CI 0.26 to 0.95) and mastery (MD 0.75; 95% CI 0.38 to 1.12). The St. George's Respiratory Questionnaire (SGRQ) for QoL reached the clinically relevant difference of four units only for the impact domain (MD -4.04; 95% CI -5.96 to -2.11, P < 0.0001). IDM showed a significantly improved disease-specific QoL on the activity domain of the SGRQ: MD -2.70 (95% CI -4.84 to -0.55, P = 0.01). There was no significant difference on the symptom domain of the SGRQ: MD -2.39 (95% CI -5.31 to 0.53, P = 0.11). According to the GRADE approach, quality of evidence on the SGRQ was scored as high quality, and on the CRQ as moderate quality evidence. Participants treated with an IDM program had a clinically relevant improvement in six-minute walking distance of 43.86 meters compared with controls after 12 months (95% CI 21.83 to 65.89; P < 0.001, moderate quality). There was a reduction in the number of participants with one or more hospital admissions over three to 12 months from 27 per 100 participants in the control group to 20 (95% CI 15 to 27) per 100 participants in the IDM group (OR 0.68; 95% CI 0.47 to 0.99, P = 0.04; number needed to treat = 15). Hospitalization days were significantly lower in the IDM group compared with controls after 12 months (MD -3.78 days; 95% CI -5.90 to -1.67, P < 0.001). Admissions and hospital days were graded as high quality evidence. No adverse effects were reported in the intervention group. No difference between groups was found on mortality (OR 0.96; 95%CI 0.52 to 1.74). There was insufficient evidence to refute or confirm the long term effectiveness of IDM. In these COPD participants, IDM not only improved disease-specific QoL and exercise capacity, but also reduced hospital admissions and hospital days per person.
Analyses were based on 491 patients from six trials, representing 90% of all patients randomised in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The power of this meta-analysis is clearly limited. The overall hazard ratio for survival of 0.75 (95% CI 0.60 to 0.96, P = 0.019) suggests a 25% relative reduction in the risk of death for chemotherapy compared to that on control. Cox regression suggests that small imbalances in patient characteristics do not bias the results in favour of chemotherapy. However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy is less clear. This IPD meta-analysis provides the best evidence currently available on the role of adjuvant chemotherapy for invasive bladder cancer. However, at present there is insufficient evidence on which to reliably base treatment decisions. These results highlight the urgent need for further research into the use of adjuvant chemotherapy. The results of appropriately sized randomised trials, such as the ongoing EORTC-30994 trial are needed before any definitive conclusions can be drawn.
We included one trial of 526 women with a twin pregnancy of two viable twins, with no known morphological abnormality, in this review. The trial compared women receiving fetal growth and Doppler ultrasounds at 25, 30 and 35 weeks' gestation to fetal growth alone. We judged the included study to be at low risk of bias however the risk of performance and detection bias were unclear. The primary outcome was the perinatal mortality rate (after randomisation), for which there was no evidence of a clear difference between the fetal growth + Doppler and the fetal growth alone groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.32 to 2.41, low-quality evidence) with similar rates in both groups (seven events in the Dopper + fetal growth group and eight in the fetal growth alone group). No clear differences were seen between the two regimens for the other outcomes in this review: stillbirth (RR 0.67, 95% CI 0.11 to 3.99), neonatal death (RR 1.01, 95% CI 0.29 to 3.46, low-quality evidence), gestational age at birth (weeks) (mean difference 0.10, 95% CI -0.39 to 0.59, moderate-quality evidence), infant requiring ventilation (RR 0.86, 95% CI 0.59 to 1.25), admission to special care or intensive care units (RR 0.96, 95% CI 0.88 to 1.05), caesarean section (any) (RR 1.00, 95% CI 0.81 to 1.23, high-quality evidence), elective caesarean section (RR 1.06, 95% CI 0.77 to 1.47), emergency caesarean section (RR 0.93, 95% CI 0.66 to 1.32), induction of labour (RR 1.10, 95% CI 0.80 to 1.50, moderate-quality evidence) or antenatal hospital admission (RR 0.96, 95% CI 0.80 to 1.15, high-quality evidence). The number of preterm births before 28 weeks' gestation was not reported in the included study. For the mortality-related outcomes, event numbers were small. The included study did not report the majority of our maternal and infant secondary outcomes. Infant outcomes not reported included fetal acidosis, Apgar scores less than 7 at five minutes and preterm birth before 37 and 34 weeks' gestation. The maternal outcomes; length of antenatal hospital stay, timely diagnosis of significant complications, rate of preterm, prelabour rupture of membranes and women's level of satisfaction with their care were not reported. The study did not classify twin pregnancies according to their chorionicity. An awareness of the chorionicity may have improved applicability of this data set. We downgraded outcomes assessed using GRADE for imprecision of effect estimates. This review is based on one small study which was underpowered for detection of rare outcomes such as perinatal mortality, stillbirth and neonatal death. There is insufficient evidence from randomised controlled trials to inform best practice for fetal ultrasound surveillance regimens when caring for women with a twin pregnancy. More studies are needed to evaluate the effects of currently used ultrasound surveillance regimens in twin pregnancies. Future research could report on the important maternal and infant outcomes as listed in this review.
There were minimal differences identified between multi-session psychosocial interventions and standard educational interventions for both injection and sexual risk behaviour. Although it should be noted there were large pre-post changes for both groups suggesting both were effective in reducing risk behaviours. In addition, there was some evidence of benefit for multi-session psychosocial interventions when compared with minimal controls. Subgroup analyses suggest that people in formal treatment are likely to respond to multi-session psychosocial interventions. It also appears single-gender groups may be associated with greater benefit. There is limited support for the widespread use of formal multi-session psychosocial interventions for reducing injection and sexual risk behaviour. Brief standard education interventions appear to be a more cost-effective option. Further research is required to assess if there are particular groups of drug users more likely to respond to such interventions.
We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD. Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence). Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence). Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence). Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence). One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence). No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD.
The 18 included trials tested seven comparisons in a total of 2615 mainly female and older participants with a total of 2619 fractures. All trials had methodological flaws that may affect the validity of their results. Three trials of 355 participants comparing a fixed nail plate (Jewett or McLaughlin) with the sliding hip screw (SHS) found an increased risk of fixation failure for fixed nail plates. The two trials of 433 participants comparing the Resistance Augmented Bateaux (RAB) plate with the SHS had contrasting results, notably in terms of operative complications, fixation failure and anatomical restoration. One trial of 100 participants comparing the Pugh nail and the SHS found no significant difference between implants. Three trials of 458 participants compared the Medoff plate with the SHS. There was a trend to higher blood losses and longer operation times for the Medoff plate along with a trend to a lower risk of fixation failure with the Medoff plate for unstable trochanteric fractures. Two trials of 676 participants compared the Medoff plate with three different screw-plate systems. There were no statistically significant differences in outcome for trochanteric fractures. For subtrochanteric fractures, there was a lower fixation failure rate for the Medoff plate but no evidence for differences in longer-term outcomes. Four trials of 396 participants comparing the Gotfried percutaneous compression plate (PCCP) with a SHS found a trend to lower blood loss and transfusion requirements for the PCCP but no other confirmed differences in outcomes between implants. Three of the trials reported intra-operative problems with the PCCP, some of which precluded its use. Three trials of 200 participants comparing external fixation with a SHS found less operative trauma for the external fixation. Final outcome appeared similar. The markedly increased fixation failure rate of fixed nail plates compared with the SHS is a major consideration and thus the SHS appears preferable. There was insufficient evidence from other comparisons of extramedullary implants or on the use of external fixators to draw definite conclusions.
There were 12 randomised controlled trials with 14 comparisons included in the review, with a total sample of 500 participants across all comparisons. Included studies were typically very small (n = 20 to 72), all except one were assessed as being at high risk of bias, and all reported short-term outcomes. For the purposes of pooling, studies were divided into seven clinically homogenous comparisons according to the patient population (acute or chronic LBP) and the nature of the control intervention. Most of the comparisons (five out of seven) included only one study, one comparison had two studies, and one comparison included seven studies. The meta-analyses provided low-quality evidence that MET provided no additional benefit when added to other therapies on the outcomes of chronic pain and disability in the short-term (weighted mean difference (WMD) for pain 0.00, 95% CI -2.97 to 2.98 on a 100-point scale; standardised mean difference (SMD) for disability -0.18, 95% CI -0.43 to 0.08, 7 studies, 232 participants). There was low-quality evidence that MET produced no clinically relevant differences in pain compared to sham MET (mean difference (MD) 14.20, 95% CI -10.14 to 38.54, 1 study, 20 participants). For the comparison of MET to other conservative therapies for acute non-specific LBP, there was very low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -10.72, 95% CI -32.57 to 11.13, 2 studies, 88 participants) and functional status (MD 0.87, 95% CI -6.31 to 8.05, 1 study, 60 participants). For the comparison of MET to other conservative therapies for chronic non-specific LBP, there was low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -9.70, 95% CI -20.20 to 0.80, 1 study, 30 participants) and functional status (MD -4.10, 95% CI -9.53 to 1.33, 1 study, 30 participants). There was low-quality evidence of no clinically relevant difference for the addition of MET to other interventions for acute non-specific LBP for the outcome of pain (MD -3, 95% CI -11.37 to 5.37, 1 study, 40 participants) and low-quality evidence of an effect in favour of MET for functional status (MD -17.6, 95% CI -27.05 to -8.15, 1 study, 40 participants). For chronic non-specific LBP, there was low-quality evidence of an effect in favour of MET for the addition of MET to other interventions for the outcomes of pain (MD -34.1, 95% CI -38.43 to -29.77, 1 study, 30 participants) and functional status (MD -22, 95% CI -27.41 to -16.59, 1 study, 30 participants). Lastly, there was low-quality evidence of no difference for the addition of MET to another manual intervention compared to the same intervention with other conservative therapies for the outcomes of pain (MD 5.20, 95% CI -3.03 to 13.43, 1 study, 20 participants) and functional status (MD 6.0, 95% CI -0.49 to 12.49, 1 study, 20 participants). No study reported on our other primary outcome of general well-being. Seven studies reported that no adverse events were observed, whereas the other five studies did not report any information on adverse events. The quality of research related to testing the effectiveness of MET is poor. Studies are generally small and at high risk of bias due to methodological deficiencies. Studies conducted to date generally provide low-quality evidence that MET is not effective for patients with LBP. There is not sufficient evidence to reliably determine whether MET is likely to be effective in practice. Large, methodologically-sound studies are necessary to investigate this question.
The studies analysed were in two groups: those comparing anticholinergics with placebo and those comparing the combination of anticholinergics with short acting ß2 -agonists versus short acting ß2 -agonists alone. The former group had 13 studies involving 205 participants included in this review, and the latter 9 studies involving 440 patients. Generally methodological quality was poorly reported, and there were some reservations with respect to the quality of the studies. Despite the limited number of studies that could be combined, anticholinergic agents in comparison with placebo resulted in more favourable symptom scores particularly in respect of daytime dyspnoea (WMD -0.09 (95%CI -0.14, -0.04, 3 studies, 59 patients). Daily peak flow measurements also showed a statistically significant improvement for the anticholinergic (e.g. morning PEF: WMD =14.38 litres/min (95%CI 7.69, 21.08; 3 studies, 59 patients). However the clinical significance is small and in terms of peak flow measurements equates to approximately a 7% increase over placebo. The more clinically relevant comparison of a combination of anticholinergic plus short acting ß2 -agonist versus short acting ß2 -agonist alone gave no evidence in respect of symptom scores or peak flow rates of any significant differences between the two regimes. Again there are reservations with respect to the quality of the information from which these conclusions are drawn. An update search in August 2004 did not identify any new studies. Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there may be a sub-group of patients who derive some benefit and a trial of treatment in individual patients may still be justified. The role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma and any future trials might draw on the messages derived from this review.
We identified 13 eligible cohort studies including 2837 participants with a hearing test after treatment with a platinum analogue for different types of childhood cancers. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. Participants were treated with cisplatin, carboplatin or both, in varying doses. The reported prevalence of hearing loss varied considerably between 0% and 90.1%; none of the studies provided data on tinnitus. Three studies reported a prevalence of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the prevalence of hearing loss still varied widely between 1.7% and 90.1%. All studies were very heterogeneous with regard to, for example, definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-tumour treatment, other ototoxic drugs and length of follow-up. Therefore, pooling of results was not possible. Only two studies included a control group of people who had not received platinum treatment. In one study, the prevalence of hearing loss was 67.1% (95% confidence interval (CI) 59.3% to 74.1%) in platinum-treated participants, while in the control participants it was 7.4% (95% CI 6.2% to 8.8%). However, hearing loss was detected by screening in survivors treated with platinum analogues and by clinical presentation in control participants. It is uncertain what the effect of this difference in follow-up/diagnostic testing was. In the other study, the prevalence of hearing loss was 20.1% (95% CI 17.4% to 23.2%) in platinum-treated participants and 0.4% (95% CI 0.12% to 1.6%) in control participants. As neither study was a randomized controlled trial or controlled clinical trial, the calculation of a risk ratio was not feasible as it is very likely that both groups differed more than only the platinum treatment. Only two studies evaluated possible risk factors using multivariable analysis. One study identified a significantly higher risk of hearing loss in people treated with cisplatin 400 mg/m2 plus carboplatin 1700 mg/m2 as compared to treatment with cisplatin 400 mg/m2 or less, irrespective of the definition of hearing loss. They also identified a significantly higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (using a surrogate marker) as compared to people not treated with them, for three out of four definitions of hearing loss. The other study reported that age at treatment (odds ratio less than 1 for each single-unit increase) and single maximum cisplatin dose (odds ratio greater than 1 for each single-unit increase) were significant predictors for hearing loss, while gender was not. This systematic review shows that children treated with platinum analogues are at risk for developing hearing loss, but the exact prevalence and risk factors remain unclear. There were no data available for tinnitus. Based on the currently available evidence we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up protocols including frequency of testing. Counselling regarding the prevention of noise pollution can be considered, such as the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medication. Before definitive conclusions on the prevalence and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. Accurate and transparent reporting of findings will make it possible for readers to appraise the results of these studies critically.
We included two studies, involving a total of 94 participants, in the review. Continuous veno-venous hemofiltration versus no intervention We included one study in which 64 participants with severe acute pancreatitis were randomized to undergo CVVH (32 participants) or no intervention (32 participants). There were no deaths in either group (very low-quality evidence). Adverse events, length of stay in the intensive care unit (ICU), length of hospital stay, total hospital cost, and quality of life were not reported in the study. One type of continuous veno-venous hemofiltration versus a different type of continuous veno-venous hemofiltration We included one study in which 30 participants with severe acute pancreatitis were randomized to undergo high-volume CVVH (15 participants) or standard CVVH (15 participants). High-volume CVVH may lead to little or no difference in in-hospital mortality rates (20.0% in the high-volume CVVH group versus 33.3% in the standard CVVH group; risk ratio (RR) 0.60, 95% confidence interval (CI) 0.17 to 2.07; 30 participants; 1 study; low-quality evidence). We are uncertain whether high-volume hemofiltration reduces rates of adverse events (13.3% in both groups; RR 1.00, 95% CI 0.16 to 6.20; 30 participants; 1 study; very low-quality evidence). Length of ICU stay, length of hospital stay, total hospital cost, and quality of life were not reported in the study. The quality of the current evidence is very low or low. For both comparisons addressed in this review, data are sparse. It is unclear whether CVVH has any effect on mortality or complications in patients with severe acute pancreatitis. It is also unclear whether high-volume CVVH is superior, equivalent or inferior to standard CVVH in patients with severe acute pancreatitis.
Five studies involving 3,070 individuals met the criteria for inclusion in the meta-analysis. All interventions for promoting use of booster seats among 4 to 8 year olds demonstrated a positive effect (relative risk (RR) 1.43; 95% confidence intervals (CI) 1.05 to 1.96). Incentives combined with education demonstrated a beneficial effect (RR 1.32, 95% CI 1.12 to 1.55; n = 1,898). Distribution of free booster seats combined with education also had a beneficial effect (RR 2.34; 95% CI 1.50 to 3.63; n = 380) as did education-only interventions (RR 1.32; 95% CI 1.16 to 1.49; n = 563). One study which evaluated enforcement of booster seat law met the criteria for inclusion in the meta-analysis, but demonstrated no marked beneficial effect. Available evidence suggests that interventions to increase use of booster seats among children age four to eight years are effective. Combining incentives (booster seat discount coupons or gift certificates) or distribution of free booster seats with education demonstrated marked beneficial outcomes for acquisition and use of booster seats for four to eight year olds. There is some evidence of beneficial effect of legislation on acquisition and use of booster seats but this was mainly from uncontrolled before-and-after studies, which did not meet the criteria for inclusion in the meta-analysis.
Sixteen trials were identified, including 558 participants. Eleven trials were of cross-over design. Eleven trials included only people with faecal incontinence related to liquid stool (either chronic diarrhoea, following ileoanal pouch or rectal surgery, or due to use of a weight-reducing drug). Two trials were amongst people with weak anal sphincters, one in participants with faecal impaction and bypass leakage, and one in geriatric patients. In one trial there was no specific cause for faecal incontinence. Seven trials tested anti-diarrhoeal drugs to reduce faecal incontinence and other bowel symptoms (loperamide, diphenoxylate plus atropine, and codeine). Six trials tested drugs that enhance anal sphincter function (phenylepinephrine gel and sodium valproate). Two trials evaluated osmotic laxatives (lactulose) for the treatment of faecal incontinence associated with constipation in geriatric patients. One trial assessed the use of zinc-aluminium ointment for faecal incontinence. No studies comparing drugs with other treatment modalities were identified. There was limited evidence that antidiarrhoeal drugs and drugs that enhance anal sphincter tone may reduce faecal incontinence in patients with liquid stools. Loperamide was associated with more adverse effects (such as constipation, abdominal pain, diarrhoea, headache and nausea) than placebo. However, the dose may be titrated to the patient's symptoms to minimise side effects while achieving continence. The drugs acting on the sphincter sometimes resulted in local dermatitis, abdominal pain or nausea. Laxative use in geriatric patients reduced faecal soiling and the need for help from nurses. Zinc-aluminium ointment was associated with improved quality of life, with no reported adverse effects. However, the observed improvement in quality of life was seen in the placebo group as well as the treatment group. It should be noted that all the included trials in this review had small sample sizes and short duration of follow-up. 'Risk of bias' assessment was unclear for most of the domains as there was insufficient information. There were no data suitable for meta-analysis. The small number of trials identified for this review assessed several different drugs in a variety of patient populations. The focus of most of the included trials was on the treatment of diarrhoea, rather than faecal incontinence. There is little evidence to guide clinicians in the selection of drug therapies for faecal incontinence. Larger, well-designed controlled trials, which use the recommendations and principles set out in the CONSORT statement, and include clinically important outcome measures, are required.
We included six studies: five small, cross-over studies with 174 participants, and one parallel group study with 170 participants. Participants were treated with levetiracetam (2000 mg to 3000 mg daily) or placebo for between four and 14 weeks. Each study included participants with a different type of neuropathic pain; central pain due to multiple sclerosis, pain following spinal cord injury, painful polyneuropathy, central post-stroke pain, postherpetic neuralgia, and post-mastectomy pain. None of the included studies provided first or second tier evidence. The evidence was very low quality, downgraded because of the small size of the treatment arms, and because studies reported results using last observation carried forward (LOCF) imputation for withdrawals or using only participants who completed the study according to the protocol, where there were greater than 10% withdrawals. There were insufficient data for a pooled efficacy analysis in particular neuropathic pain conditions, but individual studies did not show any analgesic effect of levetiracetam compared with placebo. We did pool results for any outcome considered substantial pain relief (≥ 50% pain intensity reduction or ‘complete’ or ‘good’ responses on the verbal rating scale) for four studies with dichotomous data; response rates across different types of neuropathic pain was similar with levetiracetam (10%) and placebo (12%), with no statistical difference (risk ratio 0.9; 95% confidence interval (CI) 0.4 to1.7). We pooled data across different conditions for adverse events and withdrawals. Based on very limited data, significantly more participants experienced an adverse event with levetiracetam than with placebo (number needed to treat for an additional harmful event (NNH) 8.0 (95% CI 4.6 to 32)). There were significantly more adverse event withdrawals with levetiracetam (NNH 9.7 (6.7 to 18)). The amount of evidence for levetiracetam in neuropathic pain conditions was very small and potentially biased because of the methods of analysis used in the studies. There was no indication that levetiracetam was effective in reducing neuropathic pain, but it was associated with an increase in participants who experienced adverse events and who withdrew due to adverse events.
We included in the review seven studies with a total of 852 participants. The methodological quality of the included studies was generally ranked as showing low risk of bias in most domains, with the exception of one study, which did not mask participants. We were able to include data from 838 participants in the meta-analysis. We found no statistically significant differences between participants receiving air and those given saline in any of the outcomes evaluated: inability to locate the epidural space (three trials, 619 participants) (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.33 to 2.31, low-quality evidence); accidental intravascular catheter placement (two trials, 223 participants) (RR 0.90, 95% CI 0.33 to 2.45, low-quality evidence); accidental subarachnoid catheter placement (four trials, 682 participants) (RR 2.95, 95% CI 0.12 to 71.90, low-quality evidence); combined spinal epidural failure (two trials, 400 participants) (RR 0.98, 95% CI 0.44 to 2.18, low-quality evidence); unblocked segments (five studies, 423 participants) (RR 1.66, 95% CI 0.72 to 3.85); and pain measured by VAS (two studies, 395 participants) (mean difference (MD) -0.09, 95% CI -0.37 to 0.18). With regard to adverse effects, we found no statistically significant differences between participants receiving air and those given saline in the occurrence of paraesthesias (three trials, 572 participants) (RR 0.89, 95% CI 0.69 to 1.15); difficulty in advancing the catheter (two trials, 227 participants) (RR 0.91, 95% CI 0.32 to 2.56); catheter replacement (two trials, 501 participants) (RR 0.69, 95% CI 0.26 to 1.83); and postdural puncture headache (one trial, 110 participants) (RR 0.83, 95% CI 0.12 to 5.71). Low-quality evidence shows that results do not differ between air and saline in terms of the loss of resistance technique for identification of the epidural space and reduction of complications. Applicability might be compromised, as most of the results described in this review were obtained from parturient patients. This review underlines the need to conduct well-designed trials in this field.
Eleven studies with 818 infants met the criteria for inclusion in this review. Four trials with 329 infants assessed the use of an H2 receptor antagonist for prevention of upper gastrointestinal bleeding in high-risk newborn infants. Meta-analysis of these four trials identified a reduction in any upper gastrointestinal bleeding when using an H2 receptor antagonist (typical risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.58; typical risk difference (RD) −0.20, 95% CI −0.28 to −0.11; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 9). The quality of evidence was moderate. A single trial with 53 infants assessing prevention of upper gastrointestinal bleeding reported no difference in mortality in infants assigned H2 receptor antagonist versus no treatment; however the quality of evidence was very low. Seven trials with 489 infants assessed an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) for treatment of gastrointestinal bleeding in newborn infants. Meta-analysis of two trials (131 infants) showed no difference in mortality from use of a H2 receptor antagonist compared to no treatment. The quality of evidence was low. Meta-analysis of two trials (104 infants) showed a reduction in duration of upper gastrointestinal bleeding from use of an inhibitor of gastric acid compared to no treatment (mean difference −1.06 days, 95% CI −1.28 to −0.84). The quality of evidence was very low. Meta-analysis of six trials (451 infants) showed a reduction in continued upper gastrointestinal bleeding from use of any inhibitor of gastric acid compared to no treatment (typical RR 0.36, 95% CI 0.26 to 0.49; typical RD −0.26, 95% CI −0.33, −0.19; NNTB 4, 95% CI 3 to 5). The quality of evidence was low. There were no significant subgroup differences in duration of upper gastrointestinal bleeding or of continued upper gastrointestinal bleeding according to type of inhibitor of gastric acid. A single trial (38 infants) reported no difference in anaemia requiring blood transfusion from use of a H2 receptor antagonist compared to no treatment. Although no serious adverse events were reported from the use of a H2 receptor antagonist or proton pump inhibitor, some neonatal morbidities — including necrotising enterocolitis, ventilator-associated pneumonia, duration of ventilation and respiratory support, and duration of hospital stay — were not reported. Long-term outcome was not reported. There is moderate-quality evidence that use of an H2 receptor antagonist reduces the risk of gastrointestinal bleeding in newborn infants at high risk of gastrointestinal bleeding. There is low-quality evidence that use of an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) reduces the duration of upper gastrointestinal bleeding and the incidence of continued gastric bleeding in newborn infants with gastrointestinal bleeding. However, there is no evidence that use of an inhibitor of gastric acid in newborn infants affects mortality or the need for blood transfusion. As no study reported the incidence of necrotising enterocolitis, ventilator- or hospital-associated pneumonia, sepsis, or long-term outcome, the safety of inhibitors of gastric acid secretion is unclear.
The database search identified 3,253 references. Sixteen trials fulfilled the inclusion criteria. Psychological interventions show a small beneficial effect on depression compared to usual care (range of SMD of depression scores across trials and time frames: -0.81;0.12). Based on one trial per outcome, no beneficial effects on mortality rates, cardiac events, cardiovascular hospitalizations and QoL were found, except for the psychosocial dimension of QoL. Furthermore, no differences on treatment outcomes were found between the varying psychological approaches. The review provides evidence of a small beneficial effect of pharmacological interventions with selective serotonin reuptake inhibitors (SSRIs) compared to placebo on depression outcomes (pooled SMD of short term depression change scores: -0.24 [-0.38,-0.09]; pooled OR of short term depression remission: 1.80 [1.18,2.74]). Based on one to three trials per outcome, no beneficial effects regarding mortality, cardiac events and QoL were found. Hospitalization rates (pooled OR of three trials: 0.58 [0.39,0.85] and emergency room visits (OR of one trial: 0.58 [0.34,1.00]) were reduced in trials of pharmacological interventions compared to placebo. No evidence of a superior effect of Paroxetine (SSRI) versus Nortriptyline (TCA) regarding depression outcomes was found in one trial. Psychological interventions and pharmacological interventions with SSRIs may have a small yet clinically meaningful effect on depression outcomes in CAD patients. No beneficial effects on the reduction of mortality rates and cardiac events were found. Overall, however, the evidence is sparse due to the low number of high quality trials per outcome and the heterogeneity of examined populations and interventions.
One trial assessing smoking cessation advice for 94 infertile women smokers fulfilled the criteria for this review, but the trial did not report on the review's primary outcome of live birth or any other fertility-related outcomes. This trial of women attending a fertility clinic showed that smoking cessation advice tailored to a woman's "stage-of-change" (readiness to stop smoking) did not show significant evidence of a difference in stage (including smoking cessation rates) compared with standard clinical advice. No RCTs were located that assessed the effects of preconception advice on the chance of a live birth or other fertility outcomes in people who perceived that they may be infertile and were investigating the possibility of medical treatment to address subfertility. Given the lack of RCTs evaluating the effectiveness of preconception lifestyle advice for people in the afore-mentioned population, this review cannot provide guidance for clinical practice in this area. However, it does highlight the need for further research into this important subject.
This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies. Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourse Live birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) −0.00, 95% CI −0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing. Letrozole compared to laparoscopic ovarian drilling There is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI −0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence). Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.
Two trials (involving 59 mothers) that examined the use of domperidone in a total of 59 mother-infant pairs met the inclusion criteria. Meta-analysis of these trials showed a modest increase in expressed breastmilk (EBM) of 99.49 mL/day (95% confidence intervals -1.94 to 200.92; random-effects, T² 3511.62, I² 63%) in mothers given domperidone. Both trials gave the same dose of domperidone (10 mg three times per day) with a duration of seven days in the smaller trial and 14 days in the larger. Neither trial showed significant improvements in longer-term outcomes of breastfeeding in a preterm population and no adverse effects were reported. Two studies with a total of 59 mothers suggest modest improvements in short-term EBM volumes when a medication is used after insufficient EBM occurs in mothers following preterm delivery. In both studies, the medication was commenced ≧14 days post delivery and following insufficient EBM supply with other lactation supports. Currently, no studies support prophylactic use of a galactagogue medication at any gestation. Use of any galactagogue medication has only been examined at more than 14 days post delivery and after full lactation support has been given. Further trials should examine larger groups of preterm mothers and consider breastfeeding outcomes over a longer period.
We included 11 studies that looked at diagnostic accuracy of one or two index tests: four studies (277 suspected fractures) looked at CT, five studies (221 suspected fractures) looked at MRI and six studies (543 suspected fractures) looked at BS. Four of the studies made direct comparisons: two studies compared CT and MRI, one study compared CT and BS, and one study compared MRI and BS. Overall, the studies were of moderate to good quality, but relevant clinical information during evaluation of CT, MRI or BS was mostly unclear or unavailable. As few studies made direct comparisons between tests with the same participants, our results are based on data from indirect comparisons, which means that these results are more susceptible to bias due to confounding. Nonetheless, the direct comparisons showed similar patterns of differences in sensitivity and specificity as for the pooled indirect comparisons. Summary sensitivity and specificity of CT were 0.72 (95% confidence interval (CI) 0.36 to 0.92) and 0.99 (95% CI 0.71 to 1.00); for MRI, these were 0.88 (95% CI 0.64 to 0.97) and 1.00 (95% CI 0.38 to 1.00); for BS, these were 0.99 (95% CI 0.69 to 1.00) and 0.86 (95% CI 0.73 to 0.94). Indirect comparisons suggest that diagnostic accuracy of BS was significantly higher than CT and MRI; and CT and MRI have comparable diagnostic accuracy. The low prevalence of a true fracture among suspected fractures (median = 20%) means the lower specificity for BS is problematic. For example, in a cohort of 1000 patients, 112 will be over-treated when BS is used for diagnosis. If CT is used, only 8 will receive unnecessary treatment. In terms of missed fractures, BS will miss 2 fractures and CT will miss 56 fractures. Although quality of the included studies is moderate to good, findings are based on only 11 studies and the confidence intervals for the summary estimates are wide for all three tests. Well-designed direct comparison studies including CT, MRI and BS could give valuable additional information. Bone scintigraphy is statistically the best diagnostic modality to establish a definitive diagnosis in clinically suspected fractures when radiographs appear normal. However, physicians must keep in mind that BS is more invasive than the other modalities, with safety issues due to level of radiation exposure, as well as diagnostic delay of at least 72 hours. The number of overtreated patients is substantially lower with CT and MRI. Prior to performing comparative studies, there is a need to raise the initially detected prevalence of true fractures in order to reduce the effect of the relatively low specificity in daily practice. This can be achieved by improving clinical evaluation and initial radiographical assessment.
For this update we added 14 new included studies (3489 participants), and excluded four studies. We also identified 20 additional reports of completed or ongoing studies that have not been published in full. The earlier review included 47 studies. This update included 61 studies. Most compared topical NSAIDs in the form of a gel, spray, or cream with a similar topical placebo; 5311 participants were treated with a topical NSAID, 3470 with placebo, and 220 with an oral NSAID. This was a 63% increase in the number of included participants over the previous version of this review. We also identified a number of studies in clinical trial registries with unavailable results amounting to about 5900 participants for efficacy and 5300 for adverse events. Formulations of topical diclofenac, ibuprofen, ketoprofen, piroxicam, and indomethacin demonstrated significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebo (moderate or high quality data). Benzydamine did not. Three drug and formulation combinations had NNTs for clinical success below 4. For diclofenac, the Emulgel® formulation had the lowest NNT of 1.8 (95% CI 1.5 to 2.1) in two studies using at least 50% pain intensity reduction as the outcome. Diclofenac plasters other than Flector® also had a low NNT of 3.2 (2.6 to 4.2) based on good or excellent responses in some studies. Ketoprofen gel had an NNT of 2.5 (2.0 to 3.4), from five studies in the 1980s, some with less well defined outcomes. Ibuprofen gel had an NNT of 3.9 (2.7 to 6.7) from two studies with outcomes of marked improvement or complete remission. All other drug and formulation combinations had NNT values above 4, indicating lesser efficacy. There were insufficient data to compare reliably individual topical NSAIDs with each other or the same oral NSAID. Local skin reactions were generally mild and transient, and did not differ from placebo (high quality data). There were very few systemic adverse events (high quality data) or withdrawals due to adverse events (low quality data). Topical NSAIDs provided good levels of pain relief in acute conditions such as sprains, strains and overuse injuries, probably similar to that provided by oral NSAIDs. Gel formulations of diclofenac (as Emugel®), ibuprofen, and ketoprofen, and some diclofenac patches, provided the best effects. Adverse events were usually minimal. Since the last version of this review, the new included studies have provided additional information. In particular, information on topical diclofenac is greatly expanded. The present review supports the previous review in concluding that topical NSAIDs are effective in providing pain relief, and goes further to demonstrate that certain formulations, mainly gel formulations of diclofenac, ibuprofen, and ketoprofen, provide the best results. Large amounts of unpublished data have been identified, and this could influence results in updates of this review.
We found no randomised clinical trials comparing PAIR versus no or sham intervention. We identified only two randomised clinical trials, one comparing PAIR versus surgical treatment (n = 50 participants) and the other comparing PAIR (with or without albendazole) versus albendazole alone (n = 30 participants). Both trials were graded as 'adequate' for allocation concealment; however, generation of allocation sequence and blinding methods were 'unclear' in both. Compared to surgery, PAIR plus albendazole obtained similar cyst disappearance and mean cyst diameter with fewer adverse events (32% versus 84%, P < 0.001) and fewer days in hospital (mean + SD) ( 4.2 + 1.5 versus 12.7 + 6.5 days, P < 0.001). Compared to albendazole, PAIR with or without albendazole obtained significantly more (P < 0.01) cyst reduction and symptomatic relief. PAIR seems promising, but there is insufficient evidence to support or refute PAIR with or without benzimidazole coverage for treating patients with uncomplicated hepatic hydatid cyst. Further well-designed randomised clinical trials are necessary to address the topic.
We included four RCTs with 167 participants. Risk of bias of the included studies was high, as none of them reported method of randomization, allocation concealment or blinding. Only one trial mentioned our primary outcome of duration of anaesthesia. The mean difference in duration of anaesthesia with use of adrenaline with lidocaine was 3.20 hours (95% confidence interval (CI) 2.48 to 3.92 hours; one RCT, 20 participants; low-quality evidence). No trial reported adverse events such as ischaemia distal to the injection site, and no trial reported cost analysis. One trial mentioned the secondary outcome of duration of postoperative pain relief, but available data were insufficient for analysis of the findings. Two trials reported the secondary outcome of reduced bleeding during surgery. Bleeding during surgery was observed in nine out of 52 participants as compared with 25 out of 51 participants in the adrenaline with lidocaine and plain lidocaine groups, respectively. The risk ratio for bleeding in the adrenaline with lidocaine group was 0.35 (95% CI 0.19 to 0.65; two RCTs, 103 participants; low-quality evidence). From the limited data available, evidence is insufficient to recommend use or avoidance of adrenaline in digital nerve blocks. The evidence provided in this review indicates that addition of adrenaline to lidocaine may prolong the duration of anaesthesia and reduce the risk of bleeding during surgery, although the quality of the evidence is low. We have identified the need for researchers to conduct large trials that focus on other important outcomes such as adverse events, cost analysis and duration of postoperative pain relief.
Out of 173 articles screened, three studies were included. There were two comparisons: chlorhexidine dressing following alcohol cleansing versus polyurethane dressing following povidone-iodine cleansing (one study); and silver-alginate patch versus control (two studies). A total of 855 infants from level III neonatal intensive care units (NICUs) were evaluated, 705 of whom were from a single study. All studies were at high risk of bias for blinding of care personnel or unclear risk of bias for blinding of outcome assessors. There was moderate-quality evidence for all major outcomes. The single study comparing chlorhexidine dressing/alcohol cleansing against polyurethane dressing/povidone-iodine cleansing showed no significant difference in the risk of CRBSI (RR 1.18, 95% CI 0.53 to 2.65; RD 0.01, 95% CI −0.02 to 0.03; 655 infants, moderate-quality evidence) and sepsis without a source (RR 1.06, 95% CI 0.75 to 1.52; RD 0.01, 95% CI −0.04 to 0.06; 705 infants, moderate-quality evidence). There was a significant reduction in the risk of catheter colonisation favouring chlorhexidine dressing/alcohol cleansing group (RR 0.62, 95% CI 0.45 to 0.86; RD −0.09, 95% CI −0.15 to −0.03; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 33; 655 infants, moderate-quality evidence). However, infants in the chlorhexidine dressing/alcohol cleansing group were significantly more likely to develop contact dermatitis, with 19 infants in the chlorhexidine dressing/alcohol cleansing group having developed contact dermatitis compared to none in the polyurethane dressing/povidone-iodine cleansing group (RR 43.06, 95% CI 2.61 to 710.44; RD 0.06, 95% CI 0.03 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 17, 95% CI 13 to 33; 705 infants, moderate-quality evidence). The roles of chlorhexidine dressing in the outcomes reported were unclear, as the two assigned groups received different co-interventions in the form of different skin cleansing agents prior to catheter insertion and during each dressing change. In the other comparison, silver-alginate patch versus control, the data for CRBSI were analysed separately in two subgroups as the two included studies reported the outcome using different denominators: one using infants and another using catheters. There were no significant differences between infants who received silver-alginate patch against infants who received standard line dressing in CRBSI, whether expressed as the number of infants (RR 0.50, 95% CI 0.14 to 1.78; RD −0.12, 95% CI −0.33 to 0.09; 1 study, 50 participants, moderate-quality evidence) or as the number of catheters (RR 0.72, 95% CI 0.27 to 1.89; RD −0.05, 95% CI −0.20 to 0.10; 1 study, 118 participants, moderate-quality evidence). There was also no significant difference between the two groups in mortality (RR 0.55, 95% CI 0.15 to 2.05; RD −0.04, 95% CI −0.13 to 0.05; two studies, 150 infants, I² = 0%, moderate-quality evidence). No adverse skin reaction was recorded in either group. Based on moderate-quality evidence, chlorhexidine dressing/alcohol skin cleansing reduced catheter colonisation, but made no significant difference in major outcomes like sepsis and CRBSI compared to polyurethane dressing/povidone-iodine cleansing. Chlorhexidine dressing/alcohol cleansing posed a substantial risk of contact dermatitis in preterm infants, although it was unclear whether this was contributed mainly by the dressing material or the cleansing agent. While silver-alginate patch appeared safe, evidence is still insufficient for a recommendation in practice. Future research that evaluates antimicrobial dressing should ensure blinding of caregivers and outcome assessors and ensure that all participants receive the same co-interventions, such as the skin cleansing agent. Major outcomes like sepsis, CRBSI and mortality should be assessed in infants of different gestation and birth weight.
Three eligible studies were identified, all comparing the use of an FIS with a VLS. All studies were small, with only 131 participants in total across all trials. It was impossible for the intubators to be unaware of the device used, so all studies were at high risk of performance and detection bias for outcomes related to intubation. Because of substantial differences in design between the studies, we did not combine their results in meta-analyses. The results for all outcomes were inconclusive, with no differences noted between FIS and VLS. Two studies with experienced intubators reported first attempt success rates greater than 70% in both groups and less than 5% of participants requiring a change of intubation device. No evidence was found of any difference in difficulty or time taken between FIS and VLS intubation. No serious complications or airway trauma was reported, so we were unable to address these outcomes. Bleeding was uncommon, occurring in less than 5% of participants, and we found no evidence that it was more likely in the FIS group. One small study with a novice intubator reported no successful intubations using an FIS and compared with the use of an intubating SAD and stylet, as well as with a VLS. With only five participants in each group, no conclusions can be drawn from these additional comparisons. The evidence base is sparse, and the existing literature does not address the clinical questions of patient safety posed by this review. We are therefore unable to draw any conclusions on safety or effectiveness. More primary research is needed to investigate optimal intubation techniques in obese patients, and new studies should be powered to detect differences in complications and in success rates rather than process measures such as speed, which are of limited clinical importance.
We included four trials (4608 women), but only two studies contributed data to the review's analyses (n = 4472). The studies contributing data were assessed as of high risk of bias overall. One of these studies was cluster-randomised and conducted in a low-income country and the other study was carried out in a high-income country. All four included studies assessed blood loss in the third stage of labour. Birth attendants estimated blood loss in two trials. The third trial assessed the hematocrit level on the second day postpartum to determine the effect of the bleeding. The fourth study measured PPH ≥ 500 mL. Nipple stimulation versus no treatment One study (4385 women) compared the effect of suckling versus no treatment. Blood loss was not measured in 114 women (59 in control group and 55 in suckling group). After excluding twin pregnancies, stillbirths and neonatal deaths, the main analyses for this trial were performed on 4227 vaginal deliveries. In terms of maternal death or severe morbidity, one maternal death occurred in the suckling group due to retained placenta (risk ratio (RR) 3.03, 95% confidence interval (CI) 0.12 to 74.26; one study, participants = 4227; very low quality evidence); severe morbidity was not mentioned. Severe PPH (≥ 1000 mL) was not reported in this study. The incidence of PPH (≥ 500 mL) was similar in the suckling and no treatment groups (RR 0.95, 95% CI 0.77 to 1.16; one study, participants = 4227; moderate quality). There were no group differences between nipple stimulation and no treatment regarding blood loss in the third stage of labour (mean difference (MD) 2.00, 95% CI -7.39 to 11.39; one study, participants = 4227; low quality). The rates of retained placenta were similar (RR 1.01, 95% CI 0.14 to 7.16; one study, participants = 4227; very low quality evidence), as were perinatal deaths (RR 1.06, 95% CI 0.57 to 1.98; one study, participants = 4271; low quality), and maternal readmission to hospital (RR 1.01, 95% CI 0.14 to 7.16; one study, participants = 4227; very low quality). We downgraded the evidence for this comparison for risk of bias concerns in the one included trial (inappropriate analyses for cluster design) and for imprecision (wide CIs crossing the line of no difference and, for some outcomes, few events). Many maternal secondary outcomes (including side effects) were not reported. Similarly, most neonatal secondary outcomes were not reported. Nipple stimulation versus oxytocin Another study compared the effect of nipple stimulation (via a breast pump) with oxytocin. Eighty-seven women were recruited but only 85 women were analysed. Severe PPH ≥ 1000 mL and maternal death or severe morbidity were not reported. There was no clear effect of nipple stimulation on blood loss (MD 15.00, 95% CI -24.50 to 54.50; one study, participants = 85; low quality evidence), or on postnatal anaemia compared to the oxytocin group (MD -0.40, 95% CI -2.22 to 1.42; one study, participants = 85; low quality evidence). We downgraded evidence for this comparison due to risk of bias concerns in the one included trial (alternate allocation) and for imprecision (wide CIs crossing the line of no difference and small sample size). Many maternal secondary outcomes (including side effects) were not reported, and none of this review's neonatal secondary outcomes were reported. None of the included studies reported one of this review's primary outcomes: severe PPH ≥ 1000 mL. Only one study reported on maternal death or severe morbidity. There were limited secondary outcome data for maternal outcomes and very few secondary outcome data for neonatal outcomes. There was no clear differences between nipple stimulation (suckling) versus no treatment in relation to maternal death, the incidence of PPH (≥ 500 mL), blood loss in the third stage of labour, retained placenta, perinatal deaths or maternal readmission to hospital. Whilst these data are based on a single study with a reasonable sample size, the quality of these data are mostly low or very low. There is insufficient evidence to evaluate the effect of nipple stimulation for reducing postpartum haemorrhage during the third stage of labour and more evidence from high-quality studies is needed. Further high-quality studies should recruit adequate sample sizes, assess the impact of nipple stimulation compared to uterotonic agents such as syntometrine and oxytocin, and report on important outcomes such as those listed in this review.
Only one trial with an unclear risk of bias in the majority of domains was included in the study; the overall study quality was judged to be low. This factorial trial of 256 women compared three types of postal reminder strategies (in a total of 213 women) with usual care (no postal reminder, 43 women) and reported on the uptake of four possible types of glucose tests. The three strategies investigated were: reminders sent to both the woman and the physician; reminder sent to the woman only; and reminder sent to the physician only, all issued approximately three months after the woman had given birth. There was low-quality evidence that all three reminder interventions increased uptake of oral glucose tolerance tests compared with usual care (no reminder system): reminders to the woman and the physician (uptake 60% versus 14%): risk ratio 4.23 (95% confidence interval (CI) 1.85 to 9.71); 116 participants); reminder to the woman only (uptake 55% versus 14%): RR 3.87 (95% CI 1.68 to 8.93); 111 participants); reminder to the physician only (uptake 52% versus 14%): RR 3.61 (95% CI 1.50 to 8.71); 66 participants). This represented an increase in uptake from 14% in the no reminder group to 57% across the three reminder groups. There was also an increase in uptake of fasting glucose tests in the reminder group compared with the usual care group: reminders to the woman and the physician versus no reminder (uptake 63% versus 40%): RR 1.57 (95% CI 1.01 to 2.44); reminder to the woman only (uptake 71% versus 40%): RR 1.78 (95% CI 1.16 to 2.73); reminder to the physician only (uptake 68% versus 40%): RR 1.69 (95% CI 1.06 to 2.72). Uptake of random glucose and glycated haemoglobin A1c tests was low, and no statistically significant differences were seen between the reminder and no reminder groups for these tests. Uptake of any test was higher in each of the reminder groups compared with the no reminder group (RR 1.65 (95% CI 1.12 to 2.41); 1.73 (95% CI 1.18 to 2.52); and 1.55 (95% CI 1.01 to 2.38) in the respective reminder groups. The trial did not report this review's other primary outcomes (proportion of women diagnosed with type 2 diabetes or showing impaired glucose tolerance or impaired fasting glucose after giving birth; or health-related quality of life). Nor did it report any secondary review outcomes such as diabetes-associated morbidity, lifestyle changes, need for insulin, recurrence of GDM or women's and/or health professionals' views of the intervention. No adverse events of the intervention were reported. Subgroup interaction tests gave no indication that dual reminders (to both women and physicians) were more successful than single reminders to either women or physicians alone. It was also not clear if test uptakes between women in the reminder and no reminder groups differed by type of glucose test undertaken. Results from the only trial that fulfilled our inclusion criteria showed low-quality evidence for a marked increase in the uptake of testing for type 2 diabetes in women with previous GDM following the issue of postal reminders. The effects of other forms of reminder systems need to be assessed to see whether test uptake also increases when email and telephone reminders are deployed. We also need a better understanding of why some women fail to take opportunities to be screened postpartum. As the ultimate aim of increasing postpartum testing is to prevent the subsequent development of type 2 diabetes, it is important to determine whether increased test uptake rates also increase women's use of preventive strategies such as lifestyle modifications.
Six randomised, double-blind studies between 12 and 24 weeks' long met the inclusion criteria. Five studies contributed data to the meta-analysis, assigning 2781 people with stable asthma to the comparison of interest. The definition of stable asthma and inclusion criteria varied across studies, and Global Initiative for Asthma (GINA) criteria were not used. Risk of bias across studies was generally low, and most evidence was rated as moderate quality. Stopping LABA might increase the number of people having exacerbations and requiring oral corticosteroids (odds ratio (OR) 1.74, 95% confidence interval (CI) 0.83 to 3.65; participants = 1257; studies = 4), although the confidence intervals did not exclude the possibility that stopping LABA was beneficial; over 17 weeks, 19 people per 1000 who continued their LABA had an exacerbation, compared with 32 per 1000 when LABA were stopped (13 more per 1000, 95% CI 3 fewer to 46 more). People who stopped LABA had worse scores on the Asthma Control Questionnaire (mean difference (MD) 0.24, 95% CI 0.13 to 0.35; participants = 645; studies = 3) and on measures of asthma-related quality of life (standardised mean difference (SMD) 0.36, 95% CI 0.15 to 0.57; participants = 359; studies = 2) than those who continued LABA, but the effects were not clinically relevant. Too few events occurred for investigators to tell whether stopping LABA has a greater effect on serious adverse events compared with continuing LABA+ICS (OR 0.82, 95% CI 0.28 to 2.42; participants = 1342; studies = 5), and no study reported exacerbations requiring an emergency department visit or hospitalisation as a separate outcome. Stopping LABA may result in fewer adverse events of any kind compared with continuing, although the effect was not statistically significant (OR 0.83, 95% CI 0.66 to 1.05; participants = 1339; studies = 5), and stopping LABA made people more likely to withdraw from participation in research studies (OR 1.95, 95% CI 1.47 to 2.58; participants = 1352; studies = 5). This review suggests that stopping LABA in adults who have stable asthma while they are taking a combination of LABA and ICS inhalers may increase the likelihood of asthma exacerbations that require treatment with oral corticosteroids, but this is not certain. Stopping LABA may slightly reduce asthma control and quality of life, but evidence was insufficient to show whether this had an effect on important outcomes such as serious adverse events and exacerbations requiring hospital admission, and longer trials are warranted. Trialists should include patient-important outcomes such as asthma control and quality of life and should use validated measurement tools. Definitions of exacerbations should be provided.
We identified six trials, involving 479 subjects, comparing incision and drainage of perianal abscess alone versus incision and drainage with fistula treatment. Metaanalysis showed a significant reduction in recurrence, persistent abscess/fistula or repeat surgery in favour of fistula surgery at the time of abscess incision and drainage (RR=0.13, 95% Confidence Interval of RR = 0.07-0.24). Transient manometric reduction in anal sphincter pressures, without clinical incontinence, may occur after treatment of low fistulae with abscess drainage. Incontinence at one year following drainage with fistula surgery was not statistically significant (pooled RR 3.06, 95% Confidence Interval 0.7-13.45) with heterogeneity demonstrable between the trials (Chi2 =5.39,df=3, p=0.14, I2 =44.4%). The published evidence shows fistula surgery with abscess drainage significantly reduces recurrence or persistence of abscess/fistula, or the need for repeat surgery. There was no statistically significant evidence of incontinence following fistula surgery with abscess drainage. This intervention may be recommended in carefully selected patients.
This review included 12 multicentre RCTs randomly assigning 9547 participants with stable COPD. All the studies were industry-sponsored and had similar inclusion criteria with relatively good methodological quality. All but one study included in the meta-analysis were double-blind and scored low risk of bias. The study duration ranged from four weeks to 52 weeks. Participants were more often males, mainly Caucasians, mean age ranging from 61.7 to 65.6 years, and with a smoking history of 10 or more pack years. They had moderate to severe symptoms at randomisation; the mean post-bronchodilator forced expiratory volume in one second (FEV1) was between 46% and 57.6% of the predicted normal value, and the mean St George's Respiratory Questionnaire score (SGRQ) ranged from 45.1 to 50.4 when reported. There was no difference between aclidinium and placebo in all-cause mortality (low quality) and number of patients with exacerbations requiring a short course of oral steroids or antibiotics, or both (moderate quality). Aclidinium improved quality of life by lowering the SGRQ total score with a mean difference of -2.34 (95% CI -3.18 to -1.51; I2 = 48%, 7 trials, 4442 participants) when compared to placebo. More patients on aclidinium achieved a clinically meaningful improvement of at least four units decrease in SGRQ total score (OR 1.49; 95% CI 1.31 to 1.70; I2 = 34%; number needed to treat (NNT) = 10, 95% CI 8 to 15, high quality evidence) over 12 to 52 weeks than on placebo. Aclidinium also resulted in a significantly greater improvement in pre-dose FEV1 than placebo with a mean difference of 0.09 L (95% CI 0.08 to 0.10; I2 = 39%, 9 trials, 4963 participants). No trials assessed functional capacity. Aclidinium reduced the number of patients with exacerbations requiring hospitalisation by 4 to 20 fewer per 1000 over 4 to 52 weeks (OR 0.64; 95% CI 0.46 to 0.88; I2 = 0%, 10 trials, 5624 people; NNT = 77, 95% CI 51 to 233, high quality evidence) compared to placebo. There was no difference in non-fatal serious adverse events (moderate quality evidence) between aclidinium and placebo. Compared to tiotropium, aclidinium did not demonstrate significant differences for exacerbations requiring oral steroids or antibiotics, or both, exacerbation-related hospitalisations and non-fatal serious adverse events (very low quality evidence). Inadequate data prevented the comparison of aclidinium to formoterol or other LABAs. Aclidinium is associated with improved quality of life and reduced hospitalisations due to severe exacerbations in patients with moderate to severe stable COPD compared to placebo. Overall, aclidinium did not significantly reduce mortality, serious adverse events or exacerbations requiring oral steroids or antibiotics, or both. Currently, the available data are insufficient and of very low quality in comparisons of the efficacy of aclidinium versus tiotropium. The efficacy of aclidinium versus LABAs cannot be assessed due to inaccurate data. Thus additional trials are recommended to assess the efficacy and safety of aclidinium compared to other LAMAs or LABAs.
A total of 43 randomised controlled trials (4,364 participants) were included in this review. Very few trials provided data suitable for inclusion in a meta-analysis. Among the five trials that yielded data assessing the daily frequency of hot flushes suitable for pooling, no significant difference overall was noted in the incidence of hot flushes between participants taking Promensil (a red clover extract) and those given placebo (mean difference (MD) -0.93, 95% confidence interval (CI) -1.95 to 0.10, I2 = 31%). No evidence indicated a difference in percentage reduction in hot flushes in two trials between Promensil and placebo (MD 20.15, 95% CI -12.08 to 52.38, I2 = 82%). Four trials that were not combined in meta-analyses suggested that extracts with high (> 30 mg/d) levels of genistein consistently reduced the frequency of hot flushes. Individual results from the remaining trials were compared in broad subgroups such as dietary soy, soy extracts and other types of phytoestrogens that could not be combined. Some of these trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats when compared with placebo, but many trials were small and were determined to be at high risk of bias. A strong placebo effect was noted in most trials, with a reduction in frequency ranging from 1% to 59% with placebo. No indication suggested that discrepant results were due to the amount of isoflavone in the active treatment arm, the severity of vasomotor symptoms or trial quality factors. Also, no evidence indicated that these treatments caused oestrogenic stimulation of the endometrium or the vagina or other adverse effects when used for up to two years. No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated.
Twenty-eight trials involving 107,362 women in seven countries are included in this updated review. Five studies involving 3,124 women did not contribute outcome data and we excluded them from the analyses. The methodological quality of the included trials was mixed, with significant numbers of studies at high or unclear risk of bias due to: inadequate allocation concealment (N = 20); lack of blinding of outcome assessment (N = 20); incomplete outcome data (N = 19); selective reporting (N = 22) and bias from other potential sources (N = 17). Healthcare professional-led breastfeeding education and support versus standard care The studies pooled here compare professional health workers delivering breastfeeding education and support during the prenatal and postpartum periods with standard care. Interventions included promotion campaigns and counselling, and all took place in a formal setting. There was evidence from five trials involving 564 women for improved rates ofbreastfeeding initiation among women who received healthcare professional-led breastfeeding education and support (average risk ratio (RR) 1.43, 95% confidence interval (CI) 1.07 to 1.92; Tau² = 0.07, I² = 62%, low-quality evidence) compared to those women who received standard care. We downgraded evidence due to design limitations and heterogeneity. The outcome of early initiation of breastfeeding was not reported in the studies under this comparison. Non-healthcare professional-led breastfeeding education and support versus standard care There was evidence from eight trials of 5712 women for improved rates of breastfeeding initiation among women who received interventions from non-healthcare professional counsellors and support groups (average RR 1.22, 95% CI 1.06 to 1.40; Tau² = 0.02, I² = 86%, low-quality evidence) compared to women who received standard care. In three trials of 76,373 women, there was no clear difference between groups in terms of the number of women practicing early initiation of breastfeeding (average RR 1.70, 95% CI 0.98 to 2.95; Tau² = 0.18, I² = 78%, very low-quality evidence). We downgraded the evidence for a combination of design limitations, heterogeneity and imprecision (wide confidence intervals crossing the line of no effect). Other comparisons Other comparisons in this review also looked at the rates of initiation of breastfeeding and there were no clear differences between groups for the following comparisons of combined healthcare professional-led education with peer support or community educator versus standard care (2 studies, 1371 women) or attention control (1 study, 237 women), breastfeeding education using multimedia (a self-help manual or a video) versus routine care (2 studies, 497 women); early mother-infant contact versus standard care (2 studies, 309 women); and community-based breastfeeding groups versus no breastfeeding groups (1 study, 18,603 women). None of these comparisons reported data on early initiation of breastfeeding. This review found low-quality evidence that healthcare professional-led breastfeeding education and non-healthcare professional-led counselling and peer support interventions can result in some improvements in the number of women beginning to breastfeed. The majority of the trials were conducted in the USA, among women on low incomes and who varied in ethnicity and feeding intention, thus limiting the generalisability of these results to other settings. Future studies would ideally be conducted in a range of low- and high-income settings, with data on breastfeeding rates over various timeframes, and explore the effectiveness of interventions that are initiated prior to conception or during pregnancy. These might include well-described interventions, including health education, early and continuing mother-infant contact, and initiatives to help mothers overcome societal barriers to breastfeeding, all with clearly defined outcome measures.
We found 41 trials (>33,000 participants) which met our inclusion criteria. Four trials, which directly compared the same intervention in stage-based and standard versions, found no clear advantage for the staging component. Stage-based versus standard self-help materials (two trials) gave a relative risk (RR) of 0.93 (95% CI 0.62 to 1.39). Stage-based versus standard counselling (two trials) gave a relative risk of 1.00 (95% CI 0.82 to 1.22). Six trials of stage-based self-help systems versus any standard self-help support demonstrated a benefit for the staged groups, with an RR of 1.27 (95% CI 1.01 to 1.59). Twelve trials comparing stage-based self help with 'usual care' or assessment-only gave an RR of 1.32 (95% CI 1.17 to 1.48). Thirteen trials of stage-based individual counselling versus any control condition gave an RR of 1.24 (95% CI 1.08 to 1.42). These findings are consistent with the proven effectiveness of these interventions in their non-stage-based versions. The evidence was unclear for telephone counselling, interactive computer programmes or training of doctors or lay supporters. This uncertainty may be due in part to smaller numbers of trials. Based on four trials using direct comparisons, stage-based self-help interventions (expert systems and/or tailored materials) and individual counselling were neither more nor less effective than their non-stage-based equivalents. Thirty-one trials of stage-based self help or counselling interventions versus any control condition demonstrated levels of effectiveness which were comparable with their non-stage-based counterparts. Providing these forms of practical support to those trying to quit appears to be more productive than not intervening. However, the additional value of adapting the intervention to the smoker's stage of change is uncertain. The evidence is not clear for other types of staged intervention, including telephone counselling, interactive computer programmes and training of physicians or lay supporters. The evidence does not support the restriction of quitting advice and encouragement only to those smokers perceived to be in the preparation and action stages.
We identified 24 eligible trials with a total of 7279 adult participants randomised. Two studies focused on relapse prevention among smokers who had recently stopped smoking, and the remaining 22 studies were concerned with smoking cessation for smokers who wished to quit. Eleven studies were with women only and one with men only. Most studies recruited fairly inactive people. Most of the trials employed supervised, group-based cardiovascular-type exercise supplemented by a home-based exercise programme and combined with a multi-session cognitive behavioural smoking cessation programme. The comparator in most cases was a multi-session cognitive behavioural smoking cessation programme alone. Overall, we judged two studies to be at low risk of bias, 11 at high risk of bias, and 11 at unclear risk of bias. Among the 21 studies analysed, we found low-certainty evidence, limited by potential publication bias and by imprecision, comparing the effect of exercise plus smoking cessation support with smoking cessation support alone on smoking cessation outcomes (RR 1.08, 95% CI 0.96 to 1.22; I2 = 0%; 6607 participants). We excluded one study from this analysis as smoking abstinence rates for the study groups were not reported. There was no evidence of subgroup differences according to the type of exercise promoted; the subgroups considered were: cardiovascular-type exercise alone (17 studies), resistance training alone (one study), combined cardiovascular-type and resistance exercise (one study) and type of exercise not specified (two studies). The results were not significantly altered when we excluded trials with high risk of bias, or those with special populations, or those where smoking cessation intervention support was not matched between the intervention and control arms. Among the two relapse prevention studies, we found very low-certainty evidence, limited by risk of bias and imprecision, that adding exercise to relapse prevention did not improve long-term abstinence compared with relapse prevention alone (RR 0.98, 95% CI 0.65 to 1.47; I2 = 0%; 453 participants). There is no evidence that adding exercise to smoking cessation support improves abstinence compared with support alone, but the evidence is insufficient to assess whether there is a modest benefit. Estimates of treatment effect were of low or very low certainty, because of concerns about bias in the trials, imprecision and publication bias. Consequently, future trials may change these conclusions.
Ten randomised controlled trials were available for analysis. The quality of included studies was adequate, though in some trials the numbers were small and they were inadequately powered for equivalence or to detect significant differences. Comparisons were made between various modalities of treatments. There were no significant difference in recurrence rates or incontinence rates in any of the studied comparisons except in the case of advancement flaps. There were more recurrences in the glue plus flap group, a significant difference that favoured the flap only technique. It was also noted that Fibrin glue and advancement flap procedures report low incontinence rates.In the review of literature of non-randomised trials, most trials on fibrin glue indicate good healing in simple fistulae with low incontinence rates. There are very few randomized controlled trials comparing the various modalities of surgery for fistula in ano. While post operative pain, time to healing and discharge from hospital affect quality of life, recurrence and incontinence are the most important. As it turns out, there seems to be no major difference between the various techniques used as far as recurrence rates are concerned. The use of Fibrin glue and advancement flaps are associated with low incontinence rates. There is a crying need for well powered, well conducted randomised controlled trials comparing various modes of treatment of fistula in ano. Newer operations like the anal fistula plug and the LIFT procedure need to be evaluated by randomised clinical trials.
We included 141 studies that involved 15,141 participants and evaluated 122 blood biomarkers. All the studies were of poor methodological quality. Studies evaluated the blood biomarkers either in a specific phase of the menstrual cycle or irrespective of the cycle phase, and they tested for them in serum, plasma or whole blood. Included women were a selected population with a high frequency of endometriosis (10% to 85%), in which surgery was indicated for endometriosis, infertility work-up or ovarian mass. Seventy studies evaluated the diagnostic performance of 47 blood biomarkers for endometriosis (44 single-marker tests and 30 combined tests of two to six blood biomarkers). These were angiogenesis/growth factors, apoptosis markers, cell adhesion molecules, high-throughput markers, hormonal markers, immune system/inflammatory markers, oxidative stress markers, microRNAs, tumour markers and other proteins. Most of these biomarkers were assessed in small individual studies, often using different cut-off thresholds, and we could only perform meta-analyses on the data sets for anti-endometrial antibodies, interleukin-6 (IL-6), cancer antigen-19.9 (CA-19.9) and CA-125. Diagnostic estimates varied significantly between studies for each of these biomarkers, and CA-125 was the only marker with sufficient data to reliably assess sources of heterogeneity. The mean sensitivities and specificities of anti-endometrial antibodies (4 studies, 759 women) were 0.81 (95% confidence interval (CI) 0.76 to 0.87) and 0.75 (95% CI 0.46 to 1.00). For IL-6, with a cut-off value of > 1.90 to 2.00 pg/ml (3 studies, 309 women), sensitivity was 0.63 (95% CI 0.52 to 0.75) and specificity was 0.69 (95% CI 0.57 to 0.82). For CA-19.9, with a cut-off value of > 37.0 IU/ml (3 studies, 330 women), sensitivity was 0.36 (95% CI 0.26 to 0.45) and specificity was 0.87 (95% CI 0.75 to 0.99). Studies assessed CA-125 at different thresholds, demonstrating the following mean sensitivities and specificities: for cut-off > 10.0 to 14.7 U/ml: 0.70 (95% CI 0.63 to 0.77) and 0.64 (95% CI 0.47 to 0.82); for cut-off > 16.0 to 17.6 U/ml: 0.56 (95% CI 0.24, 0.88) and 0.91 (95% CI 0.75, 1.00); for cut-off > 20.0 U/ml: 0.67 (95% CI 0.50 to 0.85) and 0.69 (95% CI 0.58 to 0.80); for cut-off > 25.0 to 26.0 U/ml: 0.73 (95% CI 0.67 to 0.79) and 0.70 (95% CI 0.63 to 0.77); for cut-off > 30.0 to 33.0 U/ml: 0.62 (95% CI 0.45 to 0.79) and 0.76 (95% CI 0.53 to 1.00); and for cut-off > 35.0 to 36.0 U/ml: 0.40 (95% CI 0.32 to 0.49) and 0.91 (95% CI 0.88 to 0.94). We could not statistically evaluate other biomarkers meaningfully, including biomarkers that were assessed for their ability to differentiate endometrioma from other benign ovarian cysts. Eighty-two studies evaluated 97 biomarkers that did not differentiate women with endometriosis from disease-free controls. Of these, 22 biomarkers demonstrated conflicting results, with some studies showing differential expression and others no evidence of a difference between the endometriosis and control groups. Of the biomarkers that were subjected to meta-analysis, none consistently met the criteria for a replacement or triage diagnostic test. A subset of blood biomarkers could prove useful either for detecting pelvic endometriosis or for differentiating ovarian endometrioma from other benign ovarian masses, but there was insufficient evidence to draw meaningful conclusions. Overall, none of the biomarkers displayed enough accuracy to be used clinically outside a research setting. We also identified blood biomarkers that demonstrated no diagnostic value in endometriosis and recommend focusing research resources on evaluating other more clinically useful biomarkers.
A total of 24 studies met our inclusion criteria. Seventeen studies provided data for the primary analysis: six studies (434 children) included data on procalcitonin, 13 studies (1638 children) included data on CRP, and six studies (1737 children) included data on ESR (some studies had data on more than one test). The summary sensitivity estimates (95% CI) for the procalcitonin, CRP, ESR tests at the aforementioned cutoffs were 0.86 (0.72 to 0.93), 0.94 (0.85 to 0.97), and 0.87 (0.77 to 0.93), respectively. The summary specificity values for procalcitonin, CRP, and ESR tests at these cutoffs were 0.74 (0.55 to 0.87), 0.39 (0.23 to 0.58), and 0.48 (0.33 to 0.64), respectively. The ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. A low CRP value (< 20 mg/L) appears to be somewhat useful in ruling out pyelonephritis (decreasing the probability of pyelonephritis to < 20%), but unexplained heterogeneity in the data prevents us from making recommendations at this time. The procalcitonin test seems better suited for ruling in pyelonephritis, but the limited number of studies and the marked heterogeneity between studies prevents us from reaching definitive conclusions. Thus, at present, we do not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.
Twelve double-blind RCTs (n=700) met the inclusion criteria. The meta-analysis was done on seven studies using the total score on the Hamilton Anxiety (HAM-A) scale as a common outcome measure. The result suggests a significant effect towards a reduction of the HAM-A total score in patients receiving kava extract compared with patients receiving placebo (weighted mean difference: 3.9, 95% confidence interval: 0.1 to 7.7; p = 0.05; n = 380). The results of the five studies that were not submitted to meta-analysis largely support these findings. Adverse events as reported in the reviewed trials were mild, transient and infrequent. Compared with placebo, kava extract is an effective symptomatic treatment for anxiety although, at present, the size of the effect seems small. The effect lacks robustness and is based on a relatively small sample. The data available from the reviewed studies suggest that kava is relatively safe for short-term treatment (1 to 24 weeks), although more information is required. Rigorous trials with large sample sizes are needed to clarify the existing uncertainties. Also, long-term safety studies of kava are required.
We included 44 RCTs with a total of 12,284 participants (6042 in SEQ and 6242 in STT). The overall analysis showed that SEQ was significantly more effective than STT (82% vs 75% in the intention-to-treat analysis; RD 0.09, 95% confidence interval (CI) 0.06 to 0.11; P < 0.001, moderate-quality evidence). Results were highly heterogeneous (I² = 75%), and 20 studies did not demonstrate differences between therapies. Reporting by geographic region (RD 0.09, 95% CI 0.06 to 0.12; studies = 44; I² = 75%, based on low-quality evidence) showed that differences between SEQ and STT were greater in Europe (RD 0.16, 95% CI 0.14 to 0.19) when compared to Asia, Africa or South America. European studies also showed a tendency towards better efficacy with SEQ; however, this tendency was reversed in 33% of the Asian studies. Africa reported the closest risk difference (RD 0.14 , 95% 0.07 to 0.22) to Europe among studied regions, but confidence intervals were wider and therefore the quality of the evidence showing SEQ to be superior to STT was reduced for this region. Based on high-quality evidence, subgroup analyses showed that SEQ and STT therapies were equivalent when STT lasted for 14 days. Although, overall, the mean eradication proportion with SEQ was over 80%, we noted a tendency towards a lower average effect with this regimen in the more recent studies (2008 and after); weighted linear regression showed that the efficacies of both regimens evolved differently over the years, having a higher reduction in the efficacy of SEQ (-1.72% yearly) than in STT (-0.9% yearly). In these more recent studies (2008 and after) we were also unable to detect the superiority of SEQ over STT when STT was given for 10 days. Based on very low-quality evidence, subgroup analyses on antibiotic resistance showed that the widest difference in efficacy between SEQ and STT was in the subgroup analysis based on clarithromycin-resistant participants, in which SEQ reached a 75% average efficacy versus 43% with STT. Reporting on adverse events (AEs) (RD 0.00, 95% CI -0.02 to 0.02; participants = 8103; studies = 27; I² = 26%, based on high-quality evidence) showed no significant differences between SEQ and STT (20.4% vs 19.5%, respectively) and results were homogeneous. The quality of the studies was limited due to a lack of systematic reporting of the factors affecting risk of bias. Although randomisation was reported, its methodology (e.g. algorithms, number of blocks) was not specified in several studies. Additionally, the other 'Risk of bias' domains (such as allocation concealment of the sequence randomisation, or blinding during either performance or outcome assessment) were also unreported. However, subgroup analyses as well as sensitivity analyses or funnel plots indicated that treatment outcomes were not influenced by the quality of the included studies. On the other hand, we rated 'length of STT' and AEs for the main outcome as high-quality according to GRADE classification; but we downgraded 'publication date' quality to moderate, and 'geographic region' and 'antibiotic resistance' to low- and very low-quality, respectively. Our meta-analysis indicates that prior to 2008 SEQ was more effective than STT, especially when STT was given for only seven days. Nevertheless, the apparent advantage of sequential treatment has decreased over time, and more recent studies do not show SEQ to have a higher efficacy versus STT when STT is given for 10 days. Based on the results of this meta-analysis, although SEQ offers an advantage when compared with STT, it cannot be presented as a valid alternative, given that neither SEQ nor STT regimens achieved optimal efficacy ( ≥ 90% eradication rate).
We included 12 controlled trials that recruited 982 infants. There was heterogeneity between trials for the outcome IVH, with three trials finding a significant decrease in IVH and one trial finding an increase in IVH in the group receiving phenobarbital. Meta-analysis showed no difference between the phenobarbital-treated group and the control group in either all IVH (typical risk ratio (RR) 0.91; 95% CI 0.77 to 1.08), severe IVH (typical RR 0.77; 95% CI 0.58 to 1.04), posthaemorrhagic ventricular dilation (typical RR 0.89; 95% CI 0.38 to 2.08), severe neurodevelopmental impairment (typical RR 1.44; 95% CI 0.41 to 5.04) or death before hospital discharge (typical RR 0.88; 95% CI 0.64 to 1.21). There was a consistent trend in the trials towards increased use of mechanical ventilation in the phenobarbital-treated group, which was supported by the meta-analysis (typical RR 1.18; 95% CI 1.06 to 1.32; typical risk difference 0.129; 95% CI 0.04 to 0.21), but there was no significant difference in pneumothorax, acidosis or hypercapnia. Postnatal administration of phenobarbital cannot be recommended as prophylaxis to prevent IVH in preterm infants and is associated with an increased need for mechanical ventilation.
Eighteen trials (reporting 20 study comparisons) met the review entry criteria. We report findings from 18 group comparisons where data were available (6343 participants, of whom 1692 were children). Ciclesonide versus placebo: The short duration of the included studies means that there is a lack of data with respect to the impact of ciclesonide on asthma exacerbations. At doses of 100 mcg/d or less up to 400 mcg/d in mild to moderate asthma, ciclesonide improved lung function, asthma symptoms and rescue inhaler use, compared with placebo. Dose response outcomes: Comparisons of 100 versus 200 mcg/d, 100 versus 400 mcg/d and 400 versus 800 mcg/d did not yield significant differences in lung function outcomes.  Adverse event data were not available in sufficient detail to permit assessment of the safety profile of this drug. Ciclesonide was more effective than placebo, in the short term, in improving lung function in patients with mild to moderate asthma previously treated with inhaled corticosteroids. There remain questions as to dose response, and the lack of data on the longer term impact on exacerbations and safety profile should be addressed in future studies.
The search identified three studies in which 2,261 participants were randomized to receive either ADT alone, or taxane-based chemotherapy at a dose of 75mg per square meter of body surface area at three-weekly intervals for six or nine cycles in addition to ADT. Primary outcomes Early treatment with taxane-based chemotherapy in addition to ADT probably reduces death from any cause compared to ADT alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.68 to 0.87; moderate-certainty evidence); this would result in 94 fewer deaths per 1,000 men (95% CI 51 to 137 fewer deaths). We downgraded the certainty of evidence due to study limitations related to potential performance bias. Based on the results of one study with 375 participants, the addition of taxane-based chemotherapy to ADT may increase the incidence of Grade III to V adverse events compared to ADT alone (risk ratio (RR) 2.98, 95% CI 2.19 to 4.04; low-certainty evidence); this would result in 405 more Grade III to V adverse events per 1,000 men (95% CI 243 to 621 more events). We downgraded the certainty of evidence due to study limitations and imprecision. Secondary outcomes Early taxane-based chemotherapy in addition to ADT probably reduces the risk of prostate cancer-specific death (RR 0.79, 95% CI 0.70 to 0.89; moderate-certainty evidence). We downgraded the certainty of evidence due to study limitations related to potential performance and detection bias. The addition of taxane-based chemotherapy also probably reduces disease progression compared to ADT alone (HR 0.63, 95% CI 0.56 to 0.71; moderate-certainty evidence). We downgraded the certainty of evidence because of study limitations related to potential performance bias. The addition of taxane-based chemotherapy to ADT may result in a large increase in the risk of treatment discontinuation due to adverse events (RR 79.41, 95% CI 4.92 to 1282.78; low-certainty evidence). We downgraded the certainty of evidence due to study limitations and imprecision. This estimate is derived from a single study with no events in the control arm but a discontinuation rate of 20% in the intervention arm. Taxane-based chemotherapy may increase the incidence of adverse events of any grade (RR 1.11, 95% CI 1.06 to 1.17; low-certainty evidence). We downgraded our assessment of the certainty of evidence due to very serious study limitations. There may be a small improvement, which may not be clinically important, in quality of life at 12 months with combination treatment (mean difference (MD) 2.85 on the Functional Assessment of Cancer Therapy—Prostate scale, 95% CI 0.13 higher to 5.57 higher; low-certainty evidence). We downgraded the certainty of evidence for study limitations related to potential performance, detection and attrition bias. Compared to ADT alone, the early (within 120 days of beginning ADT) addition of taxane-based chemotherapy to ADT for hormone-sensitive prostate cancer probably prolongs both overall and disease-specific survival and delays disease progression. There may be an increase in toxicity with taxane-based chemotherapy in combination with ADT. There may also be a small, clinically unimportant improvement in quality of life at 12 months with taxane-based chemotherapy and ADT treatment.
This review includes eight RCTs (767 participants analysed in morning and evening arms). The trials used different lipid-lowering regimens with statins (lovastatin: two trials; simvastatin: three trials; fluvastatin: two trials; pravastatin: one trial). All trials compared the effects between morning and evening statin administration. Trial length ranged from four to 14 weeks. We found a high risk of bias in the domain of selective reporting in three trials and in the domain of incomplete outcome data in one trial of the eight trials included. None of the studies included were judged to be at low risk of bias. None of the included RCTs reported data on cardiovascular mortality, cardiovascular morbidity, incidence of cardiovascular events, or deaths from any cause. Pooled results showed no evidence of a difference in total cholesterol (MD 4.33, 95% CI -1.36 to 10.01), 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence), low-density lipoprotein cholesterol (LDL-C) levels (MD 4.85 mg/dL, 95% CI -0.87 to 10.57, 473 participants, five trials, mean follow-up 9 weeks, low-quality evidence), high-density lipoprotein cholesterol (HDL-C) (MD 0.54, 95% CI -1.08 to 2.17, 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence) or triglycerides (MD -8.91, 95% CI -22 to 4.17, 510 participants, five trials, mean follow-up 9 weeks, low-quality evidence) between morning and evening statin administration. With regard to safety outcomes, five trials (556 participants) reported adverse events. Pooled analysis found no differences in statins adverse events between morning and evening intake (OR 0.71, 95% CI 0.44 to 1.15, 556 participants, five trials, mean follow-up 9 weeks, low-quality evidence). Limited and low-quality evidence suggested that there were no differences between chronomodulated treatment with statins in people with hyperlipidaemia as compared to conventional treatment with statins, in terms of clinically relevant outcomes. Studies were short term and therefore did not report on our primary outcomes, cardiovascular clinical events or death. The review did not find differences in adverse events associated with statins between both regimens. Taking statins in the evening does not have an effect on the improvement of lipid levels with respect to morning administration. Further high-quality trials with longer-term follow-up are needed to confirm the results of this review.
We identified three RCTs, all of which compared EVLA with surgery; one also compared UGFS with surgery. There were no trials comparing RFA with surgery. The EVLA versus surgery comparison included 311 participants: 185 received EVLA and 126 received surgery. In the UGFS comparison, each treatment group contained 21 people. For several outcomes in the EVLA comparison, only a single study provided relevant data; as a result, the current review is limited in its ability to demonstrate meaningful results for some planned outcomes. The quality of evidence according to GRADE was moderate to low for the outcome measures in the EVLA versus surgery comparison, but low for the UGFS versus surgery comparison. Reasons for downgrading in the EVLA versus surgery comparison were risk of bias (for some outcomes, the outcome assessors were not blinded; and in one study the EVLA-surgery allocation of 2:1 did not appear to be prespecified); imprecision (data were only available from a single small study and the CIs were relatively wide); indirectness (one trial reported results at six months rather than one year and was inadequately powered for SSV varices-only analysis). Reasons for downgrading in the UGFS versus surgery comparison were imprecision (only one trial offered UGFS and several participants were missing from the analysis) and a limitation in design (the study was inadequately powered for SSV participants alone). For the EVLA versus surgery comparison, recanalisation or persistence of reflux at six weeks occurred less frequently in the EVLA group than in the surgery group (OR 0.07, 95% CI 0.02 to 0.22; I2 = 51%; 289 participants, 3 studies, moderate-quality evidence). Recurrence of reflux at one year was also less frequent in the EVLA group than in the surgery group (OR 0.24, 95% CI 0.07 to 0.77; I2 = 0%; 119 participants, 2 studies, low-quality evidence). For the outcome clinical evidence of recurrence (i.e. presence of new visible varicose veins) at one year, there was no difference between the two treatment groups (OR 0.54, 95% CI 0.17 to 1.75; 99 participants, 1 study, low-quality evidence). Four participants each in the EVLA and surgery groups required reintervention due to technical failure (99 participants, 1 study, moderate-quality evidence). There was no difference between the two treatment groups for disease-specific quality of life (QoL) (Aberdeen Varicose Veins Questionnaire) either at six weeks (mean difference (MD) 0.15, 95% CI -1.65 to 1.95; I2 = 0%; 265 participants, 2 studies, moderate-quality evidence), or at one year (MD -1.08, 95% CI -3.39 to 1.23; 99 participants, 1 study, low-quality evidence). Main complications reported at six weeks were sural nerve injury, wound infection and deep venous thrombosis (DVT) (one DVT case in each treatment group; EVLA: 1/161, 0.6%; surgery 1/104, 1%; 265 participants, 2 studies, moderate-quality evidence). For the UGFS versus surgery comparison, there were insufficient data to detect clear differences between the two treatment groups for the two outcomes recanalisation or persistence of reflux at six weeks (OR 0.34, 95% CI 0.06 to 2.10; 33 participants, 1 study, low-quality evidence), and recurrence of reflux at one year (OR 1.19, 95% CI 0.29 to 4.92; 31 participants, 1 study, low-quality evidence). No other outcomes could be reported for this comparison because the study data were not stratified according to saphenous vein. Moderate- to low-quality evidence exists to suggest that recanalisation or persistence of reflux at six weeks and recurrence of reflux at one year are less frequent when EVLA is performed, compared with conventional surgery. For the UGFS versus conventional surgery comparison, the quality of evidence is assessed to be low; consequently, the effectiveness of UGFS compared with conventional surgery in the treatment of SSV varices is uncertain. Further RCTs for all comparisons are required with longer follow-up (at least five years). In addition, measurement of outcomes such as recurrence of reflux, time taken to return to work, duration of procedure, pain, etc., and choice of time points during follow-up should be standardised such that future trials evaluating newer technologies can be compared efficiently.
Six randomised trials fulfilled the inclusion criteria. Two hundred and one randomised participants (male = 174) were included. The risk of bias in all the included trials was high. Five trials compared interferon alpha with no treatment in the control group. One of these trials had two treatment arms with a higher dose and lower dose of interferon alpha and a no-treatment control group. We analysed both treatment regimens as a single group in a primary analysis and as separate groups in the subgroup analysis of different interferon dosages. The sixth trial compared only a higher dose of interferon alpha with a lower dose. Meta-analysis of five trials comparing interferon alpha with no-treatment control group included 169 participants. There were seven drop-outs in the treatment group and nine in the control group. One patient out of 92 (1.1%) died in the interferon alpha group compared with zero out of 77 (0.0%) in the no-intervention control group (risk ratio (RR)) 3.00; 95% confidence interval (CI) 0.14 to 66.5). Interferon alpha led to failure of end of treatment virological response in 62/92 (67.4%) of the patients compared with 71/77 (92.2%) in the untreated controls (RR 0.76, 95% CI 0.66 to 0.87, P = 0.0001 by fixed-effect model and RR 0.71, 95% CI 0.43 to 1.16, P = 0.17 by random-effects model). Failure of normalisation of alanine aminotransferase (ALT) at the end of treatment was seen in 60/92 (65.2%) patients treated with interferon alpha versus 76/77 (98.7%) in the control group (RR 0.69, 95% CI 0.59 to 0.80, P < 0.00001). Sustained virological response was not achieved in 76/92 (82.6%) of patients on interferon compared with 73/77 (94.8%) of controls (RR 0.89, 95% CI 0.80 to 0.98, P = 0.02). Serum alanine aminotransferase was abnormal in 81/92 (88.0%) treated with interferon alpha patients at six months post-treatment follow-up compared with 76/77 (98.7%) in controls (RR 0.92, 95% CI 0.84 to 0.99, P = 0.04). There was no significant histological improvement in 67/92 (72.8%) patients treated with interferon alpha compared with 65/77 (84.4%) in controls (RR 0.86, 95% CI 0.74 to 1.00, P = 0.06). Two trials comparing a higher dose of interferon alpha with the lower dose showed no significant difference in sustained virological response (76.7% compared with 90.0%) (RR 0.85, 95% CI 0.68 to 1.07, P = 0.16). Adverse events such as flu-like symptoms, asthenia, weight loss, alopecia, thrombocytopenia, and leukopenia were reported in all these trials and the adverse events were related to interferon alpha. These were common and sometimes severe. One patient in the treatment group was reported to have died by suicide towards the end of the study period. Interferon alpha does not seem to cure hepatitis D in most patients. The agent seems effective in suppressing viral and liver disease activity in some patients, but this improvement is not sustained in the majority of patients. We cannot exclude overestimation of benefits and underestimation of harms due to high risk of bias (systematic errors) and high risk play of chance (random errors). Therefore, more randomised trials with large sample sizes and less risk of bias are needed before interferon can be recommended or refuted.
The latest search found four new trials and updated follow-up data on three trials included in the original review. Eighteen randomised control trials (19 trial arms; 56,934 participants) were included. Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (OR 0.86, 95% CI 0.79 to 0.94); as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81), combined fatal and non-fatal CHD events RR 0.73 (95% CI 0.67 to 0.80) and combined fatal and non-fatal stroke (RR 0.78, 95% CI 0.68 to 0.89). Reduction of revascularisation rates (RR 0.62, 95% CI 0.54 to 0.72) was also seen. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event. Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins.
A total of 431 participants undergoing elective laparoscopic cholecystectomy were randomised to formal patient education (215 participants) versus standard care (216 participants) in four trials. The patient education included verbal education, multimedia DVD programme, computer-based multimedia programme, and PowerPoint presentation in the four trials. All the trials were of high risk of bias. One trial including 212 patients reported mortality. There was no mortality in either group in this trial. None of the trials reported surgery-related morbidity, quality of life, proportion of patients discharged as day-procedure laparoscopic cholecystectomy, the length of hospital stay, return to work, or the number of unplanned visits to the doctor. There were insufficient details to calculate the mean difference and 95% CI for the difference in pain scores at 9 to 24 hours (1 trial; 93 patients); and we did not identify clear evidence of an effect on patient knowledge (3 trials; 338 participants; SMD 0.19; 95% CI -0.02 to 0.41; very low quality evidence), patient satisfaction (2 trials; 305 patients; SMD 0.48; 95% CI -0.42 to 1.37; very low quality evidence), or patient anxiety (1 trial; 76 participants; SMD -0.37; 95% CI -0.82 to 0.09; very low quality evidence) between the two groups. A total of 173 participants undergoing elective laparoscopic cholecystectomy were randomised to electronic consent with repeat-back (patients repeating back the information provided) (92 participants) versus electronic consent without repeat-back (81 participants) in one trial of high risk of bias. The only outcome reported in this trial was patient knowledge. The effect on patient knowledge between the patient education with repeat-back versus patient education without repeat-back groups was imprecise and based on 1 trial of 173 participants; SMD 0.07; 95% CI -0.22 to 0.37; very low quality evidence). Due to the very low quality of the current evidence, the effects of formal patient education provided in addition to the standard information provided by doctors to patients compared with standard care remain uncertain. Further well-designed randomised clinical trials of low risk of bias are necessary.
Over 900 children were recruited for the secretin trials. Twenty-five established standardised outcome measures were reported to assess core features of ASD, communication, behaviour, visuospatial skills, affect and adverse events. One standardised measure of global impression was also used. No more than four studies used any one outcome measure similarly. When duration from the start of the intervention to outcome assessment was known, outcomes were reported at between three and six weeks. Meta-analysis of data was not possible but there is now consistency of findings, with RCTs of the efficacy of secretin in autism not showing improvements for core features of ASD. There is no evidence that single or multiple dose intravenous secretin is effective and as such currently it should not be recommended or administered as a treatment for ASD. Further experimental assessment of secretin's effectiveness for ASD can only be justified if there is new high-quality and replicated scientific evidence that either finds that secretin has a role in neurotransmission in a way that could benefit all children with ASD or identifies important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing.
Forty-four trials were included. The antibiotics assessed were cefepime, ceftazidime, piperacillin-tazobactam, imipenem and meropenem. Adequate allocation concealment and generation were reported in about half of the trials and only two trials were double-blinded. The risk for all-cause mortality was significantly higher with cefepime compared to other beta-lactams (RR 1.39, 95% CI 1.04 to 1.86, 21 trials, 3471 participants), without heterogeneity and with higher RRs in trials at low risk for bias. There were no differences in secondary outcomes but for a non-significantly higher rate of bacterial superinfections with cefepime. Mortality was significantly lower with piperacillin-tazobactam compared to other antibiotics (RR 0.56, 95% CI 0.34 to 0.92, 8 trials, 1314 participants), without heterogeneity. Carbapenems resulted in similar all-cause mortality and a lower rate of clinical failure and antibiotic modifications as compared to other antibiotics, but a higher rate of diarrhea caused by Clostridium difficile. Current evidence supports the use of piperacillin-tazobactam in locations where antibiotic resistance profiles do not mandate empirical use of carbapenems. Carbapenems result in a higher rate of antibiotic-associated and Clostridium difficile-associated diarrhea. There is a high level of evidence that all-cause mortality is higher with cefepime compared to other beta-lactams and it should not be used as monotherapy for patients with febrile neutropenia.
The review authors discovered no new trials in the new searches in June 2009, November 2011, or January 2016. Six trials with 587 participants provided data for the primary outcome. According to moderate quality evidence, the disability grade change after four weeks in the corticosteroid groups was not significantly different from that in the control groups, mean difference (MD) 0.36 less improvement (95% confidence intervals (CI) 0.16 more to 0.88 less improvement). In four trials of oral corticosteroids with 120 participants in total, there was very low quality evidence of less improvement after four weeks with corticosteroids than without corticosteroids, MD 0.82 disability grades less improvement (95% CI 0.17 to 1.47 grades less). In two trials with a combined total of 467 participants, there was moderate quality evidence of no significant difference of a disability grade more improvement after four weeks with intravenous corticosteroids (MD 0.17, 95% CI -0.06 to 0.39). According to moderate quality evidence, there was also no significant difference between the corticosteroid treated and control groups for improvement by one or more grades after four weeks (risk ratio (RR) 1.08, 95% CI 0.93 to 1.24) or for death or disability after one year (RR 1.51, 95% CI 0.91 to 2.5). We found high quality evidence that the occurrence of diabetes was more common (RR 2.21, 95% CI 1.19 to 4.12) and hypertension less common (RR 0.15, 95% CI 0.05 to 0.41) in the corticosteroid-treated participants. According to moderate quality evidence, corticosteroids given alone do not significantly hasten recovery from GBS or affect the long-term outcome. According to very low quality evidence, oral corticosteroids delay recovery. Diabetes requiring insulin was more common and hypertension less common with corticosteroids based on high quality evidence.
Ten randomised controlled trials were included. Limitations in the design, conduct and reporting of these trials resulted in unclear or high risk of bias assessments relating to allocation concealment, assessor blinding, incomplete and selective outcome reporting. Only limited pooling of the data was possible. Neuromuscular training was the basis of conservative treatment evaluated in four trials. Neuromuscular training compared with no training resulted in better ankle function scores at the end of four weeks training (Ankle Joint Functional Assessment Tool (AJFAT): mean difference (MD) 3.00, 95% CI 0.3 to 5.70; 1 trial, 19 participants; Foot and Ankle Disability Index (FADI) data: MD 8.83, 95% CI 4.46 to 13.20; 2 trials, 56 participants). The fourth trial (19 participants) found no significant difference in the functional outcome after six weeks training programme on a cyclo-ergometer with a bi-directional compared with a traditional uni-directional pedal. Longer-term follow-up data were not available for these four trials. Four studies compared surgical procedures for chronic ankle instability. One trial (40 participants) found more nerve injuries after tenodesis than anatomical reconstruction (risk ratio (RR) 5.50, 95% CI 1.39 to 21.71). One trial (99 participants) comparing dynamic versus static tenodesis excluded 17 patients allocated dynamic tenodesis because their tendons were too thin. The same trial found that dynamic tenodesis resulted in higher numbers of people with unsatisfactory function (RR 8.62, 95% CI 1.97 to 37.77, 82 participants). One trial comparing techniques of lateral ankle ligament reconstruction (60 participants) found that operating time was shorter using the reinsertion technique than the imbrication method (MD -9.00 minutes, 95% CI -13.48 to -4.52).   Two trials (70 participants) compared functional mobilisation with immobilisation after surgery. These found early mobilisation led to earlier return to work (MD -2.00 weeks, 95% CI -3.06 to -0.94; 1 trial) and to sports (MD -3.00 weeks, 95% CI -4.49 to -1.51; 1 trial). Neuromuscular training alone appears effective in the short term but whether this advantage would persist on longer-term follow-up is not known. While there is insufficient evidence to support any one surgical intervention over another surgical intervention for chronic ankle instability, it is likely that there are limitations to the use of dynamic tenodesis. After surgical reconstruction, early functional rehabilitation appears to be superior to six weeks immobilisation in restoring early function.
Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). Amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups, except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response (low quality of evidence). One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons. This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.
We added six studies to this update. Overall, we included 23 studies (2669 participants). For the majority of outcomes (two-thirds), we could not perform a meta-analysis since outcomes were not measured, or data were provided by one trial only. No study reported data on the number of participants with pain intensity reduction of at least 50% from baseline. Only one study reported data on the number of participants below 30/100 mm on the Visual Analogue Scale (VAS) in pain intensity (very low-quality evidence). Psychological interventions did not reduce pain intensity in the short-term interval (g 0.39, 95% CI -0.18 to 0.96, 2 studies, 104 participants, low-quality evidence), medium-term interval (g -0.02, 95% CI -0.24 to 0.20, 4 studies, 413 participants, moderate-quality evidence) or in the long-term interval (g 0.05, 95% CI -0.20 to 0.30, 2 studies, 200 participants, moderate-quality evidence). No study reported data on median time to re-medication or on number of participants re-medicated. Only two studies provided data on postoperative analgesic use in the short-term interval, showing that psychological interventions did not reduce the use of analgesic medication (g 1.18, 95% CI -2.03 to 4.39, 2 studies, 104 participants, low-quality evidence). Studies revealed that psychological interventions reduced mental distress in the medium-term (g 0.37, 95% CI 0.13 to 0.60, 13 studies, 1388 participants, moderate-quality evidence) and likewise in the long-term interval (g 0.32, 95% CI 0.10 to 0.53, 14 studies, 1586 participants, moderate-quality evidence). Psychological interventions did not improve mobility in the medium-term interval (g 0.23, 95% CI -0.22 to 0.67, 3 studies, 444 participants, low-quality evidence), nor in the long-term interval (g 0.09, 95% CI -0.10 to 0.28, 4 studies, 458 participants, moderate-quality evidence). Only two studies reported data on time to extubation, indicating that psychological interventions reduced the time to extubation (g 0.56, 95% CI 0.08 to 1.03, 2 studies, 154 participants, low-quality evidence). Overall, the very low to moderate quality of the body of evidence on the efficacy of psychological interventions for acute pain after open heart surgery cannot be regarded as sufficient to draw robust conclusions. Most 'Risk of bias' assessments were low or unclear. We judged selection bias (random sequence generation) and attrition bias to be mostly low risk for included studies. However, we judged the risk of selection bias (allocation concealment), performance bias, detection bias and reporting bias to be mostly unclear. In line with the conclusions of our previous review, there is a lack of evidence to support or refute psychological interventions in order to reduce postoperative pain in participants undergoing open heart surgery. We found moderate-quality evidence that psychological interventions reduced mental distress in participants undergoing open heart surgery. Given the small numbers of studies, it is not possible to draw robust conclusions on the efficacy of psychological interventions on outcomes such as analgesic use, mobility, and time to extubation respectively on adverse events or harms of psychological interventions.
A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level). The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP: mean difference (MD) -1.09 mmHg (95% confidence interval (CI): -1.63 to -0.56; P = 0.0001); 89 studies, 8569 participants; DBP: + 0.03 mmHg (MD 95% CI: -0.37 to 0.43; P = 0.89); 90 studies, 8833 participants. High-quality evidence. Black people with normotension: SBP: MD -4.02 mmHg (95% CI:-7.37 to -0.68; P = 0.002); seven studies, 506 participants; DBP: MD -2.01 mmHg (95% CI:-4.37 to 0.35; P = 0.09); seven studies, 506 participants. Moderate-quality evidence. Asian people with normotension: SBP: MD -0.72 mmHg (95% CI: -3.86 to 2.41; P = 0.65); DBP: MD -1.63 mmHg (95% CI:-3.35 to 0.08; P =0.06); three studies, 393 participants. Moderate-quality evidence. White people with hypertension: SBP: MD -5.51 mmHg (95% CI: -6.45 to -4.57; P < 0.00001); 84 studies, 5925 participants; DBP: MD -2.88 mmHg (95% CI: -3.44 to -2.32; P < 0.00001); 85 studies, 6001 participants. High-quality evidence. Black people with hypertension: SBP MD -6.64 mmHg (95% CI:-9.00 to -4.27; P = 0.00001); eight studies, 619 participants; DBP -2.91 mmHg (95% CI:-4.52, -1.30; P = 0.0004); eight studies, 619 participants. Moderate-quality evidence. Asian people with hypertension: SBP: MD -7.75 mmHg (95% CI:-11,44 to -4.07; P < 0.0001) nine studies, 501 participants; DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15; P = 0.0006). Moderate-quality evidence. In plasma or serum, there was a significant increase in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.03), cholesterol (P < 0.0005) and triglyceride (P < 0.0006) with low sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week. Sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a decrease in SBP/DBP of 1/0 mmHg in white participants with normotension and a decrease in SBP/DBP of 5.5/2.9 mmHg in white participants with hypertension. A few studies showed that these effects in black and Asian populations were greater. The effects on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL: (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%).
1162 people from 13 studies were randomised to trifluoperazine or placebo. For global improvement, small short-term studies favoured trifluoperazine (n=95, 3 RCTs, RR 0.62 CI 0.49 to 0.78 NNT 3 CI 2 to 4). Loss to follow up was about 12% in both groups (n=280, 7 RCTs, RR 0.99 CI 0.62 to 1.57) and more people allocated trifluoperazine used antiparkinson drugs to alleviate movements disorders compared with placebo (n=195, 4 RCTs, RR 5.06 CI 2.49 to 10.27, NNH 4 CI 2 to 9). 2230 people from 49 studies were randomised to trifluoperazine or another older generation antipsychotic. Trifluoperazine was not clearly different in terms of 'no substantial improvement' (n=1016, 27 RCTs, RR 1.06 CI 0.98 to 1.14) or leaving the study early (n=930, 22 RCTs, RR 1.15 CI 0.83 to 1.58). Almost identical numbers of people reported at least one adverse event (˜60%) in each group (n=585, 14 RCTs, RR 0.99 CI 0.87 to 1.13), although trifluoperazine was more likely to cause extrapyramidal adverse effects overall when compared to low potency antipsychotics such as chlorpromazine (n=130, 3 RCTs, RR 1.66 CI 1.03 to 2.67, NNH 6 CI 3 to 121). One small study (n=38) found no clear differences between trifluoperazine and the atypical drug, sulpiride. Although there are shortcomings and gaps in the data, there appears to be enough consistency over different outcomes and periods to confirm that trifluoperazine is an antipsychotic of similar efficacy to other commonly used neuroleptics for people with schizophrenia. Its adverse events profile is similar to that of other drugs. It has been claimed that trifluoperazine is effective at low doses for patients with schizophrenia but this does not appear to be based on good quality trial based evidence.
We included 16 trials involving 4759 participants. Analysis did not show a significant overall difference for subjective health status (standardised mean difference (SMD) -0.03, 95% confidence interval (CI) -0.11 to 0.04, P = 0.34) or extended activities of daily living (SMD 0.04, 95% CI -0.03 to 0.11, P = 0.22). There was no overall significant effect for the outcome of carer subjective health status (SMD 0.04, 95% CI -0.05 to 0.14, P = 0.37). Patients with mild to moderate disability (Barthel 15 to 19) had a significant reduction in dependence (odds ratio (OR) 0.62, 95% CI 0.44 to 0.87, P = 0.006). This would equate to 10 fewer dependent patients (95% CI 17 fewer to 4 fewer) for every 100 patients seen by the stroke liaison worker. Similar results were seen for the outcome of death or dependence for the subgroup with Barthel 15 to 19 (OR 0.55, 95% CI 0.38 to 0.81, P = 0.002). This risk difference equates to 11 fewer dead or dependent patients (95% CI 17 fewer to 4 fewer) for every 100 patients seen by the stroke liaison worker. There is no evidence for the effectiveness of this multifaceted intervention in improving outcomes for all groups of patients or carers. Patients with mild to moderate disability benefit from a reduction in death and disability. Patients and carers do report improved satisfaction with some aspects of service provision.
Four trials are now included in the review, with 753 participants. They were different in many ways including the intervention, duration, outcomes and control group so pooling of data was not possible. Overall, the quality of the evidence was rated as very low. Re-analysis of outcomes using data from the published studies found no significant effects of respite care compared to no respite care on any caregiver variable. When respite care was compared to polarity therapy a significant effect was found in favour of polarity therapy for caregiver perceived stress (n = 38, MD 5.80, 95% CI 1.43 to 10.17), but not for other measures of psychological health and other caregiver outcomes. No studies reported evaluable data on outcomes related to the people with dementia. Current evidence does not demonstrate any benefits or adverse effects from the use of respite care for people with dementia or their caregivers. These results should be treated with caution, however, as they may reflect the lack of high quality research in this area rather than an actual lack of benefit. Given the frequency with which respite care is advocated and provided, well-designed trials are needed in this area.
We found no RCTs comparing ICS and LABA combination with either placebo or usual care. We included one RCT that compared combined ICS and LABA with high-dose ICS in 40 adults with non-CF bronchiectasis without co-existent asthma. All participants received three months of high-dose budesonide dipropionate treatment (1600 micrograms). After three months, participants were randomly assigned to receive either high-dose budesonide dipropionate (1600 micrograms per day) or a combination of budesonide with formoterol (640 micrograms of budesonide and 18 micrograms of formoterol) for three months. The study was not blinded. We assessed it to be an RCT with overall high risk of bias. Data analysed in this review showed that those who received combined ICS-LABA (in stable state) had a significantly better transition dyspnoea index (mean difference (MD) 1.29, 95% confidence interval (CI) 0.40 to 2.18) and cough-free days (MD 12.30, 95% CI 2.38 to 22.2) compared with those receiving ICS after three months of treatment. No significant difference was noted between groups in quality of life (MD -4.57, 95% CI -12.38 to 3.24), number of hospitalisations (odds ratio (OR) 0.26, 95% CI 0.02 to 2.79) or lung function (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Investigators reported 37 adverse events in the ICS group versus 12 events in the ICS-LABA group but did not mention the number of individuals experiencing adverse events. Hence differences between groups were not included in the analyses. We assessed the overall evidence to be low quality. In adults with bronchiectasis without co-existent asthma, during stable state, a small single trial with a high risk of bias suggests that combined ICS-LABA may improve dyspnoea and increase cough-free days in comparison with high-dose ICS. No data are provided for or against, the use of combined ICS-LABA in adults with bronchiectasis during an acute exacerbation, or in children with bronchiectasis in a stable or acute state. The absence of high quality evidence means that decisions to use or discontinue combined ICS-LABA in people with bronchiectasis may need to take account of the presence or absence of co-existing airway hyper-responsiveness and consideration of adverse events associated with combined ICS-LABA.
The previous version of this review included one randomised controlled trial involving 327 patients and 159 healthcare providers at baseline. It compared an email to physicians containing patient-specific osteoporosis risk information and guidelines for evaluation and treatment versus usual care (no email). This study was at high risk of bias for the allocation concealment and blinding domains. The email reminder changed health professional actions significantly, with professionals more likely to provide guideline-recommended osteoporosis treatment (bone density measurement or osteoporosis medication, or both) when compared with usual care. The evidence for its impact on patient behaviours or actions was inconclusive. One measure found that the electronic medical reminder message impacted patient behaviour positively (patients had a higher calcium intake), and two found no difference between the two groups. The study did not assess health service outcomes or harms. No new studies were identified for this update. Only one study was identified for inclusion, providing insufficient evidence for guiding clinical practice in regard to the use of email for clinical communication between healthcare professionals. Future research should aim to utilise high-quality study designs that use the most recent developments in information technology, with consideration of the complexity of email as an intervention.
This updated review included a total of 22 trials which randomised 76,864 people with CHD to an education intervention or a 'no education' comparator. Nine new trials (8215 people) were included for this update. We judged most included studies as low risk of bias across most domains. Educational 'dose' ranged from one 40 minute face-to-face session plus a 15 minute follow-up call, to a four-week residential stay with 11 months of follow-up sessions. Control groups received usual medical care, typically consisting of referral to an outpatient cardiologist, primary care physician, or both. We found no difference in effect of education-based interventions on total mortality (13 studies, 10,075 participants; 189/5187 (3.6%) versus 222/4888 (4.6%); random effects risk ratio (RR) 0.80, 95% CI 0.60 to 1.05; moderate quality evidence). Individual causes of mortality were reported rarely, and we were unable to report separate results for cardiovascular mortality or non-cardiovascular mortality. There was no evidence of a difference in effect of education-based interventions on fatal and/or non fatal myocardial infarction (MI) (2 studies, 209 participants; 7/107 (6.5%) versus 12/102 (11.8%); random effects RR 0.63, 95% CI 0.26 to 1.48; very low quality of evidence). However, there was some evidence of a reduction with education in fatal and/or non-fatal cardiovascular events (2 studies, 310 studies; 21/152 (13.8%) versus 61/158 (38.6%); random effects RR 0.36, 95% CI 0.23 to 0.56; low quality evidence). There was no evidence of a difference in effect of education on the rate of total revascularisations (3 studies, 456 participants; 5/228 (2.2%) versus 8/228 (3.5%); random effects RR 0.58, 95% CI 0.19 to 1.71; very low quality evidence) or hospitalisations (5 studies, 14,849 participants; 656/10048 (6.5%) versus 381/4801 (7.9%); random effects RR 0.93, 95% CI 0.71 to 1.21; very low quality evidence). There was no evidence of a difference between groups for all cause withdrawal (17 studies, 10,972 participants; 525/5632 (9.3%) versus 493/5340 (9.2%); random effects RR 1.04, 95% CI 0.88 to 1.22; low quality evidence). Although some health-related quality of life (HRQoL) domain scores were higher with education, there was no consistent evidence of superiority across all domains. We found no reduction in total mortality, in people who received education delivered as part of cardiac rehabilitation, compared to people in control groups (moderate quality evidence). There were no improvements in fatal or non fatal MI, total revascularisations or hospitalisations, with education. There was some evidence of a reduction in fatal and/or non-fatal cardiovascular events with education, but this was based on only two studies. There was also some evidence to suggest that education-based interventions may improve HRQoL. Our findings are supportive of current national and international clinical guidelines that cardiac rehabilitation for people with CHD should be comprehensive and include educational interventions together with exercise and psychological therapy. Further definitive research into education interventions for people with CHD is needed.
Two RCTs were included in the review (106 participants). Neither study reported live birth rate. Vitrification was associated with an increased clinical pregnancy rate compared to slow freezing (RR 3.86, 95% CI 1.63 to 9.11, P = 0.002, 2 RCTs, 106 women, I2 = 8%, moderate quality evidence). The effect of vitrification compared to slow freezing on ongoing pregnancy rates was only reported in one small study, with inconclusive findings (RR 6.07, 95% CI 0.86 to 43.04, P = 0.07, one RCT, 28 women, low quality evidence). No data were reported on adverse effects, nor were any other outcomes reported in the included trials. The evidence was limited by imprecision. We assessed the included studies as at low to unclear risk of bias as the methods were not well described. Oocyte vitrification compared to slow freezing probably increases clinical pregnancy rates in women undergoing assisted reproduction. However, the total number of women and pregnancies were low and the imprecision is high which limits applicability. The effect on ongoing pregnancy is uncertain as data were sparse. No data were available on live births or adverse effects.
We found 51 studies (52 papers), mostly from high-income countries and mostly describing women's perspectives. We assessed our level of confidence in each finding using the GRADE-CERQual approach. We had high or moderate confidence in many of our findings. Where we only had low or very low confidence in a finding, we have indicated this. Labour companions supported women in four different ways. Companions gave informational support by providing information about childbirth, bridging communication gaps between health workers and women, and facilitating non-pharmacological pain relief. Companions were advocates, which means they spoke up in support of the woman. Companions provided practical support, including encouraging women to move around, providing massage, and holding her hand. Finally, companions gave emotional support, using praise and reassurance to help women feel in control and confident, and providing a continuous physical presence. Women who wanted a companion present during labour and childbirth needed this person to be compassionate and trustworthy. Companionship helped women to have a positive birth experience. Women without a companion could perceive this as a negative birth experience. Women had mixed perspectives about wanting to have a male partner present (low confidence). Generally, men who were labour companions felt that their presence made a positive impact on both themselves (low confidence) and on the relationship with their partner and baby (low confidence), although some felt anxious witnessing labour pain (low confidence). Some male partners felt that they were not well integrated into the care team or decision-making. Doulas often met with women before birth to build rapport and manage expectations. Women could develop close bonds with their doulas (low confidence). Foreign-born women in high-income settings may appreciate support from community-based doulas to receive culturally-competent care (low confidence). Factors affecting implementation included health workers and women not recognising the benefits of companionship, lack of space and privacy, and fearing increased risk of infection (low confidence). Changing policies to allow companionship and addressing gaps between policy and practice were thought to be important (low confidence). Some providers were resistant to or not well trained on how to use companions, and this could lead to conflict. Lay companions were often not integrated into antenatal care, which may cause frustration (low confidence). We compared our findings from this synthesis to the companionship programmes/approaches assessed in Bohren’s review of effectiveness. We found that most of these programmes did not appear to address these key features of labour companionship. We have high or moderate confidence in the evidence contributing to several of these review findings. Further research, especially in low- and middle-income settings and with different cadres of healthcare providers, could strengthen the evidence for low- or very low-confidence findings. Ahead of implementation of labour companionship, researchers and programmers should consider factors that may affect implementation, including training content and timing for providers, women and companions; physical structure of the labour ward; specifying clear roles for companions and providers; integration of companions; and measuring the impact of companionship on women’s experiences of care. Implementation research or studies conducted on labour companionship should include a qualitative component to evaluate the process and context of implementation, in order to better interpret results and share findings across contexts.
Five studies were included, of which four with a total of 282 participants provided data. No meta-analysis was possible due to heterogeneity of comparisons within included studies as well as inadequate reporting of data. All studies were considered to be at either moderate or high risk of bias. The results of this systematic review indicate that there is no clinical or statistical difference between systematic desensitisation and any of the control interventions (either waiting list control, systematic desensitisation combined with group therapy or in vitro (with women under instruction by the therapist) desensitisation) for the treatment of vaginismus. The drop-out rates were higher in the waiting list groups. A clinically relevant effect of systematic desensitisation when compared with any of the control interventions cannot be ruled out. None of the included trials compared other behaviour therapies (e.g. cognitive behaviour therapy, sex therapy) to pharmacological interventions. The findings are limited by the evidence available and as such conclusions about the efficacy of interventions for the treatment of vaginismus should be drawn cautiously.
The review included 16 RCTs. Fourteen RCTs (1745 women) were included in the meta-analysis. Only three studies reported live birth per couple. No evidence of a statistically significant difference was noted between IUI and FSP in live birth (OR 0.94, 95% CI 0.59 to 1.49, three RCTs, 633 women, I2 = 0%, low-quality evidence) or clinical pregnancy (OR 0.75, 95% CI 0.49 to 1.12, 14 RCTs, 1745 women, I2 = 52%, low-quality evidence). These findings suggest that for a couple with a 13% chance of live birth using FSP, the chance when using IUI will be between 8% and 19%; and that for a couple with a 19% chance of pregnancy using FSP, the chance of pregnancy when using IUI will be between 10% and 20%. Nor was evidence found of a statistically significant difference between IUI and FSP in per-pregnancy of multiple pregnancy (OR 0.96, 95% CI 0.44 to 2.07, eight RCTs, 197 women, I2 = 0%, low-quality evidence), miscarriage (OR 1.23, 95% CI 0.60 to 2.53, seven RCTs, 199 women, I2 = 0%, low-quality evidence) or ectopic pregnancy (OR 1.71, 95% CI 0.42 to 6.88, four RCTs, 111 women, I2 = 0%, very low quality evidence). Substantial heterogeneity was noted for the outcome of clinical pregnancy (I2 = 54%), for which no clear explanation was provided. Currently no clear evidence suggests any difference between IUI and FSP with respect to their effectiveness and safety for treating couples with non-tubal subfertility. However, a high level of uncertainty is evident in the findings, and additional research may be useful.
We identified two trials comparing pancreatic resection versus other treatments for patients with locally advanced pancreatic cancer. Ninety eight patients were randomised to pancreatic resection (n = 47) or palliative treatment (n = 51) in the two trials included in this review. Both trials were at high risk of bias. Both trials included patients who had locally advanced pancreatic cancer which involved the serosa anteriorly or retroperitoneum posteriorly or involved the blood vessels. Such pancreatic cancers would be considered generally unresectable. One trial included patients with pancreatic cancer in different locations of the pancreas including the head, neck and body (n = 42). The patients allocated to the pancreatic resection group underwent partial pancreatic resection (pancreatoduodenectomy with lymph node clearance or distal pancreatic resection with lymph node clearance) in this trial; the control group received palliative treatment with chemoradiotherapy. In the other trial, only patients with cancer in the head or neck of the pancreas were included (n = 56). The patients allocated to the pancreatic resection group underwent en bloc total pancreatectomy with splenectomy and vascular reconstruction in this trial; the control group underwent palliative bypass surgery with chemoimmunotherapy. The pancreatic resection group had lower mortality than the palliative treatment group (HR 0.38; 95% CI 0.25 to 0.58, very low quality evidence). Both trials followed the survivors up to at least five years. There were no survivors at two years in the palliative treatment group in either trial. Approximately 40% of the patients who underwent pancreatic resection were alive in the pancreatic resection group at the end of three years. This difference in survival was statistically significant (RR 22.68; 95% CI 3.15 to 163.22). The difference persisted at five years of follow-up (RR 8.65; 95% CI 1.12 to 66.89). Neither trial reported severe adverse events but it is likely that a significant proportion of patients suffered from severe adverse events in both groups. The overall peri-operative mortality in the resection group in the two trials was 2.5%. None of the trials reported quality of life. The estimated difference in the length of total hospital stay (which included all admissions of the patient related to the treatment) between the two groups was imprecise (MD -23.00 days; 95% CI -59.05 to 13.05, very low quality evidence). The total treatment costs were significantly lower in the pancreatic resection group than the palliative treatment group (MD -10.70 thousand USD; 95% CI -14.11 to -7.29, very low quality evidence). There is very low quality evidence that pancreatic resection increases survival and decreases costs compared to palliative treatments for selected patients with locally advanced pancreatic cancer and venous involvement. When sufficient expertise is available, pancreatic resection could be considered for selected patients with locally advanced pancreatic cancer who are willing to accept the potentially increased morbidity associated with the procedure. Further randomised controlled trials are necessary to increase confidence in the estimate of effect and to assess the quality of life of patients and the cost-effectiveness of pancreatic resection versus palliative treatment for locally advanced pancreatic cancer.
One study was identified that compared protein containing synthetic surfactants (PCSS) to protein free synthetic surfactants. Infants who received protein containing synthetic surfactant compared to protein free synthetic surfactant did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks postmenstrual age (PMA) [RR 0.89 (95% CI 0.71, 1.11)], chronic lung disease at 36 weeks PMA [RR 0.89 (95% CI 0.78, 1.03)], or the combined outcome of mortality or chronic lung disease at 36 weeks PMA [RR 0.88 (95% CI 0.77, 1.01)]. Among the secondary outcomes, a decrease in the incidence of respiratory distress syndrome at 24 hours of age was demonstrated in the group that received PCSS [RR 0.83 (95% CI 0.72, 0.95). In the one trial comparing protein containing synthetic surfactants compared to protein free synthetic surfactant for the prevention of RDS, no statistically different clinical differences in death and chronic lung disease were noted. Clinical outcomes between the two groups were generally similar although the group receiving protein containing synthetic surfactants did have decreased incidence of respiratory distress syndrome. Further well designed studies comparing protein containing synthetic surfactant to the more widely used animal derived surfactant extracts are indicated.
The review currently includes one randomised trial from mainland China with 153 participants that lasted two months and compared flupenthixol with chlorpromazine. The exact methods of sequence generation and allocation concealment were not reported, and medication was provided in an open manner. There were no data on the outcomes that we had a priori selected for a 'Summary of findings' table. There was no significant difference between flupenthixol and chlorpromazine in the participants' general mental state at endpoint as measured by the Brief Psychiatric Rating Scale (BPRS) total score (1 randomised controlled trial (RCT), n = 153, MD 2.20 95% confidence interval (CI) -1.25 to 5.65). Chlorpromazine was associated with significantly less dizziness (1 RCT, n = 153, MD 0.12 95% CI 0.01 to 0.23); dystonia (1 RCT, n = 153, MD 0.29 95% CI 0.13 to 0.45); unsteady gait (1 RCT, n = 153, MD 0.46 95% CI 0.28 to 0.64); reduced facial expression (1 RCT, n = 153, MD 0.27 95% CI 0.09 to 0.45); restlessness (1 RCT, n = 153, MD 0.69 95% CI 0.45 to 0.93); rigidity (elbow) (1 RCT, n = 153, MD 0.48 95% CI 0.28 to 0.68); and tremor (1 RCT, n = 153, MD 0.56 95% CI 0.34 to 0.78). Chlorpromazine produced more dryness of mouth than flupenthixol (1 RCT, n = 153, MD -0.14 95% CI -0.25 to -0.03). The evidence base of flupenthixol versus low-potency first-generation antipsychotics is currently restricted to one randomised comparison with chlorpromazine. The few reported data do not suggest a difference in efficacy, but flupenthixol appeared to produce more movement disorders and dizziness, while chlorpromazine was associated with the anticholinergic side effect - dryness of mouth. More trials are needed to make conclusions about the relative effects of flupenthixol and low-potency antipsychotics.
We included one RCT which was a pilot study with 19 participants that compared HFNC therapy with oxygen delivery via a head box. In this study, we judged the risk of selection, attrition and reporting bias to be low, and we judged the risk of performance and detection bias to be unclear due to lack of blinding. The median oxygen saturation (SpO2) was higher in the HFNC group at eight hours (100% versus 96%, P = 0.04) and at 12 hours (99% versus 96%, P = 0.04) but similar at 24 hours. There was no clear evidence of a difference in total duration of oxygen therapy, time to discharge or total length of stay between groups. No adverse events were reported in either group and no participants in either group required further respiratory support. Five ongoing trials were identified but no data were available in May 2013. We were not able to perform a meta-analysis. There is insufficient evidence to determine the effectiveness of HFNC therapy for treating infants with bronchiolitis. The current evidence in this review is of low quality, from one small study with uncertainty about the estimates of effect and an unclear risk of performance and detection bias. The included study provides some indication that HFNC therapy is feasible and well tolerated. Further research is required to determine the role of HFNC in the management of bronchiolitis in infants. The results of the ongoing studies identified will contribute to the evidence in future updates of this review.
We included 45 studies, and based on the criteria for PET-CT positivity, we categorised the included studies into three groups: Activity > background (18 studies, N = 2823, prevalence of N2 and N3 nodes = 679/2328), SUVmax ≥ 2.5 (12 studies, N = 1656, prevalence of N2 and N3 nodes = 465/1656), and Other/mixed (15 studies, N = 1616, prevalence of N2 to N3 nodes = 400/1616). None of the studies reported (any) adverse events. Under-reporting generally hampered the quality assessment of the studies, and in 30/45 studies, the applicability of the study populations was of high or unclear concern. The summary sensitivity and specificity estimates for the 'Activity > background PET-CT positivity criterion were 77.4% (95% CI 65.3 to 86.1) and 90.1% (95% CI 85.3 to 93.5), respectively, but the accuracy estimates of these studies in ROC space showed a wide prediction region. This indicated high between-study heterogeneity and a relatively large 95% confidence region around the summary value of sensitivity and specificity, denoting a lack of precision. Sensitivity analyses suggested that the overall estimate of sensitivity was especially susceptible to selection bias; reference standard bias; clear definition of test positivity; and to a lesser extent, index test bias and commercial funding bias, with lower combined estimates of sensitivity observed for all the low 'Risk of bias' studies compared with the full analysis. The summary sensitivity and specificity estimates for the SUVmax ≥ 2.5 PET-CT positivity criterion were 81.3% (95% CI 70.2 to 88.9) and 79.4% (95% CI 70 to 86.5), respectively.In this group, the accuracy estimates of these studies in ROC space also showed a very wide prediction region. This indicated very high between-study heterogeneity, and there was a relatively large 95% confidence region around the summary value of sensitivity and specificity, denoting a clear lack of precision. Sensitivity analyses suggested that both overall accuracy estimates were marginally sensitive to flow and timing bias and commercial funding bias, which both lead to slightly lower estimates of sensitivity and specificity. Heterogeneity analyses showed that the accuracy estimates were significantly influenced by country of study origin, percentage of participants with adenocarcinoma, (¹⁸F)-2-fluoro-deoxy-D-glucose (FDG) dose, type of PET-CT scanner, and study size, but not by study design, consecutive recruitment, attenuation correction, year of publication, or tuberculosis incidence rate per 100,000 population. This review has shown that accuracy of PET-CT is insufficient to allow management based on PET-CT alone. The findings therefore support National Institute for Health and Care (formally 'clinical') Excellence (NICE) guidance on this topic, where PET-CT is used to guide clinicians in the next step: either a biopsy or where negative and nodes are small, directly to surgery. The apparent difference between the two main makes of PET-CT scanner is important and may influence the treatment decision in some circumstances. The differences in PET-CT accuracy estimates between scanner makes, NSCLC subtypes, FDG dose, and country of study origin, along with the general variability of results, suggest that all large centres should actively monitor their accuracy. This is so that they can make reliable decisions based on their own results and identify the populations in which PET-CT is of most use or potentially little value.
Ten new studies have been added to this update; 18 studies with a total 1215 participants are now included. These examined effects of music therapy over the short, medium, and long-term, with treatment dosage varying from seven to 240 sessions. Overall, most information is from studies at low or unclear risk of bias A positive effect on global state was found for music therapy compared to standard care (medium term, 2 RCTs, n = 133, RR 0.38 95% confidence interval (CI) 0.24 to 0.59, low-quality evidence, number needed to treat for an additional beneficial outcome NNTB 2, 95% CI 2 to 4). No binary data were available for other outcomes. Medium-term continuous data identified good effects for music therapy on negative symptoms using the Scale for the Assessment of Negative Symptoms (3 RCTs, n = 177, SMD - 0.55 95% CI -0.87 to -0.24, low-quality evidence). General mental state endpoint scores on the Positive and Negative Symptoms Scale were better for music therapy (2 RCTs, n = 159, SMD -0.97 95% CI -1.31 to -0.63, low-quality evidence), as were average endpoint scores on the Brief Psychiatric Rating Scale (1 RCT, n = 70, SMD -1.25 95% CI -1.77 to -0.73, moderate-quality evidence). Medium-term average endpoint scores using the Global Assessment of Functioning showed no effect for music therapy on general functioning (2 RCTs, n = 118, SMD -0.19 CI -0.56 to 0.18, moderate-quality evidence). However, positive effects for music therapy were found for both social functioning (Social Disability Screening Schedule scores; 2 RCTs, n = 160, SMD -0.72 95% CI -1.04 to -0.40), and quality of life (General Well-Being Schedule scores: 1 RCT, n = 72, SMD 1.82 95% CI 1.27 to 2.38, moderate-quality evidence). There were no data available for adverse effects, service use, engagement with services, or cost. Moderate- to low-quality evidence suggests that music therapy as an addition to standard care improves the global state, mental state (including negative and general symptoms), social functioning, and quality of life of people with schizophrenia or schizophrenia-like disorders. However, effects were inconsistent across studies and depended on the number of music therapy sessions as well as the quality of the music therapy provided. Further research should especially address the long-term effects of music therapy, dose-response relationships, as well as the relevance of outcome measures in relation to music therapy.
We identified 40 RCTs of various pharmacological interventions including intravenous ketamine (14 RCTs), oral gabapentin (10 RCTs), oral pregabalin (5 RCTs), non-steroidal anti-inflammatories (3 RCTs), intravenous steroids (3 RCTs), oral N-methyl-D-aspartate (NMDA) blockers (3 RCTs), oral mexiletine (2 RCTs), intravenous fentanyl (1 RCT), intravenous lidocaine (1 RCT), oral venlafaxine (1 RCT) and inhaled nitrous oxide (1 RCT). Meta-analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine but not gabapentin or pregabalin. Results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to the overestimation of treatment effect. Additional evidence from better, well designed, large-scale trials is needed in order to more rigorously evaluate pharmacological interventions for the prevention of chronic pain after surgery. Furthermore, available evidence does not support the efficacy of gabapentin, pregabalin, non-steroidal anti-inflammatories, intravenous steroids, oral NMDA blockers, oral mexiletine, intravenous fentanyl, intravenous lidocaine, oral venlafaxine or inhaled nitrous oxide for the prevention of chronic postoperative pain.
Seventeen trials satisfied the inclusion criteria. Four trials evaluated preventative interventions for HSV lesions, three trials for viral isolates, and eight trials evaluated both outcome measures. A single trial reported on the cost of prophylaxis for HSV. Two trials evaluating treatment reported on time to healing, duration of viral shedding and relief of pain. No trials reported on duration of hospital stay, amount of analgesia or patient quality of life. In placebo controlled trials, aciclovir was found to be effective for the prevention of HSV infections as measured by oral lesions or viral isolates (RR = 0.16, 95% confidence interval (CI) 0.08 to 0.31 nine trials; RR = 0.17, 95% CI 0.07 to 0.37 nine trials). There is no evidence that valaciclovir is more efficacious than aciclovir, or that higher doses of valaciclovir are more effective than lower doses. Placebo was found to be more effective than prostaglandin E for prevention of viral isolates (RR = 1.87, 95% CI 1.12 to 3.14 one trial). Aciclovir was also found to be effective for the treatment of HSV in terms of duration of viral shedding (median of 2.5 days versus 17.0 days, P = 0.0002; 2 days compared to more than 9, P = 0.0008), time to first decrease in pain (median 3 days compared to 16, P = 0.04), complete resolution of pain (9.9 days compared to 13.6 days, P = 0.01; median of 6 days compared to 16, P = 0.05), 50% healing (median of 6 days compared to 11, P = 0.01) and total healing (median 13.9 days compared to 20.7 days, P = 0.08; median of 8 days compared to 21, P = 0.0). There is evidence that aciclovir is efficacious in the prevention and treatment of herpes simplex virus infections. There is no evidence that valaciclovir is more efficacious than aciclovir, or that a high dose of valaciclovir is better than a low dose of valaciclovir. There is evidence that as a prophylaxis, placebo is more efficacious than prostaglandin E. However, in all included trials, risk of bias is unclear.
We included eleven studies (523 participants) in this review. Ten studies had two arms and one had three arms that were all relevant to this review. Three studies compared a hydrogel dressing with a basic wound contact dressing; three studies compared a hydrogel dressing with a hydrocolloid dressing; three studies compared a hydrogel dressing with another hydrogel dressing; one study compared a hydrogel dressing with a foam dressing; one study compared a hydrogel dressing with a dextranomer paste dressing and one study compared a hydrogel dressing with a topical treatment (collagenase). Limited data were available for analyses in this review: we conducted no meta-analyses. Where data were available there was no evidence of a difference between hydrogel and alternative treatments in terms of complete wound healing or adverse events. One small study reported that using hydrogel dressings was, on average, less costly than hydrocolloid dressings, but this estimate was imprecise and its methodology was not clear. All included studies were small, had short follow-up times and were at unclear risk of bias. It is not clear if hydrogel dressings are more or less effective than other treatments in healing pressure ulcers or if different hydrogels have different effects, Most trials in this field are very small and poorly reported so that risk of bias is unclear.
We now have included 174 trials involving 17,244 participants. Aripiprazole was compared with clozapine, quetiapine, risperidone, ziprasidone and olanzapine. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differences between groups). When compared with clozapine, there were no significant differences for global state (no clinically significant response, n = 2132, 29 RCTs, low quality evidence); mental state (BPRS, n = 426, 5 RCTs, very low quality evidence); or leaving the study early for any reason (n = 240, 3 RCTs, very low quality evidence). Quality of life score using the WHO-QOL-100 scale demonstrated significant difference, favouring aripiprazole (n = 132, 2 RCTs, RR 2.59 CI 1.43 to 3.74, very low quality evidence). General extrapyramidal symptoms (EPS) were no different between groups (n = 520, 8 RCTs,very low quality evidence). No study reported general functioning or service use. When compared with quetiapine, there were no significant differences for global state (n = 991, 12 RCTs, low quality evidence); mental state (PANSS positive symptoms, n = 583, 7 RCTs, very low quality evidence); leaving the study early for any reason (n = 168, 2 RCTs, very low quality evidence), or general EPS symptoms (n = 348, 4 RCTs, very low quality evidence). Results were significantly in favour of aripiprazole for quality of life (WHO-QOL-100 total score, n = 100, 1 RCT, MD 2.60 CI 1.31 to 3.89, very low quality evidence). No study reported general functioning or service use. When compared with risperidone, there were no significant differences for global state (n = 6381, 80 RCTs, low quality evidence); or leaving the study early for any reason (n = 1239, 12 RCTs, very low quality evidence). Data were significantly in favour of aripiprazole for improvement in mental state using the BPRS (n = 570, 5 RCTs, MD 1.33 CI 2.24 to 0.42, very low quality evidence); with higher adverse effects seen in participants receiving risperidone of general EPS symptoms (n = 2605, 31 RCTs, RR 0.39 CI 0.31 to 0.50, low quality evidence). No study reported general functioning, quality of life or service use. When compared with ziprasidone, there were no significant differences for global state (n = 442, 6 RCTs, very low quality evidence); mental state using the BPRS (n = 247, 1 RCT, very low quality evidence); or leaving the study early for any reason (n = 316, 2 RCTs, very low quality evidence). Weight gain was significantly greater in people receiving aripiprazole (n = 232, 3 RCTs, RR 4.01 CI 1.10 to 14.60, very low quality evidence). No study reported general functioning, quality of life or service use. When compared with olanzapine, there were no significant differences for global state (n = 1739, 11 RCTs, very low quality evidence); mental state using PANSS (n = 1500, 11 RCTs, very low quality evidence); or quality of life using the GQOLI-74 scale (n = 68, 1 RCT, very low quality of evidence). Significantly more people receiving aripiprazole left the study early due to any reason (n = 2331, 9 RCTs, RR 1.15 CI 1.05 to 1.25, low quality evidence) and significantly more people receiving olanzapine gained weight (n = 1538, 9 RCTs, RR 0.25 CI 0.15 to 0.43, very low quality evidence). None of the included studies provided outcome data for the comparisons of 'service use' or 'general functioning'. Information on all comparisons is of limited quality, is incomplete and problematic to apply clinically. The quality of the evidence is all low or very low. Aripiprazole is an antipsychotic drug with an important adverse effect profile. Long-term data are sparse and there is considerable scope for another update of this review as new data emerge from ongoing larger, independent pragmatic trials.
Twenty-nine studies were included. Twenty-three studies on 3189 participants compared self management versus usual care; six studies on 499 participants compared different components of self management on a head-to-head basis. Although we included non-randomised controlled clinical trials as well as RCTs in this review, we restricted the primary analysis to RCTs only and reported these trials in the abstract. In the 23 studies with a usual care control group, follow-up time ranged from two to 24 months. The content of the interventions was diverse. A statistically relevant effect of self management on HRQoL was found (St George's Respiratory Questionnaire (SGRQ) total score, mean difference (MD) -3.51, 95% confidence interval (CI) -5.37 to -1.65, 10 studies, 1413 participants, moderate-quality evidence). Self management also led to a lower probability of respiratory-related hospitalisations (odds ratio (OR) 0.57, 95% CI 0.43 to 0.75, nine studies, 1749 participants, moderate-quality evidence) and all cause hospitalisations (OR 0.60; 95% CI 0.40 to 0.89, 6 studies, 1365 participants, moderate-quality evidence). Over one year of follow-up, eight (95% CI 5 to 14) participants with a high baseline risk of respiratory-related hospital admission needed to be treated to prevent one participant with at least one hospital admission, and 20 (95% CI 15 to 35) participants with a low baseline risk of hospitalisation needed to be treated to prevent one participant with at least one respiratory-related hospital admission. No statistically significant effect of self management on mortality (OR 0.79, 95% CI 0.58 to 1.07, 8 studies, 2134 participants, very low-quality evidence) was detected. Also, dyspnoea measured by the (modified) Medical Research Council Scale ((m)MRC) was reduced in individuals who participated in self management (MD -0.83, 95% CI -1.36 to -0.30, 3 studies, 119 participants, low-quality evidence). The difference in exercise capacity as measured by the six-minute walking test was not statistically significant (MD 33.69 m, 95% CI -9.12 to 76.50, 6 studies, 570 participants, very low-quality evidence). Subgroup analyses depending on the use of an exercise programme as part of the intervention revealed no statistically significant differences between studies with and without exercise programmes in our primary outcomes of HRQoL and respiratory-related hospital admissions. We were unable to pool head-to-head trials because of heterogeneity among interventions and controls; thus results are presented narratively within the review. Self management interventions in patients with COPD are associated with improved health-related quality of life as measured by the SGRQ, a reduction in respiratory-related and all cause hospital admissions, and improvement in dyspnoea as measured by the (m)MRC. No statistically significant differences were found in other outcome parameters. However, heterogeneity among interventions, study populations, follow-up time and outcome measures makes it difficult to formulate clear recommendations regarding the most effective form and content of self management in COPD.
Only two underpowered trials (reporting 36 and 40 patients) were identified. These differed markedly in their inclusion criteria and treatment protocols. Both stated that they used placebo. However, allocation concealment was unclear. Only one trial reported any patient deaths. No significant improvement in mortality was identified (odds ratio (OR) 0.42, 95% confidence interval (CI) 0.10 to 1.76). Improvements in serum markers of liver inflammation and liver histology were identified. Potentially prognostically linked markers such as bilirubin and albumin were incompletely reported. Bone mineral density (weighted mean difference -2.84%, 95% CI -4.16 to -1.53) and the number of patients with any adverse event (OR 8.99, 95% CI 2.15 to 37.58) were significantly increased in the glucocorticosteroid group. There is insufficient data to support or reject the use of glucocorticosteroids for patients with primary biliary cirrhosis. It may be appropriate to consider a large prospective randomised clinical trial on this topic.
Among 22 eligible trials, 17 pairs of groups comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X2 = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, body mass index and skeletal maturation reported with low quality of evidence due to imprecision. In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents’ and physicians’ concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.
Unfortunately, we did not find any relevant studies to include. One non-randomised trial, published in 1961, suggested beneficial effects for those admitted to mother and baby units. For the experimental group, more women were able to care for their baby on their own and experienced fewer early relapses on their return home compared with standard care. Care practices for people with schizophrenia have changed dramatically over the past 40 years and a sensitively designed pragmatic trial is possible and justified. Mother and bay units are reportedly common in the UK but less common in other countries and rare or non-existent in the developing world. However, there does not appear to be any trial-based evidence for the effectiveness of these units. This lack of data is of concern as descriptive studies have found poor outcomes such as anxious attachment and poor development for children of mothers with schizophrenia and a greater risk of the children being placed under supervised or foster care. Effective care of both mothers and babies during this critical time may be crucial to prevent poor clinical and parenting outcomes. Good, relevant research is urgently needed.
We included five studies involving 266 participants (136 intervention; 130 control). All participants were adult stroke survivors, living in the community or a care home. Programmes to improve community ambulation consisted of walking practice in a variety of settings and environments in the community, or an indoor activity that mimicked community walking (including virtual reality or mental imagery). Three studies were funded by government agencies, and two had no funding. From two studies of 198 people there was low quality evidence for the effect of intervention on participation compared with control (SMD, 0.08, 95% confidence interval (CI) -0.20 to 0.35 (using inverse variance). The CI for the effect of the intervention on gait speed was wide and does not exclude no difference (MD 0.12, 95% CI -0.01 to 0.24; four studies, 98 participants, low quality evidence). We considered the quality of the evidence to be low for all the remaining outcomes in our review: Community Walk Test (MD -6.35, 95% CI -21.59 to 8.88); Walking Ability Questionnaire (MD 0.53, 95% CI -5.59 to 6.66); Six-Minute Walk Test (MD 39.62 metres, 95% CI -8.26 to 87.51) and self-efficacy (SMD 0.32, 95% CI -0.09 to 0.72). We downgraded the quality of the evidence because of a high risk of bias and imprecision. There is currently insufficient evidence to establish the effect of community ambulation interventions or to support a change in clinical practice. More research is needed to determine if practicing outdoor or community walking will improve participation and community ambulation skills for stroke survivors living in the community.
We included 13 studies, involving 920 randomised participants. There was considerable heterogeneity among study designs, including the comparator arms (placebo, opioid, another NSAID, or a different regimen of ketorolac), dosing regimens (routes and timing of administration, single versus multiple dose), outcome assessment methods, and types of surgery. Mean study population ages ranged from 356 days to 13.9 years. The majority of studies chose a dose of either 0.5 mg/kg (as a single or multiple dose regimen) or 1 mg/kg (single dose with 0.5 mg/kg for any subsequent doses). One study administered interventions intraoperatively; the remainder administered interventions postoperatively, often after the participant reported moderate to severe pain. There were insufficient data to perform meta-analysis for either of our primary outcomes: participants with at least 50% pain relief; or mean postoperative pain intensity. Four studies individually reported statistically significant reductions in pain intensity when comparing ketorolac with placebo, but the studies were small and had various risks of bias, primarily due to incomplete outcome data and small sample sizes. We found limited data available for the secondary outcomes of participants requiring rescue medication and opioid consumption. For the former, we saw no clear difference between ketorolac and placebo; 74 of 135 (55%) participants receiving ketorolac required rescue analgesia in the post-anaesthesia care unit (PACU) versus 81 of 127 (64%) receiving placebo (relative risk (RR) 0.85, 95% confidence interval (CI) 0.71 to 1.00, P = 0.05; 4 studies, 262 participants). For opioid consumption in the PACU, we saw no clear difference between ketorolac and placebo (P = 0.61). For the time period zero to four hours after administration of the interventions, participants receiving ketorolac received 1.58 mg less intravenous morphine equivalents than those receiving placebo (95% CI -2.58 mg to -0.57 mg, P = 0.002; 2 studies, 129 participants). However, we are uncertain whether ketorolac has an important effect on opioid consumption, as the data were sparse and the results were inconsistent. Only one study reported data for opioid consumption when comparing ketorolac with an opioid. There were no clear differences between the ketorolac and opioid group at any time point. There were no data assessing this outcome for the comparison of ketorolac with another NSAID. There were insufficient data to allow us to analyze overall adverse event or serious adverse event rates. Although the majority of serious adverse events reported in those receiving ketorolac involved bleeding, the number of events was too low to conclude that bleeding risk was increased in those receiving ketorolac perioperatively. There was not a statistically significant increase in event rates for any specific adverse event, either in pooled analysis or in single studies, when comparing ketorolac and placebo. When comparing ketorolac with opioids or other NSAIDs, there were too few data to make any conclusions regarding event rates. Lastly, withdrawals due to adverse events were vary rare in all groups, reflecting the acute nature of such studies. We assessed the quality of evidence for all outcomes for each comparison (placebo or active) as very low, due to issues with risk of bias in individual studies, imprecision, heterogeneity between studies, and low overall numbers of participants and events. Due to the lack of data for our primary outcomes, and the very low-quality evidence for secondary outcomes, the efficacy and safety of ketorolac in treating postoperative pain in children were both uncertain. The evidence was insufficient to support or reject its use.
One study fulfilled the review criteria. In this study, 150 preterm infants of less than 32 weeks' gestation undergoing 60 second DCC were randomized to a group who received respiratory support in the form of continuous positive airway pressure (CPAP) or positive pressure ventilation during DCC and a group that did not receive respiratory support during the procedure. Mortality during hospital admission was not significantly different between groups with wide confidence intervals (CI) for magnitude of effect (risk ratio (RR) 1.67, 95% CI 0.41 to 6.73). The study did not report neurodevelopmental disability and death or disability at two to three years of age. There were no significant differences between groups in condition at birth (Apgar scores or intubation in the delivery room), use of inotropic agents (RR 1.25, CI 0.63 to 2.49), and receipt of blood transfusion (RR 1.03, 95% CI 0.70 to 1.54). In addition, there were no significant differences in the incidences of any intraventricular haemorrhage (RR 1.50, 95% CI 0.65 to 3.46) and severe intraventricular haemorrhage (RR 1.33, 95% CI 0.31 to 5.75). Several continuous variables were reported in subgroups depending on method of delivery. Unpublished data for each group as a whole was made available and showed peak haematocrit in the first 24 hours and duration of phototherapy did not differ significantly. Overall, the quality of evidence for several key neonatal outcomes (e.g. mortality and intraventricular haemorrhage) was low because of lack of precision with wide CIs. The results from one study with wide CIs for magnitude of effect do not provide evidence either for or against the use of respiratory support before clamping the umbilical cord. A greater body of evidence is required as many of the outcomes of interest to the review occurred infrequently. Similarly, the one included study cannot answer the question of whether the intervention is or is not harmful.
A total of four studies (305 participants) met the inclusion criteria. All of these studies sought to determine the effectiveness of different acupuncture techniques in the treatment of persistent and intractable hiccups. All four studies had a high risk of bias, did not compare the intervention with placebo, and failed to report side effects or adverse events for either the treatment or control groups. Due to methodological differences we were unable to perform a meta-analysis of the results. No studies investigating pharmacological interventions for persistent and intractable hiccups met the inclusion criteria. There is insufficient evidence to guide the treatment of persistent or intractable hiccups with either pharmacological or non-pharmacological interventions. The paucity of high quality studies indicate a need for randomised placebo-controlled trials of both pharmacological and non-pharmacological treatments. As the symptom is relatively rare, trials would need to be multi-centred and possibly multi-national.
We included three trials with a total of 128 participants in this review. The duration of zinc supplementation ranged between four and 12 weeks. Risk of bias was unclear for most studies regarding selection bias (random sequence generation, allocation concealment) and detection bias (blinding of outcome assessment). No study reported on our key outcome measures (incidence of type 2 diabetes mellitus, adverse events, health-related quality of life, all-cause mortality, diabetic complications, socioeconomic effects). Evaluation of insulin resistance as measured by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) showed neutral effects when comparing zinc supplementation with control (two trials; 114 participants). There were neutral effects for trials comparing zinc supplementation with placebo for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (2 studies, 70 participants). The one trial comparing zinc supplementation with exercise also showed neutral effects for total cholesterol, HDL and LDL cholesterol, and a mean difference in triglycerides of -30 mg/dL (95% confidence interval (CI) -49 to -10) in favour of zinc supplementation (53 participants). Various surrogate laboratory parameters were also analysed in the included trials. There is currently no evidence on which to base the use of zinc supplementation for the prevention of type 2 diabetes mellitus. Future trials should investigate patient-important outcome measures such as incidence of type 2 diabetes mellitus, health-related quality of life, diabetic complications, all-cause mortality and socioeconomic effects.
Eighty-six studies met the inclusion criteria, recruiting 16,160 participants. In non-oral steroid treated asthmatics with mild and moderate disease FP resulted in improvements from baseline compared with placebo across all dose ranges (100 to 1000 mcg/d) in FEV1 (between 0.1 to 0.43 litres); morning PEF (between 23 and 46 L/min); symptom scores (based on a standardised scale, between 0.44 and 0.7); reduction in rescue beta-2 agonist use (between 1 and 1.4 puffs/day). High dose FP increased the number of patients who could withdraw from prednisolone: FP 1000-1500 mcg/day Peto Odds Ratio 14.07 (95% CI 7.17 to 27.57). FP at all doses led to a greater likelihood of sore throat, hoarseness and oral Candidiasis. Doses of FP in the range 100-1000 mcg/day are effective. In most patients with mild-moderate asthma improvements with low dose FP are only a little less than those associated with high doses when compared with placebo. High dose FP appears to have worthwhile oral-corticosteroid reducing properties. FP use is accompanied by an increased likelihood of oropharyngeal side effects.
We included eight studies involving 353 children in the review. These studies reported different types of interventions (lignocaine or bupivacaine), observation times, and forms of measuring and describing the outcomes, making it difficult to conduct meta-analyses. In the comparison of infraorbital nerve block versus placebo, there was a large effect in mean postoperative pain scores (our first primary outcome) favouring the intervention group (standardised mean difference (SMD) -3.54, 95% confidence interval (CI) -6.13 to -0.95; very low-quality evidence; 3 studies; 120 children). Only one study reported the duration of analgesia (in hours) (second primary outcome) with a difference favouring the intervention group (mean difference (MD) 8.26 hours, 95% CI 5.41 to 11.11; very low-quality evidence) and less supplemental analgesic requirements in the intervention group (risk ratio (RR) 0.05, 95% CI 0.01 to 0.18; low-quality evidence). In the comparison of infraorbital nerve block versus intravenous analgesia, there was a difference favouring the intervention group in mean postoperative pain scores (SMD -1.50, 95% CI -2.40 to -0.60; very low-quality evidence; 2 studies; 107 children) and in the time to feeding (MD -9.45 minutes, 95% CI -17.37 to -1.53; moderate-quality evidence; 2 studies; 128 children). No significant adverse events (third primary outcome) were associated with the intervention, although three studies did not report this outcome. Five out of eight studies found no unwanted side effects after the nerve blocks. Overall, the included studies were at low or unclear risk of bias. The reasons for downgrading the quality of the evidence using GRADE related to the lack of information about randomisation methods and allocation concealment in the studies, very small sample sizes, and heterogeneity of outcome reporting. There is low- to very low-quality evidence that infraorbital nerve block with lignocaine or bupivacaine may reduce postoperative pain more than placebo and intravenous analgesia in children undergoing cleft lip repair. Further studies with larger samples are needed. Future studies should standardise the observation time and the instruments used to measure outcomes, and stratify children by age group.
We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela. TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I2 = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I2 = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I2 = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I2 = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I2 = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I2 = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events). Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.
Overall, there appeared to be an improvement in CVI related signs and symptoms with HCSE compared with placebo. Leg pain was assessed in seven placebo-controlled trials. Six reported a significant reduction of leg pain in the HCSE groups compared with the placebo groups, while another reported a statistically significant improvement compared with baseline. One trial suggested a weighted mean difference (WMD) of 42.4 mm (95% confidence interval (CI) 34.9 to 49.9) measured on a 100 mm visual analogue scale. Leg volume was assessed in seven placebo-controlled trials. Six trials (n = 502) suggested a WMD of 32.1ml (95% CI 13.49 to 50.72) in favour of HCSE compared with placebo. One trial indicated that HCSE may be as effective as treatment with compression stockings. Adverse events were usually mild and infrequent. The evidence presented suggests that HCSE is an efficacious and safe short-term treatment for CVI. However, several caveats exist and larger, definitive RCTs are required to confirm the efficacy of this treatment option.
We included nine studies involving 1044 randomised participants. The studies took place in several countries and had different funding sources. No study was at low risk of bias in all domains. We classified all included studies as at unclear or high risk of bias in two or more domains. Seven included studies focused mainly on obstetric outcomes. One study included non-pregnancy-related cases, and one study included both pregnancy-related cases and other patients with positive results for aPL antibodies. The remaining studies concerned women with aPL antibodies and a history of pregnancy failure. Four studies compared anticoagulant with or without acetylsalicylic acid (ASA) versus ASA only and observed no clear difference in thrombosis risk (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.25 to 3.77; 4 studies; 493 participants; low-quality evidence). No major bleeding was reported, but minor bleeding risk (nasal bleeding, menorrhagia) was higher in the anticoagulant with ASA group as compared with ASA alone in one study (RR 22.45, 95% CI 1.34 to 374.81; 1 study; 164 participants; low-quality evidence). In one study ASA was compared with placebo, and there were no clear differences in thrombosis (RR 5.21, 95% CI 0.63 to 42.97; 1 study; 98 participants; low-quality evidence) or minor bleeding risk between the groups (RR 3.13, 95% CI 0.34 to 29.01; 1 study; 98 participants; low-quality evidence), and no major bleeding was observed. Two studies compared ASA with low molecular weight heparin (LMWH) versus placebo or intravenous immunoglobulin (IVIG), and no thrombotic events were observed in any of the groups. Moreover, there were no clear differences in the risk of bleeding requiring transfusion (RR 9.0, 95% CI 0.49 to 164.76; 1 study; 180 participants; moderate-quality evidence) or postpartum bleeding (RR 1.30, 95% CI 0.60 to 2.81; 1 study; 180 participants; moderate-quality evidence) between the groups. Two studies compared ASA with high-dose LMWH versus ASA with low-dose LMWF or unfractionated heparin (UFH); no thrombotic events or major bleeding was reported. Mortality and quality of life data were not reported for any of the comparisons. There is insufficient evidence to demonstrate benefit or harm of using anticoagulants with or without ASA versus ASA alone in people with aPL antibodies and a history of recurrent pregnancy loss and with no such history; ASA versus placebo in people with aPL antibodies; and ASA with LMWH versus placebo or IVIG, and ASA with high-dose LMWH versus ASA with low-dose LMWH or UFH, in women with aPL antibodies and a history of recurrent pregnancy loss, for the primary prevention of thrombotic events. In a mixed population of people with a history of previous pregnancy loss and without such a history treated with anticoagulant combined with ASA, the incidence of minor bleeding (nasal bleeding, menorrhagia) was increased when compared with ASA alone. Studies that are adequately powered and that focus mainly on thrombotic events are needed to draw any firm conclusions on the primary prevention of thrombotic events in people with antiphospholipid antibodies.
We identified 31 studies, and 13 fulfilled the criteria for inclusion. We described trials that were not eligible for the review in the Discussion. The included studies involved a total of 85 participants, but the number in each individual trial was small; the largest treatment trial included 19 participants and the smallest study included only one participant. There was no benefit with: D-ribose, glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatine. Minimal subjective benefit was found with low dose creatine and ramipril only for patients with a polymorphism known as the D/D angiotensin converting enzyme (ACE) phenotype. A carbohydrate-rich diet resulted in better exercise performance compared with a protein-rich diet. Two studies of oral sucrose given at different times and in different amounts before exercise showed an improvement in exercise performance. Four studies reported adverse effects. Oral ribose caused diarrhoea and symptoms suggestive of hypoglycaemia including light-headedness and hunger. In one study, branched chain amino acids caused a deterioration of functional outcomes. Dantrolene was reported to cause a number of adverse effects including tiredness, somnolence, dizziness and muscle weakness. Low dose creatine (60 mg/kg/day) did not cause side-effects but high-dose creatine (150 mg/kg/day) worsened the symptoms of myalgia. Although there was low quality evidence of improvement in some parameters with creatine, oral sucrose, ramipril and a carbohydrate-rich diet, none was sufficiently strong to indicate significant clinical benefit.
This updated review includes 260 trials and 68 different antibiotics, including 24 cephalosporins and 43,451 participants. Many studies had multiple variables that separated the two study groups; these could not be compared to other studies that tested one antibiotic and had a single variable separating the two groups. We did not consider the risk of bias arising from attrition and lack of blinding of outcome assessors to affect the results for surgical wound infection. Meta-analyses demonstrated a statistically significant difference in postoperative surgical wound infection when prophylactic antibiotics were compared to placebo/no treatment (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.28 to 0.41, high quality evidence). This translates to a reduction in risk from 39% to 13% with prophylactic antibiotics. The slightly higher risk of wound infection with short-term compared with long-term duration antibiotic did not reach statistical significance (RR 1.10, 95% CI 0.93 to 1.30). Similarly risk of would infection was slightly higher with single-dose antibiotics when compared with multiple dose antibiotics, but the results are compatible with benefit and harm (RR 1.30, 95% CI 0.81 to 2.10). Additional aerobic coverage and additional anaerobic coverage both showed statistically significant improvements in surgical wound infection rates (RR 0.44, 95% CI 0.29 to 0.68 and RR 0.47, 95% CI 0.31 to 0.71, respectively), as did combined oral and intravenous antibiotic prophylaxis when compared to intravenous alone (RR 0.56, 95% CI 0.43 to 0.74), or oral alone (RR 0.56, 95% CI 0.40 to 0.76). Comparison of an antibiotic with anaerobic specificity to one with aerobic specificity showed no significant advantage for either one (RR 0.84, 95% CI 0.30 to 2.36). Two small studies compared giving antibiotics before or after surgery and no significant difference in this timing was found (RR 0.67, 95% CI 0.21 to 2.15). Established gold-standard regimens recommended in major guidelines were no less effective than any other antibiotic choice. This review has found high quality evidence that antibiotics covering aerobic and anaerobic bacteria delivered orally or intravenously (or both) prior to elective colorectal surgery reduce the risk of surgical wound infection. Our review shows that antibiotics delivered within this framework can reduce the risk of postoperative surgical wound infection by as much as 75%. It is not known whether oral antibiotics would still have these effects when the colon is not empty. This aspect of antibiotic dosing has not been tested. Further research is required to establish the optimal timing and duration of dosing, and the frequency of longer-term adverse effects such as Clostridium difficile pseudomembranous colitis.
We screened 3028 titles, and included one Italian cluster RCT with 16 general medicine wards (inpatient units in hospitals) and 232 carers of cancer patients in this updated review. We judged the study to be at a high risk of bias overall, mainly due to a lack of blinding and rates of attrition. Only 34% of the participants (range 14% to 75% on individual wards) were cared for in accordance with the care pathway as planned. However, these issues were to be expected due to the nature of the intervention and condition. The study population was all cancer patients in their last days of life. Participants were allocated to care using the Liverpool Care Pathway (LCP-I, Italian version of a continuous quality improvement programme of end-of-life care) or to standard care. The primary outcomes of this review were physical symptom severity, psychological symptom severity, quality of life, and any adverse effects. Physical symptom severity was assessed as overall control of pain, breathlessness, and nausea and vomiting. There was very low quality evidence of a difference in overall control of breathlessness that favoured the Liverpool Care Pathway group compared to usual care: the study reported an odds ratio (OR) of 2.0 with 95% confidence intervals (CIs) 1.1 to 3.8. Very low quality evidence of no difference was found for pain (OR 1.3, 95% CI 0.7 to 2.6, P = 0.461) and nausea and vomiting (OR 1.5, 95% CI 0.7 to 3.2, P = 0.252). None of the other primary outcomes were assessed by the study. Limited data on advance care planning were collected by the study authors, making results for this secondary outcome unreliable. None of our other secondary outcomes were assessed by the study. There is limited available evidence concerning the clinical, physical, psychological or emotional effectiveness of end-of-life care pathways.
We included 11 trials in this review with a total of 1228 participants, ranging from age 45 to 94. The studies were generally at unclear risk of bias due to poorly reported trial methods. No study reported presenting visual acuity, so we report both uncorrected (UCVA) and best corrected visual acuity (BCVA). Studies varied in visual acuity assessment methods and time frames at which outcomes were reported. Participants in the phacoemulsification group were more likely to achieve UCVA of 6/12 or more at three months (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.36 to 2.41, two studies, 492 participants) and one year (RR 1.99, 95% CI 1.45 to 2.73, one study, 439 participants). People in the phacoemulsification group were also more likely to achieve BCVA of 6/12 or more at three months (RR 1.12, 95% CI 1.03 to 1.22, four studies, 645 participants) and one year (RR 1.06, 95% CI 0.99 to 1.14, one study, 439 participants), but the difference between the two groups was smaller. No trials reported BCVA less than 6/60 but three trials reported BCVA worse than 6/9 and 6/18: there were fewer events of this outcome in the phacoemulsification group than the ECCE group at both the three-month (RR 0.33, 95% CI 0.20 to 0.55, three studies, 604 participants) and 12-month time points (RR 0.62, 95% CI 0.36 to 1.05, one study, 439 participants). Three trials reported posterior capsule rupture: this occurred more commonly in the ECCE group than the phacoemulsification group but small numbers of events mean the true effect is uncertain (Peto odds ratio (OR) 0.56, 95% CI 0.26 to 1.22, three studies, 688 participants). Iris prolapse, cystoid macular oedema and posterior capsular opacification were also higher in the ECCE group than the phacoemulsification group. Phacoemulsification surgical costs were higher than ECCE in two studies. A third study reported similar costs for phacoemulsification and ECCE up to six weeks postoperatively, but following this time point ECCE incurred additional costs due to additional visits, spectacles and laser treatment to achieve a similar outcome. Removing cataract by phacoemulsification may result in a better visual acuity compared to ECCE, with a lower complication rate. The review is currently underpowered to detect differences for rarer outcomes, including poor visual outcome. The lower cost of ECCE may justify its use in a patient population where high-volume surgery is a priority, however, there are a lack of data comparing phacoemulsification and ECCE in lower-income settings.
Our search identified no RCTs investigating the role of increased water intake for the prevention of urinary stone formation in participants with no history of urinary stones (primary prevention). We found one RCT assessing the effects of increased water intake versus standard water intake for the prevention of urinary stone formation in people with a history of urinary stones (secondary prevention). This trial randomised 220 participants (110 participants in the intervention group with increased water intake and 110 in the control group with standard water intake). Increased water intake was defined as achieving a urine volume of at least 2.0 L per day by drinking water. Based on this study, increased water intake may decrease stone recurrences (RR 0.45, 95% CI 0.24 to 0.84; 199 participants; low-certainty evidence); this corresponds to 149 fewer (43 fewer to 205 fewer) stone recurrences per 1000 participants with 270 stone recurrence per 1000 participants over five years in the control group. Increased water intake may also prolong the time to urinary stone recurrence compared to standard water intake (HR 0.40, 95% CI 0.20 to 0.79; 199 participants; low-certainty evidence); based on a stone recurrence rate of 270 per 1000 participants over five years, this corresponds to 152 fewer (209 fewer to 50 fewer) recurrences per 1000 participants. For both outcomes we downgraded the certainty of evidence for study limitations and imprecision. We found no evidence for the outcome of adverse events We found no RCT evidence on the role of increased water intake for primary prevention of urinary stones. For secondary prevention, increased water intake achieving a urine volume of at least 2.0 L/day may reduce urinary stone recurrence and prolong time to recurrence for people with a history of urinary stone disease. However, our confidence in these findings is limited. We did not find evidence for adverse events.
All studies were retrospective, and the majority reported consecutive sampling of cases. Sensitivity and specificity results were available from 38 studies involving 11,181 participants (3200 with invasive cancer, 1055 with borderline tumours and 6926 with benign tumours, determined by paraffin section as the reference standard). The median prevalence of malignancy was 29% (interquartile range (IQR) 23% to 36%, range 11% to 63%). We assessed test performance using two thresholds for the frozen section test. Firstly, we used a test threshold for frozen sections, defining positive test results as invasive cancer and negative test results as borderline and benign tumours. The average sensitivity was 90.0% (95% confidence interval (CI) 87.6% to 92.0%; with most studies typically reporting range of 71% to 100%), and average specificity was 99.5% (95% CI 99.2% to 99.7%; range 96% to 100%). Similarly, we analysed sensitivity and specificity using a second threshold for frozen section, where both invasive cancer and borderline tumours were considered test positive and benign cases were classified as negative. Average sensitivity was 96.5% (95% CI 95.5% to 97.3%; typical range 83% to 100%), and average specificity was 89.5% (95% CI 86.6% to 91.9%; typical range 58% to 99%). Results were available from the same 38 studies, including the subset of 3953 participants with a frozen section result of either borderline or invasive cancer, based on final diagnosis of malignancy. Studies with small numbers of disease-negative cases (borderline cases) had more variation in estimates of specificity. Average sensitivity was 94.0% (95% CI 92.0% to 95.5%; range 73% to 100%), and average specificity was 95.8% (95% CI 92.4% to 97.8%; typical range 81% to 100%). Our additional analyses showed that, if the frozen section showed a benign or invasive cancer, the final diagnosis would remain the same in, on average, 94% and 99% of cases, respectively. In cases where the frozen section diagnosis was a borderline tumour, on average 21% of the final diagnoses would turn out to be invasive cancer. In three studies, the same pathologist interpreted the index and reference standard tests, potentially causing bias. No studies reported blinding pathologists to index test results when reporting paraffin sections. In heterogeneity analyses, there were no statistically significant differences between studies with pathologists of different levels of expertise. In a hypothetical population of 1000 patients (290 with cancer and 80 with a borderline tumour), if a frozen section positive test result for invasive cancer alone was used to diagnose cancer, on average 261 women would have a correct diagnosis of a cancer, and 706 women would be correctly diagnosed without a cancer. However, 4 women would be incorrectly diagnosed with a cancer (false positive), and 29 with a cancer would be missed (false negative). If a frozen section result of either an invasive cancer or a borderline tumour was used as a positive test to diagnose cancer, on average 280 women would be correctly diagnosed with a cancer and 635 would be correctly diagnosed without. However, 75 women would be incorrectly diagnosed with a cancer and 10 women with a cancer would be missed. The largest discordance is within the reporting of frozen section borderline tumours. Investigation into factors leading to discordance within centres and standardisation of criteria for reporting borderline tumours may help improve accuracy. Some centres may choose to perform surgical staging in women with frozen section diagnosis of a borderline ovarian tumour to reduce the number of false positives. In their interpretation of this review, readers should evaluate results from studies most typical of their population of patients.
We included twenty-six studies (2726 infants) in the analysis. The heterogeneity of participants, methods and results precluded an extensive quantitative synthesis. Of the 21 studies comparing iron supplementation with controls, none evaluated neurodevelopmental status as an outcome. Of thirteen studies reporting at least one growth parameter as an outcome, only one study of poor quality found a significant benefit of iron supplementation. Regarding haematological outcomes, no benefit for iron supplementation was demonstrated within the first 8.5 weeks of postnatal life (16 trials), except by two poor quality studies. After this age, most studies reported a higher mean haemoglobin in iron-supplemented infants. We were only able to include a limited number of studies in a quantitative meta-analysis, which suggested the haemoglobin concentration in iron-supplemented infants was higher by about 6 g/L at six to nine months. One study comparing high dose and low dose iron supplementation monitored neurodevelopmental outcome for one year, without finding any significant difference between the groups. One study comparing early versus late commencement of iron supplementation found no difference in cognitive outcome, but an increased rate of abnormal neurological examination in the late iron group at five years of age. The studies comparing high and low doses of iron indicated that there was no discernible haematological benefit in exceeding 'standard' doses of iron (i.e. 2 mg/kg/day to 3 mg/kg/day). The available data suggest that infants who receive iron supplementation have a slightly higher haemoglobin level, improved iron stores and a lower risk of developing iron deficiency anaemia when compared with those who are unsupplemented. However, it is unclear whether iron supplementation in preterm and low birth weight infants has long term benefits in terms of neurodevelopmental outcome and growth. The optimum timing and duration of iron supplementation remains unclear.
Seventeen studies were not randomised and this increases the potential for selection bias. In addition, there was imbalance in the baseline characteristics of the participants included in all studies. All studies were classified as having a elevate risk of bias. The assessment of methodological quality of all non-randomized studies included in meta-analysis performed by the STROBE checklist has allowed us to identify several methodological limits in most of the analysed studies. At present, the information from the single RCT included (Ruers 2010) comes from an abstract of 2010 ASCO Annual Meeting where the allocation concealment was not reported; however in original protocol allocation concealment was adequately reported (EORTC 40004 protocol). The heterogeneity regarding interventions, comparisons and outcomes rendered the data not suitable. This systematic review gathers information from several controlled clinical trials and observational studies which are vulnerable to different types of bias. The imbalance between characteristics of patients in the allocated groups appears to be the main concern. Only one randomised clinical trial (published as an abstract), comparing 60 patients receiving RFA plus CT versus 59 patients receiving CT alone, was identified. This study showed that PFS was significantly higher in the group that received RFA. However, it was not able to provide information on overall survival. In conclusion, evidence from the included studies are insufficient to recommend RFA for a radical oncological treatment of CRLMs.
Six studies are included in this review. Three studies were mainly conducted in adults, two were conducted in older children (5 to16 years) and one in infants (18 to 25 months). Trial duration was 4 to 52 weeks. Doses of oxatomide varied between studies, ranging from 1 mg/kg/day for infants to 180 mg/day for adults. Only data on adverse events was suitable for meta-analysis. Although PEF did not change significantly in any of the studies, the FVC and FEV1 improved significantly in two. There was no uniform change in symptom scores. There was no significant difference between oxatomide and placebo treatment in use of inhaled corticosteroid or bronchodilator. Two studies showed significant improvement with oxatomide as judged subjectively by physicians. Adverse events, analysed using data from four parallel and one cross over study, showed oxatomide to be associated with a significantly higher risk of any adverse event (OR: 2.97, 95%CI: 1.69 to 5.22) and drowsiness (OR: 5.22,95%CI: 2.53 to 10.74). There is no evidence to show that oxatomide has a significant effect on the control of stable asthma. Some studies reported significant benefits in subjective parameters. There was improvement in some lung function outcomes reported, but this were not consistent across measures or studies and may represent reporting bias. Adverse events, including drowsiness, were significantly greater with oxatomide than placebo.
We found three RCTs with a total of 58 participants that were eligible for inclusion. There was significant variability between the trials in interventions, methodology and outcome measures and therefore we did not perform meta-analysis. One study reported on the use of 2% CsA in maize oil and two on the use of a commercial emulsion of 0.05% CsA. Of these three studies, one showed a beneficial effect of topical CsA in controlling signs and symptoms of AKC, one in controlling signs of AKC and one did not show evidence of an improvement. Only two studies analysed the effect of topical CsA in reducing topical steroid use; one showed a significant reduction in topical steroid use with CsA, but the other did not show evidence of this improvement. No serious adverse events were reported in the trials. This systematic review highlights the relative scarcity of controlled clinical trials assessing the efficacy of topical CsA therapy in AKC and suggests that evidence on the efficacy and safety of topical CsA treatment in patients with CsA remains limited. However, the data suggest that topical CsA may provide clinical and symptomatic relief in AKC and may help to reduce topical steroid use in patients with steroid-dependent or steroid-resistant AKC. No serious adverse events were reported. Reported adverse events in patients treated with topical CsA include intense stinging and eyelid skin maceration. One patient in the placebo group developed a severe allergic response to maize antigens. However, the total number of patients in the trials was too small to assess the safety of this treatment. Additional well-designed and powered RCTs of topical CsA in AKC are needed. Ideal study designs should include adequate randomisation and concealment of allocation; masking of participants, personnel and outcome assessors; adequate follow-up periods and minimisation of attrition bias; and comparison groups with similar clinical and epidemiologic characteristics. Samples should be large enough to provide sufficient statistical power to assess the safety of CsA and to detect clinically relevant treatment effect sizes of the primary outcomes. Analyses should be appropriate to the study’s design and outcome measures. Moreover, standardisation of outcome measures and follow-up periods across studies would be beneficial to maximise study comparability.
Two randomized controlled trials, for a total of 182 infants, met the inclusion criteria of this review. Both trials compared antithrombin with placebo. We found no significant differences in the rates of intraventricular hemorrhage (typical RR 1.30, CI 95% 0.87 to 1.93, typical RD 0.09, 95% CI −0.05 to 0.23; 2 studies, 175 infants; I² = 18% for RR and I² = 42% for RD) and severe intraventricular hemorrhage (typical RR 1.04, CI 95% 0.55 to 1.94; typical RD 0.01, 95% CI −0.11 to 0.12; 2 studies, 175 infants; I² = 0% for RR and I² = 0% for RD). Among secondary outcomes, we found no significant differences in terms of neonatal mortality (typical RR 2.00, CI 95% 0.62 to 6.45; typical RD 0.04, 95% CI −0.03 to 0.12; 2 studies, 182 infants; I² = 46% for RR and I² = 61% for RD) and in the other specified outcomes, such as bronchopulmonary dysplasia. The quality of the evidence supporting these findings is limited due to the imprecision of the estimates. The administration of antithrombin seems not to reduce the incidence and severity of intraventricular hemorrhage in very preterm infants. Limited evidence is available on other clinically relevant outcomes. Given the imprecision of the estimate, the results of this systematic review are consistent with either a benefit or a detrimental effect of antithrombin and do not provide a definitive answer to the review question.
Ninety-eight studies, involving 2,605,044 people, are included in this review. Fifty-four studies involving 812,705 people were comparable enough to be included in at least one meta-analysis. Thirty-five (65%) studies were RCTs. Nineteen (35%) of the studies included in the meta-analysis provided IPD. There was a lack of evidence that home safety interventions reduced rates of thermal injuries or poisoning. There was some evidence that interventions may reduce injury rates after adjusting CBA studies for baseline injury rates (IRR 0.89, 95% CI 0.78 to 1.01). Greater reductions in injury rates were found for interventions delivered in the home (IRR 0.75, 95% CI 0.62 to 0.91), and for those interventions not providing safety equipment (IRR 0.78, 95% CI 0.66 to 0.92). Home safety interventions were effective in increasing the proportion of families with safe hot tap water temperatures (OR 1.41, 95% CI 1.07 to 1.86), functional smoke alarms (OR 1.81, 95% CI 1.30 to 2.52), a fire escape plan (OR 2.01, 95% CI 1.45 to 2.77), storing medicines (OR 1.53, 95% CI 1.27 to 1.84) and cleaning products (OR 1.55, 95% CI 1.22 to 1.96) out of reach, having syrup of ipecac (OR 3.34, 95% CI 1.50 to 7.44) or poison control centre numbers accessible (OR 3.30, 95% CI 1.70 to 6.39), having fitted stair gates (OR 1.61, 95% CI 1.19 to 2.17), and having socket covers on unused sockets (OR 2.69, 95% CI 1.46 to 4.96). Interventions providing free, low cost or discounted safety equipment appeared to be more effective in improving some safety practices than those interventions not doing so. There was no consistent evidence that interventions were less effective in families whose children were at greater risk of injury. Home safety interventions most commonly provided as one-to-one, face-to-face education, especially with the provision of safety equipment, are effective in increasing a range of safety practices. There is some evidence that such interventions may reduce injury rates, particularly where interventions are provided at home. Conflicting findings regarding interventions providing safety equipment on safety practices and injury outcomes are likely to be explained by two large studies; one clinic-based study provided equipment but did not reduce injury rates and one school-based study did not provide equipment but did demonstrate a significant reduction in injury rates. There was no consistent evidence that home safety education, with or without the provision of safety equipment, was less effective in those participants at greater risk of injury. Further studies are still required to confirm these findings with respect to injury rates.
Eighteen RCTs with 1250 participants met our inclusion criteria. The studies were conducted in hospital settings in low, middle and high income countries. Blood loss We found significant reductions in blood loss with the following interventions: vaginal misoprostol (2 RCTs, 89 women: MD -97.88 ml, 95% CI -125.52 to -70.24; I2 = 43%; moderate-quality evidence); intramyometrial vasopressin (3 RCTs, 128 women: MD -245.87 ml, 95% CI -434.58 to -57.16; I2 = 98%; moderate-quality evidence); intramyometrial bupivacaine plus epinephrine (1 RCT, 60 women: MD -68.60 ml, 95% CI -93.69 to -43.51; low-quality evidence); intravenous tranexamic acid (1 RCT, 100 women: MD -243 ml, 95% CI -460.02 to -25.98; low-quality evidence); gelatin-thrombin matrix (1 RCT, 50 women: MD -545.00 ml, 95% CI -593.26 to -496.74; low-quality evidence); intravenous ascorbic acid (1 RCT, 102 women: MD -411.46 ml, 95% CI -502.58 to -320.34; low-quality evidence); vaginal dinoprostone (1 RCT, 108 women: MD -131.60 ml, 95% CI -253.42 to -9.78; low-quality evidence); loop ligation of the myoma pseudocapsule (1 RCT, 70 women: MD -305.01 ml, 95% CI -354.83 to -255.19; low-quality evidence); a fibrin sealant patch (1 RCT, 70 women: MD -26.50 ml, 95% CI -44.47 to -8.53; low-quality evidence), a Foley catheter tied around the cervix (1 RCT, 93 women: MD -240.70 ml, 95% CI -359.61 to -121.79; low-quality evidence), and a polyglactin suture round both cervix and infundibulopelvic ligament (1 RCT, 28 women: MD -1870.0 ml, 95% CI -2547.16 to 1192.84; low-quality evidence). There was no good evidence of an effect on blood loss with oxytocin, morcellation or clipping of the uterine artery. Need for blood transfusion We found significant reductions in the need for blood transfusion with vasopressin (2 RCTs, 90 women: OR 0.15, 95% CI 0.03 to 0.74; I2 = 0%; moderate-quality evidence); tourniquet tied round the cervix (1 RCT, 98 women: OR 0.22, 95% CI 0.09 to 0.55; low-quality evidence); tourniquet tied round both cervix and infundibulopelvic ligament (1 RCT, 28 women: OR 0.02, 95% CI 0.00 to 0.23; low-quality evidence); gelatin-thrombin matrix (1 RCT, 100 women: OR 0.01, 95% CI 0.00 to 0.10; low-quality evidence) and dinoprostone (1 RCT, 108 women: OR 0.17, 95% CI 0.04 to 0.81; low-quality evidence), but no evidence of effect on the need for blood transfusion with misoprostol, oxytocin, tranexamic acid, ascorbic acid, loop ligation of the myoma pseudocapsule and a fibrin sealant patch. There were insufficient data on the adverse effects and costs of the different interventions. At present there is moderate-quality evidence that misoprostol or vasopressin may reduce bleeding during myomectomy, and low-quality evidence that bupivacaine plus epinephrine, tranexamic acid, gelatin-thrombin matrix, ascorbic acid, dinoprostone, loop ligation, a fibrin sealant patch, a peri-cervical tourniquet or a tourniquet tied round both cervix and infundibulopelvic ligament may reduce bleeding during myomectomy. There is no evidence that oxytocin, morcellation and temporary clipping of the uterine artery reduce blood loss. Further well designed studies are required to establish the effectiveness, safety and costs of different interventions for reducing blood loss during myomectomy.
53 trials were included, most of which were cluster-randomised. The reporting quality of trials was poor, only 3.8% of them reporting adequate method of randomisation and program allocation concealment. Incomplete data was adequately addressed in 23% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively. Six of the 11 trials evaluating alcohol-specific interventions showed some evidence of effectiveness compared to a standard curriculum. In 14 of the 39 trials evaluating generic interventions, the program interventions demonstrated significantly greater reductions in alcohol use either through a main or subgroup effect. Gender, baseline alcohol use, and ethnicity modified the effects of interventions. Results from the remaining 3 trials with interventions targeting cannabis, alcohol, and/or tobacco were inconsistent. This review identified studies that showed no effects of preventive interventions, as well as studies that demonstrated statistically significant effects. There was no easily discernible pattern in characteristics that would distinguish trials with positive results from those with no effects. Most commonly observed positive effects across programs were for drunkenness and binge drinking. Current evidence suggests that certain generic psychosocial and developmental prevention programs can be effective and could be considered as policy and practice options. These include the Life Skills Training Program, the Unplugged program, and the Good Behaviour Game. A stronger focus of future research on intervention program content and delivery context is warranted.
Four studies (187 children) met the inclusion criteria. Three studies were carried out in children with cystic fibrosis and one study included children with paediatric malignant disease. Overall there was a low risk of bias for blinding and incomplete outcome data.Two studies had a high risk of bias for allocation concealment. Few statistical differences were found in the outcomes we assessed between treatment and control groups, except change in total energy intake at six and 12 months, mean difference 304.86 kcal per day (95% confidence interval 5.62 to 604.10) and mean difference 265.70 kcal per day (95% confidence interval 42.94 to 485.46), respectively. However, these were based on the analysis of just 58 children in only one study. Only two chronic diseases were included in these analyses, cystic fibrosis and paediatric malignant disease. No other studies were identified which assessed the effectiveness of oral protein calorie supplements in children with other chronic diseases. Oral protein calorie supplements are widely used to improve the nutritional status of children with a number of chronic diseases. We identified a small number of studies assessing these products in children with cystic fibrosis and paediatric malignant disease, but were unable to draw any conclusions based on the limited data extracted. We recommend a series of large, randomised controlled trials be undertaken investigating the use of these products in children with different chronic diseases. Until further data are available, we suggest these products are used with caution.
Eight studies involving 22,018 participants met our eligibility criteria. Five studies (n = 18,962) assessed the safety and effectiveness of surgical abortion procedures administered by mid-level providers compared to doctors. Three studies (n = 3056) assessed the safety and effectiveness of medical abortion procedures. The surgical abortion studies (one RCT and four cohort studies) were carried out in the United States, India, South Africa and Vietnam. The medical abortion studies (two RCTs and one cohort study) were carried out in India, Sweden and Nepal. The studies included women with gestational ages up to 14 weeks for surgical abortion and nine weeks for medical abortion. Risk of selection bias was considered to be low in the three RCTs, unclear in four observational studies and high in one observational study. Concealment bias was considered to be low in the three RCTs and high in all five observational studies. Although none of the eight studies performed blinding of the participants to the provider type, we considered the performance bias to be low as this is part of the intervention. Detection bias was considered to be high in all eight studies as none of the eight studies preformed blinding of the outcome assessment. Attrition bias was low in seven studies and high in one, with over 20% attrition. We considered six studies to have unclear risk of selective reporting bias as their protocols had not been published. The remaining two studies had published their protocols. Few other sources of bias were found. Based on an analysis of three cohort studies, the risk of surgical abortion failure was significantly higher when provided by mid-level providers than when procedures were administered by doctors (RR 2.25, 95% CI 1.38 to 3.68), however the quality of evidence for this outcome was deemed to be very low. For surgical abortion procedures, we found no significant differences in the risk of complications between mid-level providers and doctors (RR 0.99, 95% CI 0.17 to 5.70 from RCTs; RR 1.38, 95% CI 0.70 to 2.72 from observational studies). When we combined the data for failure and complications for surgical abortion we found no significant differences between mid-level providers and doctors in both the observational study analysis (RR 1.36, 95% CI 0.86 to 2.14) and the RCT analysis (RR 3.07, 95% CI 0.16 to 59.08). The quality of evidence of the outcome for RCT studies was considered to be low and for observational studies very low. For medical abortion procedures the risk of failure was not different for mid-level providers or doctors (RR 0.81, 95% CI 0.48 to 1.36 from RCTs; RR 1.09, 95% CI 0.63 to 1.88 from observational studies). The quality of evidence of this outcome for the RCT analysis was considered to be high, although the quality of evidence of the observational studies was considered to be very low. There were no complications reported in the three medical abortion studies. There was no statistically significant difference in the risk of failure for medical abortions performed by mid-level providers compared with doctors. Observational data indicate that there may be a higher risk of abortion failure for surgical abortion procedures administered by mid-level providers, but the number of studies is small and more robust data from controlled trials are needed. There were no statistically significant differences in the risk of complications for first trimester surgical abortions performed by mid-level providers compared with doctors.
We included eight studies involving 4488 participants. Regarding quality of evidence, trials showed differences in study population, study design, type of antibiotic, and definition of infection; however, primary outcomes among the included studies were consistent. Mortality rate in the preventive antibiotic group was not significantly different from that in the control group (373/2208 (17%) vs 360/2214 (16%); RR 1.03, 95% confidence interval (CI) 0.87 to 1.21; high-quality evidence). The number of participants with a poor functional outcome (death or dependency) in the preventive antibiotic therapy group was also not significantly different from that in the control group (1158/2168 (53%) vs 1182/2164 (55%); RR 0.99, 95% CI 0.89 to 1.10; moderate-quality evidence). However, preventive antibiotic therapy did significantly reduce the incidence of 'overall' infections in participants with acute stroke from 26% to 19% (408/2161 (19%) vs 558/2156 (26%); RR 0.71, 95% CI 0.58 to 0.88; high-quality evidence). This finding was highly significant for urinary tract infections (81/2131 (4%) vs 204/2126 (10%); RR 0.40, 95% CI 0.32 to 0.51; high-quality evidence), whereas no preventive effect for pneumonia was found (222/2131 (10%) vs 235/2126 (11%); RR 0.95, 95% CI 0.80 to 1.13; high-quality evidence). No major side effects of preventive antibiotic therapy were reported. Only two studies qualitatively assessed the occurrence of elevated body temperature; therefore, these results could not be pooled. Only one study reported length of hospital stay. Preventive antibiotics had no effect on functional outcome or mortality, but significantly reduced the risk of 'overall' infections. This reduction was driven mainly by prevention of urinary tract infection; no effect for pneumonia was found.
We included 63 studies with 7768 participants; six studies were quasi-randomized and the remaining were RCTs. All participants were undergoing cardiac surgery, and in most studies, at least some of the participants were previously taking beta-blockers. Types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. In twelve studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in nine studies this was before surgery, in 20 studies during surgery, and in the remaining studies beta-blockers were started postoperatively. Overall, we found that most studies did not report sufficient details for us to adequately assess risk of bias. In particular, few studies reported methods used to randomize participants to groups. In some studies, participants in the control group were given beta-blockers as rescue therapy during the study period, and all studies in which the control was standard care were at high risk of performance bias because of the open-label study design. No studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. We judged 68% studies to be at high risk of bias in at least one domain. Study authors reported few deaths (7 per 1000 in both the intervention and control groups), and we found low-certainty evidence that beta-blockers may make little or no difference to all-cause mortality at 30 days (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.47 to 1.90; 29 studies, 4099 participants). For myocardial infarctions, we found no evidence of a difference in events (RR 1.05, 95% CI 0.72 to 1.52; 25 studies, 3946 participants; low-certainty evidence). Few study authors reported cerebrovascular events, and the evidence was uncertain (RR 1.37, 95% CI 0.51 to 3.67; 5 studies, 1471 participants; very low-certainty evidence). Based on a control risk of 54 per 1000, we found low-certainty evidence that beta-blockers may reduce episodes of ventricular arrhythmias by 32 episodes per 1000 (RR 0.40, 95% CI 0.25 to 0.63; 12 studies, 2296 participants). For atrial fibrillation or flutter, there may be 163 fewer incidences with beta-blockers, based on a control risk of 327 incidences per 1000 (RR 0.50, 95% CI 0.42 to 0.59; 40 studies, 5650 participants; low-certainty evidence). However, the evidence for bradycardia and hypotension was less certain. We found that beta-blockers may make little or no difference to bradycardia (RR 1.63, 95% CI 0.92 to 2.91; 12 studies, 1640 participants; low-certainty evidence), or hypotension (RR 1.84, 95% CI 0.89 to 3.80; 10 studies, 1538 participants; low-certainty evidence). We used GRADE to downgrade the certainty of evidence. Owing to studies at high risk of bias in at least one domain, we downgraded each outcome for study limitations. Based on effect size calculations in the previous review, we found an insufficient number of participants in all outcomes (except atrial fibrillation) and, for some outcomes, we noted a wide confidence interval; therefore, we also downgraded outcomes owing to imprecision. The evidence for atrial fibrillation and length of hospital stay had a moderate level of statistical heterogeneity which we could not explain, and we, therefore, downgraded these outcomes for inconsistency. We found no evidence of a difference in early all-cause mortality, myocardial infarction, cerebrovascular events, hypotension and bradycardia. However, there may be a reduction in atrial fibrillation and ventricular arrhythmias when beta-blockers are used. A larger sample size is likely to increase the certainty of this evidence. Four studies awaiting classification may alter the conclusions of this review.
We included four RCTs (N = 238 participants) that explored: a two-day workshop-based transition preparation training for adolescents with spina bifida; a nurse-led, one-on-one, teaching session with the additional support of a ‘health passport’ for adolescents with heart disease; a web- and SMS-based educational intervention for adolescents with a range of different conditions; and a structured comprehensive transition programme with a transition co-ordinator for adolescents with type 1 diabetes. One study evaluating a one-on-one nurse-led intervention, and one evaluating a technology-based intervention suggested that these interventions may lead to slight improvements in transitional readiness and chronic disease self-management measured at six- to eight-month follow-ups (low certainty evidence). Results with the TRAQ self-management tool were: MD 0.20; 95% CI -0.16 to 0.56 and MD 0.43; 95% CI; -0.09 to 0.95; with the TRAQ self-advocacy tool: MD 0.37; 95% CI -0.06 to 0.80; and with the PAM tool were: MD 10; 95% CI 2.96 to 17.04. In contrast, transition-preparation training delivered via a two-day workshop for patients with spina bifida may lead to little or no difference in measures of self-care practice and general health behaviours when measured using the DSCPI-90©. Two studies evaluated the use of health services. One study evaluated a technology-based intervention and another a comprehensive transition programme; these interventions may lead to slightly more young people taking positive steps to initiate contact with health professionals themselves (Relative risk (RR): 4.87; 95% CI 0.24 to 98.12 and RR 1.50; 95% CI 0.32 to 6.94, respectively; low certainty evidence. Young people’s knowledge of their disease may slightly improve with a nurse-led, one-on-one intervention to prepare young people for transition to an adult congenital heart programme (MD 14; 95% CI 2.67 to 25.33; one study; low certainty evidence). Disease-specific outcome measures were reported in two studies, both of which led to little or no difference in outcomes (low certainty evidence). One study found little or no difference between intervention and control groups. A second study found that follow-up HbA1c in young people with type 1 diabetes mellitus increased by 1.2% for each percentage increase in baseline HbA1c, independent of treatment group (1.2%; 95% CI 0.4 to 1.9; P = 0.01). Transition interventions may lead to little or no difference in well-being or quality of life as measured with the PARS III or PedsQ (two studies; low certainty evidence). Both the technology-based intervention and the two-day workshop for young people with spina bifida found little or no difference between intervention and control groups (MD 1.29; 95% CI -4.49 to 7.07). One study did not report the data. Four telephone support calls from a transition co-ordinator may lead to little or no difference in rates of transfer from paediatric to adult diabetes services (one study; low certainty evidence). At 12-month follow-up, there was little or no difference between groups of young people receiving usual care or a telephone support (RR 0.80; 95% CI 0.59 to 1.08)). They may slightly reduce the risk of disease-related hospital admissions at 12-month follow-up (RR 0.29; 95% CI 0.03 to 2.40). The available evidence (four small studies; N = 238), covers a limited range of interventions developed to facilitate transition in a limited number of clinical conditions, with only four to 12 months follow-up. These follow-up periods may not be long enough for any changes to become apparent as transition is a lengthy process. There was evidence of improvement in patients' knowledge of their condition in one study, and improvements in self-efficacy and confidence in another, but since few studies were eligible for this review, and the overall certainty of the body of this evidence is low, no firm conclusions can be drawn about the effectiveness of the evaluated interventions. Further research is very likely to have an important impact on our confidence in the intervention effect and likely could change our conclusions. There is considerable scope for the rigorous evaluation of other models of transitional care, reporting on clinical outcomes with longer term follow-up.
We retrieved 28,098 references, from which we identified 29 potential articles. Four RCTs (in 11 reports) met the inclusion criteria.The sample sizes ranged from 27 to 135 (total 245 participants). Time poststroke varied from less than one week (n = 1), to one to three months (n = 2), or a median of 51 months (n = 1). Stroke severity ranged from a median of one to six on the National Institutes of Health Stroke Scale (NIHSS). Three studies were conducted in inpatient rehabilitation, and one was in a university laboratory. All studies compared use of activity monitor plus another intervention (e.g. a walking retraining programme or an inpatient rehabilitation programme) versus the other intervention alone. Three studies reported on the primary outcome of daily step counts. There was no clear effect for the use of activity monitors in conjunction with other interventions on step count in a community setting (mean difference (MD) -1930 steps, 95% confidence interval (CI) -4410 to 550; 1 RCT, 27 participants; very low-quality evidence), or in an inpatient rehabilitation setting (MD 1400 steps, 95% CI -40 to 2840; 2 RCTs, 83 participants; very low-quality evidence). No studies reported the primary outcome moderate-to-vigorous physical activity, but one did report time spent in moderate and vigorous intensity activity separately: this study reported that an activity monitor in addition to usual inpatient rehabilitation increased the time spent on moderate intensity physical activity by 4.4 minutes per day (95% CI 0.28 to 8.52; 1 RCT, 48 participants; low-quality evidence) compared with usual rehabilitation alone, but there was no clear effect for the use of an activity monitor plus usual rehabilitation for increasing time spent in vigorous intensity physical activity compared to usual rehabilitation (MD 2.6 minutes per day, 95% CI -0.8 to 6; 1 RCT, 48 participants; low-quality evidence). The overall risk of bias was low, apart from high-risk for blinding of participants and study personnel. None of the included studies reported any information relating to adverse effects. Only four small RCTs with 274 participants (three in inpatient rehabilitation and one in the community) have examined the efficacy of activity monitors for increasing physical activity after stroke. Although these studies showed activity monitors could be incorporated into practice, there is currently not enough evidence to support the use of activity monitors to increase physical activity after stroke.
There were nine studies (total 366 participants randomised) included in this review of non-pharmacological interventions for dry mouth which were divided into three comparisons. Eight studies were assessed at high risk of bias in at least one domain and the remaining study was at unclear risk of bias. Five small studies (total 153 participants, with dry mouth following radiotherapy treatment) compared acupuncture with placebo. Four were assessed at high risk and one at unclear risk of bias. Two trials reported outcome data for dry mouth in a form suitable for meta-analysis. The pooled estimate of these two trials (70 participants, low quality evidence) showed no difference between acupuncture and control in dry mouth symptoms (SMD -0.34, 95% CI -0.81 to 0.14, P value 0.17, I2 = 39%) with the confidence intervals including both a possible reduction or a possible increase in dry mouth symptoms. Acupuncture was associated with more adverse effects (tiny bruises and tiredness which were mild and temporary). There was a very small increase in unstimulated whole saliva (UWS) at the end of 4 to 6 weeks of treatment (three trials, 71 participants, low quality evidence) (MD 0.02 ml/minute, 95% CI 0 to 0.04, P value 0.04, I2 = 57%), and this benefit persisted at the 12-month follow-up evaluation (two trials, 54 participants, low quality evidence) (UWS, MD 0.06 ml/minute, 95% CI 0.01 to 0.11, P value 0.03, I2 = 10%). For the outcome of stimulated whole saliva (SWS, three trials, 71 participants, low quality evidence) there was a benefit favouring acupuncture (MD 0.19 ml/minute, 95% CI 0.07 to 0.31, P value 0.002, I2 = 1%) an effect which also persisted at the 12-month follow-up evaluation (SWS MD 0.28 ml/minute, 95% CI 0.09 to 0.47, P value 0.004, I2 = 0%) (two trials, 54 participants, low quality evidence). Two small studies, both at high risk of bias, compared the use of an electrostimulation device with a placebo device in participants with Sjögren's Syndrome (total 101 participants). A further study, also at high risk of bias, compared acupuncture-like electrostimulation of different sets of points in participants who had previously been treated with radiotherapy. None of these studies reported the outcome of dry mouth. There was no difference between electrostimulation and placebo in the outcomes of UWS or SWS at the end of the 4-week treatment period in the one study (very low that provided data for these outcomes. No adverse effects were reported. A single study at high risk of bias, compared the stimulatory effect of powered versus manual toothbrushing and found no difference for the outcomes of UWS or SWS. There is low quality evidence that acupuncture is no different from placebo acupuncture with regard to dry mouth symptoms, which is the most important outcome. This may be because there were insufficient participants included in the two trials to show a possible effect or it may be that there was some benefit due to 'placebo' acupuncture which could have biased the effect to the null. There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms. It is well known that dry mouth symptoms may be problematic even when saliva production is increased, yet only two of the trials that evaluated acupuncture reported dry mouth symptoms, a worrying reporting bias. There is some low quality evidence that acupuncture results in a small increase in saliva production in patients with dry mouth following radiotherapy. There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms or saliva production in patients with Sjögren's Syndrome. Reported adverse effects of acupuncture are mild and of short duration, and there were no reported adverse effects from electrostimulation.
We included six studies; five (1863 participants) in painful diabetic neuropathy (PDN) and one (159 participants) in fibromyalgia. All were placebo-controlled and titrated to a target dose of 200 mg, 400 mg or 600 mg lacosamide daily, given as a divided dose. Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to known to impart major bias where, as here, adverse event withdrawal rates were high. This, together with small numbers of patients and events for most outcomes at most doses meant that most results were of low quality, with moderate quality evidence available for some efficacy outcomes for 400 mg lacosamide. There were too few data for analysis of the 200 mg dose for painful diabetic neuropathy or any dose for fibromyalgia. In painful diabetic neuropathy, lacosamide 400 mg provided statistically increased rates of achievement of "moderate" and "substantial" benefit (at least 30% and at least 50% reduction from baseline in patient-reported pain respectively) and the patient global impression of change outcome of "much or very much improved". In each case the extra proportion benefiting above placebo was about 10%, yielding numbers needed to treat to benefit compared with placebo of 10 to 12. For lacosamide 600 mg there was no consistent benefit over placebo. There was no significant difference between any dose of lacosamide and placebo for participants experiencing any adverse event or a serious adverse event, but adverse event withdrawals showed a significant dose response. The number needed to treat to harm for adverse event withdrawal was 11 for lacosamide 400 mg and 4 for the 600 mg dose. Lacosamide has limited efficacy in the treatment of peripheral diabetic neuropathy. Higher doses did not give consistently better efficacy, but were associated with significantly more adverse event withdrawals. Where adverse event withdrawals are high with active treatment compared with placebo and when last observation carried forward imputation is used, as in some of these studies, significant overestimation of treatment efficacy can result. It is likely, therefore, that lacosamide is without any useful benefit in treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at all.
We included 14 RCTs that randomised 931 participants. Interventions assessed included: low-level laser therapy (LLLT) (4 studies); vibratory devices (5 studies); chewing adjuncts (3 studies); brain wave music or cognitive behavioural therapy (1 study) and post-treatment communication in the form of a text message (1 study). Twelve studies involved self-report assessment of pain on a continuous scale and two studies used questionnaires to assess the nature, intensity and location of pain. We combined data from two studies involving 118 participants, which provided low-quality evidence that LLLT reduced pain at 24 hours by 20.27 mm (95% CI -24.50 to -16.04, P < 0.001; I² = 0%). LLLT also appeared to reduce pain at six hours, three days and seven days. Results for the other comparisons assessed are inconclusive as the quality of the evidence was very low. Vibratory devices were assessed in five studies (272 participants), four of which were at high risk of bias and one unclear. Chewing adjuncts (chewing gum or a bite wafer) were evaluated in three studies (181 participants); two studies were at high risk of bias and one was unclear. Brain wave music and cognitive behavioural therapy were evaluated in one trial (36 participants) assessed at unclear risk of bias. Post-treatment text messaging (39 participants) was evaluated in one study assessed at high risk of bias. Adverse effects were not measured in any of the studies. Overall, the results are inconclusive. Although available evidence suggests laser irradiation may help reduce pain during orthodontic treatment in the short term, this evidence is of low quality and therefore we cannot rely on the findings. Evidence for other non-pharmacological interventions is either very low quality or entirely lacking. Further prospective research is required to address the lack of reliable evidence concerning the effectiveness of a range of non-pharmacological interventions to manage orthodontic pain. Future studies should use prolonged follow-up and should measure costs and possible harms.
Of 6947 identified citations, 19 RCTs fulfilled the eligibility criteria. These trials enrolled 9650 participants. Trial registries' searches identified nine registered but unpublished trials, two of which were labeled as 'ongoing trials'. In all included RCTs, the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin appears to have no effect on mortality at 12 months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.93 to 1.03; risk difference (RD) 10 fewer per 1000; 95% CI 35 fewer to 15 more; moderate certainty of evidence) and mortality at 24 months (RR 0.99; 95% CI 0.96 to 1.01; RD 8 fewer per 1000; 95% CI 31 fewer to 8 more; moderate certainty of evidence). Heparin therapy reduces the risk of symptomatic VTE (RR 0.56; 95% CI 0.47 to 0.68; RD 30 fewer per 1000; 95% CI 36 fewer to 22 fewer; high certainty of evidence), while it increases in the risks of major bleeding (RR 1.30; 95% 0.94 to 1.79; RD 4 more per 1000; 95% CI 1 fewer to 11 more; moderate certainty of evidence) and minor bleeding (RR 1.70; 95% 1.13 to 2.55; RD 17 more per 1000; 95% CI 3 more to 37 more; high certainty of evidence). Results failed to confirm or to exclude a beneficial or detrimental effect of heparin on thrombocytopenia (RR 0.69; 95% CI 0.37 to 1.27; RD 33 fewer per 1000; 95% CI 66 fewer to 28 more; moderate certainty of evidence); quality of life (moderate certainty of evidence). Heparin appears to have no effect on mortality at 12 months and 24 months. It reduces symptomatic VTE and likely increases major and minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy should balance the benefits and downsides, and should integrate the patient's values and preferences. Editorial note:This is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Sixteen trials met the inclusion criteria, involving 1643 children of whom 865 received a simple behavioural intervention. Within each comparison, outcomes were mostly addressed by single trials, precluding meta-analysis. The only exception was bladder training versus enuresis alarm therapy which included two studies and demonstrated that alarm therapy was superior to bladder training. In single small trials, rewards, lifting and waking and bladder training were each associated with significantly fewer wet nights, higher full response rates and lower relapse rates compared to controls. Simple behavioural interventions appeared to be less effective when compared with other known effective interventions (such as enuresis alarm therapy and drug therapies with imipramine and amitriptyline). However, the effect was not sustained at follow-up after completion of treatment for the drug therapies. Based on one small trial, cognitive therapy also appeared to be more effective than rewards. When one simple behavioural therapy was compared with another, there did not appear to be one therapy that was more effective than another. Simple behavioural methods may be superior to no active treatment but appear to be inferior to enuresis alarm therapy and some drug therapy (such as imipramine and amitriptyline). Simple behavioural therapies could be tried as first line treatment before considering enuresis alarm therapy or drug therapy, which may be more demanding and have adverse effects, although evidence supporting their efficacy is lacking.
Nineteen studies (907 participants) met the inclusion criteria for this review. We included 13 studies (770 participants) in meta-analyses (417 traumatic brain injury, 304 stroke, 49 other acquired brain injury) reducing to 660 participants once non-included intervention groups were removed from three and four group studies. We were unable to obtain data from the remaining six studies. Three studies (134 participants) compared cognitive rehabilitation with sensorimotor therapy. None reported our primary outcome; data from one study was available relating to secondary outcomes including concept formation and ADL. Six studies (333 participants) compared cognitive rehabilitation with no treatment or placebo. None reported our primary outcome; data from four studies demonstrated no statistically significant effect of cognitive rehabilitation on secondary outcomes. Ten studies (448 participants) compared two different cognitive rehabilitation approaches. Two studies (82 participants) reported the primary outcome; no statistically significant effect was found. Data from eight studies demonstrated no statistically significant effect on the secondary outcomes. We explored the effect of restorative interventions (10 studies, 468 participants) and compensative interventions (four studies, 128 participants) and found no statistically significant effect compared with other interventions. We identified insufficient high-quality evidence to reach any generalised conclusions about the effect of cognitive rehabilitation on executive function, or other secondary outcome measures. Further high-quality research comparing cognitive rehabilitation with no intervention, placebo or sensorimotor interventions is recommended.
Six studies met the inclusion criteria but were limited by small sample sizes, various treatment regimes used and outcomes assessed. The studies were overall of unclear quality. Data could only be pooled for the outcomes of treatment failure and hospitalisation. Other data could not be combined due to divergent outcome measurements. Meta-analysis revealed that children who received anticholinergics alone were significantly more likely to have treatment failure compared to those who received beta2-agonists from four trials on 171 children (odds ratio (OR) 2.27; 95% CI 1.08 to 4.75). Also, treatment failure on anticholinergics alone was more likely than when anticholinergics were combined with beta2-agonists from four trials on 173 children (OR 2.65; 95% CI 1.2 to 5.88). Data on clinical scores/symptoms that were measured on different scales were conflicting. Individual trials reported that lung function was superior in the combination group when compared with anticholinergic agents used alone. The use of anticholinergics was not found to be associated with significant side effects. In children over the age of two years with acute asthma exacerbations, inhaled anticholinergics as single agent bronchodilators were less efficacious than beta2-agonists. Inhaled anticholinergics were also less efficacious than inhaled anticholinergics combined with beta2-agonists. Inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations.
The review included 10 RCTs (757 couples). The quality of the evidence was low or very low for all comparisons. The main limitations in the evidence were failure to describe study methods, serious imprecision and inconsistency. IUI versus TI (five RCTs) Two RCTs compared IUI with TI in natural cycles. There were no data on live birth or OHSS. We found no evidence of a difference in pregnancy rates (2 RCTs, 62 couples: odds ratio (OR) 4.57, 95% confidence interval (CI) 0.21 to 102, very low quality evidence; there were no events in one of the studies). Three RCTs compared IUI with TI both in cycles with OH. We found no evidence of a difference in live birth rates (1 RCT, 81 couples: OR 0.89, 95% CI 0.30 to 2.59; low quality evidence) or pregnancy rates (3 RCTs, 202 couples: OR 1.51, 95% CI 0.74 to 3.07; I2 = 11%, very low quality evidence). One RCT reported data on OHSS. None of the 62 women had OHSS. One RCT compared IUI in cycles with OH with TI in natural cycles. We found no evidence of a difference in live birth rates (1 RCT, 44 couples: OR 3.14, 95% CI 0.12 to 81.35; very low quality evidence). Data on OHSS were not available. IUI in cycles with OH versus IUI in natural cycles (five RCTs) We found no evidence of a difference in live birth rates (3 RCTs, 346 couples: OR 1.34, 95% CI 0.77 to 2.33; I2 = 0%, very low quality evidence) and pregnancy rates (4 RCTs, 399 couples: OR 1.68, 95% CI 1.00 to 2.82; I2 = 0%, very low quality evidence). There were no data on OHSS. IVF versus IUI in natural cycles or cycles with OH (two RCTs) We found no evidence of a difference in live birth rates between IVF versus IUI in natural cycles (1 RCT, 53 couples: OR 0.77, 95% CI 0.25 to 2.35; low quality evidence) or IVF versus IUI in cycles with OH (2 RCTs, 86 couples: OR 1.03, 95% CI 0.43 to 2.45; I2 = 0%, very low quality evidence). One RCT reported data on OHSS. None of the women had OHSS. Overall, we found no evidence of a difference between any of the groups in rates of live birth, pregnancy or adverse events (multiple pregnancy, miscarriage). However, most of the evidence was very low quality. There were no studies on IUI in natural cycles versus TI in stimulated cycles, IVF versus TI, ICSI versus TI, ICSI versus IUI (with OH) or ICSI versus IVF. We found insufficient evidence to determine whether there was any difference in safety and effectiveness between different treatments for male subfertility. More research is needed.
One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 μg/kg/h or placebo on day 4 after intubation. We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group. At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation.
We identified four reviews reporting on 32 studies. Two reviews scored 7 on the AMSTAR criteria (moderate, score 5 to 7, quality) and two scored 9 (high, score 8 to 11, quality). The reported quality of the included studies was, by a variety of methods, low to moderate. Payment for working for a specified time period was generally ineffective, improving 3/11 outcomes from one study reported in one review. Payment for each service, episode or visit was generally effective, improving 7/10 outcomes from five studies reported in three reviews; payment for providing care for a patient or specific population was generally effective, improving 48/69 outcomes from 13 studies reported in two reviews; payment for providing a pre-specified level or providing a change in activity or quality of care was generally effective, improving 17/20 reported outcomes from 10 studies reported in two reviews; and mixed and other systems were of mixed effectiveness, improving 20/31 reported outcomes from seven studies reported in three reviews. When looking at the effect of financial incentives overall across categories of outcomes, they were of mixed effectiveness on consultation or visit rates (improving 10/17 outcomes from three studies in two reviews); generally effective in improving processes of care (improving 41/57 outcomes from 19 studies in three reviews); generally effective in improving referrals and admissions (improving 11/16 outcomes from 11 studies in four reviews); generally ineffective in improving compliance with guidelines outcomes (improving 5/17 outcomes from five studies in two reviews); and generally effective in improving prescribing costs outcomes (improving 28/34 outcomes from 10 studies in one review). Financial incentives may be effective in changing healthcare professional practice. The evidence has serious methodological limitations and is also very limited in its completeness and generalisability. We found no evidence from reviews that examined the effect of financial incentives on patient outcomes.
Fifteen eligible trials were identified, but six were excluded. The following interventions were compared in the nine included studies: different non-surgical interventions (five trials); adjunctive treatments to non-surgical interventions (one trial); different surgical interventions (two trials); adjunctive treatments to surgical interventions (one trial). Follow-up ranged from 3 months to 4 years. No study was judged to be at low risk of bias. Statistically significant differences were observed in two small single trials judged to be at unclear or high risk of bias. After 4 months, adjunctive local antibiotics to manual debridement in patients who lost at least 50% of the bone around implants showed improved mean probing attachment levels (PAL) of 0.61 mm (95% confidence interval (CI) 0.40 to 0.82) and reduced probing pockets depths (PPD) of 0.59 mm (95% CI 0.39 to 0.79). After 4 years, patients with peri-implant infrabony defects > 3 mm treated with Bio-Oss and resorbable barriers gained 1.4 mm more PAL (95% CI 0.24 to 2.56) and 1.4 mm PPD (95% CI 0.81 to 1.99) than patients treated with a nanocrystalline hydroxyapatite. There is no reliable evidence suggesting which could be the most effective interventions for treating peri-implantitis. This is not to say that currently used interventions are not effective. A single small trial at unclear risk of bias showed the use of local antibiotics in addition to manual subgingival debridement was associated with a 0.6 mm additional improvement for PAL and PPD over a 4-month period in patients affected by severe forms of peri-implantitis. Another small single trial at high risk of bias showed that after 4 years, improved PAL and PPD of about 1.4 mm were obtained when using Bio-Oss with resorbable barriers compared to a nanocrystalline hydroxyapatite in peri-implant infrabony defects. There is no evidence from four trials that the more complex and expensive therapies were more beneficial than the control therapies which basically consisted of simple subgingival mechanical debridement. Follow-up longer than 1 year suggested recurrence of peri-implantitis in up to 100% of the treated cases for some of the tested interventions. As this can be a chronic disease, re-treatment may be necessary. Larger well-designed RCTs with follow-up longer than 1 year are needed.
20 parallel-group trials were included. The reporting quality of trials was poor, only 25% and 5% of them reporting adequate method of randomisation and program allocation concealment, respectively. Incomplete data was adequately addressed in about half of the trials and this information was unclear for about 20% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively. 12 of the 20 trials showed some evidence of effectiveness compared to a control or other intervention group, with persistence of effects ranging from 3 months to 3 years. Of the remaining 8 trials, one trial reported significant effects using one-tailed tests and 7 trials reported no significant effects of the multi-component interventions for reducing alcohol misuse. Assessment of the additional benefit of multiple versus single component interventions was possible in 7 trials with multiple arms. Only one of the 7 trials clearly showed a benefit of components delivered in more than one setting. There is some evidence that multi-component interventions for alcohol misuse prevention in young people can be effective. However, there is little evidence that interventions with multiple components are more effective than interventions with single components.
For this update to the original review, the search identified 65 potentially relevant articles. Twelve studies met the inclusion criteria (872 participants). Four trials studied the efficacy of electrical stimulation (313 participants), three trials studied exercises (199 participants), and five studies compared or combined some form of physical therapy with acupuncture (360 participants). For most outcomes we were unable to perform meta-analysis because the interventions and outcomes were not comparable. For the primary outcome of incomplete recovery after six months, electrostimulation produced no benefit over placebo (moderate quality evidence from one study with 86 participants). Low quality comparisons of electrostimulation with prednisolone (an active treatment) (149 participants), or the addition of electrostimulation to hot packs, massage and facial exercises (22 participants), reported no significant differences. Similarly a meta-analysis from two studies, one of three months and the other of six months duration (142 participants) found no statistically significant difference in synkinesis, a complication of Bell's palsy, between participants receiving electrostimulation and controls. A single low quality study (56 participants), which reported at three months, found worse functional recovery with electrostimulation (mean difference (MD) 12.00 points (scale of 0 to 100) 95% confidence interval (CI) 1.26 to 22.74). Two trials of facial exercises, both at high risk of bias, found no difference in incomplete recovery at six months when exercises were compared to waiting list controls or conventional therapy. There is evidence from a single small study (34 participants) of moderate quality that exercises are beneficial on measures of facial disability to people with chronic facial palsy when compared with controls (MD 20.40 points (scale of 0 to 100), 95% CI 8.76 to 32.04) and from another single low quality study with 145 people with acute cases treated for three months, in which significantly fewer participants developed facial motor synkinesis after exercise (risk ratio 0.24, 95% CI 0.08 to 0.69). The same study showed statistically significant reduction in time for complete recovery, mainly in more severe cases (47 participants, MD -2.10 weeks, 95% CI -3.15 to -1.05) but this was not a prespecified outcome in this meta analysis. Acupuncture studies did not provide useful data as all were short and at high risk of bias. None of the studies included adverse events as an outcome. There is no high quality evidence to support significant benefit or harm from any physical therapy for idiopathic facial paralysis. There is low quality evidence that tailored facial exercises can help to improve facial function, mainly for people with moderate paralysis and chronic cases. There is low quality evidence that facial exercise reduces sequelae in acute cases. The suggested effects of tailored facial exercises need to be confirmed with good quality randomised controlled trials.
Fifty-one published and unpublished trials (representing 55 group comparisons, 10,797 participants) met the inclusion criteria. In asthmatics with mild to moderate disease who were not on oral steroids, FP did not exhibit a dose-response effect in the lower dose comparisons in FEV1 (50mcg, 100mcg, 200mcg and 4-500mcg daily). There were no statistically significant differences between 4-500mcg and 800-1000mcg, and between 50-100 and 800-1000mcg of FP. When 200mcg was compared with 800-1000mcg daily FEV1 favoured the four/five fold increase. For PEF, a dose response was present with FP when low and moderate, and low and high doses of FP were compared. There was no evidence of a dose-response effect on symptoms or rescue beta-2 agonist use. The likelihood of hoarseness and oral candidiasis was significantly greater for the higher doses (800 to 1000 µg/day). People with oral steroid-dependent asthma treated with FP (2000 µg/day) were significantly more likely to reduce oral prednisolone than those on 1000 to 1500 µg/day (Peto odds Ratio 2.8, 95% CI 1.3 to 6.3). The highest dose also allowed a significant reduction in daily oral prednisolone dose compared to 1000 to 1500 µg/day (WMD 2.0 mg/day, 95% CI 0.1 to 4.0 mg/day). We have not found evidence of a pronounced dose response in FEV1 with increasing doses of fluticasone. The number of studies contributing to our primary outcomes was low. At dose ratios of 1:2, there are statistically significant differences in favour of the higher dose in morning peak flow across the low dose range. The clinical impact of these differences is open to interpretation. Patients with moderate disease achieve similar levels of asthma control on medium doses of fluticasone (400 to 500 µg/day) as they do on high doses (800 to 1000 µg/day). More work in severe asthma would help to confirm that doses of FP above 500 µg/day confer greater benefit in this subgroup than doses of around 200 µg/day. In oral corticosteroid-dependent asthmatics, reductions in prednisolone requirement may be gained with FP 2000 µg/day.
We included 21 trials (19 adult, two paediatric) totaling 1676 participants (1628 adults, 48 children) in this updated review. Pooled data from 16 eligible trials reporting weaning duration indicated that automated closed loop systems reduced the geometric mean duration of weaning by 30% (95% confidence interval (CI) 13% to 45%), however heterogeneity was substantial (I2 = 87%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of an effect on mortality rates, hospital LOS, reintubation rates, self-extubation and use of non-invasive ventilation following extubation. Prolonged mechanical ventilation > 21 days and tracheostomy were reduced in favour of automated systems (relative risk (RR) 0.51, 95% CI 0.27 to 0.95 and RR 0.67, 95% CI 0.50 to 0.90 respectively). Overall the quality of the evidence was high with the majority of trials rated as low risk. Automated closed loop systems may result in reduced duration of weaning, ventilation and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.
Twenty-six randomised trials involving 3388 participants were included. Overall the quality of trials, as reported, was poor. None of the studies investigated incidence of hypothyroidism, changes in weight, health-related quality of life, ophthalmopathy progression or economic outcomes. Four trials examined the effect of duration of therapy on relapse rates, and when using the titration regimen 12 months was superior to six months, but there was no benefit in extending treatment beyond 18 months. Twelve trials examined the effect of block-replace versus titration block-regimens. The relapse rates were similar in both groups at 51% in the block-replace group and 54% in the titration block-group (OR 0.86, 95% confidence interval (CI) 0.68 to1.08) though adverse effects (rashes (10% versus 6%) and withdrawing due to side effects (16% versus 9%)) were significantly higher in the block-replace group. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups was not significant (OR 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up (OR 1.15, 95% CI 0.79 to 1.67). Two studies considered the addition of immunosuppressive agents. The results which were in favour of the interventions would need to be validated in other populations. The evidence suggests that the optimal duration of antithyroid drug therapy for the titration regimen is 12 to 18 months. The titration (low dose) regimen had fewer adverse effects than the block-replace (high dose) regimen and was no less effective. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Immunosuppressive therapies need further evaluation.
We included 11 randomised controlled trials involving 2796 people. The quality of these studies was moderate to low, with most of the studies at unclear risk of bias in terms of random sequence generation and allocation concealment, and high risk of bias for blinded outcome assessment and selective outcome reporting. Five trials involving 581 people compared consumer-providers to professionals in similar roles within mental health services (case management roles (4 trials), facilitating group therapy (1 trial)). There were no significant differences in client quality of life (mean difference (MD) -0.30, 95% confidence interval (CI) -0.80 to 0.20); depression (data not pooled), general mental health symptoms (standardised mean difference (SMD) -0.24, 95% CI -0.52 to 0.05); client satisfaction with treatment (SMD -0.22, 95% CI -0.69 to 0.25), client or professional ratings of client-manager relationship; use of mental health services, hospital admissions and length of stay; or attrition (risk ratio 0.80, 95% CI 0.58 to 1.09) between mental health teams involving consumer-providers or professional staff in similar roles. There was a small reduction in crisis and emergency service use for clients receiving care involving consumer-providers (SMD -0.34 (95%CI -0.60 to -0.07). Past or present consumers who provided mental health services did so differently than professionals; they spent more time face-to-face with clients, and less time in the office, on the telephone, with clients' friends and family, or at provider agencies. Six trials involving 2215 people compared mental health services with or without the addition of consumer-providers. There were no significant differences in psychosocial outcomes (quality of life, empowerment, function, social relations), client satisfaction with service provision (SMD 0.76, 95% CI -0.59 to 2.10) and with staff (SMD 0.18, 95% CI -0.43 to 0.79), attendance rates (SMD 0.52 (95% CI -0.07 to 1.11), hospital admissions and length of stay, or attrition (risk ratio 1.29, 95% CI 0.72 to 2.31) between groups with consumer-providers as an adjunct to professional-led care and those receiving usual care from health professionals alone. One study found a small difference favouring the intervention group for both client and staff ratings of clients' needs having been met, although detection bias may have affected the latter. None of the six studies in this comparison reported client mental health outcomes. No studies in either comparison group reported data on adverse outcomes for clients, or the financial costs of service provision. Involving consumer-providers in mental health teams results in psychosocial, mental health symptom and service use outcomes for clients that were no better or worse than those achieved by professionals employed in similar roles, particularly for case management services. There is low quality evidence that involving consumer-providers in mental health teams results in a small reduction in clients' use of crisis or emergency services. The nature of the consumer-providers' involvement differs compared to professionals, as do the resources required to support their involvement. The overall quality of the evidence is moderate to low. There is no evidence of harm associated with involving consumer-providers in mental health teams. Future randomised controlled trials of consumer-providers in mental health services should minimise bias through the use of adequate randomisation and concealment of allocation, blinding of outcome assessment where possible, the comprehensive reporting of outcome data, and the avoidance of contamination between treatment groups. Researchers should adhere to SPIRIT and CONSORT reporting standards for clinical trials. Future trials should further evaluate standardised measures of clients' mental health, adverse outcomes for clients, the potential benefits and harms to the consumer-providers themselves (including need to return to treatment), and the financial costs of the intervention. They should utilise consistent, validated measurement tools and include a clear description of the consumer-provider role (eg specific tasks, responsibilities and expected deliverables of the role) and relevant training for the role so that it can be readily implemented. The weight of evidence being strongly based in the United States, future research should be located in diverse settings including in low- and middle-income countries.
Thirteen studies on 1505 infants were included. Infants given opioids showed reduced premature infant pain profile (PIPP) scores compared to the control group (weighted mean difference -1.71; 95% confidence interval -3.18 to -0.24). Differences in execution and reporting of trials mean that this meta-analysis should be interpreted with caution. Heterogeneity was significantly high in all analyses of pain, even when lower quality studies were excluded and analysis limited to very preterm newborns. Meta-analyses of mortality, duration of mechanical ventilation, and long and short-term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (weighted mean difference 2.10 days; 95% confidence interval 0.35 to 3.85). One study compared morphine with a sedative: the treatments showed similar pain scores, but morphine had fewer adverse effects. There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam. Further research is needed.
We included nine trials involving 1371 participants. Overall, results were mixed. Regarding five trials in clinical populations, three assessed smoking cessation behaviours, all featuring arterial scanning procedures to assess cardiovascular risk, and reported a statistically significant effect favouring the intervention, producing a pooled odds ratio (OR) of 2.81 (95% confidence interval (CI) 1.23 to 6.41, P = 0.01). One of these trials also measured physical activity and reported no statistically significant difference between the groups. A further trial measured skin examination behaviour following a skin photography procedure for assessing moles, and reported a statistically significant increase in favour of the intervention, with an OR of 4.86 (95% CI 1.95 to 12.10, P = 0.0007). The final clinical population trial measured a range of dietary intake and medication usage behaviours and featured an arterial scanning procedure assessing cardiovascular risk, and reported no statistically significant effects. Among the four trials in non-clinical populations, all featuring ultraviolet (UV) photography to highlight UV-related skin damage, a statistically significant result favouring the intervention was found in one trial for reducing tanning booth use, producing a mean difference (MD) of -1.10 (95% CI -1.90 to -0.30, P = .007) and one trial reported an outcome on which the control condition was favoured, with an MD of 0.45 (95% CI 0.04 to 0.86, P = 0.03) on intentional hours spent in the sun. In two further trials, no statistically significant behavioral effects were reported regarding time spent in the sun or sun protection behaviours. There was no evidence of significant adverse effects in the included trials, although this was not well reported. Due to the limited nature of the available evidence and the mixed results that were found, no strong statements can be made about the effectiveness of communicating medical imaging results to change health behaviour. Only three trials in clinical populations were similar enough in term of setting, intervention and outcome to allow meta-analysis. We suggest, however, that targeted interventions using medical imaging technologies may be effective in certain contexts, or as applied to certain behaviours, but that this should be considered on an intervention by intervention basis, and not assumed as a general principle.
Five studies (833 participants) were included; one was a very small pilot study of 7 participants. All studies compared oral ω-3FA supplements against placebo. Four studies enrolled participants with arteriovenous grafts (AVGs), and the other had participants with arteriovenous fistulas (AVFs). The risk of bias for both efficacy and safety outcomes was unclear for all studies, due mainly to incomplete reporting for allocation concealment and incompleteness of study follow-up. In AVF patients, ω-3FA supplementation probably makes little or no difference to the 12-month risk of patency loss (1 study, 536 participants: RR 1.01, 95% CI 0.84 to 1.21; moderate certainty evidence), risk of death (1 study, 567 participants: RD 0.00, 95% CI -0.03 to 0.02; moderate certainty evidence) and risk of hospitalisation (1 study, 567 participants: RD 0.00, 95% CI -0.08 to 0.08; low certainty evidence). There was no information on cardiovascular events and major bleeding. In AVG patients, it is very uncertain whether ω-3FA supplementation reduces the risk of patency loss within 6 months (2 studies, 41 participants: RR 0.91, 95% CI 0.36 to 2.28; very low certainty evidence) or 12 months (2 studies, 220 participants: RR 0.59, 95% CI 0.27 to 1.31; very low certainty evidence). ω-3FA supplementation may make little or no difference to the risk of death within 6 to 12 months in AVG patients (4 studies, 261 participants: RD 0.01, 95% CI -0.05 to 0.07; low certainty evidence). It is very uncertain if ω-3FA supplementation increases the risk of hospitalisation (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence), changes the risk of cardiovascular events (4 studies, 261 participants: RD -0.02, 95% CI -0.11 to 0.07; very low certainty evidence), or increases the risk of major bleeding (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence) within 6 to 12 months in AVG patients. There may be an increase in the risk of mild gastrointestinal adverse reactions (3 studies, 65 participants: RD 0.25, 95% CI 0.07 to 0.43; low certainty evidence) such as a sensation of bloatedness, gas or a fishy aftertaste. In CKD patients with an AVF, there is moderate certainty that ω-3FA supplementation makes little or no difference to preventing patency loss; and in patients with an AVG, it is very uncertain that ω-3FA supplementation prevents patency loss within 12 months.
We identified seven RCTs involving 403 participants. All the trials were at unclear risk of bias. Trials compared the use of phototherapy with standard care only (six trials) or sham phototherapy (one trial). Only one of the trials included a third arm in which another type of phototherapy was applied. Overall, there was insufficient evidence to determine the relative effects of phototherapy for healing pressure ulcers. Time to complete healing was reported in three studies. Two studies showed the ultraviolet (UV) treated group had a shorter mean time to complete healing than the control group (mean difference -2.13 weeks (95% CI -3.53 to -0.72, P value 0.003)). One study reported that the laser group had a longer mean time to complete healing than the control group (mean difference 5.77 weeks; 95% CI -0.25 to 11.79). However, this result should be interpreted with caution, as these were small studies and the findings may have been due to chance. Three studies reported proportions of ulcers healed with a variety of results. One study reported a different outcome measure, and the other two studies had different treatment durations. These variations did not allow us to pool the studies and draw any conclusions as to whether phototherapy is effective or not. Adverse effects were reported in only two studies that compared phototherapy with control; the risk ratio for adverse events was imprecise. One study reported risk ratio (RR) 0.72 (95%CI 0.18 to 2.80). However, another study reported RR 0.89 (95% CI: 0.71 to 1.12) based on the number of events in each group, rather than the number of people with events. Among five studies reporting the rate of change in ulcer area, three studies found no statistically significant difference between the two groups. Pooling was not undertaken because of differences in outcome measures reported. The results were based on data from trials with unclear risk of bias for which generation of the randomisation sequence, concealment allocation and blinding of outcome assessors were unclear. No studies reported on quality of life, length of hospital stay, pain or cost. We are very uncertain as to the effects of phototherapy in treating pressure ulcers. The quality of evidence is very low due to the unclear risk of bias and small number of trials available for analysis. The possibility of benefit or harm of this treatment cannot be ruled out. Further research is recommended.
We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation. The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence). Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence). Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.
We identified two studies with a total of 79 participants. One study, with 41 participants, compared cyclobenzaprine with clonazepam and with placebo. Participants taking cyclobenzaprine had some improvement of pain intensity compared to those on clonazepam, mean difference (MD) -0.25 (95% CI, -0.41 to -0.09; P value 0.002) and placebo, MD -0.25 (95% CI, 0.41 to -0.09; P value 0.002). The other study, with 38 participants, compared cyclobenzaprine with lidocaine infiltration. Thirty days after treatment there were statistically non-significant differences between comparison groups, favoring lidocaine infiltration, for the mean for global pain, MD 0.90 (95% CI -0.35 to 2.15, P value 0.16), and for the mean for pain at digital compression, MD 0.60 (95% CI -0.55 to 1.75, P value 0.30). There were no life-threatening adverse events associated with the medications. There was insufficient evidence to support the use of cyclobenzaprine in the treatment of MP. We identified only two small studies in which a total of 35 participants were given cyclobenzaprine, and it was not possible to estimate risks for benefits or harms. Further high quality RCTs of cyclobenzaprine for treating MP need to be conducted before firm conclusions on its effectiveness and safety can be made. Experts in this area should elect cut-off points for participants to identify whether a patient has achieved a clinically relevant reduction of pain (primary outcome), so that their results can be combined easily into future versions of this review.
Two randomised controlled trials have examined the effect of the aminosteroid tirilazad mesylate on death and disability following head injury. To date, only the results of one of these trials are available for analysis. The risk of death in patients treated with tirilazad was almost identical to those given placebo RR = 1.05 (95% confidence interval 0.86 to 1.29). The risk of death and severe disability in patients treated with tirilazad was again almost identical to those given placebo RR = 1.07 (95% confidence interval 0.93 to 1.23). There is no evidence to support the routine use of aminosteroids in the management of traumatic head injury. On the basis of the existing evidence from randomised trials of aminosteroids in head injury, it is not possible to refute the possibility of moderate but potentially clinically important benefits or harms. A further randomised controlled trial of tirilazad mesylate with 1156 participants has been completed, the results of which should become available in the near future.
Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.
From 2667 references, we identified two randomized studies, in six reports, that included 431 participants. All participants were clinically staged to have at least T3 and/or node positive thoracic esophageal carcinoma, 93% of which was squamous cell histology. The risk of methodological bias of the included studies was low to moderate. High-quality evidence found the addition of esophagectomy had little or no difference on overall survival (HR 0.99, 95% CI 0.79 to 1.24; P = 0.92; I² = 0%; two trials). Neither study reported PFS, therefore, freedom from loco-regional relapse was used as a proxy. Moderate-quality evidence suggested that the addition of esophagectomy probably improved freedom from locoregional relapse (HR 0.55, 95% CI 0.39 to 0.76; P = 0.0004; I² = 0%; two trials), but low-quality evidence suggested it may increase the risk of treatment-related mortality (RR 5.11, 95% CI 1.74 to 15.02; P = 0.003; I² = 2%; two trials). The other pre-specified outcomes (quality of life, treatment-related toxicity, and use of salvage procedures for dysphagia) were reported by only one study, which found very low-quality evidence that use of esophagectomy was associated with reduced short-term QoL (MD 0.93, 95% CI 0.24 to 1.62), and low-quality evidence that it reduced use of salvage procedures for dysphagia (HR 0.52, 95% CI 0.36 to 0.75). Neither study compared treatment-related morbidity between treatment groups. Based on the available evidence, the addition of esophagectomy to chemoradiotherapy in locally advanced esophageal squamous cell carcinoma, provides little or no difference on overall survival, and may be associated with higher treatment-related mortality. The addition of esophagectomy probably delays locoregional relapse, however, this end point was not well defined in the included studies. It is undetermined whether these results can be applied to the treatment of adenocarcinomas, tumors involving the distal esophagus and gastro-esophageal junction, and to people with poor response to chemoradiation.
We identified 21 trials and included three, reporting results from 131 participants lasting between three months and one year. Two trials compared supplements to additional nutritional advice and one to no intervention. Two of the included trials recruited only children. In one trial the risk of bias was low across all domains, in a second trial the risk of bias was largely unclear and in the third mainly low. Blinding of participants was unclear in two of the trials. Also, in one trial the clinical condition of groups appeared to be unevenly balanced at baseline and in another trial there were concerns surrounding allocation concealment. There were no significant differences between people receiving supplements or dietary advice alone for change in weight, height, body mass index, z score or other indices of nutrition or growth. Changes in weight (kg) at three, six and 12 months respectively were: mean difference (MD) 0.32 (95% confidence interval (CI) -0.09 to 0.72); MD 0.47 (95% CI -0.07 to 1.02 ); and MD 0.16 (-0.68 to 1.00). Total calorie intake was greater in people taking supplements at 12 months, MD 265.70 (95% CI 42.94 to 488.46). There were no significant differences between the groups for anthropometric measures of body composition, lung function, gastro-intestinal adverse effects or activity levels. Moderate quality evidence exists for the outcomes of changes in weight and height and low quality evidence exists for the outcomes of change in total calories, total fat and total protein intake as results are applicable only to children between the ages of 2 and 15 years and many post-treatment diet diaries were not returned. Evidence for the rate of adverse events in the treatment groups was extremely limited and judged to be of very low quality Oral calorie supplements do not confer any additional benefit in the nutritional management of moderately malnourished children with cystic fibrosis over and above the use of dietary advice and monitoring alone. While nutritional supplements may be used, they should not be regarded as essential. Further randomised controlled trials are needed to establish the role of short-term oral protein energy supplements in people with cystic fibrosis and acute weight loss and also for the long-term nutritional management of adults with cystic fibrosis or advanced lung disease, or both.
We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results. PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.
Two trials met the inclusion criteria. Faix 1988 randomised 42 premature infants with radiological diagnosis of NEC. Infants were randomised to receive either intravenous ampicillin and gentamicin or ampicillin, gentamicin and clindamycin. Hansen 1980 randomised 20 infants with NEC to receive intravenous ampicillin and gentamicin with or without enteral gentamicin. In the study by Faix 1988, there were no statistical differences in mortality (RR 1.10; 95% CI 0.32 to 3.83) or bowel perforation (RR 2.20; 95% CI 0.45 to 10.74) between the two groups although there was a trend towards higher rate of strictures in the group that received clindamycin (RR 7.20; 95% CI 0.97 to 53.36). The Hansen 1980 study showed no statistically significant difference in death, bowel perforation or development of strictures. There was insufficient evidence to recommend a particular antibiotic regimen for the treatment of NEC. There were concerns about adverse effects following the usage of clindamycin, related to the development of strictures. To address this issue a large randomised controlled trial needs to be performed.
We included 10 trials involving 1967 patients undergoing 2157 operations. The quality of trials was generally poor. Follow up varied from hospital discharge to five years. Carotid patch angioplasty was associated with a reduction in the risk of ipsilateral stroke during the perioperative period (odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15 to 0.63, P = 0.001) and long-term follow up (OR 0.32, 95%CI 0.16 to 0.63, P = 0.001). It was also associated with a reduced risk of perioperative arterial occlusion (OR 0.18, 95% CI 0.08 to 0.41, P < 0.0001), and decreased restenosis during long-term follow up in eight trials (OR 0.24, 95% CI 0.17 to 0.34, P < 0.00001). These results are more certain than those of the previous review since the number of operations and events have increased. However, the sample sizes are still relatively small, data were not available from all trials, and there was significant loss to follow up. Very few arterial complications, including haemorrhage, infection, cranial nerve palsies and pseudo-aneurysm formation were recorded with either patch or primary closure. No significant correlation was found between use of patch angioplasty and the risk of either perioperative or long-term all-cause death rates. Limited evidence suggests that carotid patch angioplasty may reduce the risk of perioperative arterial occlusion and restenosis. It would appear to reduce the risk of ipsilateral stroke and there is a non significant trend towards a reduction in perioperative any stroke rate and all-cause case fatality.
As a result of searches undertaken in 2014, we found one new study and in 2016 more data for already included studies. Five relevant studies with 1132 participants (585 are relevant to this review) are now included. All are hospital-based trials and, despite over 60 years of chlorpromazine use, have durations of less than six months and all are at least at moderate risk of bias. We found only data on low-dose (≤ 400 mg/day) versus medium-dose chlorpromazine (401 mg/day to 800 mg/day) and low-dose versus high-dose chlorpromazine (> 800 mg/day). When low-dose chlorpromazine (≤ 400 mg/day) was compared to medium-dose chlorpromazine (401 mg/day to 800 mg/day), there was no clear benefit of one dose over the other for both global and mental state outcomes (low-quality and very low-quality evidence). There was also no clear evidence for people in one dosage group being more likely to leave the study early, over the other dosage group (moderate-quality evidence). Similar numbers of participants from each group experienced agitation and restlessness (very low-quality evidence). However, significantly more people in the medium-dose group (401 mg/day to 800 mg/day) experienced extrapyramidal symptoms in the short term (2 RCTS, n = 108, RR 0.47, 95% CI 0.30 to 0.74, moderate-quality evidence). No data for death were available. When low-dose chlorpromazine (≤ 400 mg/day) was compared to high-dose chlorpromazine (> 800 mg/day), data from one study with 416 patients were available. Clear evidence of a benefit of the high dose was found with regards to global state. The low-dose group had significantly fewer people improving (RR 1.13, 95% CI 1.01 to 1.25, moderate-quality evidence). There was also a marked difference between the number of people leaving the study from each group for any reason, with significantly more people leaving from the high-dose group (RR 0.60, 95% CI 0.40 to 0.89, moderate-quality evidence). More people in the low-dose group had to leave the study due to deterioration in behaviour (RR 2.70, 95% CI 1.34 to 5.44, low-quality evidence). There was clear evidence of a greater risk of people experiencing extrapyramidal symptoms in general in the high-dose group (RR 0.43, 95% CI 0.32 to 0.59, moderate-quality evidence). One death was reported in the high-dose group yet no effect was shown between the two dosage groups (RR 0.33, 95% CI 0.01 to 8.14, moderate-quality evidence). No data for mental state were available. The dosage of chlorpromazine has changed drastically over the past 50 years with lower doses now being the preferred of choice. However, this change was gradual and arose not due to trial-based evidence, but due to clinical experience and consensus. Chlorpromazine is one of the most widely used antipsychotic drugs yet appropriate use of lower levels has come about after many years of trial and error with much higher doses. In the absence of high-grade evaluative studies, clinicians have had no alternative but to learn from experience. However, such an approach can lack scientific rigor and does not allow for proper dissemination of information that would assist clinicians find the optimum treatment dosage for their patients. In the future, data for recently released medication should be available from high-quality trials and studies to provide optimum treatment to patients in the shortest amount of time.
A total of 12 randomised trials were identified, totaling 843 patients. The size of the randomised clinical trials ranged from 30 to 155 patients. Both preoperative (neoadjuvant) and postoperative (adjuvant), systemic and locoregional (+/- embolisation), chemo- and immunotherapy interventions were tested. Treatment regimens and patients selected were not comparable, so no pooling was done. Only one regimen using preoperative transcatheter arterial chemoembolisation with doxorubicin was similar in two trials. Four of the twelve trials reported survival benefit at five years when given adjuvant or neoadjuvant therapy. Disease-free survival was reported in nine trials, and the estimated hazard ratios show that disease-free survival was significant in two trials at five years. These two trials had not shown a survival advantage, but the recurrence was significantly lower in patients given adjuvant or neoadjuvant therapy. The highest toxicity rate was in a trial using oral 1-hexylcarbamoyl 5-fluorouracil which resulted in 12 out of 38 patients being withdrawn from the trial because of adverse events. There is no clear evidence for efficacy of any of the adjuvant and neo-adjuvant protocols reviewed, but there is some evidence to suggest that adjuvant therapy may be beneficial offering prolonged disease-free survival. In order to detect a realistic treatment advantage, larger trials with lower risk of systematic error will have to be conducted.
We included two RCTs, that randomised 514 pregnant women (347 women analysed) at a mean gestational age of 22 weeks. Both trials were conducted in the outpatient department of the same two hospitals in the USA between 1993 and 2001, and had a follow-up of 14 days. One of the trials was sponsored by a drug company. We considered both trials to be at a high risk of bias. One trial compared ceftriaxone (125 mg, intramuscular) with cefixime (400 mg, oral); the other trial had three arms, and assessed ceftriaxone (250 mg, intramuscular) versus either amoxicillin (3 g, oral) plus probenecid (1 g, oral) or spectinomycin (2 g, intramuscular). We did not include the spectinomycin data because this medication is no longer produced. We were unable to conduct meta-analysis because the trials compared different medications. We found inconclusive evidence that there were clear differences in the cure of gonococcal infections (genital, extragenital, or both) between intramuscular ceftriaxone versus oral amoxicillin plus oral probenecid (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.98 to 1.16; one RCT; 168 women; very low-quality evidence) or intramuscular ceftriaxone versus oral cefixime (RR 0.99, 95% CI 0.91 to 1.08; one RCT; 95 women; very low-quality evidence). Neither of the trials reported on two of this review's primary maternal outcomes: incidence of obstetric complications (miscarriage, premature rupture of membranes, preterm delivery, or fetal death), or disseminated gonococcal infection, or on the incidence of neonatorum ophthalmia in the neonates. One trial reported one case of vomiting in the oral amoxacillin plus probenecid group. Trials reported pain at the injection sites, but did not quantify it. Hyperberbilurrubinemia was more frequent in neonates whose mothers were exposed to ceftriaxone. There were no clear differences between groups for neonatal malformation. This Cochrane Review found high levels of cure of gonococcal infections in pregnancy with the given antibiotic regimens. However, the evidence in this review is inconclusive as it does not support one particular regimen over another. This conclusion was based on very low-quality evidence (downgraded for poor trial design, imprecision) from two trials (involving 514 women), which we assessed to be at a high risk of bias for a number of domains. The harm profiles of the antibiotic regimes featured in this review remain unknown. High-quality RCTs are needed, with sufficient power to assess the clinical effectiveness and potential harms of antibiotics in pregnant women with gonorrhoea. These should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT),conducted following CONSORT recommendations, and based on Patient-Centered Outcomes Research Institute (PCORI) outcomes.
Eight RCTs involving 358,750 participants were included. These trials investigated two available and three pre-licensure vaccines. Two RCTs assessing efficacy of the commercially available inactivated Nakayama vaccine were identified. A two-dose schedule of the licensed vaccine provided significant protection of 95% (95% CI 10% to 100%) for one year only, while two doses of an unpurified precursor vaccine protected children by 81% (95% CI 45% to 94%) in year one and by 59% (95% CI 2% to 83%) in year two. Serious adverse events were not observed. Mild and moderate episodes of injection site soreness, fever, headache, and nausea were reported in less than 6% of children receiving inactivated vaccine compared to 0.6% of unvaccinated controls. One cluster-RCT compared the live-attenuated SA14-14-2 vaccine (widely used in China) with no intervention measuring adverse events. Fever was reported in 2.7% of vaccinees compared to 3.1% of controls, while 0.1% of both groups suffered diarrhoea or seizures. Four small pre-licensure RCTs assessing a genetically engineered vaccine and two cell culture-derived inactivated vaccines revealed high immunogenicity and relative safety. Only one of the three currently used vaccines has been assessed for efficacy in a RCT. Other RCTs have assessed their safety, however, and they appear to cause only occasional mild or moderate adverse events. Further trials of effectiveness and safety are needed for the currently used vaccines, especially concerning dose levels and schedules. Trials investigating several new vaccines are planned or in progress.
Twenty-two randomised trials were included in the review (N = 695). Studies were highly variable in their country of origin, sample size, participant age, intervention delivery type, and outcome measures. Risk of bias was variable across categories. There were very few studies for which there was adequate blinding of participants and personnel, and some were also judged at high risk of bias in blinding of outcome assessors. There was also evidence of some bias in sequence generation and allocation concealment. Not all studies reported data that fell within the pre-defined primary outcome categories for the review, instead many studies reported measures which were intervention-specific (e.g. emotion recognition). The wide range of measures used within each outcome category and the mixed results from these measures introduced further complexity when interpreting results. Studies were grouped into four main categories according to intervention target/primary outcome measure. These were: emotion recognition studies, joint attention and social communication studies, imitation studies, and studies teaching ToM itself. Within the first two of these categories, a sub-set of studies were deemed suitable for meta-analysis for a limited number of key outcomes. There was very low quality evidence of a positive effect on measures of communication based on individual results from three studies. There was low quality evidence from 11 studies reporting mixed results of interventions on measures of social interaction, very low quality evidence from four studies reporting mixed results on measures of general communication, and very low quality evidence from four studies reporting mixed results on measures of ToM ability. The meta-analysis results we were able to generate showed that interventions targeting emotion recognition across age groups and working with people within the average range of intellectual ability had a positive effect on the target skill, measured by a test using photographs of faces (mean increase of 0.75 points, 95% confidence interval (CI) 0.22 to 1.29 points, Z = 2.75, P < 0.006, four studies, N = 105). Therapist-led joint attention interventions can promote production of more joint attention behaviours within adult-child interaction (mean increase of 0.55 points, 95% CI 0.11 to 0.99 points, Z = 2.45, P value = 0.01, two studies, N = 88). Further analysis undermines this conclusion somewhat by demonstrating that there was no clear evidence that intervention can have an effect on joint attention initiations as measured using a standardised assessment tool (mean increase of 0.23 points, 95% CI -0.48 to 0.94 points, Z = 0.63, P value = 0.53, three studies, N = 92). No adverse effects were apparent. While there is some evidence that ToM, or a precursor skill, can be taught to people with ASD, there is little evidence of maintenance of that skill, generalisation to other settings, or developmental effects on related skills. Furthermore, inconsistency in findings and measurement means that evidence has been graded of 'very low' or 'low' quality and we cannot be confident that suggestions of positive effects will be sustained as high-quality evidence accumulates. Further longitudinal designs and larger samples are needed to help elucidate both the efficacy of ToM-linked interventions and the explanatory value of the ToM model itself. It is possible that the continuing refinement of the ToM model will lead to better interventions which have a greater impact on development than those investigated to date.
This review included 63 trials which randomised 14,486 people with CHD. This latest update identified 16 new trials (3872 participants). The population included predominantly post-MI and post-revascularisation patients and the mean age of patients within the trials ranged from 47.5 to 71.0 years. Women accounted for fewer than 15% of the patients recruited. Overall trial reporting was poor, although there was evidence of an improvement in quality of reporting in more recent trials. As we found no significant difference in the impact of exercise-based CR on clinical outcomes across follow-up, we focused on reporting findings pooled across all trials at their longest follow-up (median 12 months). Exercise-based CR reduced cardiovascular mortality compared with no exercise control (27 trials; risk ratio (RR) 0.74, 95% CI 0.64 to 0.86). There was no reduction in total mortality with CR (47 trials, RR 0.96, 95% CI 0.88 to 1.04). The overall risk of hospital admissions was reduced with CR (15 trials; RR 0.82, 95% CI 0.70 to 0.96) but there was no significant impact on the risk of MI (36 trials; RR 0.90, 95% CI 0.79 to 1.04), CABG (29 trials; RR 0.96, 95% CI 0.80 to 1.16) or PCI (18 trials; RR 0.85, 95% CI 0.70 to 1.04). There was little evidence of statistical heterogeneity across trials for all event outcomes, and there was evidence of small study bias for MI and hospitalisation, but no other outcome. Predictors of clinical outcomes were examined across the longest follow-up of studies using univariate meta-regression. Results show that benefits in outcomes were independent of participants' CHD case mix (proportion of patients with MI), type of CR (exercise only vs comprehensive rehabilitation) dose of exercise, length of follow-up, trial publication date, setting (centre vs home-based), study location (continent), sample size or risk of bias. Given the heterogeneity in outcome measures and reporting methods, meta-analysis was not undertaken for HRQL. In five out of 20 trials reporting HRQL using validated measures, there was evidence of significant improvement in most or all of the sub-scales with exercise-based CR compared to control at follow-up. Four trial-based economic evaluation studies indicated exercise-based CR to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life years. The quality of the evidence for outcomes reported in the review was rated using the GRADE method. The quality of the evidence varied widely by outcome and ranged from low to moderate. This updated Cochrane review supports the conclusions of the previous version of this review that, compared with no exercise control, exercise-based CR reduces the risk of cardiovascular mortality but not total mortality. We saw a significant reduction in the risk of hospitalisation with CR but not in the risk of MI or revascularisation. We identified further evidence supporting improved HRQL with exercise-based CR. More recent trials were more likely to be well reported and include older and female patients. However, the population studied in this review still consists predominantly of lower risk individuals following MI or revascularisation. Further well conducted RCTs are needed to assess the impact of exercise-based CR in higher risk CHD groups and also those presenting with stable angina. These trials should include validated HRQL outcome measures, explicitly report clinical event outcomes including mortality and hospital admissions, and assess costs and cost-effectiveness.
We included two trials (535 women) in the review. The trials found no difference between groups for the primary outcomes of pain intensity, assisted vaginal birth (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.48 to 2.28, one trial, 513 women; RR 0.83, 95% CI 0.06 to 11.70, one trial, 22 women), and caesarean section (RR 0.98, 95% CI 0.49 to 1.94, one trial, 513 women; RR 2.54, 95% CI 0.11 to 56.25, one trial, 22 women); there were more babies admitted to neonatal intensive care in the control group of one trial (RR 0.08, 95% CI 0.00 to 1.42, one trial, 513 women) but this difference did not reach statistical significance. The trials found no differences between groups for the secondary outcomes of use of pharmacological pain relief (RR 0.35, 95% CI 0.04 to 3.32, one trial, 513 women; RR 2.50, 95% CI 0.31 to 20.45, one trial, 22 women), spontaneous vaginal delivery (RR 1.00, 95% CI 0.94 to 1.06, one trial, 513 women; RR 0.93, 95% CI 0.67 to 1.28, one trial, 22 women) or length of labour and augmentation (RR 1.14, 95% CI 0.90 to 1.45, one trial, 513 women). The risk of bias was low in the trials. There is a lack of studies evaluating the role of aromatherapy for pain management in labour. Further research is needed before recommendations can be made for clinical practice.
Only six RCTs met the criteria for inclusion. The study characteristics differed substantially in terms of healthcare settings, the nature of the interventions studied and outcome measures reported. In three studies that compared the effect of an education-centred complex intervention with usual care or written instructions, only little evidence of benefit was found. Three studies compared the effect of more intensive and comprehensive complex interventions with usual care. One study found a significant and cost-effective reduction, one of lower extremity amputations (RR 0.30, 95% CI 0.31 to 0.71). One other study found a significant reduction of both amputation and foot ulcers. The last study reported improvement of patients' self care behaviour. All six included RCTs were at high risk of bias, with hardly any of the predefined quality assessment criteria met. There is no high-quality research evidence evaluating complex interventions for preventing diabetic foot ulceration and insufficient evidence of benefit.
A total of 59 studies, mostly of low quality, were included in the review, involving multiple treatment comparisons between sertraline and other antidepressant agents. Evidence favouring sertraline over some other antidepressants for the acute phase treatment of major depression was found, either in terms of efficacy (fluoxetine) or acceptability/tolerability (amitriptyline, imipramine, paroxetine and mirtazapine). However, some differences favouring newer antidepressants in terms of efficacy (mirtazapine) and acceptability (bupropion) were also found. In terms of individual side effects, sertraline was generally associated with a higher rate of participants experiencing diarrhoea. This systematic review and meta-analysis highlighted a trend in favour of sertraline over other antidepressive agents both in terms of efficacy and acceptability, using 95% confidence intervals and a conservative approach, with a random effects analysis. However, the included studies did not report on all the outcomes that were pre-specified in the protocol of this review. Outcomes of clear relevance to patients and clinicians were not reported in any of the included studies.
The updated review included 16 new studies involving 25,819 participants, resulting in a total of 42 studies including 33,840 participants. We used the Cochrane risk of bias tool and assessed three studies at high risk of bias; the remainder were considered to have a low risk of bias. We included 26 studies that predominantly evaluated organisational interventions and 16 that evaluated educational and behavioural interventions for participants. We pooled results where appropriate, although some clinical and methodological heterogeneity was present. Educational and behavioural interventions showed no clear differences on any of the review outcomes, which include mean systolic and diastolic blood pressure, mean body mass index, achievement of HbA1c target, lipid profile, mean HbA1c level, medication adherence, or recurrent cardiovascular events. There was moderate-quality evidence that organisational interventions resulted in improved blood pressure control, in particular an improvement in achieving target blood pressure (odds ratio (OR) 1.44, 95% confidence interval (CI) 1.09 to1.90; 13 studies; 23,631 participants). However, there were no significant changes in mean systolic blood pressure (mean difference (MD), -1.58 mmHg 95% CI -4.66 to 1.51; 16 studies; 17,490 participants) and mean diastolic blood pressure (MD -0.91 mmHg 95% CI -2.75 to 0.93; 14 studies; 17,178 participants). There were no significant changes in the remaining review outcomes. We found that organisational interventions may be associated with an improvement in achieving blood pressure target but we did not find any clear evidence that these interventions improve other modifiable risk factors (lipid profile, HbA1c, medication adherence) or reduce the incidence of recurrent cardiovascular events. Interventions, including patient education alone, did not lead to improvements in modifiable risk factor control or the prevention of recurrent cardiovascular events.
We identified six randomised controlled trials that met inclusion criteria (607 participants). We found moderate quality evidence from two studies of no difference between methadone and buprenorphine in self reported opioid use (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.08 to 1.63) or opioid positive urine drug tests (RR 0.81, 95% CI 0.56 to 1.18). There was low quality evidence from three studies of no difference in retention between buprenorphine and methadone maintenance treatment (RR 0.69, 95% CI 0.39 to 1.22). There was moderate quality evidence from two studies of no difference between methadone and buprenorphine on adverse events (RR 1.10, 95% CI 0.64 to 1.91). We found low quality evidence from three studies favouring maintenance buprenorphine treatment over detoxification or psychological treatment in terms of fewer opioid positive urine drug tests (RR 0.63, 95% CI 0.43 to 0.91) and self reported opioid use in the past 30 days (RR 0.54, 95% CI 0.31 to 0.93). There was no difference on days of unsanctioned opioid use (standardised mean difference (SMD) -0.31, 95% CI -0.66 to 0.04). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on retention in treatment (RR 0.33, 95% CI 0.23 to 0.47). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on adverse events (RR 0.19, 95% CI 0.06 to 0.57). The main weaknesses in the quality of the data was the use of open-label study designs. There was low to moderate quality evidence supporting the use of maintenance agonist pharmacotherapy for pharmaceutical opioid dependence. Methadone or buprenorphine appeared equally effective. Maintenance treatment with buprenorphine appeared more effective than detoxification or psychological treatments. Due to the overall low to moderate quality of the evidence and small sample sizes, there is the possibility that the further research may change these findings.
We have included four studies, published between 1974 and 2003, randomising 276 people with schizophrenia to receive either chlorpromazine or clotiapine. The studies were poor at concealing allocation of treatment and blinding of outcome assessment. Our main outcomes of interest were clinically important change in global and mental state, specific change in negative symptoms, incidence of movement disorder (dyskinesia), leaving the study early for any reason, and costs. All reported data were short-term (under six months' follow-up). The trials did not report data for the important outcomes of clinically important change in global or mental state, or cost of care. Improvement in mental state was reported using the Positive and Negative Syndrome Scale (PANSS). When chlorpromazine was compared with clotiapine the average improvement scores for mental state using the PANSS total was higher in the clotiapine group (1 RCT, N = 31, MD 11.50 95% CI 9.42 to 13.58, very low-quality evidence). The average change scores on the PANSS negative sub-scale were similar between treatment groups (1 RCT, N = 21, MD -0.97 95% CI -2.76 to 0.82, very low-quality evidence). There was no clear difference in incidence of dyskinesia (1 RCT, N = 68, RR 3.00 95% CI 0.13 to 71.15, very low-quality evidence). Similar numbers of participants left the study early from each treatment group (3 RCTs, N = 158, RR 0.68 95% CI 0.24 to 1.88, very low-quality evidence). Clinically important changes in global and mental state were not reported. Only one trial reported the average change in overall mental state; results favour clotiapine but these limited data are very difficult to trust due to methodological limitations of the study. The comparative effectiveness of chlorpromazine compared to clotiapine on change in global state remains unanswered. Results in this review suggest chlorpromazine and clotiapine cause similar adverse effects, although again, the quality of evidence for this is poor, making firm conclusions difficult.
We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women. DHA-P versus artemether-lumefantrine In Africa, over 28 days follow-up, DHA-P is superior to artemether-lumefantrine at preventing further parasitaemia (PCR-unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA-P (PCR-adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA-P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR-unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence). In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence). Compared to artemether-lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence). DHA-P versus artesunate plus mefloquine In Asia, over 28 days follow-up, DHA-P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR-unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA-P in two trials (PCR-adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half-lives and no consistent benefit in preventing new infections has been seen over 63 days follow-up (PCR-unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence). In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR-unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR-adjusted treatment failure: one trial, 435 participants, low quality evidence). DHA-P is associated with less nausea, vomiting, dizziness, sleeplessness, and palpitations compared to artesunate plus mefloquine (moderate quality evidence). DHA-P was associated with more frequent prolongation of the QTc interval (low quality evidence), but no cardiac arrhythmias were reported. In Africa, dihydroartemisinin-piperaquine reduces overall treatment failure compared to artemether-lumefantrine, although both drugs have PCR-adjusted failure rates of less than 5%. In Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.
We found 43 studies that met the inclusion criteria, and more evidence was provided for fluticasone (26 studies; n = 21,247) than for budesonide (17 studies; n = 10,150). Evidence from the budesonide studies was more inconsistent and less precise, and the studies were shorter. The populations within studies were more often male with a mean age of around 63, mean pack-years smoked over 40 and mean predicted forced expiratory volume of one second (FEV1) less than 50%. High or uneven dropout was considered a high risk of bias in almost 40% of the trials, but conclusions for the primary outcome did not change when the trials at high risk of bias were removed in a sensitivity analysis. Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality), and no evidence suggested that this outcome was reduced by delivering it in combination with salmeterol or vilanterol (subgroup differences: I2 = 0%, P value 0.51), or that different doses, trial duration or baseline severity significantly affected the estimate. Budesonide also increased non-fatal serious adverse pneumonia events compared with placebo, but the effect was less precise and was based on shorter trials (OR 1.62, 95% CI 1.00 to 2.62; six more per 1000 treated over nine months; moderate quality). Some of the variation in the budesonide data could be explained by a significant difference between the two commonly used doses: 640 mcg was associated with a larger effect than 320 mcg relative to placebo (subgroup differences: I2 = 74%, P value 0.05). An indirect comparison of budesonide versus fluticasone monotherapy revealed no significant differences with respect to serious adverse events (pneumonia-related or all-cause) or mortality. The risk of any pneumonia event (i.e. less serious cases treated in the community) was higher with fluticasone than with budesonide (OR 1.86, 95% CI 1.04 to 3.34); this was the only significant difference reported between the two drugs. However, this finding should be interpreted with caution because of possible differences in the assignment of pneumonia diagnosis, and because no trials directly compared the two drugs. No significant difference in overall mortality rates was observed between either of the inhaled steroids and the control interventions (both high-quality evidence), and pneumonia-related deaths were too rare to permit conclusions to be drawn. Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort data and established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significant difference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potential confounding factor in their comparison. Primary research should accurately measure pneumonia outcomes and should clarify both the definition and the method of diagnosis used, especially for new formulations and combinations for which little evidence of the associated pneumonia risk is currently available. Similarly, systematic reviews and cohorts should address the reliability of assigning 'pneumonia' as an adverse event or cause of death and should determine how this affects the applicability of findings.
Four studies with a total of 136 participants were included. Two studies compared the use of plugs versus no plugs, one study compared two sizes of the same brand of plug, and one study compared two brands of plugs. In all included studies there was considerable dropout (in total 48 (35%) dropped out before the end of the study) for varying reasons. Data presented are thus subject to potential bias. 'Pseudo-continence' was, however, achieved by some of those who continued to use plugs, at least in the short-term. In a comparison of two different types of plug, plug loss was less often reported and overall satisfaction was greater during use of polyurethane plugs than polyvinyl-alcohol plugs. The available data were limited and incomplete, and not all pre-specified outcomes could be evaluated. Consequently, only tentative conclusions are possible. The available data suggest that anal plugs can be difficult to tolerate. However, if they are tolerated they can be helpful in preventing incontinence. Plugs could then be useful in a selected group of people either as a substitute for other forms of management or as an adjuvant treatment option. Plugs come in different designs and sizes; the review showed that the selection of the type of plug can impact on its performance.
Sixteen trials (1565 participants) met the inclusion criteria. Seven studies investigated some form of patient education. In six of these studies this education was combined with other behavioural change interventions including tailoring daily routines to promote adherence to eye drops. Eight studies compared different drug regimens (one of these trials also compared open and masked monitoring) and one study investigated a reminder device. The studies were of variable quality and some were at considerable risk of bias; in general, the length of follow-up was short at less than six months with only two studies following up to 12 months. Different interventions and outcomes were reported and so it was not possible to produce an overall estimate of effect. There was some evidence from three studies that education combined with personalised interventions, that is, more complex interventions, improved adherence to ocular hypotensive therapy. There was less information on other outcomes such as persistence and intraocular pressure, and no information on visual field defects, quality of life and cost. There was weak evidence as to whether people on simpler drug regimens were more likely to adhere and persist with their ocular hypotensive therapy. A particular problem was the interpretation of cross-over studies, which in general were not reported correctly. One study investigated a reminder device and monitoring but the study was small and inconclusive. Although complex interventions consisting of patient education combined with personalised behavioural change interventions, including tailoring daily routines to promote adherence to eye drops, may improve adherence to glaucoma medication, overall there is insufficient evidence to recommend a particular intervention. The interventions varied between studies and none of the included studies reported on the cost of the intervention. Simplified drug regimens also could be of benefit but again the current published studies do not provide conclusive evidence. Future studies should follow up for at least one year, and could benefit from standardised outcomes.
Twelve trials (1241 patients) evaluated antibiotic prophylaxis compared with placebo or no antibiotic prophylaxis. All trials were at risk of bias. Antibiotic prophylaxis compared with no intervention or placebo was associated with beneficial effects on mortality (RR 0.79, 95% CI 0.63 to 0.98), mortality from bacterial infections (RR 0.43, 95% CI 0.19 to 0.97), bacterial infections (RR 0.36, 95% CI 0.27 to 0.49), rebleeding (RR 0.53, 95% CI 0.38 to 0.74), days of hospitalisation (MD -1.91, 95% CI -3.80 to -0.02), bacteraemia (RR 0.25, 95% CI 0.15 to 0.40), pneumonia (RR 0.45, 95% CI 0.27 to 0.75), spontaneous bacterial peritonitis (RR 0.29, 95% CI 0.15 to 0.57), and urinary tract infections (RR 0.23, 95% CI 0.12 to 0.41). No serious adverse events were reported. The trials showed no significant heterogeneity of effects. Another five trials (650 patients) compared different antibiotic regimens. Data could not be combined as each trial used different antibiotic regimen. None of the examined antibiotic regimen was superior to the control regimen regarding mortality or bacterial infections. Prophylactic antibiotic use in patients with cirrhosis and upper gastrointestinal bleeding significantly reduced bacterial infections, and seems to have reduced all-cause mortality, bacterial infection mortality, rebleeding events, and hospitalisation length. These benefits were observed independently of the type of antibiotic used; thus, no specific antibiotic can be preferred. Therefore, antibiotic selection should be made considering local conditions such as bacterial resistance profile and treatment cost.
Two trials (92 participants) met our inclusion criteria. Participants in both trials were followed for 12 months. Neither trial compared surgery to placebo surgery. One trial (40 randomised participants) compared open surgical excision with eccentric exercises, and the other compared arthroscopic surgery with sclerosing injections (52 randomised participants). Due to the nature of the interventions, neither the participants or the investigators were blinded to the group allocation, resulting in the potential for performance and detection bias. Some outcomes were selectively not recorded, leading to reporting bias. Overall, the certainty of the evidence from these studies was low for all outcomes due to the potential for bias, and imprecision due to small sample sizes. Compared with eccentric exercises, low-certainty evidence indicates that open surgical excision provides no clinically important benefits with respect to knee pain, function or global assessment of success. At 12 months, mean knee pain — measured by pain with standing jump on a 10-point scale (lower scores indicating less pain) — was 1.7 points (standard deviation (SD) 1.6) in the eccentric training group and 1.3 (SD 0.8) in the surgical group (one trial, 40 participants). This equates to an absolute pain reduction of 4% (ranging from 4% worse to 12% better, the minimal clinically important difference being 15%) and a relative reduction in pain of 10% better (ranging from 30% better to 10% worse) in the treatment group. At 12 months, function on the zero- to 100-point Victorian Institute of Sport Assessment (VISA) scale was 65.7 (SD 23.8) in the eccentric training group and 72.9 (SD 11.7) in the surgical group (one trial, 40 participants). This equates to an absolute change of 7% better function (ranging from 4% worse to 19% better) and relative change of 25% better (ranging from 15% worse to 65% better, the minimal clinically important difference being 13%). Participant global assessment of success was measured by the number of people with no pain at 12 months: 7/20 participants in the eccentric training group reported no pain, compared with 5/20 in the open surgical group (risk ratio (RR) 0.71 (95% CI 0.27 to 1.88); one trial, 40 participants). There were no withdrawals, but five out of 20 people from the eccentric exercise group crossed over to open surgical excision. Quality of life, adverse events and tendon ruptures were not measured. Compared with sclerosing injection, low-certainty evidence indicates that arthroscopic surgery may provide a reduction in pain and improvement in participant global assessment of success, however further studies are likely to change these results. At 12 months, mean pain with activities, measured on a 100-point scale (lower scores indicating less pain), was 41.1 (SD 28.5) in the sclerosing injection group and 12.8 (SD 19.3) in the arthroscopic surgery group (one trial, 52 participants). This equates to an absolute pain reduction of 28% better (ranging from 15% to 42% better, the minimal clinically important difference being 15%), and a relative change of 41% better (ranging from 21% to 61% better). At 12 months, the mean participant global assessment of success, measured by satisfaction on a 100-point scale (scale zero to 100, higher scores indicating greater satisfaction), was 52.9 (SD 32.6) in the sclerosing injection group and 86.8 (SD 20.8) in the arthroscopic surgery group (one trial, 52 participants). This equates to an absolute improvement of 34% (ranging from 19% to 49%). In both groups, one participant (4%) withdrew from the study. Functional outcome scores, including the VISA score, were not reported. Quality-of-life assessment, adverse events, and specifically the proportion with a tendon rupture, were not reported. We did not perform subgroup analysis to assess differences in outcome between arthroscopic or open surgical excision, as we did not identify more than one study with a common comparator. We are uncertain if surgery is beneficial over other therapeutic interventions, namely eccentric exercises or injectables. Low-certainty evidence shows that surgery for patellar tendinopathy may not provide clinically important benefits over eccentric exercise in terms of pain, function or participant-reported treatment success, but may provide clinically meaningful pain reduction and treatment success when compared with sclerosing injections. However, further research is likely to change these results. The evidence was downgraded two levels due to the small sample sizes and susceptibility to bias. We are uncertain if there are additional risks associated with surgery as study authors failed to report adverse events. Surgery seems to be embedded in clinical practice for late-stage patella tendinopathy, due to exhaustion of other therapeutic methods rather than evidence of benefit.
We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported. MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death-censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody-treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta-regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro-emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures. Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue-invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue-invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on.
We included two studies (involving a total of 49 women). Each study compared yoga to a different comparator, therefore we were unable to combine the data in a meta-analysis. A third study that has been completed but not yet fully reported is awaiting assessment. One included study was a six-week study comparing yoga to a waiting list in 19 women with either urgency urinary incontinence or stress urinary incontinence. We judged the certainty of the evidence for all reported outcomes as very low due to performance bias, detection bias, and imprecision. The number of women reporting cure was not reported. We are uncertain whether yoga results in satisfaction with cure or improvement of incontinence (risk ratio (RR) 6.33, 95% confidence interval (CI) 1.44 to 27.88; an increase of 592 from 111 per 1000, 95% CI 160 to 1000). We are uncertain whether there is a difference between yoga and waiting list in condition-specific quality of life as measured on the Incontinence Impact Questionnaire Short Form (mean difference (MD) 1.74, 95% CI -33.02 to 36.50); the number of micturitions (MD -0.77, 95% CI -2.13 to 0.59); the number of incontinence episodes (MD -1.57, 95% CI -2.83 to -0.31); or the bothersomeness of incontinence as measured on the Urogenital Distress Inventory 6 (MD -0.90, 95% CI -1.46 to -0.34). There was no evidence of a difference in the number of women who experienced at least one adverse event (risk difference 0%, 95% CI -38% to 38%; no difference from 222 per 1000, 95% CI 380 fewer to 380 more). The second included study was an eight-week study in 30 women with urgency urinary incontinence that compared mindfulness-based stress reduction (MBSR) to an active control intervention of yoga classes. The study was unblinded, and there was high attrition from both study arms for all outcome assessments. We judged the certainty of the evidence for all reported outcomes as very low due to performance bias, attrition bias, imprecision and indirectness. The number of women reporting cure was not reported. We are uncertain whether women in the yoga group were less likely to report improvement in incontinence at eight weeks compared to women in the MBSR group (RR 0.09, 95% CI 0.01 to 1.43; a decrease of 419 from 461 per 1000, 95% CI 5 to 660). We are uncertain about the effect of MBSR compared to yoga on reports of cure or improvement in incontinence, improvement in condition-specific quality of life measured on the Overactive Bladder Health-Related Quality of Life Scale, reduction in incontinence episodes or reduction in bothersomeness of incontinence as measured on the Overactive Bladder Symptom and Quality of Life-Short Form at eight weeks. The study did not report on adverse effects. We identified few trials on yoga for incontinence, and the existing trials were small and at high risk of bias. In addition, we did not find any studies of economic outcomes related to yoga for urinary incontinence. Due to the lack of evidence to answer the review question, we are uncertain whether yoga is useful for women with urinary incontinence. Additional, well-conducted trials with larger sample sizes are needed.
We included three studies with a total of 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate and valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS, or becoming seizure-free. Concerning tolerability, we ranked AEs associated with topiramate as moderate to severe, while we ranked 59% of AEs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group. Overall we judged all three studies to be at high risk of attrition bias and at unclear risk of reporting bias. We judged all three studies to be at low to unclear bias for the remaining risk of bias domains (random sequence, allocation, blinding). We judged the quality of the evidence from the studies to be very low. We have found no new studies since the last version of this review was published in 2017. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but has no clear benefits over valproate in terms of efficacy. Well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.
Our search found 782 potentially relevant references. From these, we included three trials without a control group, with 283 participants. In addition, we identified 14 ongoing trials evaluating nivolumab, of which two are randomised. Risk of bias of the three included studies was moderate to high. All of the participants were in relapsed stage, most of them were heavily pretreated and had received at least two previous treatments, most of them had also undergone ASCT. As we did not identify any RCTs, we could not use the software RobotReviewer to assess risk of bias. The software identified correctly that one study was not an RCT and did not extract any trial data, but extracted characteristics of the other two studies (although also not RCTs) in a sufficient way. Two studies with 260 participants evaluated OS. After six months, OS was 100% in one study and median OS (the timepoint when only 50% of participants were alive) was not reached in the other trial after a median follow-up of 18 months (interquartile range (IQR) 15 to 22 months) (very low certainty evidence, due to observational trial design, heterogenous patient population in terms of pretreatments and various follow-up times (downgrading by 1 point)). In one study, one out of three cohorts reported quality of life. It was unclear whether there was an effect on quality of life as only a subset of participants filled out the follow-up questionnaire (very low certainty evidence). Three trials (283 participants) evaluated progression-free survival (PFS) (very low certainty evidence). Six-month PFS ranged between 60% and 86%, and median PFS ranged between 12 and 18 months. All three trials (283 participants) reported complete response rates, ranging from 12% to 29%, depending on inclusion criteria and participants' previous treatments (very low certainty evidence). One trial (243 participants) reported drug-related grade 3 or 4 adverse events (AEs) only after a median follow-up of 18 months (IQR 15 to 22 months); these were fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%). The other two trials (40 participants) reported 23% to 52% grade 3 or 4 AEs after six months' follow-up (very low certainty evidence). Only one trial (243 participants) reported drug-related serious AEs; 2% of participants developed infusion reactions and 1% pneumonitis (very low certainty evidence). None of the studies reported treatment-related mortality. To date, data on OS, quality of life, PFS, response rate, or short- and long-term AEs are available from small uncontrolled trials only. The three trials included heavily pretreated participants, which had previously undergone regimens of BV or ASCT. For these participants, median OS was not reached after follow-up times of at least 16 months (more than 50% of participants with a limited life expectancy were alive at this timepoint). Only one cohort out of three only reported quality of life, with limited follow-up data so that meaningful conclusions were not possible. Serious adverse events occurred rarely. Currently, data are too sparse to make a clear statement on nivolumab for people with relapsed or refractory HL except for heavily pretreated people, which had previously undergone regimens of BV or ASCT. When interpreting these results, it is important to consider that proper RCTs should confirm these findings. As there are 14 ongoing trials evaluating nivolumab, of which two are RCTs, it is possible that an update of this review will be published in the near future and that this update will show different results to those reported here.
Sixty-six randomised trials, involving 8302 participants, met the inclusion criteria. Methodological quality was generally low. Sixty-nine different herbal medicines were tested in the included trials, which compared herbal medicines with placebo, hypoglycaemic drugs, or herbal medicines plus hypoglycaemic drugs.   Compared with placebo, Holy basil leaves, Xianzhen Pian, Qidan Tongmai, traditional Chinese formulae (TCT), Huoxue Jiangtang Pingzhi, and Inolter showed significantly hypoglycaemic response. Compared with hypoglycaemic drugs including glibenclamide, tolbutamide, or gliclazide, seven herbal medicines demonstrated a significant better metabolic control, including Bushen Jiangtang Tang, Composite Trichosanthis, Jiangtang Kang, Ketang Ling, Shenqi Jiangtang Yin, Xiaoke Tang, and Yishen Huoxue Tiaogan. In 29 trials that evaluated herbal medicines combined with hypoglycaemic drugs, 15 different herbal preparations showed additional better effects than hypoglycaemic drugs monotherapy. Two herbal therapies combined with diet and behaviour change showed better hypoglycaemic effects than diet and behaviour change alone. No serious adverse effects from the herbal medicines were reported. Some herbal medicines show hypoglycaemic effect sin type 2 diabetes. However, these findings should be carefully interpreted due to the low methodological quality, small sample size, and limited number of trials. In the light of some positive findings, some herbal medicines deserve further examination in high-quality trials.
A total of 27 studies (1596 participants) met the inclusion criteria: 19 studies assessed evening primrose oil, and 8 studies assessed borage oil. For EPO, a meta-analysis of results from 7 studies showed that EPO failed to significantly increase improvement in global eczema symptoms as reported by participants on a visual analogue scale of 0 to 100 (MD -2.22, 95% CI -10.48 to 6.04, 176 participants, 7 trials) and a visual analogue scale of 0 to 100 for medical doctors (MD -3.26, 95% CI -6.96 to 0.45, 289 participants, 8 trials) compared to the placebo group. Treatment with BO also failed to significantly improve global eczema symptoms compared to placebo treatment as reported by both participants and medical doctors, although we could not conduct a meta-analysis as studies reported results in different ways. With regard to the risk of bias, the majority of studies were of low risk of bias; we judged 67% of the included studies as having low risk of bias for random sequence generation; 44%, for allocation concealment; 59%, for blinding; and 37%, for other biases. Implications for practice Oral borage oil and evening primrose oil lack effect on eczema; improvement was similar to respective placebos used in trials. Oral BO and EPO are not effective treatments for eczema. In these studies, along with the placebos, EPO and BO have the same, fairly common, mild, transient adverse effects, which are mainly gastrointestinal. The short-term studies included here do not examine possible adverse effects of long-term use of EPO or BO. A case report warned that if EPO is taken for a prolonged period of time (more than one year), there is a potential risk of inflammation, thrombosis, and immunosuppression; another study found that EPO may increase bleeding for people on Coumadin® (warfarin) medication. Implications for research Noting that the confidence intervals between active and placebo treatment are narrow, to exclude the possibility of any clinically useful difference, we concluded that further studies on EPO or BO for eczema would be hard to justify. This review does not provide information about long-term use of these products.
Three randomised trials used gemcitabine plus cisplatin (GCis) as one of the arms in each trial. The first randomised trial compared GCis with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) and showed no significant difference in overall survival (hazard ratio1.09, 95% CI 0.88 to 1.34, P = 0.443) however the GCis regime had fewer incidences of neutropenic sepsis (1% versus 12%, P = 0.001) and mucositis (1% versus 22%, P = 0.001). A second randomised trial compared GCis to gemcitabine plus carboplatin (GCarbo) and reported an improved, but non-significant 1-year survival rate with GCis (64% versus 37%). A third randomised trial compared GCis with gemcitabine plus cisplatin plus paclitaxel (GCisPac) and again found no significant difference in overall survival (respective medians 49 weeks versus 61 weeks). One randomised trial evaluated GCarbo against methotrexate plus carboplatin plus vinblastine (MCarboV) in patients "unfit" for cisplatin-based chemotherapy. There were more overall responses (38% versus 20%) and less severe acute toxicities (14% versus 23%) with GCarbo. In one randomised study evaluating 3-weekly gemcitabine plus paclitaxel (GPac3) versus a 2-weekly regimen overall survival was not significantly different (respective medians 13 and 9 months) however toxicities were worse with GPac3 especially alopecia (76% versus 32%). A larger trial compared gemcitabine (1 g/m2) (grams per metre squared) plus paclitaxel (175 mg/m2) (milligrams per metre squared) as a 3-weekly schedule for 6 cycles with a 2-weekly maintenance schedule. There was no significant difference in response rates, progression-free survival, disease-specific survival, and overall survival. A review of the published evidence found that one trial reported gemcitabine plus cisplatin had a better safety profile than MVAC and may be considered the first choice for treatment of metastatic bladder cancer. However, the data are limited to one trial only. Patients unable to tolerate cisplatin may benefit from gemcitabine plus carboplatin.
Four trials were eligible for inclusion, one of these trials (n =24) was on children and adolescents. All used an SSRI and prolonged exposure or a cognitive behavioural intervention. Two trials compared combination treatment with pharmacological treatment and two compared combination treatment with psychological treatment. Only two trials reported a total PTSD symptom score and these data could not be combined. There was no strong evidence to show if there were differences between the group receiving combined interventions compared to the group receiving psychological therapy (mean difference 2.44, 95% CI -2.87, 7.35 one study, n=65) or pharmacotherapy (mean difference -4.70, 95% CI -10.84 to 1.44; one study, n = 25). Trialists reported no significant differences between combination and single intervention groups in the other two studies. There were very little data reported for other outcomes, and in no case were significant differences reported. There is not enough evidence available to support or refute the effectiveness of combined psychological therapy and pharmacotherapy compared to either of these interventions alone. Further large randomised controlled trials are urgently required.
The review includes 39 trials with a total of 3509 participants. Study duration ranged between three and 12 weeks. Amitriptyline was significantly more effective than placebo in achieving acute response (18 RCTs, n = 1987, OR 2.67, 95% CI 2.21 to 3.23). Significantly fewer participants allocated to amitriptyline than to placebo withdrew from trials due to inefficacy of treatment (19 RCTs, n = 2017, OR 0.20, 95% CI 0.14 to 0.28), but more amitriptyline-treated participants withdrew due to side effects (19 RCTs, n = 2174, OR 4.15, 95% CI 2.71 to 6.35). Amitriptyline also caused more anticholinergic side effects, tachycardia, dizziness, nervousness, sedation, tremor, dyspepsia, sedation, sexual dysfunction and weight gain. In subgroup and meta-regression analyses the results of the primary outcome were robust towards publication year (1971 to 1997), mean participant age at baseline, mean amitriptyline dose, study duration in weeks, pharmaceutical sponsor, inpatient versus outpatient setting and two-arm versus three-arm design. However, higher severity at baseline was associated with higher superiority of amitriptyline (P = 0.02), while higher responder rates in the placebo groups were associated with lower superiority of amitriptyline (P = 0.05). The results of the primary outcome were rather homogeneous, reflecting comparability of the trials. However, methods of randomisation, allocation concealment and blinding were usually poorly reported. Not all studies used intention-to-treat analyses and in many of them standard deviations were not reported and often had to be imputed. Funnel plots suggested a possible publication bias, but the trim and fill method did not change the overall effect size much (seven adjusted studies, OR 2.64, 95% CI 2.24 to 3.10). Amitriptyline is an efficacious antidepressant drug. It is, however, also associated with a number of side effects. Degree of placebo response and severity of depression at baseline may moderate drug-placebo efficacy differences.
For this update, 8 additional trials were identified giving a total of 26 included studies (n=2530). 17 studies compared open wound healing with surgical closure. Healing times were faster after surgical closure compared with open healing. Surgical site infection (SSI) rates did not differ between treatments; recurrence rates were lower in open healing than with primary closure (RR 0.60, 95% CI 0.42 to 0.87). Six studies compared surgical midline with off-midline closure. Healing times were faster after off-midline closure (MD 5.4 days, 95% CI 2.3 to 8.5). SSI rates were higher after midline closure (RR 3.72, 95% CI 1.86 to 7.42) and recurrence rates were higher after midline closure (Peto OR 4.54, 95% CI 2.30 to 8.96). No clear benefit was shown for open healing over surgical closure. A clear benefit was shown in favour of off-midline rather than midline wound closure. When closure of pilonidal sinuses is the desired surgical option, off-midline closure should be the standard management.
One trial involving 92 participants with pretreated/relapsed WM compared the effect of fludarabine versus the combination of cyclophosphamide (the alkylating agent), doxorubicin and prednisone (CAP). Compared to CAP, the Hazard ratio (HR) for deaths of treatment with fludarabine was estimated to be 1.04, with a standard error of 0.30 (95% CI 0.58 to 1.48) and it indicated that the mean difference of median survival time was -4.00 months, and 16.00 months for response duration. The relative risks (RR) of response rate was 2.80 (95% CI 1.10 to 7.12). There were no statistically difference in overall survival rate and median survival months, while on the basis of response rate and response duration, fludarabine seemed to be superior to CAP for pretreated/relapsed patients with macroglobulinaemia. Although alkylating agents have been used for decades they have never actually been tested in a proper randomised trial. This review demonstrated that there is currently no evidence to suggest that alkylating agents are effective in treating Waldenstrom's macroglobulinaemia.
We included 11 RCTs involving 1583 participants (791 participants in the intervention group and 792 in the control group). We found that there was no difference between the treatment and control groups in the outcomes of death or dependency (OR 0.99, 95% CI 0.79 to 1.23) or final neurological deficit (SMD -0.09, 95% CI -0.19 to 0.01). The rate of symptomatic hypoglycaemia was higher in the intervention group (OR 14.6, 95% CI 6.6 to 32.2). In the subgroup analyses of diabetes mellitus (DM) versus non-DM, we found no difference for the outcomes of death and disability or neurological deficit. The number needed to treat was not significant for the outcomes of death and final neurological deficit. The number needed to harm was nine for symptomatic hypoglycaemia. After updating the results of our previous review, we found that the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischaemic stroke does not provide benefit in terms of functional outcome, death, or improvement in final neurological deficit and significantly increased the number of hypoglycaemic episodes. Specifically, those people whose glucose levels were maintained within a tighter range with intravenous insulin experienced a greater risk of symptomatic and asymptomatic hypoglycaemia than those people in the control group.
We included a total of 52 trials (6923 participants). The psychosocial interventions considered in the studies were: cognitive behavioural therapy (19 studies), contingency management (25 studies), motivational interviewing (5 studies), interpersonal therapy (3 studies), psychodynamic therapy (1 study), 12-step facilitation (4 studies). We judged most of the studies to be at unclear risk of selection bias; blinding of personnel and participants was not possible for the type of intervention, so all the studies were at high risk of performance bias with regard to subjective outcomes; the majority of studies did not specify whether the outcome assessors were blind. We did not consider it likely that the objective outcomes were influenced by lack of blinding. The comparisons made were: any psychosocial intervention versus no intervention (32 studies), any psychosocial intervention versus TAU (6 studies), and one psychosocial intervention versus an alternative psychosocial intervention (13 studies). Five of included studies did not provide any useful data for inclusion in statistical synthesis. We found that, when compared to no intervention, any psychosocial treatment: reduced the dropout rate (risk ratio (RR): 0.83, 95% confidence interval (CI) 0.76 to −0.91, 24 studies, 3393 participants, moderate quality evidence); increased continuous abstinence at the end of treatment (RR: 2.14, 95% CI 1.27 to −3.59, 8 studies, 1241 participants, low quality evidence); did not significantly increase continuous abstinence at the longest follow-up (RR: 2.12, 95% CI 0.77 to −5.86, 4 studies, 324 participants, low quality evidence); significantly increased the longest period of abstinence: (standardised mean difference (SMD): 0.48, 95% CI 0.34 to 0.63, 10 studies, 1354 participants, high quality evidence). However, it should be noted that the in the vast majority of the studies in this comparison the specific psychosocial treatment assessed in the experimental arm was given in add on to treatment as usual or to another specific psychosocial or pharmacological treatment which was received by both groups. So, many of the control groups in this comparison were not really untreated. Receiving some amount of treatment is not the same as not receiving any intervention, so we could argue that the overall effect of the experimental psychosocial treatment could be smaller if given in add on to TAU or to another intervention than if given to participants not receiving any intervention; this could translate to a smaller magnitude of the effect of the psychosocial intervention when it is given in add on. When compared to TAU, any psychosocial treatment reduced dropout rate (RR: 0.72, 95% CI 0.59 to 0.89, 6 studies, 516 participants, moderate quality evidence), did not increase continuous abstinence at the end of treatment (RR: 1.27, 95% CI 0.94 to 1.72, 2 studies, 224 participants, low quality evidence), did not increase longest period of abstinence (MD −3.15 days, 95% CI −10.35 to 4.05, 1 study, 110 participants, low quality evidence). No studies in this comparison assessed the outcome of continuous abstinence at longest follow-up. There were few studies comparing two or more psychosocial interventions, with small sample sizes and considerable heterogeneity in terms of the types of interventions assessed. None reported significant results. None of the studies reported harms related to psychosocial interventions. The addition of any psychosocial treatment to treatment as usual (usually characterised by group counselling or case management) probably reduces the dropout rate and increases the longest period of abstinence. It may increase the number of people achieving continuous abstinence at the end of treatment, although this might not be maintained at longest follow-up. The most studied and the most promising psychosocial approach to be added to treatment as usual is probably contingency management. However, the other approaches were only analysed in a few small studies, so we cannot rule out the possibility that the results were not significant because of imprecision. When compared to TAU, any psychosocial treatment may improve adherence, but it may not improve abstinence at the end of treatment or the longest period of abstinence. The majority of the studies took place in the United States, and this could limit the generalisability of the findings, because the effects of psychosocial treatments could be strongly influenced by the social context and ethnicity. The results of our review do not answer the most relevant clinical question, demonstrating which is the most effective type of psychosocial approach. Further studies should directly compare contingency management with the other psychosocial approaches.
We included seven randomised controlled trials with 891 participants (outpatients in secondary care). We found no quasi-randomised controlled trials. Six studies (836 participants) evaluated balneotherapy versus no treatment. One study evaluated balneotherapy versus a phlebotonic drug (melilotus officinalis) (55 participants). There was a lack of blinding of participants and investigators, imprecision and inconsistency, which downgraded the certainty of the evidence. For the balneotherapy versus no treatment comparison, there probably was no improvement in favour of balneotherapy in disease severity signs and symptom score as assessed using the Venous Clinical Severity Score (VCSS) (MD –1.66, 95% CI –4.14 to 0.83; 2 studies, 484 participants; moderate-certainty evidence). Balneotherapy probably resulted in a moderate improvement in HRQoL as assessed by the Chronic Venous Insufficiency Questionnaire 2 (CVIQ2) at three months (MD –9.38, 95% CI –18.18 to –0.57; 2 studies, 149 participants; moderate-certainty evidence), nine months (MD –10.46, 95% CI –11.81 to –9.11; 1 study; 55 participants; moderate-certainty evidence), and 12 months (MD –4.99, 95% CI –9.19 to –0.78; 2 studies, 455 participants; moderate-certainty evidence). There was no clear difference in HRQoL between balneotherapy and no treatment at six months (MD –1.64, 95% CI –9.18 to 5.89; 2 studies, 445 participants; moderate-certainty evidence). Balneotherapy probably slightly improved pain compared with no treatment (MD –1.23, 95% CI –1.33 to –1.13; 1 study; 390 participants; moderate-certainty evidence). There was no clear effect related to oedema between the two groups at 24 days (MD 43.28 mL, 95% CI –102.74 to 189.30; 2 studies, 153 participants; very-low certainty evidence). There probably was no improvement in favour of balneotherapy in the incidence of leg ulcers (OR 1.69, 95% CI 0.82 to 3.48; 2 studies, 449 participants; moderate-certainty evidence). There was probably a reduction in incidence of skin pigmentation changes in favour of balneotherapy at 12 months (pigmentation index: MD –3.59, 95% CI –4.02 to –3.16; 1 study; 59 participants; low-certainty evidence). The main complications reported included erysipelas (OR 2.58, 95% CI 0.65 to 10.22; 2 studies, 519 participants; moderate-certainty evidence), thromboembolic events (OR 0.35, 95% CI 0.09 to 1.42; 3 studies, 584 participants; moderate-certainty evidence) and palpitations (OR 0.33, 95% CI 0.01 to 8.52; 1 study; 59 participants; low-certainty evidence), with no clear evidence of an increase in reported adverse effects with balneotherapy. There were no serious adverse events reported in any of the studies. For the balneotherapy versus a phlebotonic drug (melilotus officinalis) comparison, we observed no clear difference in pain symptoms (OR 0.29, 95% CI 0.03 to 2.87; 1 study; 35 participants; very low-certainty evidence) and oedema (OR 0.21, 95% CI 0.02 to 2.27; 1 study; 35 participants; very low-certainty evidence). This single study did not report on the other outcomes of interest. We identified moderate- to low-certainty evidence that suggests that balneotherapy may result in a moderate improvement in pain, quality of life and skin pigmentation changes and has no clear effect on disease severity signs and symptoms score, adverse effects, leg ulcers and oedema when compared with no treatment. For future studies, measurements of outcomes such as disease severity sign and symptom score, quality of life, pain and oedema and choice of time points during follow-up must be standardised for adequate comparison between trials.
This review identified 17 randomized studies that addressed whether enhanced glucose control prevents the development of neuropathy. Seven of these studies were conducted in people with type 1 diabetes, eight in type 2 diabetes, and two in both types. A meta-analysis of the two studies that reported the primary outcome (incidence of clinical neuropathy) with a total of 1228 participants with type 1 diabetes revealed a significantly reduced risk of developing clinical neuropathy in those with enhanced glucose control, an annualized RD of -1.84% (95% confidence interval (CI) -1.11 to -2.56). In a similar analysis of four studies that reported the primary outcome, involving 6669 participants with type 2 diabetes, the annualized RD of developing clinical neuropathy was -0.58% (95% CI 0.01 to -1.17). Most secondary outcomes were significantly in favor of intensive treatment in both populations. However, both types of diabetic participants also had a significant increase in severe adverse events including hypoglycemic events. According to high-quality evidence, enhanced glucose control significantly prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in type 1 diabetes mellitus. In type 2 diabetes mellitus, enhanced glucose control reduces the incidence of clinical neuropathy, although this was not formally statistically significant (P = 0.06). However, enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities. Importantly, enhanced glucose control significantly increases the risk of severe hypoglycemic episodes, which needs to be taken into account when evaluating its risk/benefit ratio.
Of 3840 records screened, we identified just one conference abstract that met our inclusion criteria. This prospective cohort study assessed the efficacy and acceptability of home administration of misoprostol for early medical abortion among women living with HIV who were of less than 63 days amenorrhea in Ukraine. Medical abortion was effective in 65 of 68 cases (96%) examined. The small number of failures included incomplete abortion (n = 1), heavy bleeding (n = 1), and ongoing pregnancy (n = 1). There were no serious infections. Due to the paucity of studies, we were unable to determine if outcome differences exist between women living with HIV and women without HIV who undergo medical or surgical abortion. We found no evidence suggesting that medical or surgical abortions are unsafe for women living with HIV. While additional research would strengthen the evidence base, healthcare providers should not be deterred from providing access to safe abortion to their patients living with HIV.
We included a total of 16 randomised trials in this review. The results for primary outcomes are as follows. PDEI versus placebo: PDEIs may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI versus AB: PDEIs and ABs probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AEs (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI and AB versus AB alone: the combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AEs may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AEs per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks. PDEI and AB versus PDEI alone: the combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AEs. Study results were limited to a treatment duration of four weeks. PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AEs. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AEs (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AEs per 1000 participants (95% CI 43 fewer to 98 more per 1000). We found no trials comparing other combinations of treatments or comparing different PDEI agents. Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AEs. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AEs. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB alone or PDEI combined with 5-ARI compared to ARI alone with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.
A total of seven studies of variable quality were included in this review. Only three studies assessed the effectiveness of parenting programmes on objective measures of abuse (e.g. the incidence of child abuse, number of injuries, or reported physical abuse), and only one of these found significant differences between the intervention and control groups. Data were also extracted on over fifty outcomes that are used as predictive measures of abusive parenting. These measured a range of aspects of parenting (e.g. parental child management, discipline practices, child abuse potential and mental health), child health (e.g. emotional and behavioural adjustment) and family functioning, thereby precluding the possibility of undertaking a meta-analysis for most outcomes for which data were extracted. While none of the programmes were effective across all of the outcomes measured, many appeared to have improved some outcomes for some of the participating parents, although many failed to achieve statistical significance. There is insufficient evidence to support the use of parenting programmes to treat physical abuse or neglect. There is, however, limited evidence to show that some parenting programmes may be effective in improving some outcomes that are associated with physically abusive parenting. Further research is urgently needed.
A total of 24 studies (1201 participants) contributed data to the review. The review authors had several concerns regarding the studies. Pharmaceutical company support for manuscript preparation was a common feature; also, because common endpoints were lacking, study populations were heterogenous and variations in study design were noted, individual drug meta-analysis was not possible. Moderate-quality evidence from individual studies suggests that proton pump inhibitors (PPIs) can reduce GOR symptoms in children with confirmed erosive oesophagitis. It was not possible to demonstrate statistical superiority of one PPI agent over another. Some evidence indicates that H₂antagonists are effective in treating children with GORD. Methodological differences precluded performance of meta-analysis on individual agents or on these agents as a class, in comparison with placebo or head-to-head versus PPIs, and additional studies are required. RCT evidence is insufficient to permit assessment of the efficacy of prokinetics. Given the diversity of study designs and the heterogeneity of outcomes, it was not possible to perform a meta-analysis of the efficacy of domperidone. In younger children, the largest RCT of 80 children (one to 18 months of age) with GOR showed no evidence of improvement in symptoms and 24-hour pH probe, but improvement in symptoms and reflux index was noted in a subgroup treated with domperidone and co-magaldrox(Maalox® ). In another RCT of 17 children, after eight weeks of therapy. 33% of participants treated with domperidone noted an improvement in symptoms (P value was not significant). In neonates, the evidence is even weaker; one RCT of 26 neonates treated with domperidone over 24 hours showed that although reflux frequency was significantly increased, reflux duration was significantly improved. Diversity of RCT evidence was found regarding efficacy of compound alginate preparations(Gaviscon Infant® ) in infants, although as a result of these studies, Gaviscon Infant®  was changed to become aluminium-free and has been assessed in its current form in only two studies since 1999. Given the diversity of study designs and the heterogeneity of outcomes, as well as the evolution in formulation, it was not possible to perform a meta-analysis on the efficacy of Gaviscon Infant®  . Moderate evidence indicates that Gaviscon Infant® improves symptoms in infants, including those with functional reflux; the largest study of the current formulation showed improvement in symptom control but was limited by length of follow-up. No serious side effects were reported. No RCTs on pharmacological treatments for children with neurodisability were identified. Moderate evidence was found to support the use of PPIs, along with some evidence to support the use of H₂ antagonists in older children with GORD, based on improvement in symptom scores, pH indices and endoscopic/histological appearances. However, lack of independent placebo-controlled and head-to-head trials makes conclusions as to relative efficacy difficult to determine. Further RCTs are recommended. No robust RCT evidence is available to support the use of domperidone, and further studies on prokinetics are recommended, including assessments of erythromycin. Pharmacological treatment of infants with reflux symptoms is problematic, as many infants have GOR, and little correlation has been noted between reported symptoms and endoscopic and pH findings. Better evidence has been found to support the use of PPIs in infants with GORD, but heterogeneity in outcomes and in study design impairs interpretation of placebo-controlled data regarding efficacy. Some evidence is available to support the use of Gaviscon Infant®  , but further studies with longer follow-up times are recommended. Studies of omeprazole and lansoprazole in infants with functional GOR have demonstrated variable benefit, probably because of differences in inclusion criteria. No robust RCT evidence has been found regarding treatment of preterm babies with GOR/GORD or children with neurodisabilities. Initiation of RCTs with common endpoints is recommended, given the frequency of treatment and the use of multiple antireflux agents in these children.
We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures. Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).
Only one trial of limited quality compared a biphasic and monophasic preparation. The study examined 533 user cycles of a biphasic pill (500 μg norethindrone plus 35 μg ethinyl estradiol (EE) for 10 days, followed by 1000 μg norethindrone plus 35 μg EE for 11 days; Ortho 10/11) and 481 user cycles of a monophasic contraceptive pill (1500 μg norethindrone acetate plus 30 μg EE daily; Loestrin). The study found no significant differences in intermenstrual bleeding, amenorrhea and study discontinuation due to intermenstrual bleeding between the biphasic and monophasic oral contraceptive pills. Conclusions are limited by the identification of only one trial, the methodological shortcomings of that trial, and the absence of data on accidental pregnancies. However, the trial found no important differences in bleeding patterns between the biphasic and monophasic preparations studied. Since no clear rationale exists for biphasic pills and since extensive evidence is available for monophasic pills, the latter are preferred.
Since the last version of this review no new studies were found. Information was available from six studies with 1342 participants, using a variety of doses of ibuprofen and codeine. In four studies (443 participants) using ibuprofen 400 mg plus codeine 25.6 mg to 60 mg (high dose codeine) 64% of participants had at least 50% maximum pain relief with the combination compared to 18% with placebo. The NNT was 2.2 (95% confidence interval 1.8 to 2.6) (high quality evidence). In three studies (204 participants) ibuprofen plus codeine (any dose) was better than the same dose of ibuprofen (69% versus 55%) but the result was barely significant with a relative benefit of 1.3 (1.01 to 1.6) (moderate quality evidence). In two studies (159 participants) ibuprofen plus codeine appeared to be better than the same dose of codeine alone (69% versus 33%), but no analysis was done. There was no difference between the combination and placebo in the reporting of adverse events in these acute studies (moderate quality evidence). The combination of ibuprofen 400 mg plus codeine 25.6 mg to 60 mg demonstrates good analgesic efficacy. Very limited data suggest that the combination is better than the same dose of either drug alone, and that similar numbers of people experience adverse events with the combination as with placebo.
Five trials (1165 participants) were included in the review. There was no statistically significant difference between olanzapine and placebo (either alone or in combination with lithium or valproate) in terms of number of participants who experienced relapse into mood episode (random effects RR 0.68, 95% CI 0.43 to 1.07, p = 0.09; 2 studies, n=460), however restricting the analysis to the trial that compared olanzapine monotherapy versus placebo, there was a statistically significant difference in favour of olanzapine (RR 0.58, 95% CI 0.49 to 0.69, p<0.00001). No statistically significant difference was found between olanzapine and other mood stabilisers (lithium or valproate) in preventing symptomatic relapse for any mood episode, however, olanzapine was more effective than lithium in preventing symptomatic manic relapse (RR 0.59, 95% CI 0.39 to 0.89, p = 0.01; 1 study, n=361). Olanzapine either alone or as adjunctive treatment to mood stabilisers was associated with significantly greater weight gain than placebo. By contrast, olanzapine was associated with a lower rate of manic worsening, but with a higher rate of weight increase and depression than lithium. Though based on a limited amount of information, there is evidence that olanzapine may prevent further mood episodes in patients who have responded to olanzapine during an index manic or mixed episode and who have not previously had a satisfactory response to lithium or valproate. However, notwithstanding these positive results, the current evidence is stronger for lithium as first line maintenance treatment of bipolar disorder.
This review includes two RCTs (154 children aged 32 months to 11 years) of communication interventions for ASD in minimally verbal children compared with a control group (treatment as usual). One RCT used a verbally based intervention (focused playtime intervention; FPI) administered by parents in the home, whereas the other used an alternative and augmentative communication (AAC) intervention (Picture Exchange Communication System; PECS) administered by teachers in a school setting. The FPI study took place in the USA and included 70 participants (64 boys) aged 32 to 82 months who were minimally verbal and had received a diagnosis of ASD. This intervention focused on developing coordinated toy play between child and parent. Participants received 12 in-home parent training sessions for 90 minutes per session for 12 weeks, and they were also invited to attend parent advocacy coaching sessions. This study was funded by the National Institute of Child Health and Human Development, the MIND Institute Research Program and a Professional Staff Congress-City University of New York grant. The PECS study included 84 minimally verbal participants (73 boys) aged 4 to 11 years who had a formal diagnosis of ASD and who were not using PECS beyond phase 1 at baseline. All children attended autism-specific classes or units, and most classes had a child to adult ratio of 2:1. Teachers and parents received PECS training (two-day workshop). PECS consultants also conducted six half-day consultations with each class once per month over five months. This study took place in the UK and was funded by the Three Guineas Trust. Both included studies had high or unclear risk of bias in at least four of the seven 'Risk of bias' categories, with a lack of blinding for participants and personnel being the most problematic area. Using the GRADE approach, we rated the overall quality of the evidence as very low due to risk of bias, imprecision (small sample sizes and wide confidence intervals) and because there was only one trial identified per type of intervention (i.e. verbally based or AAC). Both studies focused primarily on communication outcomes (verbal and non-verbal). One of the studies also collected information on social communication. The FPI study found no significant improvement in spoken communication, measured using the expressive language domain of the Mullen Scale of Early Learning expressive language, at postintervention. However, this study found that children with lower expressive language at baseline (less than 11.3 months age-equivalent) improved more than children with better expressive language and that the intervention produced expressive language gains in some children. The PECS study found that children enrolled in the AAC intervention were significantly more likely to use verbal initiations and PECS symbols immediately postintervention; however, gains were not maintained 10 months later. There was no evidence that AAC improved frequency of speech, verbal expressive vocabulary or children's social communication or pragmatic language immediately postintervention. Overall, neither of the interventions (PECS or FPI) resulted in maintained improvements in spoken or non-verbal communication in most children. Neither study collected information on adverse events, other communication skills, quality of life or behavioural outcomes. There is limited evidence that verbally based and ACC interventions improve spoken and non-verbal communication in minimally verbal children with ASD. A substantial number of studies have investigated communication interventions for minimally verbal children with ASD, yet only two studies met inclusion criteria for this review, and we considered the overall quality of the evidence to be very low. In the study that used an AAC intervention, there were significant gains in frequency of PECS use and verbal and non-verbal initiations, but not in expressive vocabulary or social communication immediately postintervention. In the study that investigated a verbally based intervention, there were no significant gains in expressive language postintervention, but children with lower expressive language at the beginning of the study improved more than those with better expressive language at baseline. Neither study investigated adverse events, other communication skills, quality of life or behavioural outcomes. Future RCTs that compare two interventions and include a control group will allow us to better understand treatment effects in the context of spontaneous maturation and will allow further comparison of different interventions as well as the investigation of moderating factors.
Data from 52 trials and 9387 patients were included. The results for modern regimens containing cisplatin favoured chemotherapy in all comparisons and reached conventional levels of significance when used with radical radiotherapy and with supportive care. Trials comparing surgery with surgery plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death, equivalent to an absolute benefit of 5% at 5 years). Trials comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio 0.87 (13% reduction in the risk of death equivalent to an absolute benefit of 4% at 2 years), and trials comparing supportive care with supportive care plus chemotherapy gave a hazard ratio of 0.73 (27% reduction in the risk of death equivalent to a 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size of effect was seen in any subgroup of patients. In all but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison. At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in the treatment of non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.
Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. Overall quality of evidence using the GRADE approach was low, predominantly due to the lack of both participant and researcher blinding in the included studies. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention. One study compared rutosides with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was no clear evidence to support a difference in PTS improvement between the rutosides or placebo/no treatment groups (OR 1.29, 95% CI 0.69 to 2.41; 164 participants; 2 studies; low-quality evidence); or between the rutosides and ECS groups (OR 0.80, 95% CI 0.31 to 2.03; 80 participants; 1 study ; low-quality evidence). Results from one small study reported less PTS improvement in the rutosides group compared to an alternative venoactive remedy (OR 0.18, 95% CI 0.04 to 0.94; 29 participants; 1 study; low-quality evidence). There was no clear evidence to support a difference in PTS deterioration when comparing rutosides with placebo/no treatment (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); with ECS (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); or an alternative venoactive remedy (OR 0.19, 95% CI 0.01 to 4.24; 29 participants; 1 study). No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ('mild side effects' reported in 7/41 and 5/42 respectively). In the study comparing rutosides with ECS, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. The study comparing rutosides with an alternative venoactive remedy did not comment on side effects There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited low-quality evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence to support the use of rutosides in the treatment of PTS.
Due to the level of heterogeneity among studies, studies were divided into two groups; those conducted in Japan and those conducted outside Japan. Study length ranged between 12 and 13 weeks. Meta-analysis of six studies conducted outside Japan showed a mean difference (MD) in weight loss of -0.04 kg (95% CI -0.5 to 0.4; P = 0.88; I2 = 18%; 532 participants). The eight studies conducted in Japan were not similar enough to allow pooling of results and MD in weight loss ranged from -0.2 kg to -3.5 kg (1030 participants) in favour of green tea preparations. Meta-analysis of studies measuring change in body mass index (BMI) conducted outside Japan showed a MD in BMI of -0.2 kg/m2 (95% CI -0.5 to 0.1; P = 0.21; I2 = 38%; 222 participants). Differences among the eight studies conducted in Japan did not allow pooling of results and showed a reduction in BMI ranging from no effect to -1.3 kg/m2 (1030 participants), in favour of green tea preparations over control. Meta-analysis of five studies conducted outside Japan and measuring waist circumference reported a MD of -0.2 cm (95% CI -1.4 to 0.9; P = 0.70; I2 = 58%; 404 participants). Differences among the eight studies conducted in Japan did not allow pooling of results and showed effects on waist circumference ranging from a gain of 1 cm to a loss of 3.3 cm (1030 participants). Meta-analysis for three weight loss studies, conducted outside Japan, with waist-to-hip ratio data (144 participants) yielded no significant change (MD 0; 95% CI -0.02 to 0.01). Analysis of two studies conducted to determine if green tea could help to maintain weight after a period of weight loss (184 participants) showed a change in weight loss of 0.6 to -1.6 kg, a change in BMI from 0.2 to -0.5 kg/m2 and a change in waist circumference from 0.3 to -1.7 cm. In the eight studies that recorded adverse events, four reported adverse events that were mild to moderate, with the exception of two (green tea preparations group) that required hospitalisation (reported as not associated with the intervention). Nine studies reported on compliance/adherence, one study assessed attitude towards eating as part of the health-related quality of life outcome. No studies reported on patient satisfaction, morbidity or cost. Green tea preparations appear to induce a small, statistically non-significant weight loss in overweight or obese adults. Because the amount of weight loss is small, it is not likely to be clinically important. Green tea had no significant effect on the maintenance of weight loss. Of those studies recording information on adverse events, only two identified an adverse event requiring hospitalisation. The remaining adverse events were judged to be mild to moderate.
Two RCTs including a combined total of 40 participants (35 from one study and five from a second study) met the inclusion criteria. Twenty-one participants were randomised to the exercise training group and 19 participants were randomised to the control group. The included studies evaluated the effects of exercise training compared to a control group of no exercise training in people with dust-related ILDs and ARPD. The exercise training programme in both studies was in an outpatient setting for an eight-week period. The risk of bias was low in both studies. There were no reported adverse events of exercise training. Following exercise training, six-minute walk distance (6MWD) increased with a mean difference (MD) of 53.81 metres (m) (95% CI 34.36 to 73.26 m). Improvements were also seen in the domains of health-related quality of life: Chronic Respiratory Disease Questionnaire (CRQ) Dyspnoea domain (MD 2.58, 95% CI 0.72 to 4.44); CRQ Fatigue domain (MD 1.00, 95% CI 0.11 to 1.89); CRQ Emotional Function domain (MD 2.61, 95% CI 0.74 to 4.49); and CRQ Mastery domain (MD 1.51, 95% CI 0.29 to 2.72). Improvements in exercise capacity and health-related quality of life were also evident six months following the intervention period: 6MWD (MD 52.68 m, 95% CI 27.43 to 77.93 m); CRQ Dyspnoea domain (MD 3.03, 95% CI 1.41 to 4.66); CRQ Emotional Function domain (MD 5.57, 95% CI 2.34 to 8.81); and CRQ Mastery domain (MD 2.66, 95% CI 1.08 to 4.23). Exercise training did not result in improvements in the Modified Medical Research Council (MMRC) dyspnoea scale immediately following exercise training or six months following exercise training. The improvements following exercise training were similar in a subgroup of participants with dust-related ILDs and in a subgroup of participants with ARPD compared to the control group, with no statistically significant differences in treatment effects between the subgroups. The evidence examining exercise training in people with non-malignant dust-related respiratory diseases is of very low quality. This is due to imprecision in the results from the small number of trials and the small number of participants, the indirectness of evidence due to a paucity of information on disease severity and the data from one study being from a subgroup of participants, and inconsistency from high heterogeneity in some results. Therefore, although the review findings indicate that an exercise training programme is effective in improving exercise capacity and health-related quality of life in the short-term and at six months follow-up, we remain unsure of these findings due to the very low quality evidence. Larger, high quality trials are needed to determine the strength of these findings.
Nineteen trials that involved 1496 patients were included in the analysis. There was no heterogeneity of results among the studies in any outcome except diarrhoea. There was no statistically significant difference between the groups in the risk of death (risk difference (RD) 0%; 95% confidence interval (CI) -3% to 2%), risk of deafness (RD -4%; 95% CI -9% to 1%) or risk of treatment failure (RD -1%; 95% CI -4% to 2%). However, there were significantly decreased risks of culture positivity of CSF after 10 to 48 hours (RD -6%; 95% CI -11% to 0%) and statistically significant increases in the risk of diarrhoea between the groups (RD 8%; 95% CI 3% to 13%) with the third generation cephalosporins. The risk of neutropaenia and skin rash were not significantly different between the two groups. However, due to increased antibiotic resistance since the 1980s, the finding of this review should be read with caution. The review shows no clinically important difference between third generation cephalosporins (ceftriaxone or cefotaxime) and conventional antibiotics (ampicillin-chloramphenicol combination, or chloramphenicol alone). Therefore the choice of antibiotic will depend on cost and availability. The antimicrobial resistance pattern against various antibiotics needs to be closely monitored in low- to middle-income countries as well as high-income countries.
We included 14 RCTs (2050 participants) in this review. One trial on Solidago chilensis M. (Brazilian arnica) (20 participants) found very low quality evidence of reduction in perception of pain and improved flexibility with application of Brazilian arnica-containing gel twice daily as compared to placebo gel. Capsicum frutescens cream or plaster probably produces more favourable results than placebo in people with chronic LBP (three trials, 755 participants, moderate quality evidence). Based on current evidence, it is not clear whether topical capsicum cream is more beneficial for treating people with acute LBP compared to placebo (one trial, 40 participants, low quality evidence). Another trial found equivalence of C. frutescens cream to a homeopathic ointment (one trial, 161 participants, very low quality evidence). Daily doses of Harpagophytum procumbens (devil's claw), standardized to 50 mg or 100 mg harpagoside, may be better than placebo for short-term improvements in pain and may reduce use of rescue medication (two trials, 315 participants, low quality evidence). Another H. procumbens trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (Vioxx®) but was of very low quality (one trial, 88 participants, very low quality). Daily doses of Salix alba (white willow bark), standardized to 120 mg or 240 mg salicin, are probably better than placebo for short-term improvements in pain and rescue medication (two trials, 261 participants, moderate quality evidence). An additional trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (one trial, 228 participants) but was graded as very low quality evidence. S. alba minimally affected platelet thrombosis versus a cardioprotective dose of acetylsalicylate (one trial, 51 participants). One trial (120 participants) examining Symphytum officinale L. (comfrey root extract) found low quality evidence that a Kytta-Salbe comfrey extract ointment is better than placebo ointment for short-term improvements in pain as assessed by VAS. Aromatic lavender essential oil applied by acupressure may reduce subjective pain intensity and improve lateral spine flexion and walking time compared to untreated participants (one trial, 61 participants,very low quality evidence). No significant adverse events were noted within the included trials. C. frutescens (Cayenne) reduces pain more than placebo. Although H. procumbens, S. alba, S. officinale L., S. chilensis, and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions.
Ten studies were included. Two studies assessed the effect of different ways of screening submissions, one study compared open versus blinded peer review and three studies assessed the effect of different decision making procedures. Four studies considered agreement of the results of peer review processes as the outcome measure. Screening procedures appear to have little effect on the result of the peer review process. Open peer reviewers behave differently from blinded ones. Studies on decision-making procedures gave conflicting results. Agreement among reviewers and between different ways of assigning proposals or eliciting opinions was usually high. There is little empirical evidence on the effects of grant giving peer review. No studies assessing the impact of peer review on the quality of funded research are presently available. Experimental studies assessing the effects of grant giving peer review on importance, relevance, usefulness, soundness of methods, soundness of ethics, completeness and accuracy of funded research are urgently needed. Practices aimed to control and evaluate the potentially negative effects of peer review should be implemented meanwhile.
We included seven RCTs with a total of 1202 participants. Overall, we judged the risk of bias as low in four studies and high in three studies. We are uncertain whether Daikenchuto reduced time to first flatus (mean difference (MD) -11.32 hours, 95% confidence interval (CI) -17.45 to -5.19; two RCTs, 83 participants; very low-quality evidence), or time to first bowel movement (MD -9.44 hours, 95% CI -22.22 to 3.35; four RCTs, 500 participants; very low-quality evidence) following surgery. There was little or no difference in time to resumption of regular solid food following surgery (MD 3.64 hours, 95% CI -24.45 to 31.74; two RCTs, 258 participants; low-quality evidence). There were no adverse events in either arm of the five RCTs that reported on drug-related adverse events (risk difference (RD) 0.00, 95% CI -0.02 to 0.02, 568 participants, low-quality evidence). We are uncertain of the effect of Daikenchuto on patient satisfaction (MD 0.09, 95% CI -0.19 to 0.37; one RCT, 81 participants; very low-quality of evidence). There was little or no difference in the incidence of any re-interventions for postoperative ileus before leaving hospital (risk ratio (RR) 0.99, 95% CI 0.06 to 15.62; one RCT, 207 participants; moderate-quality evidence), or length of hospital stay (MD -0.49 days, 95% CI -1.21 to 0.22; three RCTs, 292 participants; low-quality evidence). Evidence from current literature was unclear whether Daikenchuto reduced postoperative ileus in patients undergoing elective abdominal surgery, due to the small number of participants in the meta-analyses. Very low-quality evidence means we are uncertain whether Daikenchuto improved postoperative flatus or bowel movement. Further well-designed and adequately powered studies are needed to assess the efficacy of Daikenchuto.
We found seven small Chinese studies (449 participants), six of which provided useable data for meta-analysis. No study compared Morita therapy with an inactive control. Unclear randomisation methods, lack of blinding and low quality reporting of outcomes were common in the included studies. We graded the overall risk of bias as high and the quality of the evidence as very low. Two social phobia studies (75 outpatients) directly compared Morita therapy with pharmacological therapy. In this comparison, the pooled RR of global state was 1.85 (95% CI 1.27 to 2.69) and the NNTB was 3 (95% CI 2 to 5), indicating a significant difference between groups favouring Morita therapy in the short term (up to 12 weeks' post-treatment). Data regarding drop-outs was insufficient and no description of adverse effects was provided. We graded the quality of the evidence for this comparison as very low, mainly due to high risk of bias in the studies and insufficient information in the results. Four studies (288 inpatients) investigated the effect of Morita therapy plus pharmacological therapy versus pharmacological therapy alone, three studies for the treatment of obsessive-compulsive disorder (OCD) (228 participants) and one study for generalised anxiety disorder (60 participants). One of the OCD studies reported incomplete data of global state while the outcome of global state was missing in the other three studies. There was no significant difference between groups for drop-outs for any reason in two OCD studies in the short term (RR 1.76, 95% CI 0.47 to 6.67; I2 = 44%). Information pertaining to drop-outs for adverse effects was unclear. We rated the risk of bias of this comparison as high. We graded the quality of the evidence as very low. The evidence base on Morita therapy for anxiety disorders was limited. All studies included in this review were conducted in China, and the results may not be applicable to Western countries. These included studies were small, provided insufficient information about drop-outs and adverse effects, and contained considerable risk of bias. Therefore, we graded the evidence as very low quality and were unable to draw conclusions on the effectiveness of Morita therapy in the treatment of anxiety disorders. Well-designed future studies that employ adequate allocation concealment, recruit large sample sizes, report drop-outs and adverse effects, and report outcomes clearly and consistently are needed to establish the effectiveness of Morita therapy for anxiety disorders.
Seventeen small trials were included, involving a total of 366 participants. Study quality was low. The temperature, duration and frequency of cold-water immersion varied between the different trials as did the exercises and settings. The majority of studies failed to report active surveillance of pre-defined adverse events. Fourteen studies compared cold-water immersion with passive intervention. Pooled results for muscle soreness showed statistically significant effects in favour of cold-water immersion after exercise at 24 hour (standardised mean difference (SMD) -0.55, 95% CI -0.84 to -0.27; 10 trials), 48 hour (SMD -0.66, 95% CI -0.97 to -0.35; 8 trials), 72 hour (SMD -0.93; 95% CI -1.36 to -0.51; 4 trials) and 96 hour (SMD -0.58; 95% CI -1.00 to -0.16; 5 trials) follow-ups. These results were heterogeneous. Exploratory subgroup analyses showed that studies using cross-over designs or running based exercises showed significantly larger effects in favour of cold-water immersion. Pooled results from two studies found cold-water immersion groups had significantly lower ratings of fatigue (MD -1.70; 95% CI -2.49 to -0.90; 10 units scale, best to worst), and potentially improved ratings of physical recovery (MD 0.97; 95% CI -0.10 to 2.05; 10 units scale, worst to best) immediately after the end of cold-water immersion. Five studies compared cold-water with contrast immersion. Pooled data for pain showed no evidence of differences between the two groups at four follow-up times (immediately, 24, 48 and 72 hours after treatment). Similar findings for pooled analyses at 24, 48 and 72 hour follow-ups applied to the four studies comparing cold-water with warm-water immersion. Single trials only compared cold-water immersion with respectively active recovery, compression and a second dose of cold-water immersion at 24 hours. There was some evidence that cold-water immersion reduces delayed onset muscle soreness after exercise compared with passive interventions involving rest or no intervention. There was insufficient evidence to conclude on other outcomes or for other comparisons. The majority of trials did not undertake active surveillance of pre-defined adverse events. High quality, well reported research in this area is required.
Three studies (generating four eligible study comparisons) were included. One study is ongoing. There was no statistically significant difference between azithromycin and benzathine penicillin treatment in the odds of cure (OR 1.04, 95% CI 0.69 to 1.56); nor any difference at three months (OR 0.97, 95% CI 0.62 to 1.50), six months (OR 1.09, 95% CI 0.76 to 1.54) or nine months (OR 1.45, 95% CI 0.46 to 6.42). Subgroup analysis by primary and latent syphilis and by dose of azithromycin (2 g and 4 g) did not explain the variation between the study results. The reporting of computed mild to tolerated adverse events, from two included trials, indicated no statistically significant difference between azithromycin and benzathine penicillin (OR 1.43, 95% CI 0.42 to 4.95), although with a high level of heterogeneity (P = 0.05, I2 = 74%). Differences in the odds of cure did not reach statistical significance when azithromycin was compared with benzathine penicillin for the treatment of early syphilis. No definitive conclusion can be made regarding the relative safety of benzathine penicillin G and azithromycin for early syphilis. Further studies on the utility of benzathine penicillin G for early syphilis are warranted.
Nine studies enrolling 645 infants met inclusion criteria. There were substantial methodological concerns in all studies comparing an opiate with a sedative. Two small studies comparing different opiates were of good methodology. Opiate (morphine) versus supportive care (one study): A reduction in time to regain birth weight and duration of supportive care and a significant increase in hospital stay was noted. Opiate versus phenobarbitone (four studies): Meta-analysis found no significant difference in treatment failure. One study reported opiate treatment resulted in a significant reduction in treatment failure in infants of mothers using only opiates. One study reported a significant reduction in days treatment and admission to the nursery for infants receiving morphine. One study reported a reduction in seizures, of borderline statistical significance, with the use of opiate. Opiate versus diazepam (two studies): Meta-analysis found a significant reduction in treatment failure with the use of opiate. Different opiates (six studies): there is insufficient data to determine safety or efficacy of any specific opiate compared to another opiate. Opiates compared to supportive care may reduce time to regain birth weight and duration of supportive care but increase duration of hospital stay. When compared to phenobarbitone, opiates may reduce the incidence of seizures but there is no evidence of effect on treatment failure. One study reported a reduction in duration of treatment and nursery admission for infants on morphine. Compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that initial opiate treatment may be restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution.
We included eleven randomised controlled trials involving 444 people, none of which were of high methodological quality. A large number of trials were excluded, mainly because of their non-randomised design. The randomisation procedures were either unclear or inadequate, using coin tossing, alternation, drawing lots or cards, or open tables of random numbers. The interventions and outcomes were too heterogeneous to be entered in a meta-analysis. Most trials examined a short-term effect up to six months after final treatment. There appeared to be a short-term effect of approximately 50% hair reduction with alexandrite and diode lasers up to six months after treatment, whereas little evidence was obtained for an effect of intense pulsed light, neodymium:YAG or ruby lasers. Long-term hair removal was not documented with any treatment. Pain, skin redness, swelling, burned hairs and pigmentary changes were infrequently reported adverse effects. Some treatments lead to temporary short-term hair removal. High quality research is needed on the effect of laser and photoepilation.
We identified 10 trials that met the inclusion criteria. The interventions involved brief training of basic-level health workers or mothers, and most provided the antimalarial for free or at a highly subsidized cost. In eight of the studies, fevers were treated presumptively without parasitological confirmation with microscopy or a rapid diagnostic test (RDT). Two studies trained community health workers to use RDTs as a component of community management of fever. Home- or community-based strategies probably increase the number of people with fever who receive an appropriate antimalarial within 24 hours (RR 2.27, 95% CI 1.79 to 2.88 in one trial; RR 9.79, 95% CI 6.87 to 13.95 in a second trial; 3099 participants, moderate quality evidence). They may also reduce all-cause mortality, but to date this has only been demonstrated in rural Ethiopia (RR 0.58, 95% CI 0.44 to 0.77, one trial, 13,677 participants, moderate quality evidence). Hospital admissions in children were reported in one small trial from urban Uganda, with no effect detected (437 participants, very low quality evidence). No studies reported on severe malaria. For parasitaemia prevalence, the study from urban Uganda demonstrated a reduction in community parasite prevalence (RR 0.22, 95% CI 0.08 to 0.64, 365 participants), but a second study in rural Burkina Faso did not (1006 participants). Home- or community-based programmes may have little or no effect on the prevalence of anaemia (three trials, 3612 participants, low quality evidence). None of the included studies reported on adverse effects of using home- or community-based programmes for treating malaria. In two studies which trained community health workers to only prescribe antimalarials after a positive RDT, prescriptions of antimalarials were reduced compared to the control group where community health workers used clinical diagnosis (RR 0.39, 95% CI 0.18 to 0.84, two trials, 5944 participants, moderate quality evidence). In these two studies, mortality and hospitalizations remained very low in both groups despite the lower use of antimalarials (two trials, 5977 participants, low quality evidence). Home- or community-based interventions which provide antimalarial drugs free of charge probably improve prompt access to antimalarials, and there is moderate quality evidence from rural Ethiopia that they may impact on childhood mortality when implemented in appropriate settings. Programmes which treat all fevers presumptively with antimalarials lead to overuse antimalarials, and potentially undertreat other causes of fever such as pneumonia. Incorporating RDT diagnosis into home- or community-based programmes for malaria may help to reduce this overuse of antimalarials, and has been shown to be safe under trial conditions.
Seventeen studies were included. One study comparing sclerotherapy to GCS in pregnancy found that sclerotherapy improved symptoms and cosmetic appearance. Three studies comparing sodium tetradecyl sulphate (STD) to alternative sclerosants found no significant differences in outcome or complication rates; another study found that sclerotherapy with STD led to improved cosmetic appearance compared with polidocanol, although there was no difference in symptoms. Sclerosant plus local anaesthetic reduced the pain from injection (one study) but had no other effects. Two studies compared foam- to conventional sclerotherapy; one found no difference in failure rate or recurrent varicose veins; a second showed short-term benefit from foam in terms of elimination of venous reflux. The recanalisation rate was no different between the two treatments. One study comparing Molefoam and Sorbo pad pressure dressings found no difference in erythema or successful sclerosis. The degree and duration of elastic compression had no significant effect on varicose vein recurrence rates, cosmetic appearance or symptomatic improvement. Evidence from RCTs suggests that the choice of sclerosant, dose, formulation (foam versus liquid), local pressure dressing, degree and length of compression have no significant effect on the efficacy of sclerotherapy for varicose veins. The evidence supports the current place of sclerotherapy in modern clinical practice, which is usually limited to treatment of recurrent varicose veins following surgery and thread veins. Surgery versus sclerotherapy is the subject of a further Cochrane Review.
We found six RCTs eligible for inclusion for three drugs: melatonin (222 participants, four studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), trazodone (30 participants, one study), and ramelteon (74 participants, one study, no peer-reviewed publication, limited information available). The participants in the trazodone study and almost all participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. All primary sleep outcomes were measured using actigraphy. In one study of melatonin, drug treatment was combined with morning bright light therapy. Only two studies made a systematic assessment of adverse effects. Overall, the evidence was at low risk of bias, although there were areas of incomplete reporting, some problems with participant attrition, related largely to poor tolerance of actigraphy and technical difficulties, and a high risk of selective reporting in one trial that contributed very few participants. The risk of bias in the ramelteon study was unclear due to incomplete reporting. We found no evidence that melatonin, at doses up to 10 mg, improved any major sleep outcome over 8 to 10 weeks in patients with AD who were identified as having a sleep disturbance. We were able to synthesize data for two of our primary sleep outcomes: total nocturnal sleep time (mean difference (MD) 10.68 minutes, 95% CI -16.22 to 37.59; N = 184; two studies), and the ratio of daytime sleep to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; N = 184; two studies). From single studies, we found no difference between melatonin and placebo groups for sleep efficiency, time awake after sleep onset, or number of night-time awakenings. From two studies, we found no effect of melatonin on cognition or performance of activities of daily living (ADL). No serious adverse effects of melatonin were reported in the included studies. We considered this evidence to be of low quality. There was low-quality evidence that trazodone 50 mg given at night for two weeks improved total nocturnal sleep time (MD 42.46 minutes, 95% CI 0.9 to 84.0; N = 30; one study), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; N = 30; one study) in patients with moderate-to-severe AD, but it did not affect the amount of time spent awake after sleep onset (MD -20.41, 95% CI -60.4 to 19.6; N = 30; one study), or the number of nocturnal awakenings (MD -3.71, 95% CI -8.2 to 0.8; N = 30; one study). No effect was seen on daytime sleep, cognition, or ADL. No serious adverse effects of trazodone were reported. Results from a phase 2 trial investigating ramelteon 8 mg administered at night were available in summary form in a sponsor's synopsis. Because the data were from a single, small study and reporting was incomplete, we considered this evidence to be of low quality in general terms. Ramelteon had no effect on total nocturnal sleep time at one week (primary outcome) or eight weeks (end of treatment) in patients with mild-to-moderate AD. The synopsis reported few significant differences from placebo for any sleep, behavioural, or cognitive outcomes; none were likely to be of clinical significance. There were no serious adverse effects from ramelteon. We discovered a distinct lack of evidence to help guide drug treatment of sleep problems in dementia. In particular, we found no RCTs of many drugs that are widely prescribed for sleep problems in dementia, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks associated with these common treatments. From the studies we identified for this review, we found no evidence that melatonin (up to 10mg) helped sleep problems in patients with moderate to severe dementia due to AD. There was some evidence to support the use of a low dose (50 mg) of trazodone, although a larger trial is needed to allow a more definitive conclusion to be reached on the balance of risks and benefits. There was no evidence of any effect of ramelteon on sleep in patients with mild to moderate dementia due to AD. This is an area with a high need for pragmatic trials, particularly of those drugs that are in common clinical use for sleep problems in dementia. Systematic assessment of adverse effects is essential.
We included 26 RCTs (total participants = 6070), nine of which had a low risk of bias. Approximately two-thirds of the included studies (N = 18) were not evaluated in the previous review. In general, there is high quality evidence that SMT has a small, statistically significant but not clinically relevant, short-term effect on pain relief (MD: -4.16, 95% CI -6.97 to -1.36) and functional status (SMD: -0.22, 95% CI -0.36 to -0.07) compared to other interventions. Sensitivity analyses confirmed the robustness of these findings. There is varying quality of evidence (ranging from low to high) that SMT has a statistically significant short-term effect on pain relief and functional status when added to another intervention. There is very low quality evidence that SMT is not statistically significantly more effective than inert interventions or sham SMT for short-term pain relief or functional status. Data were particularly sparse for recovery, return-to-work, quality of life, and costs of care. No serious complications were observed with SMT. High quality evidence suggests that there is no clinically relevant difference between SMT and other interventions for reducing pain and improving function in patients with chronic low-back pain. Determining cost-effectiveness of care has high priority. Further research is likely to have an important impact on our confidence in the estimate of effect in relation to inert interventions and sham SMT, and data related to recovery.
No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I2 = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I2 = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.
We included 33 studies involving 4002 shoulders in 3852 patients. Although 28 studies were prospective, study quality was still generally poor. Mainly reflecting the use of surgery as a reference test in most studies, all but two studies were judged as not meeting the criteria for having a representative spectrum of patients. However, even these two studies only partly recruited from primary care. The target conditions assessed in the 33 studies were grouped under five main categories: subacromial or internal impingement, rotator cuff tendinopathy or tears, long head of biceps tendinopathy or tears, glenoid labral lesions and multiple undifferentiated target conditions. The majority of studies used arthroscopic surgery as the reference standard. Eight studies utilised reference standards which were potentially applicable to primary care (local anaesthesia, one study; ultrasound, three studies) or the hospital outpatient setting (magnetic resonance imaging, four studies). One study used a variety of reference standards, some applicable to primary care or the hospital outpatient setting. In two of these studies the reference standard used was acceptable for identifying the target condition, but in six it was only partially so. The studies evaluated numerous standard, modified, or combination index tests and 14 novel index tests. There were 170 target condition/index test combinations, but only six instances of any index test being performed and interpreted similarly in two studies. Only two studies of a modified empty can test for full thickness tear of the rotator cuff, and two studies of a modified anterior slide test for type II superior labrum anterior to posterior (SLAP) lesions, were clinically homogenous. Due to the limited number of studies, meta-analyses were considered inappropriate. Sensitivity and specificity estimates from each study are presented on forest plots for the 170 target condition/index test combinations grouped according to target condition. There is insufficient evidence upon which to base selection of physical tests for shoulder impingements, and local lesions of bursa, tendon or labrum that may accompany impingement, in primary care. The large body of literature revealed extreme diversity in the performance and interpretation of tests, which hinders synthesis of the evidence and/or clinical applicability.
We identified three eligible studies after screening a total of 255 unique records. All three were performed in the United States of America and recruited substance-abusing male and female adolescents (total N=615) through homeless shelters into randomised controlled trials of independent and non-overlapping behavioural interventions. The three trials differed in theoretical background, delivery method, dosage (number of sessions,) content and outcome assessments. Overall, the variability in delivery and outcomes precluded estimation of summary of effect measures. We assessed the risk of bias to be high for each of the studies. Whilst some effect of the interventions on outcome measures were reported, heterogeneity and lack of robustness in these studies necessitate caution in interpreting the effectiveness of these interventions. The body of evidence does not permit conclusions on the impact of interventions to modify sexual risk behaviour in homeless youth; more research is required. While the psychosocial and contextual factors that fuel sexual risk behaviours among homeless youth challenge stringent methodologies of RCT's, novel ways for program delivery and trial retention are in need of development. Future trials should comply with rigorous methodology in design, delivery, outcome measurement and reporting.
We identified 26 studies that enrolling 61,264 participants. Angiotensin-converting enzyme inhibitors (ACEi) reduced the risk of new onset of microalbuminuria, macroalbuminuria or both when compared to placebo (8 studies, 11,906 patients: RR 0.71, 95% CI 0.56 to 0.89), with similar benefits in people with and without hypertension (P = 0.74), and when compared to calcium channel blockers (5 studies, 1253 participants: RR 0.60, 95% CI 0.42 to 0.85). ACEi reduced the risk of death when compared to placebo (6 studies, 11,350 participants: RR 0.84, 95% CI 0.73 to 0.97). No effect was observed for angiotensin receptor blockers (ARB) when compared to placebo for new microalbuminuria, macroalbuminuria or both (5 studies, 7653 participants: RR 0.90, 95% CI 0.68 to 1.19) or death (5 studies, 7653 participants: RR 1.12, 95% CI 0.88 to 1.41); however, meta-regression suggested possible benefits from ARB for preventing kidney disease in high risk patients. There was a trend towards benefit from use of combined ACEi and ARB for prevention of DKD compared with ACEi alone (2 studies, 4171 participants: RR 0.88, 95% CI 0.78 to 1.00).The risk of cough was significantly increased with ACEi when compared to placebo (6 studies, 11,791 patients: RR 1.84, 95% CI 1.24 to 2.72), however there was no significant difference in the risk of headache or hyperkalaemia. There was no significant difference in the risk of cough, headache or hyperkalaemia when ARB was to placebo. On average risk of bias was judged to be either low (27% to 69%) or unclear (i.e. no information available) (8% to 73%). Blinding of participants, incomplete outcome data and selective reporting were judged to be high in 23%, 31% and 31% of studies, respectively. ACEi were found to prevent new onset DKD and death in normoalbuminuric people with diabetes, and could therefore be used in this population. More data are needed to clarify the role of ARB and other drug classes in preventing DKD.
We included 10 trials in the review. Generally, we were unable to assess methodological quality; only one trial reported sufficient detail for analysis. Drugs used were piracetam, bifemalane, piribedil, bromocriptine, idebenone, and Dextran 40. We found weak evidence that patients were more likely to have improved on any language measure at the end of the trial if they had received treatment with piracetam (odds ratio (OR) 0.46, 95% confidence interval (CI) 0.3 to 0.7). Patients who were treated with piracetam were no more likely than those who took a placebo to experience unwanted effects, including death (OR 1.29, 95% CI 0.9 to 1.7). However, the differences in death rates between the two groups give rise to some concerns that there may be an increased risk of death from taking piracetam. We could not determine if drug treatment is more effective than speech and language therapy. We could not determine whether one drug is more effective than another. Drug treatment with piracetam may be effective in the treatment of aphasia after stroke. Further research is needed to explore the effects of drugs for aphasia, in particular piracetam. The safety of the drug should be of primary interest. Researchers should examine the long-term effects and whether it is more effective than speech and language therapy.
12 trials were included with a total of 8578 randomized participants. TB preventive therapy (any anti-TB drug) versus placebo was associated with a lower incidence of active TB (RR 0.68, 95% CI 0.54 to 0.85). This benefit was more pronounced in individuals with a positive tuberculin skin test (RR 0.38, 95% CI 0.25 to 0.57) than in those who had a negative test (RR 0.89, 95% CI 0.64 to 1.24). Efficacy was similar for all regimens (regardless of drug type, frequency or duration of treatment). However, compared to INH monotherapy, short-course multi-drug regimens were much more likely to require discontinuation of treatment due to adverse effects. Although there was reduction in mortality with INH monotherapy versus placebo among individuals with a positive tuberculin skin test (RR 0.74, 95% CI 0.55 to 1.00) and with INH plus rifampicin versus placebo regardless of tuberculin skin test status (RR 0.69, 95% CI 0.50 to 0.95), overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality (RR 0.94, 95% CI 0.85 to 1.05). Treatment of latent tuberculosis infection reduces the risk of active TB in HIV positive individuals especially in those with a positive tuberculin skin test. The choice of regimen will depend on factors such as availability, cost, adverse effects, adherence and drug resistance. Future studies should assess these aspects. In addition, trials evaluating the long-term effects of anti-tuberculosis chemoprophylaxis, the optimal duration of TB preventive therapy, the influence of level of immunocompromise on effectiveness and combination of anti-tuberculosis chemoprophylaxis with antiretroviral therapy are needed.
We identified 15 RCTs of ICBI conducted in various settings and populations (3917 participants). Comparing ICBI to 'minimal interventions' such as usual practice, meta-analyses showed statistically significant effects as follows: moderate effect on sexual health knowledge (SMD 0.72, 95% CI 0.27 to 1.18); small effect on safer sex self-efficacy (SMD 0.17, 95% CI 0.05 to 0.29); small effect on safer-sex intentions (SMD 0.16, 95% CI 0.02 to 0.30); and also an effect on sexual behaviour (OR 1.75, 95% CI 1.18 to 2.59). Data were insufficient for meta-analysis of biological outcomes and analysis of cost-effectiveness. In comparison with face-to-face sexual health interventions, meta-analysis was only possible for sexual health knowledge, showing that ICBI were more effective (SMD 0.36, 95% CI 0.13 to 0.58). Two further trials reported no difference in knowledge between ICBI and face-to-face intervention, but data were not available for pooling. There were insufficient data to analyse other types of outcome. No studies measured potential harms (apart from reporting any deterioration in measured outcomes). ICBI are effective tools for learning about sexual health, and they also show positive effects on self-efficacy, intention and sexual behaviour. More research is needed to establish whether ICBI can impact on biological outcomes, to understand how interventions might work, and whether they are cost-effective.
A total of 703 unique items was identified. We included 19 RCTs. There was evidence of small study biases (Egger test, P = 0.002). In 15 placebo-controlled RCTs there was an effect of antibiotic prophylaxis (pooled RR 0.59, 95% CI 0.46 to 0.75, 95% PI 0.30 to 1.14, I2 = 39%). There were insufficient data (three trials) to determine whether one regimen was superior to another. In one trial, the incidence of post-abortal upper genital tract infection was higher in women allocated to the screen-and-treat strategy (RR 1.53, 95% CI 0.99 to 2.36). Antibiotic prophylaxis at the time of first trimester surgical abortion is effective in preventing post-abortal upper genital tract infection. Evidence of between trial heterogeneity suggests that the effect might not apply to all settings, population groups or interventions. This review did not determine the most effective antibiotic prophylaxis regimen. Antibiotic choice should take into account the local epidemiology of genital tract infections, including sexually transmitted infections. Further RCTs comparing different antibiotics or combinations of antibiotics with each other would be useful. Such trials could be done in low and middle income countries and where the prevalence of genital tract infections in women presenting for abortion is high.
The review currently includes seven randomised trials and 1567 participants that compared fluphenazine with low-potency antipsychotic drugs. The size of the included studies was between 40 and 438 participants. Overall, sequence generation, allocation procedures and blinding were poorly reported. Fluphenazine was not significantly different from low-potency antipsychotic drugs in terms of response to treatment (fluphenazine 55%, low-potency drug 55%, 2 RCTs, n = 105, RR 1.06 CI 0.75 to 1.50, moderate quality evidence). There was also no significant difference in acceptability of treatment with equivocal numbers of participants leaving the studies early due to any reason (fluphenazine 36%, low-potency antipsychotics 36%, 6 RCTs, n = 1532, RR 1.00 CI 0.88 to 1.14, moderate quality evidence). There was no significant difference between fluphenazine and low-potency antipsychotics for numbers experiencing at least one adverse effect (fluphenazine 70%, low-potency antipsychotics 88%, 1 RCT, n = 65, RR 0.79 CI 0.58 to 1.07, moderate quality evidence). However, at least one movement disorder occurred significantly more frequently in the fluphenazine group (fluphenazine 15%, low-potency antipsychotics 10%, 3 RCTs, n = 971, RR 2.11 CI 1.41 to 3.15, low quality of evidence). In contrast, low-potency antipsychotics produced significantly more sedation (fluphenazine 20%, low-potency antipsychotics 64%, 1 RCT, n = 65, RR 0.31 CI 0.13 to 0.77, high quality evidence). No data were available for the outcomes of death and quality of life. The results of the primary outcome were robust in a number of subgroup and sensitivity analyses. Adverse effects such as akathisia (fluphenazine 15%, low-potency antipsychotics 6%, 5 RCTs, n = 1209, RR 2.28 CI 1.58 to 3.28); dystonia (fluphenazine 5%, low-potency antipsychotics 2%, 4 RCTs, n = 1309, RR 2.66 CI 1.25 to 5.64); loss of associated movement (fluphenazine 20%, low-potency antipsychotics 2%, 1 RCT, n = 338, RR 11.15 CI 3.95 to 31.47); rigor (fluphenazine 27%, low-potency antipsychotics 12%, 2 RCTs, n = 403, RR 2.18 CI 1.20 to 3.97); and tremor (fluphenazine 15%, low-potency antipsychotics 6%, 2 RCTs, n = 403, RR 2.53 CI 1.37 to 4.68) occurred significantly more frequently in the fluphenazine group. For other adverse effects such as dizziness (fluphenazine 8%, low-potency antipsychotics 17%, 4 RCTs, n = 1051, RR 0.49 CI 0.32 to 0.73); drowsiness (fluphenazine 18%, low-potency antipsychotics 25%, 3 RCTs, n = 986, RR 0.67 CI 0.53 to 0.86); dry mouth (fluphenazine 11%, low-potency antipsychotics 18%, 4 RCTs, n = 1051, RR 0.63 CI 0.45 to 0.89); nausea (fluphenazine 4%, low-potency antipsychotics 15%, 3 RCTs, n = 986, RR 0.25 CI 0.14 to 0.45); and vomiting (fluphenazine 3%, low-potency antipsychotics 8%, 3 RCTs, n = 986, RR 0.36 CI 0.18 to 0.72) results favoured fluphenazine with significantly more events occurring in the low-potency antipsychotic group for these outcomes. The results do not show a clear difference in efficacy between fluphenazine and low-potency antipsychotics. The number of included studies was low and their quality moderate. Therefore, further studies would be needed to draw firm conclusions about the relative effects of fluphenazine and low-potency antipsychotics.
Three studies (93 participants) that assessed cannabis in people with active CD met the inclusion criteria. One ongoing study was also identified. Participants in two of the studies were adults with active Crohn's disease who had failed at least one medical treatment. The inclusion criteria for the third study were unclear. No studies that assessed cannabis therapy in quiescent CD were identified. The studies were not pooled due to differences in the interventional drug. One small study (N = 21) compared eight weeks of treatment with cannabis cigarettes containing 115 mg of D9-tetrahydrocannabinol (THC) to placebo cigarettes containing cannabis with the THC removed in participants with active CD. This study was rated as high risk of bias for blinding and other bias (cannabis participants were older than placebo). The effects of cannabis on clinical remission were unclear. Forty-five per cent (5/11) of the cannabis group achieved clinical remission compared with 10% (1/10) of the placebo group (RR 4.55, 95% CI 0.63 to 32.56; very low certainty evidence). A difference was observed in clinical response (decrease in CDAI score of >100 points) rates. Ninety-one per cent (10/11) of the cannabis group achieved a clinical response compared to 40% (4/10) of the placebo group (RR 2.27, 95% CI 1.04 to 4.97; very low certainty evidence). More AEs were observed in the cannabis cigarette group compared to placebo (RR 4.09, 95% CI 1.15 to 14.57; very low certainty evidence). These AEs were considered to be mild in nature and included sleepiness, nausea, difficulty with concentration, memory loss, confusion and dizziness. This study did not report on serious AEs or withdrawal due to AEs. One small study (N = 22) compared cannabis oil (5% cannabidiol) to placebo oil in people with active CD. This study was rated as high risk of bias for other bias (cannabis participants were more likely than placebo participants to be smokers). There was no difference in clinical remission rates. Forty per cent (4/10) of cannabis oil participants achieved remission at 8 weeks compared to 33% (3/9) of the placebo participants (RR 1.20, 95% CI 0.36 to 3.97; very low certainty evidence). There was no difference in the proportion of participants who had a serious adverse event. Ten per cent (1/10) of participants in the cannabis oil group had a serious adverse event compared to 11% (1/9) of placebo participants (RR 0.90, 95% CI 0.07 to 12.38, very low certainty evidence). Both serious AEs were worsening Crohn's disease that required rescue intervention. This study did not report on clinical response, CRP, quality of life or withdrawal due to AEs. One small study (N= 50) compared cannabis oil (15% cannabidiol and 4% THC) to placebo in participants with active CD. This study was rated as low risk of bias. Differences in CDAI and quality of life scores measured by the SF-36 instrument were observed. The mean quality of life score after 8 weeks of treatment was 96.3 in the cannabis oil group compared to 79.9 in the placebo group (MD 16.40, 95% CI 5.72 to 27.08, low certainty evidence). After 8 weeks of treatment, the mean CDAI score was118.6 in the cannabis oil group compared to 212.6 in the placebo group (MD -94.00, 95%CI -148.86 to -39.14, low certainty evidence). This study did not report on clinical remission, clinical response, CRP or AEs. The effects of cannabis and cannabis oil on Crohn's disease are uncertain. Thus no firm conclusions regarding the efficacy and safety of cannabis and cannabis oil in adults with active Crohn's disease can be drawn. The effects of cannabis or cannabis oil in quiescent Crohn's disease have not been investigated. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn's disease. Future studies should assess the effects of cannabis in people with active and quiescent Crohn's disease. Different doses of cannabis and delivery modalities should be investigated.
We included two trials involving 312 infants. No data were available for correction of hypoglycaemia for each hypoglycaemic event. We found no evidence of a difference between dextrose gel and placebo gel for major neurosensory disability at two-year follow-up (risk ratio (RR) 6.27, 95% confidence interval (CI) 0.77 to 51.03; one trial, n = 184; quality of evidence very low). Dextrose gel compared with placebo gel or no gel did not alter the need for intravenous treatment for hypoglycaemia (typical RR 0.78, 95% CI 0.46 to 1.32; two trials, 312 infants; quality of evidence very low). Infants treated with dextrose gel were less likely to be separated from their mothers for treatment of hypoglycaemia (RR 0.54, 95% CI 0.31 to 0.93; one trial, 237 infants; quality of evidence moderate) and were more likely to be exclusively breast fed after discharge (RR 1.10, 95% CI 1.01 to 1.18; one trial, 237 infants; quality of evidence moderate). Estimated rise in blood glucose concentration following dextrose gel was 0.4 mmol/L (95% CI -0.14 to 0.94; one trial, 75 infants). Investigators in one trial reported no adverse outcomes (n = 237 infants). Treatment of infants with neonatal hypoglycaemia with 40% dextrose gel reduces the incidence of mother-infant separation for treatment and increases the likelihood of full breast feeding after discharge compared with placebo gel. No evidence suggests occurrence of adverse effects during the neonatal period or at two years' corrected age. Oral dextrose gel should be considered first-line treatment for infants with neonatal hypoglycaemia.
Of 3500 titles retrieved from the literature, 24 papers reporting on 23 studies could be included in the review. The studies were published between 1970 and 1997 and together included 1026 participants. Most were cross-over studies. Few studies provided sufficient information to judge the concealment of allocation. Four studies provided results for the percentage of symptom-free days. Pooling the results did not reveal a statistically significant difference between sodium cromoglycate and placebo. For the other pooled outcomes, most of the symptom-related outcomes and bronchodilator use showed statistically significant results, but treatment effects were small. Considering the confidence intervals of the outcome measures, a clinically relevant effect of sodium cromoglycate cannot be excluded. The funnel plot showed an under-representation of small studies with negative results, suggesting publication bias. There is insufficient evidence to be sure about the efficacy of sodium cromoglycate over placebo. Publication bias is likely to have overestimated the beneficial effects of sodium cromoglycate as maintenance therapy in childhood asthma.
We found only three RCTs, in which a total of 230 postpartum women participated. Most of our analyses were based on relatively small numbers of patients and studies. Overall, the certainty of evidence regarding the effectiveness of interventions was low, due to risk of bias and imprecision. We found very low-certainty evidence regarding the safety of interventions because of risk of bias and imprecision. Two studies had unclear risk of selection bias. One study had unclear risk of reporting bias and a high risk of other bias associated with the study protocol. Women who received an intraperitoneal instillation of lidocaine experienced lower intensity intraperitoneal pain than those given a placebo (pooled MD -3.34, 95% CI -4.19 to -2.49, three studies, 190 participants, low-certainty evidence), or an intramuscular injection of morphine (MD -4.8, 95% CI -6.43 to -3.17, one study, 40 participants, low-certainty evidence). We found no clear difference in intraperitoneal pain between women who had an intramuscular injection of morphine added to an intraperitoneal instillation of lidocaine and those who had an intraperitoneal instillation of lidocaine alone (MD -0.40, 95% CI -1.52 to 0.72, one study, 40 participants, low-certainty evidence). An intramuscular injection of morphine alone was not effective for intraperitoneal pain relief compared to placebo (MD 0.50, 95% CI -1.33 to 2.33, one study, 40 women, low-certainty evidence). None of the studies reported any serious adverse events but the evidence was very low-certainty. Intraperitoneal instillation of lidocaine may reduce the number of women requiring additional pain control when compared to placebo (RR 0.27, 95% CI 0.17 to 0.44, three studies, 190 women, low-certainty evidence). An intraperitoneal instillation of lidocaine during postpartum mini-laparotomy tubal ligation before fallopian tubes were tied may offer better intraperitoneal pain control, although the evidence regarding adverse effects is uncertain. We found no clear difference in intraperitoneal pain between women who received a combination of an injection of morphine, and intraperitoneal instillation of lidocaine and those who received an intraperitoneal instillation of lidocaine alone. These results must be interpreted with caution, since the evidence overall was low to very low-certainty.
Two studies with a total of 185 participants met the selection criteria. These trials studied all the absorbent product designs included in this review. One trial took place in nursing homes, the other in people's own homes. Gender was found to be a significant variable in both trials, and accordingly the results were analysed in gender groups. Data were presented on all included outcomes, except for quality of life. The results show that there is no single best design (i.e. one design that is significantly better than all other designs and for all users). Of the disposable designs, the more expensive pull-up and T-shaped diaper designs were not better overall than the diaper for men, but the diaper was better than the insert (the cheapest), making the diaper the most cost-effective disposable design for men both day and night. For women, disposable pull-ups were better overall than the other designs (except for those living in nursing homes when disposable diapers are better when used at night), but they are expensive. Unlike men, women in the community did not favour diapers (or T-shape diapers) and insert pads are therefore the most cost-effective alternative. Washable diapers are the least expensive design but are unacceptable to most women at any time. However, some people (particularly men living at home) prefer them at night and for them they are a cost-effective design. No firm conclusions could be drawn about the performance of designs for faecal incontinence and there was no firm evidence that there are differences in skin health between designs. Although data were available from only two eligible trials the data were sufficiently robust to make some recommendations for practice. There is evidence that different designs are better for men and women. Diapers are the most cost-effective disposable design for men. Disposable pull-ups are most preferred for women but are expensive: disposable inserts are a cheaper alternative (except in nursing homes where diapers are preferred to inserts at night). Washable diapers are the cheapest design but have limited acceptability, confined mainly to some men at night. There were not enough people in the trials to draw any conclusions about which designs are best for faecal incontinence and no particular design seemed to be better or worse for skin health. People have different preferences for absorbent product designs and using a combination (different designs for day/night, going out/staying in) may be more effective and less expensive than using one design all the time.
We screened 1290 records and found only three trials involving 154 female participants, all of whom were aged above 65 years and had had hip fracture surgery. All studies had methodological shortcomings that placed them at high or unclear risk of bias. Because of this high risk of bias, imprecise results and likelihood of publication bias, we judged the quality of the evidence for all primary outcomes to be very low. These trials tested two comparisons. One trial had three groups and contributed data to both comparisons. None of the trials reported on patient acceptability of the intervention. Two very different trials compared anabolic steroid versus control (no anabolic steroid or placebo). One trial compared anabolic steroid injections (given weekly until discharge from hospital or four weeks, whichever came first) versus placebo injections in 29 "frail elderly females". This found very low quality evidence of little difference between the two groups in the numbers discharged to a higher level of care or dead (one person in the control group died) (8/15 versus 10/14; risk ratio (RR) 0.75, 95% confidence interval (CI) 0.42 to 1.33; P = 0.32), time to independent mobilisation or individual adverse events. The second trial compared anabolic steroid injections (every three weeks for six months) and daily protein supplementation versus daily protein supplementation alone in 40 "lean elderly women" who were followed up for one year after surgery. This trial provided very low quality evidence that anabolic steroid may result in less dependency, assessed in terms of being either dependent in at least two functions or dead (one person in the control group died) at six and 12 months, but the result was also compatible with no difference or an increase in dependency (dependent in at least two levels of function or dead at 12 months: 1/17 versus 5/19; RR 0.22, 95% CI 0.03 to 1.73; P = 0.15). The trial found no evidence of between-group differences in individual adverse events. Two trials compared anabolic steroids combined with another nutritional intervention ('steroid plus') versus control (no 'steroid plus'). One trial compared anabolic steroid injections every three weeks for 12 months in combination with daily supplement of vitamin D and calcium versus calcium only in 63 women who were living independently at home. The other trial compared anabolic steroid injections every three weeks for six months and daily protein supplementation versus control in 40 "lean elderly women". Both trials found some evidence of better function in the steroid plus group. One trial reported greater independence, higher Harris hip scores and gait speeds in the steroid plus group at 12 months. The second trial found fewer participants in the anabolic steroid group were either dependent in at least two functions, including bathing, or dead at six and 12 months (one person in the control group died) (1/17 versus 7/18; RR 0.15, 95% CI 0.02 to 1.10; P = 0.06). Pooled mortality data (2/51 versus 3/51) from the two trials showed no evidence of a difference between the two groups at one year. Similarly, there was no evidence of between-group differences in individual adverse events. Three participants in the steroid group of one trial reported side effects of hoarseness and increased facial hair. The other trial reported better quality of life in the steroid plus group. The available evidence is insufficient to draw conclusions on the effects, primarily in terms of functional outcome and adverse events, of anabolic steroids, either separately or in combination with nutritional supplements, after surgical treatment of hip fracture in older people. Given that the available data points to the potential for more promising outcomes with a combined anabolic steroid and nutritional supplement intervention, we suggest that future research should focus on evaluating this combination.
We included 83 SRs; 70 had outcome data. Below we highlight key results from a subset of 36 SRs of interventions intended to prevent PTB. Outcome: preterm birth Clear evidence of benefit Four SRs reported clear evidence of benefit to prevent specific populations of pregnant women from giving birth early, including midwife-led continuity models of care versus other models of care for all women; screening for lower genital tract infections for pregnant women less than 37 weeks' gestation and without signs of labour, bleeding or infection; and zinc supplementation for pregnant women without systemic illness. Cervical cerclage showed clear benefit for women with singleton pregnancy and high risk of PTB only. Clear evidence of harm No included SR reported clear evidence of harm. No effect or equivalence For pregnant women at high risk of PTB, bedrest for women with singleton pregnancy and antibiotic prophylaxis during the second and third trimester were of no effect or equivalent to a comparator. Possible benefit Four SRs found possible benefit in: group antenatal care for all pregnant women; antibiotics for pregnant women with asymptomatic bacteriuria; pharmacological interventions for smoking cessation for pregnant women who smoke; and vitamin D supplements alone for women without pre-existing conditions such as diabetes. Possible harm One SR reported possible harm (increased risk of PTB) with intramuscular progesterone, but this finding is only relevant to women with multiple pregnancy and high risk of PTB. Another review found possible harm with vitamin D, calcium and other minerals for pregnant women without pre-existing conditions. Outcome: perinatal death Clear evidence of benefit Two SRs reported clear evidence of benefit to reduce pregnant women's risk of perinatal death: midwife-led continuity models of care for all pregnant women; and fetal and umbilical Doppler for high-risk pregnant women. Clear evidence of harm No included SR reported clear evidence of harm. No effect or equivalence For pregnant women at high risk of PTB, antibiotic prophylaxis during the second and third trimester was of no effect or equivalent to a comparator. Possible benefit One SR reported possible benefit with cervical cerclage for women with singleton pregnancy and high risk of PTB. Possible harm One SR reported possible harm associated with a reduced schedule of antenatal visits for pregnant women at low risk of pregnancy complications; importantly, these women already received antenatal care in settings with limited resources. Outcomes: preterm birth and perinatal death Unknown benefit or harm For pregnant women at high risk of PTB for any reason including multiple pregnancy, home uterine monitoring was of unknown benefit or harm. For pregnant women at high risk due to multiple pregnancy: bedrest, prophylactic oral betamimetics, vaginal progesterone and cervical cerclage were all of unknown benefit or harm. Implications for practice The overview serves as a map and guide to all current evidence relevant to PTB prevention published in the Cochrane Library. Of 70 SRs with outcome data, we identified 36 reviews of interventions with the aim of preventing PTB. Just four of these SRs had evidence of clear benefit to women, with an additional four SRs reporting possible benefit. No SR reported clear harm, which is an important finding for women and health providers alike. The overview summarises no evidence for the clinically important interventions of cervical pessary, cervical length assessment and vaginal progesterone because these Cochrane Reviews were not current. These are active areas for PTB research. The graphic icons we assigned to SR effect estimates do not constitute clinical guidance or an endorsement of specific interventions for pregnant women. It remains critical for pregnant women and their healthcare providers to carefully consider whether specific strategies to prevent PTB will be of benefit for individual women, or for specific populations of women. Implications for research Formal consensus work is needed to establish standard language for overviews of reviews and to define the limits of their interpretation. Clinicians, researchers and funders must address the lack of evidence for interventions relevant to women at high risk of PTB due to multiple pregnancy.
Three studies (866 participants) compared rectally administered sumatriptan with placebo or an active comparator. Most of the data were for the 12.5 mg and 25 mg doses. For the majority of efficacy outcomes, sumatriptan surpassed placebo. For sumatriptan 12.5 mg versus placebo the NNTs were 5.2 and 3.2 for headache relief at one and two hours, respectively. Results for the 25 mg dose were similar to the 12.5 mg dose, and there were no significant differences between the two doses for any of the outcomes analysed. The NNTs for sumatriptan 25 mg versus placebo were 4.2, 3.2, and 2.4 for pain-free at two hours, headache relief at one hour, and headache relief at two hours, respectively. Relief of functional disability was greater with sumatriptan than with placebo, with NNTs of 8.0 and 4.0 for the 12.5 mg and 25 mg doses, respectively. For the most part, adverse events were transient and mild and were more common with sumatriptan than with placebo, but there were insufficient data to perform any analyses. Direct comparison of sumatriptan with active treatments was limited to one study comparing sumatriptan 25 mg with ergotamine tartrate 2 mg + caffeine 100 mg. Based on limited amounts of data, sumatriptan 25 mg, administered rectally, is an effective treatment for acute migraine attacks, with participants in these studies experiencing a significant reduction in headache pain and functional disability within two hours of treatment. The lack of data on relief of headache-associated symptoms or incidence of adverse events limits any conclusions that can be drawn.
Six studies involving 1001 women were included. Three trials compared one counselling session with no counselling. There was no significant difference in psychological well being including anxiety, grief, depression avoidance and self-blame. One trial compared three one-hour counselling sessions with no counselling at four and 12 months. Some subscales showed statistical significance in favour of counselling and some in favour of no counselling. The results for two trials were given in narrative form as data were unavailable for meta-analyses. One trial compared multiple interventions. The other trial compared two counselling sessions with no counselling. Neither study favoured counselling. Evidence is insufficient to demonstrate that psychological support such as counselling is effective post-miscarriage. Further trials should be good quality, adequately-powered using standardised interventions and outcome measures at specific time points. The economic implications and women's satisfaction with psychological follow-up should also be explored in any future study.
In this review, we included a total of five studies comparing supervised walking exercise and alternative modes of exercise. The alternative modes of exercise therapy included cycling, strength training, and upper-arm ergometry. The studies represented a sample size of 135 participants with a low risk of bias. Overall, there was no clear evidence of a difference between supervised walking exercise and alternative modes of exercise in maximum walking distance (8.15 METs, 95% confidence interval (CI) -2.63 to 18.94, P = 0.14, equivalent of an increase of 173 metres, 95% CI -56 to 401) on a treadmill with no incline and an average speed of 3.2 km/h, which is comparable with walking in daily life. Similarly, there was no clear evidence of a difference between supervised walking exercise and alternative modes of exercise in pain-free walking distance (6.42 METs, 95% CI -1.52 to 14.36, P = 0.11, equivalent of an increase of 136 metres, 95% CI -32 to 304). Sensitivity analysis did not alter the results significantly. Quality of life measures showed significant improvements in both groups; however, because of skewed data and the very small sample size of the studies, we did not perform a meta-analysis for health-related quality of life and functional impairment. There was no clear evidence of differences between supervised walking exercise and alternative exercise modes in improving the maximum and pain-free walking distance of patients with intermittent claudication. More studies with larger sample sizes are needed to make meaningful comparisons between each alternative exercise mode and the current standard of supervised treadmill walking. The results indicate that alternative exercise modes may be useful when supervised walking exercise is not an option for the patient.
Thirteen trials (n=1154) investigated external beam radiotherapy with dosages ranging from 7.5 to 24 Gy; one additional trial (n=88) used plaque brachytherapy (15Gy at 1.75mm for 54 minutes/12.6 Gy at 4mm for 11 minutes). Most studies found effects (not always significant) that favoured treatment. Overall there was a small statistically significant reduction in risk of visual acuity loss in the treatment group. There was considerable inconsistency between trials and the trials were considered to be at risk of bias, in particular because of the lack of masking of treatment group. Subgroup analyses did not reveal any significant interactions, however, there were small numbers of trials in each subgroup (range three to five). There was some indication that trials with no sham irradiation in the control group reported a greater effect of treatment. The incidence of adverse events was low in all trials; there were no reported cases of radiation retinopathy, optic neuropathy or malignancy. Three trials found non-significant higher rates of cataract progression in the treatment group. This review currently does not provide convincing evidence that radiotherapy is an effective treatment for neovascular AMD. If further trials are to be considered to evaluate radiotherapy in AMD then adequate masking of the control group must be considered.
We included 69 trials that randomly assigned 7863 participants. Twenty-two trials compared the same beta lactam in both study arms, while the remaining trials compared different beta lactams using a broader-spectrum beta lactam in the monotherapy arm. In trials comparing the same beta lactam, we observed no difference between study groups with regard to all-cause mortality (RR 0.97, 95% CI 0.73 to 1.30) and clinical failure (RR 1.11, 95% CI 0.95 to 1.29). In studies comparing different beta lactams, we observed a trend for benefit with monotherapy for all-cause mortality (RR 0.85, 95% CI 0.71 to 1.01) and a significant advantage for clinical failure (RR 0.75, 95% CI 0.67 to 0.84). No significant disparities emerged from subgroup and sensitivity analyses, including assessment of participants with Gram-negative infection. The subgroup of Pseudomonas aeruginosa infections was underpowered to examine effects. Results for mortality were classified as low quality of evidence mainly as the result of imprecision. Results for failure were classified as very low quality of evidence because of indirectness of the outcome and possible detection bias in non-blinded trials. We detected no differences in the rate of development of resistance. Nephrotoxicity was significantly less frequent with monotherapy (RR 0.30, 95% CI 0.23 to 0.39). We found no heterogeneity for all these comparisons. We included a small subset of studies addressing participants with Gram-positive infection, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies. The addition of an aminoglycoside to beta lactams for sepsis should be discouraged. All-cause mortality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.
We included four studies with a total of 746 participants. All studies included adult patients undergoing surgery for primary tumour resection. Two studies enrolled male and female participants undergoing major abdominal surgery for cancer. One study enrolled male participants undergoing surgery for prostate cancer, and one study male participants undergoing surgery for colon cancer. Follow-up time ranged from nine to 17 years. All four studies compared general anaesthesia alone versus general anaesthesia combined with epidural anaesthesia and analgesia. All four studies are secondary data analyses of previously conducted prospective randomized controlled trials. Of the four included studies, only three contributed to the outcome of overall survival, and two each to the outcomes of progression-free survival and time to tumour progression. In our meta-analysis, we could not find an advantage for either study group for the outcomes of overall survival (hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.86 to 1.24) and progression-free survival (HR 0.88, 95% CI 0.56 to 1.38). For progression-free survival, the level of inconsistency was high. Pooled data for time to tumour progression showed a slightly favourable outcome for the control group (general anaesthesia alone) compared with the intervention group (epidural and general anaesthesia) (HR 1.50, 95% CI 1.00 to 2.25). Quality of evidence was graded low for overall survival and very low for progression-free survival and time to tumour progression. The outcome of overall survival was downgraded for serious imprecision and serious indirectness. The outcomes of progression-free survival and time to tumour progression were also downgraded for serious inconsistency and serious risk of bias, respectively. Reporting of adverse events was sparse, and data could not be analysed. Currently, evidence for the benefit of regional anaesthesia techniques on tumour recurrence is inadequate. An encouraging number of prospective randomized controlled trials are ongoing, and it is hoped that their results, when reported, will add evidence for this topic in the near future.
We found no RCTs on this topic. We included in this review 12 non-randomised studies that compared laparoscopic versus open distal pancreatectomy (1576 participants: 394 underwent laparoscopic distal pancreatectomy and 1182 underwent open distal pancreatectomy); 11 studies (1506 participants: 353 undergoing laparoscopic distal pancreatectomy and 1153 undergoing open distal pancreatectomy) provided information for one or more outcomes. All of these studies were retrospective cohort-like studies or case-control studies. Most were at unclear or high risk of bias, and the overall quality of evidence was very low for all reported outcomes. Differences in short-term mortality (laparoscopic group: 1/329 (adjusted proportion based on meta-analysis estimate: 0.5%) vs open group: 11/1122 (1%); OR 0.48, 95% CI 0.11 to 2.17; 1451 participants; nine studies; I2 = 0%), long-term mortality (HR 0.96, 95% CI 0.82 to 1.12; 277 participants; three studies; I2 = 0%), proportion of people with serious adverse events (laparoscopic group: 7/89 (adjusted proportion: 8.8%) vs open group: 6/117 (5.1%); OR 1.79, 95% CI 0.53 to 6.06; 206 participants; three studies; I2 = 0%), proportion of people with a clinically significant pancreatic fistula (laparoscopic group: 9/109 (adjusted proportion: 7.7%) vs open group: 9/137 (6.6%); OR 1.19, 95% CI 0.47 to 3.02; 246 participants; four studies; I2 = 61%) were imprecise. Differences in recurrence at maximal follow-up (laparoscopic group: 37/81 (adjusted proportion based on meta-analysis estimate: 36.3%) vs open group: 59/103 (49.5%); OR 0.58, 95% CI 0.32 to 1.05; 184 participants; two studies; I2 = 13%), adverse events of any severity (laparoscopic group: 33/109 (adjusted proportion: 31.7%) vs open group: 45/137 (32.8%); OR 0.95, 95% CI 0.54 to 1.66; 246 participants; four studies; I2 = 18%) and proportion of participants with positive resection margins (laparoscopic group: 49/333 (adjusted proportion based on meta-analysis estimate: 14.3%) vs open group: 208/1133 (18.4%); OR 0.74, 95% CI 0.49 to 1.10; 1466 participants; 10 studies; I2 = 6%) were also imprecise. Mean length of hospital stay was shorter by 2.43 days in the laparoscopic group than in the open group (MD -2.43 days, 95% CI -3.13 to -1.73; 1068 participants; five studies; I2 = 0%). None of the included studies reported quality of life at any point in time, recurrence within six months, time to return to normal activity and time to return to work or blood transfusion requirements. Currently, no randomised controlled trials have compared laparoscopic distal pancreatectomy versus open distal pancreatectomy for patients with pancreatic cancers. In observational studies, laparoscopic distal pancreatectomy has been associated with shorter hospital stay as compared with open distal pancreatectomy. Currently, no information is available to determine a causal association in the differences between laparoscopic versus open distal pancreatectomy. Observed differences may be a result of confounding due to laparoscopic operation on less extensive cancer and open surgery on more extensive cancer. In addition, differences in length of hospital stay are relevant only if laparoscopic and open surgery procedures are equivalent oncologically. This information is not available currently. Thus, randomised controlled trials are needed to compare laparoscopic distal pancreatectomy versus open distal pancreatectomy with at least two to three years of follow-up. Such studies should include patient-oriented outcomes such as short-term mortality and long-term mortality (at least two to three years); health-related quality of life; complications and the sequelae of complications; resection margins; measures of earlier postoperative recovery such as length of hospital stay, time to return to normal activity and time to return to work (in those who are employed); and recurrence of cancer.
Seven heterogeneous English language RCTs with reasonable quality were included. Three small studies (168 people) separately showed statistically significant but clinically unimportant pain relief for LLLT versus sham therapy for sub-acute and chronic low-back pain at short-term and intermediate-term follow-up (up to six months). One study (56 people) showed that LLLT was more effective than sham at reducing disability in the short term. Three studies (102 people) reported that LLLT plus exercise were not better than exercise, with or without sham in the short-term in reducing pain or disability. Two studies (90 people) reported that LLLT was not more effective than exercise, with or without sham in reducing pain or disability in the short term. Two small trials (151 people) independently found that the relapse rate in the LLLT group was significantly lower than in the control group at the six-month follow-up. No side effects were reported. Based on the heterogeneity of the populations, interventions and comparison groups, we conclude that there are insufficient data to draw firm conclusions on the clinical effect of LLLT for low-back pain. There is a need for further methodologically rigorous RCTs to evaluate the effects of LLLT compared to other treatments, different lengths of treatment, wavelengths and dosages.
In this update we did not identify any new trials for inclusion. We included five RCTs with 208 participants in the review and meta-analysis. We also identified 17 non-RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention in patients with basilar skull fractures. Most trials presented insufficient methodological detail. All studies included meningitis in their primary outcome. When we evaluated the five included RCTs, there were no significant differences between antibiotic prophylaxis groups and control groups in terms of reduction of the frequency of meningitis, all-cause mortality, meningitis-related mortality and need for surgical correction in patients with CSF leakage. There were no reported adverse effects of antibiotic administration, although one of the five RCTs reported an induced change in the posterior nasopharyngeal flora towards potentially more pathogenic organisms resistant to the antibiotic regimen used in prophylaxis. We performed a subgroup analysis to evaluate the primary outcome in patients with and without CSF leakage. We also completed a meta-analysis of all the identified controlled non-RCTs (enrolling a total of 2168 patients), which produced results consistent with the randomised data from the included studies. Using the GRADE approach, we assessed the quality of trials as moderate. Currently available evidence from RCTs does not support prophylactic antibiotic use in patients with basilar skull fractures, whether there is evidence of CSF leakage or not. Until more research is available, the effectiveness of antibiotics in patients with basilar skull fractures cannot be determined because studies published to date are flawed by biases. Large, appropriately designed RCTs are needed.
Since the original version of this review we have identified 11 new studies in women. The one study identified in the earlier version of this review was excluded in this update as it did not meet our narrower inclusion criteria to include only interventions for the treatment, not prevention, of sexual dysfunction. In total 1509 female participants were randomised across 11 trials. All trials explored interventions following treatment either for gynaecological or breast cancer. Eight trials evaluated a psychotherapeutic or psycho-educational intervention. Two trials evaluated a pharmaceutical intervention and one pelvic floor exercises. All involved heterosexual women. Eight studies were at a high risk of bias as they involved a sample of fewer than 50 participants per trial arm. The trials varied not only in intervention content but in outcome measurements, thereby restricting combined analysis. In the trials evaluating a psychotherapeutic intervention the effect on sexual dysfunction was mixed; in three trials benefit was found for some measures of sexual function and in five trials no benefit was found. Evidence from the other three trials, two on different pharmaceutical applications and one on exercise, differed and was limited by small sample sizes. Only the trial of a pH-balanced vaginal gel found significant improvements in sexual function. The trials of pharmaceutical interventions measured harm: neither reported any. Only one psychological intervention trial reported that no harm occurred because of the intervention; the other trials of psychological support did not measure harm. Since the last version of this review, the new studies do not provide clear information on the impact of interventions for sexual dysfunction following treatments for cancer in women. The sexual dysfunction interventions in this review are not representative of the range that is available for women, or of the wider range of cancers in which treatments are known to increase the risk of sexual problems. Further evaluations are needed.
We found four RCTs eligible for inclusion in this review (248 eyes of 151 participants between the ages of 6 months to 22 years). All trials were assessed as having unclear risk of bias overall due to insufficient reporting of study methods. One trial was conducted in Canada and compared anteriorization of the inferior oblique muscle with resection versus anteriorization of the inferior oblique muscle alone; one in the USA compared superior rectus recession with posterior fixation suture versus superior rectus recession alone; and two in the Czech Republic compared anteriorization of the inferior oblique muscle versus myectomy of the inferior oblique muscle. Only one trial reported data that allowed analysis of the primary outcome for this review, the proportion of participants with treatment success. The difference between inferior oblique anteriorization plus resection versus inferior oblique anteriorization alone was uncertain when measured at least four months postoperatively (risk ratio 1.13, 95% confidence interval 0.60 to 2.11, 30 participants, very low-quality evidence). Three trials measured the magnitude of hyperdeviation, but did not provide sufficient data for analysis. All four trials reported a relatively low rate of adverse events; hypotropia, limited elevation, and need for repeat surgery were reported as adverse events associated with some of the surgical interventions. No trials reported any other secondary outcome specified for our review. The four trials included in this review assessed the effectiveness of five different surgical procedures for the treatment of DVD. Nevertheless, insufficient reporting of study methods and data led to methodological concerns that undermine the conclusions of all studies. There is a pressing need for carefully executed RCTs of treatment for DVD in order to improve the evidence for the optimal management of this condition.
Two RCTs including 85 participants met our inclusion criteria. One study included people with single untreated brain metastasis (n = 64), and the other included people with solitary brain metastasis (22 consented to randomisation and 21 were analysed). We identified a third trial reported as completed and pending results this may be included in future updates of this review. The two included studies were prematurely closed due to poor participant accrual. One study compared surgery plus whole brain radiotherapy (WBRT) versus stereotactic radiosurgery alone, and the second study compared surgery plus WBRT versus stereotactic radiosurgery plus WBRT. Meta-analysis was not possible due to clinical heterogeneity between trial interventions. The overall certainty of evidence was low or very low for all outcomes due to high risk of bias and imprecision. We found no difference in overall survival in either of the two comparisons. For the comparison of surgery plus WBRT versus stereotactic radiosurgery alone: HR 0.92, 95% CI 0.48 to 1.77; 64 participants, very low-certainty evidence. We downgraded the certainty of the evidence to very low due to risk of bias and imprecision. For the comparison of surgery plus WBRT versus stereotactic radiosurgery plus WBRT: HR 0.53, 95% CI 0.20 to 1.42; 21 participants, low-certainty evidence. We downgraded the certainty of the evidence to low due to imprecision. Adverse events were reported in both trial groups in the two studies, showing no differences for surgery plus WBRT versus stereotactic radiosurgery alone (RR 0.31, 95% CI 0.07 to 1.44; 64 participants) and for surgery plus WBRT versus stereotactic radiosurgery plus WBRT (RR 0.37, 95% CI 0.05 to 2.98; 21 participants). Most of the adverse events were related to radiation toxicities. We considered the certainty of the evidence from the two comparisons to be very low due to risk of bias and imprecision. There was no difference in progression-free survival in the study comparing surgery plus WBRT versus stereotactic radiosurgery plus WBRT (HR 0.55, 95% CI 0.22 to 1.38; 21 participants, low-certainty evidence). We downgraded the evidence to low certainty due to imprecision. This outcome was not clearly reported for the other comparison. In general, there were no differences in quality of life between the two studies. The study comparing surgery plus WBRT versus stereotactic radiosurgery plus WBRT found no differences after two months using the QLQ-C30 global scale (MD -10.80, 95% CI -44.67 to 23.07; 14 participants, very low-certainty evidence). We downgraded the certainty of evidence to very low due to risk of bias and imprecision. Currently, there is no definitive evidence regarding the effectiveness and safety of surgery versus stereotactic radiotherapy on overall survival, adverse events, progression-free survival and quality of life in people with single or solitary brain metastasis, and benefits must be decided on a case-by-case basis until well powered and designed trials are available. Given the difficulties in participant accrual, an international multicentred approach should be considered for future studies.
Nineteen studies randomising a total of 2863 women were included in this review. There were three main comparison groups: 15 studies compared non-opioid drugs with placebo or no treatment (2133 women); three studies compared non-opioid drugs with opioids (563 women); and three studies compared one type of non-opioid drug with a different type or dose of non-opioid drug (590 women). Some of the studies included three or more groups and so have been put in more than one comparison. Overall, there was little difference between groups for most of the comparisons. Any differences observed for outcomes were mainly limited to one or two studies. Non-opioid drugs (sedatives) were found to offer better pain relief (mean difference (MD) -22.00; 95% confidence interval (CI) -35.86 to -8.14, one trial, 50 women), better satisfaction with pain relief (sedatives and antihistamines) (risk ratio (RR) 1.59; 95% CI 1.15 to 2.21, two trials, 204 women; RR 1.80; 95% CI 1.16 to 2.79, one trial, 223 women) and better satisfaction with the childbirth experience (RR 2.16; 95% CI 1.34 to 3.47, one trial, 40 women) when compared with placebo or no treatment. However, women having non-opioid drugs (NSAIDs or antihistamines) were less likely to be satisfied with pain relief compared with women having opioids (RR 0.50; 95% CI 0.27 to 0.94, one trial, 76 women; RR 0.73; 95% CI 0.54 to 0.98, one trial, 223 women). Women receiving the antihistamine hydroxyzine were more likely to express satisfaction with pain relief compared with the antihistamine promethazine (RR 1.21; 95% CI 1.02 to 1.43, one trial, 289 women). Women receiving sedatives were more likely to express satisfaction with pain relief compared with antihistamines (RR 1.52; 95% CI 1.06 to 2.17, one study, 157 women). The majority of studies were conducted over 30 years ago. The studies were at unclear risk of bias for most of the quality domains. Opioids appear to be superior to non-opioids in satisfaction with pain relief, while non-opioids appear to be superior to placebo for pain relief and satisfaction with the childbirth experience. There were little data and no evidence of a significant difference for any of the comparisons of non-opioids for safety outcomes. Overall, the findings of this review demonstrated insufficient evidence to support a role for non-opioid drugs on their own to manage pain during labour.
Eight trials met the inclusion criteria of this review, enrolling a total of 1612 participants. Three trials evaluated the effect of providing antihelminthics to all adults with HIV without knowledge of their helminth infection status, and five trials evaluated the effects of providing deworming drugs to HIV-positive individuals with confirmed helminth infections. Seven trials were conducted in sub-Saharan Africa and one in Thailand. Antihelminthics for people with unknown helminth infection status Providing antihelminthics (albendazole and praziquantel together or separately) to HIV-positive adults with unknown helminth infection status may have a small suppressive effect on mean viral load at six weeks but the 95% CI includes the possibility of no effect (difference in mean change −0.14 log10 viral RNA/mL, 95% CI −0.35 to 0.07, P = 0.19; one trial, 166 participants, low quality evidence). Repeated dosing with deworming drugs over two years (albendazole every three months plus annual praziquantel), probably has little or no effect on mean viral load (difference in mean change 0.01 log10 viral RNA, 95% CI: −0.03 to −0.05; one trial, 917 participants, moderate quality evidence), and little or no effect on mean CD4+ count (difference in mean change 2.60 CD4+ cells/µL, 95% CI −10.15 to 15.35; P = 0.7; one trial, 917 participants, low quality evidence). Antihelminthics for people with confirmed helminth infections Treating confirmed helminth infections in HIV-positive adults may have a small suppressive effect on mean viral load at six to 12 weeks following deworming (difference in mean change −0.13 log10 viral RNA, 95% CI −0.26 to −0.00; P = 0.04; four trials, 445 participants, low quality evidence). However, this finding is strongly influenced by a single study of praziquantel treatment for schistosomiasis. There may also be a small favourable effect on mean CD4+ cell count at 12 weeks after deworming in HIV-positive populations with confirmed helminth infections (difference in mean change 37.86 CD4+ cells/µL, 95% CI 7.36 to 68.35; P = 0.01; three trials, 358 participants, low quality evidence). Adverse events and mortality There is no indication that antihelminthic drugs impart additional risks in HIV-positive populations. However, adverse events were not well reported (very low quality evidence) and trials were underpowered to evaluate effects on mortality (low quality evidence). There is low quality evidence that treating confirmed helminth infections in HIV-positive adults may have small, short-term favourable effects on markers of HIV disease progression. Further studies are required to confirm this finding. Current evidence suggests that deworming with antihelminthics is not harmful, and this is reassuring for the routine treatment of confirmed or suspected helminth infections in people living with HIV in co-endemic areas. Further long-term studies are required to make confident conclusions regarding the impact of presumptively deworming all HIV-positive individuals irrespective of helminth infection status, as the only long-term trial to date did not demonstrate an effect.
Sixteen studies (n = 1787) met inclusion criteria for the comparison systemic corticosteroid versus placebo and 13 studies contributed data (n = 1620). Four studies (n = 298) met inclusion criteria for the comparison oral corticosteroid versus parenteral corticosteroid and three studies contributed data (n = 239). The mean age of participants with COPD was 68 years, median proportion of males 82% and mean forced expiratory volume in one second (FEV1) per cent predicted at study admission was 40% (6 studies; n = 633). We judged risk of selection, detection, attrition and reporting bias as low or unclear in all studies. We judged risk of performance bias high in one study comparing systemic corticosteroid with control and in two studies comparing intravenous corticosteroid versus oral corticosteroid. Systemic corticosteroids reduced the risk of treatment failure by over half compared with placebo in nine studies (n = 917) with median treatment duration 14 days, odds ratio (OR) 0.48 (95% confidence interval (CI) 0.35 to 0.67). The evidence was graded as high quality and it would have been necessary to treat nine people (95% CI 7 to 14) with systemic corticosteroids to avoid one treatment failure. There was moderate-quality evidence for a lower rate of relapse by one month for treatment with systemic corticosteroid in two studies (n = 415) (hazard ratio (HR) 0.78; 95% CI 0.63 to 0.97). Mortality up to 30 days was not reduced by treatment with systemic corticosteroid compared with control in 12 studies (n = 1319; OR 1.00; 95% CI 0.60 to 1.66). FEV1, measured up to 72 hours, showed significant treatment benefits (7 studies; n = 649; mean difference (MD) 140 mL; 95% CI 90 to 200); however, this benefit was not observed at later time points. The likelihood of adverse events increased with corticosteroid treatment (OR 2.33; 95% CI 1.59 to 3.43). Overall, one extra adverse effect occurred for every six people treated (95% CI 4 to 10). The risk of hyperglycaemia was significantly increased (OR 2.79; 95% CI 1.86 to 4.19). For general inpatient treatment, duration of hospitalisation was significantly shorter with corticosteroid treatment (MD -1.22 days; 95% CI -2.26 to -0.18), with no difference in length of stay the intensive care unit (ICU) setting. Comparison of parenteral versus oral treatment showed no significant difference in the primary outcomes of treatment failure, relapse or mortality or for any secondary outcomes. There was a significantly increased rate of hyperglycaemia in one study (OR 4.89; 95% CI 1.20 to 19.94). There is high-quality evidence to support treatment of exacerbations of COPD with systemic corticosteroid by the oral or parenteral route in reducing the likelihood of treatment failure and relapse by one month, shortening length of stay in hospital inpatients not requiring assisted ventilation in ICU and giving earlier improvement in lung function and symptoms. There is no evidence of benefit for parenteral treatment compared with oral treatment with corticosteroid on treatment failure, relapse or mortality. There is an increase in adverse drug effects with corticosteroid treatment, which is greater with parenteral administration compared with oral treatment.
We included three RCTs, one from New Zealand, one from Japan and one from China, published between 2015 and 2019. Together, these trials enrolled 114 adults (228 eyes). Two studies used a paired-eye (inter-eye comparison) design to evaluate the effects of a sham (control) IPL treatment relative to an actual IPL treatment. One study randomised individuals to either an IPL intervention combined with meibomian gland expression (MGX), or MGX alone (standard therapy). The study follow-up periods ranged from 45 days to nine months. None of the trials were at low risk of bias in all seven domains. The first authors of two included studies were in receipt of funding from patents or the manufacturers of IPL devices. The funding sources and declaration of interests were not given in the report of the third included trial. All three trials evaluated the effect of IPL on dry eye symptoms, quantified using the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire. Pooling data from two trials that used a paired-eye design, the summary estimate for these studies indicated little to no reduction in dry eye symptoms with IPL relative to a sham intervention (mean difference (MD) –0.33 units, 95% confidence interval (CI) –2.56 to 1.89; I² = 0%; 2 studies, 144 eyes). The other study was not pooled as it had a unit-of-analysis error, but reported a reduction in symptoms in favour of IPL (MD –4.60, 95% CI –6.72 to –2.48; 84 eyes). The body of evidence for this outcome was of very low certainty, so we are uncertain about the effect of IPL on dry eye symptoms. There were no relevant combinable data for any of the other secondary outcomes, thus the effect of IPL on clinical parameters relevant to dry eye disease are currently unclear. For sodium fluorescein TBUT, two studies indicated that there may be an improvement in favour of IPL (MD 2.02 seconds, 95% CI 0.87 to 3.17; MD 2.40 seconds, 95% CI 2.27 to 2.53; 172 eyes total; low-certainty evidence). We are uncertain of the effect of IPL on non-invasive tear break-up time (MD 5.51 seconds, 95% CI 0.79 to 10.23; MD 3.20, 95% CI 3.09 to 3.31 seconds; two studies; 140 eyes total; very low-certainty evidence). For tear osmolarity, one study indicated that there may be an improvement in favour of IPL (MD –7.00 mOsmol/L, 95% –12.97 to –1.03; 56 eyes; low-certainty evidence). We are uncertain of the effect of IPL on meibomian gland orifice plugging (MD –1.20 clinical units, 95% CI –1.24 to –1.16; 84 eyes; very low-certainty evidence). We are uncertain of the effect of IPL on corneal sodium fluorescein staining. One study reported no evidence of a difference between the IPL and sham intervention arms at three months of follow-up (P = 0.409), and a second study reported data favouring IPL (MD –1.00 units, 95% CI –1.07 to –0.93 units; 172 eyes in total; very low-certainty evidence). We considered the incidence of adverse events at the study endpoint, as a measure of safety. As most trials did not specifically report adverse events, the safety of IPL as a treatment for MGD could also not be determined with any certainty. Very low-certainty results from individual studies suggest some adverse effects that may be experienced by participants, include mild pain and burning, and the potential for partially losing eyelashes (due to clinician error). This systematic review finds a scarcity of RCT evidence relating to the effectiveness and safety of IPL as a treatment for MGD. Whether IPL is of value for modifying the symptoms or signs of evaporative dry eye disease is currently uncertain. Due to a lack of comprehensive reporting of adverse events, the safety profile of IPL in this patient population is also unclear. The current limitations in the evidence base should be considered by clinicians using this intervention to treat MGD, and outlined to individuals potentially undergoing this procedure with the intent of treating dry eye disease. The results of the 14 RCTs currently in progress will be of major importance for establishing a more definitive answer regarding the effectiveness and safety of IPL for treating MGD. We intend to update this review when results from these trials become available.
Three placebo-controlled RCTs (714 adult participants) were included. The participants had moderate to severely active CD (CDAI 220 to 450). Two studies were rated as at low risk of bias and one study was rated as at unclear risk of bias. Seventy-six per cent (342/451) of adalimumab participants failed to achieve clinical remission at four weeks compared to 91% (240/263) of placebo participants (RR 0.85, 95% CI 0.79 to 0.90; high-certainty evidence). Forty-four per cent (197/451) of adalimumab participants compared to 66% (173/263) of placebo participants failed to achieve a 70-point clinical response at four weeks (RR 0.68, 95% CI 0.59 to 0.79; high-certainty evidence). At four weeks, 57% (257/451) of adalimumab participants failed to achieve a 100-point clinical response compared to 76% (199/263) of placebo participants (RR 0.77, 95% CI 0.69 to 0.86; high-certainty evidence). Sixty-two per cent (165/268) of adalimumab participants experienced an AE compared to 72% (188/263) of participants in the placebo group (RR 0.90, 95% CI 0.74 to 1.09; moderate-certainty evidence). Two percent (6/268) of adalimumab participants experienced a SAE compared to 5% (13/263) of participants in the placebo group (RR 0.44, 95% CI 0.17 to 1.15; low-certainty evidence). Lastly, 1% (3/268) of adalimumab participants withdrew due to AEs compared to 3% (8/268) of participants in the placebo group (RR 0.38, 95% CI 0.11 to 1.30; low-certainty evidence). Commonly reported adverse events included injection site reactions, abdominal pain, fatigue, worsening CD and nausea. Quality of life data did not allow for meta-analysis. Three studies reported better quality of life at four weeks with adalimumab (measured with either Inflammatory Bowel Disease Questionnaire or Short-Form 36; moderate-certainty evidence). Endoscopic remission and response, histologic remission and response, and steroid withdrawal were not reported in the included studies. High-certainty evidence suggests that adalimumab is superior to placebo for induction of clinical remission and clinical response in people with moderate to severely active CD. Although the rates of AEs, SAEs and withdrawals due to AEs were lower in adalimumab participants compared to placebo, we are uncertain about the effect of adalimumab on AEs due to the low number of events. Therefore, no firm conclusions can be drawn regarding the safety of adalimumab in CD. Futher studies are required to look at the long-term effectiveness and safety of using adalimumab in participants with CD.
Eight trials randomised 384 patients with chronic hepatitis C to glucocorticosteroids plus interferon versus interferon plus placebo/no intervention, glucocorticosteroids versus interferon, or glucocorticosteroids versus placebo. Glucocorticosteroids treatment given as short pre-treatment followed by interferon or as long-term parallel treatment combined with interferon versus interferon monotherapy had no significant effect on mortality (no deaths occurred; 342 patients), virological response at six months follow-up (RR 0.85; 95% CI 0.52 to 1.38; 38 patients), or biochemical response at six months follow-up (RR 0.95; 95% CI 0.84 to 1.06; 307 patients). There was no significant difference in serious adverse events between combination therapy versus interferon monotherapy (RR 4.76; 95% CI 0.24 to 93.19; 342 patients). Glucocorticosteroids versus interferon had no significant effect on mortality (RR 2.33; 95% CI 0.27 to 17.80; 13 patients) or virological response at follow-up (RR 1.17; 95% CI 0.86 to 1.58; 13 patients). We found no trials on glucocorticosteroids for acute hepatitis C. There is insufficient evidence neither to confirm nor exclude both beneficial and harmful effects of glucocorticosteroids for chronic hepatitis C with or without autoimmune disorders. This Review is not able to rule out potential serious adverse effects of glucocorticosteroids. Therefore, this Review cannot establish whether glucocorticosteroids treatment can be safely administrated for indications requiring glucocorticosteroids without analysing for hepatitis C virus. The effect of glucocorticosteroids for acute hepatitis C has not been examined in randomised trials.
We identified no trials comparing RFA versus placebo, no intervention, or liver transplantation. We identified and included 11 randomised clinical trials with 1819 participants that included four comparisons: RFA versus hepatic resection (three trials, 578 participants); RFA versus percutaneous ethanol injection (six trials, 1088 participants) including one three-armed trial that also investigated RFA versus acetic acid injection; RFA versus microwave ablation (one trial, 72 participants); and RFA versus laser ablation (one trial, 81 participants). Ten of the eleven included trials reported on the primary outcome of this review, overall survival. Rates of major complications or procedure-related deaths were reported in 10 trials. The overall risk of bias was considered low in five trials and high in six trials. For a subgroup analysis, we included only low risk of bias trials. Regarding the comparison RFA versus hepatic resection, there was moderate-quality evidence from two low risk of bias trials that hepatic resection seems more effective than RFA regarding overall survival (HR 0.56; 95% CI 0.40 to 0.78) and two-year survival (HR 0.38; 95% CI 0.17 to 0.84). However, if we included a third trial with high risk of bias, the difference became insignificant (overall survival: HR 0.71; 95% CI 0.44 to 1.15). With regards to the outcomes event-free survival and local progression, hepatic resection also yielded better results than RFA. However, the number of complications was higher in surgically treated participants (odds ratio (OR) 8.24; 95% CI 2.12 to 31.95). RFA seemed superior to percutaneous ethanol or acetic acid injection regarding overall survival (HR 1.64; 95% CI 1.31 to 2.07). The RR for mortality was also in favour of RFA, but did not reach statistical significance (150/490 (30.6%) people in the percutaneous ethanol or acetic acid group versus 119/496 (24.0%) people in the RFA group; RR 1.76; 95% CI 0.97 to 3.22). The proportion of adverse events did not differ significantly between RFA and percutaneous ethanol or acetic acid injection (HR 0.70; 95% CI 0.33 to 1.48). Trial sequential analyses revealed that the number of participants in the included trials was insufficient and that more trials are needed to assess the effects of RFA versus other interventions. The effects of RFA versus no intervention, chemotherapeutic treatment, or liver transplantation are unknown. We found moderate-quality evidence that hepatic resection is superior to RFA regarding survival. However, RFA might be associated with fewer complications and a shorter hospital stay than hepatic resection. We found moderate-quality evidence showing that RFA seems superior to percutaneous ethanol injection regarding survival. There were too sparse data to recommend or refute ablation achieved by techniques other than RFA. More randomised clinical trials with low risk of bias and low risks of random errors assessing the effect of RFA are needed.
We included eight RCTs, with 1083 participants. All studies compared a form of probiotic (Lactobacillus casei rhamnosus; Lactobacillus plantarum; Synbiotic 2000FORTE; Ergyphilus; combination Bifidobacterium longum + Lactobacillus bulgaricus + Streptococcus thermophilus) versus a control group (placebo; glutamine; fermentable fibre; peptide; chlorhexidine). The analysis of all RCTs showed that the use of probiotics decreased the incidence of VAP (odds ratio (OR) 0.70, 95% confidence interval (CI) 0.52 to 0.95, low quality evidence). However, the aggregated results were uncertain for ICU mortality (OR 0.84, 95% CI 0.58 to 1.22 very low quality evidence), in-hospital mortality (OR 0.78, 95% CI 0.54 to 1.14, very low quality evidence), incidence of diarrhoea (OR 0.72, 95% CI 0.47 to 1.09, very low quality evidence), length of ICU stay (mean difference (MD) -1.60, 95% CI -6.53 to 3.33, very low quality evidence), duration of mechanical ventilation (MD -6.15, 95% CI -18.77 to 6.47, very low quality evidence) and antibiotic use (OR 1.23, 95% CI 0.51 to 2.96, low quality evidence). Antibiotics for VAP were used for a shorter duration (in days) when participants received probiotics in one small study (MD -3.00, 95% CI -6.04 to 0.04). However, the CI of the estimated effect was too wide to exclude no difference with probiotics. There were no reported events of nosocomial probiotic infections in any included study. The overall methodological quality of the included studies, based on our 'Risk of bias' assessments, was moderate with half of the included studies rated as a 'low' risk of bias; however, we rated four included studies as a 'high' risk of bias across one or more of the domains. The study limitations, differences in probiotics administered and participants, and small sample sizes across the included studies mean that the power to detect a trend of overall effect may be limited and chance findings cannot be excluded. To explore the influence of some potential confounding factors in the studies, we conducted an intention-to-treat (ITT) analysis, which did not change the inference of per-protocol analysis. However, our sensitivity analysis did not indicate a significant difference between groups for instances of VAP. Evidence suggests that use of probiotics is associated with a reduction in the incidence of VAP. However, the quality of the evidence is low and the exclusion of the one study that did not provide a robust definition of VAP increased the uncertainty in this finding. The available evidence is not clear regarding a decrease in ICU or hospital mortality with probiotic use. Three trials reported on the incidence of diarrhoea and the pooled results indicate no clear evidence of a difference. The results of this meta-analysis do not provide sufficient evidence to draw conclusions on the efficacy and safety of probiotics for the prevention of VAP in ICU patients.
Six studies involving 126 participants who completed the study protocols were included. Most studies recruited participants with severe to very severe COPD (mean forced expiratory volume in one second (FEV1) ranged from 26% to 48% predicted). There was an increase in percentage change peak and endurance exercise capacity with NIV during training (mean difference in peak exercise capacity 17%, 95% confidence interval (CI) 7% to 27%, 60 participants, low-quality evidence; mean difference in endurance exercise capacity 59%, 95% CI 4% to 114%, 48 participants, low-quality evidence). However, there was no clear evidence of a difference between interventions for all other measures of exercise capacity. The results for HRQL assessed using the St George's Respiratory Questionnaire do not rule out an effect of NIV (total score mean 2.5 points, 95% CI -2.3 to 7.2, 48 participants, moderate-quality evidence). Physical activity was not assessed in any study. There was an increase in training intensity with NIV during training of 13% (95% CI 1% to 27%, 67 participants, moderate-quality evidence), and isoload lactate was lower with NIV (mean difference -0.97 mmol/L, 95% CI -1.58mmol/L to -0.36 mmol/L, 37 participants, moderate-quality evidence). The effect of NIV on dyspnoea or the number of dropouts between interventions was uncertain, although again results were imprecise. No adverse events and no information regarding cost were reported. Only one study blinded participants, whereas three studies used blinded assessors. Adequate allocation concealment was reported in four studies. The small number of included studies with small numbers of participants, as well as the high risk of bias within some of the included studies, limited our ability to draw strong evidence-based conclusions. Although NIV during lower limb exercise training may allow people with COPD to exercise at a higher training intensity and to achieve a greater physiological training effect compared with exercise training alone or exercise training with sham NIV, the effect on exercise capacity is unclear. Some evidence suggests that NIV during exercise training improves the percentage change in peak and endurance exercise capacity; however, these findings are not consistent across other measures of exercise capacity. There is no clear evidence that HRQL is better or worse with NIV during training. It is currently unknown whether the demonstrated benefits of NIV during exercise training are clinically worthwhile or cost-effective.
Two studies were eligible for inclusion. In one study only one of our primary outcomes was available: the duration of cannula patency for the first cannula used per infant was slightly longer in the continuous infusion group, but not significantly so, with a mean difference of -4.3 hours (95% CI -18.2 to 9.7). In the second study, only one of our primary outcomes was available: the mean (SD) number cannulas used per infant in the first 48 hours was less in the intermittent flush group with a mean difference of -0.76 cannulas (95% CI -1.37 to -0.15). No results were available for any of our other primary outcomes: in the published report, results were reported per catheter rather than per infant, a number of infants received more than one intravenous catheter (39 infants received an unknown number of catheters). The overall duration of cannula patency was significantly longer in the intermittent flush group with a mean duration of patency in the intermittent flush group of 2.1 days (SD 1.0) compared with the continuous infusion group where the mean duration of patency was 1.0 days (SD 0.5) - Student's t test P value 0.0003. It is difficult to draw reliable conclusions given the way the data were analysed and reported in the two included studies. The reliability of the results is uncertain. However, given the caution in interpreting these data, it should also be noted that the use of intermittent flushes was not associated in either study with a decreased cannula life or any other disadvantages, thus lending some support for the use of intermittent flushing of cannulas in a selected population in neonatal nurseries.
Our primary objective was to assess effects of INO on mortality. We found no statistically significant effects of INO on longest follow-up mortality: 250/654 deaths (38.2%) in the INO group compared with 221/589 deaths (37.5%) in the control group (RR 1.04, 95% CI 0.9 to 1.19; I² statistic = 0%; moderate quality of evidence). We found no statistically significant effects of INO on mortality at 28 days: 202/587 deaths (34.4%) in the INO group compared with 166/518 deaths (32.0%) in the control group (RR 1.08, 95% CI 0.92 to 1.27; I² statistic = 0%; moderate quality of evidence). In children, there was no statistically significant effects of INO on mortality: 25/89 deaths (28.1%) in the INO group compared with 34/96 deaths (35.4%) in the control group (RR 0.78, 95% CI 0.51 to 1.18; I² statistic = 22%; moderate quality of evidence). Our secondary objective was to assess the benefits and harms of INO. For partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), we found significant improvement at 24 hours (mean difference (MD) 15.91, 95% CI 8.25 to 23.56; I² statistic = 25%; 11 trials, 614 participants; moderate quality of evidence). For the oxygenation index, we noted significant improvement at 24 hours (MD -2.31, 95% CI -2.73 to -1.89; I² statistic = 0%; five trials, 368 participants; moderate quality of evidence). For ventilator-free days, the difference was not statistically significant (MD -0.57, 95% CI -1.82 to 0.69; I² statistic = 0%; five trials, 804 participants; high quality of evidence). There was a statistically significant increase in renal failure in the INO groups (RR 1.59, 95% CI 1.17 to 2.16; I² statistic = 0%; high quality of evidence). Evidence is insufficient to support INO in any category of critically ill patients with AHRF. Inhaled nitric oxide results in a transient improvement in oxygenation but does not reduce mortality and may be harmful, as it seems to increase renal impairment.
Predominantly older people with trochanteric fractures were treated in the 11 included trials. One trial (65 participants undergoing fixation with a fixed nail-plate) found no statistically significant differences between osteotomy versus anatomical reduction.   Four trials, involving 465 participants undergoing fixation with a sliding hip screw (SHS), compared osteotomy versus anatomical reduction. Osteotomy was associated with an increased operative blood loss and length of surgery. There were no statistically significant differences for mortality, morbidity or measures of anatomical deformity. Two trials (138 participants) compared SHS fixation of a trochanteric hip fracture augmented with cement against a standard fixation. There were no reoperations even for the four cases of fixation failure in the cement group. The cement group had significantly better quality of life scores at six months. One trial (200 participants) comparing compression versus no compression of a trochanteric fracture in conjunction with SHS fixation found no significant differences between the two groups. One trial (120 participants) found a tendency to improved outcomes with a hydroxyapatite coated lag screw, but none reached statistical significance. One trial (19 participants) reported reduced temperatures when using a modified reaming method. Another trial (50 participants) found reduced bone marrow intravascular embolism, detected by oesophageal ultrasound, when a Gamma nail was inserted with a distal pressure venting hole in the femur. There is inadequate evidence to support the use of osteotomy for internal fixation of a trochanteric hip fracture. Similarly, there is insufficient evidence to support the use of the other techniques examined in the trials included in this review.
One trial met the inclusion criteria; a placebo-controlled trial of 17,826 children and adults living in rural villages in Ghana and Tanzania (Africa) and Bangladesh (Asia). Villagers with no previous medical training were trained to recognize the symptoms of severe malaria, administer rectal artesunate and refer patients to hospital. The trained villagers were supervised during the trial period. In the African sites only children aged 6 to 72 months were enrolled, whereas in Bangladesh, older children and adults were also enrolled. In young children (aged 6 to 72 months) there were fewer deaths following rectal artesunate than with placebo (RR 0.74; 95% CI 0.59 to 0.93; one trial; 8050 participants; moderate quality evidence), while in older children and adults there were more deaths in those given rectal artesunate (RR 2.21; 95% CI 1.18 to 4.15; one trial; 4018 participants; low quality evidence). In Africa, only 56% of participants reached a secondary healthcare facility within six hours compared to over 90% in Asia. There were no differences between the intervention and control groups in the proportion of participants reaching a healthcare facility within six hours (RR 0.99; 95% CI 0.98 to 1.01; 12,068 participants), or in the proportion with parasitaemia (RR 1.00; 95% CI 0.98 to 1.02; 17,826 participants), or with coma or convulsions on arrival (RR 1.01; 95% CI 0.90 to 1.14; 12,068 participants). There are no existing trials that compare rectal versus intramuscular artesunate. In rural areas without access to injectable antimalarials rectal artesunate provided before transfer to a referral facility probably reduces mortality in severely ill young children compared to referral without treatment. However, the unexpected finding of possible higher mortality in older children and adults has to be taken into account in forming any national or local policies about pre-referral rectal artesunate.
Forty three trials involving 3957 women were included. There were 11 comparisons in this review. Pregnancy rates are reported here since results of live birth rates were lacking.  Seven studies (n = 556) were pooled comparing gonadotrophins with anti-oestrogens showing significant higher pregnancy rates with gonadotrophins (OR 1.8, 95% CI 1.2 to 2.7). Five studies (n = 313) compared anti-oestrogens with aromatase inhibitors reporting no significant difference (OR 1.2 95% CI 0.64 to 2.1). The same could be concluded comparing different types of gonadotrophins (9 studies included, n = 576). Four studies (n = 415) reported that gonadotrophins alone are more effective than with the addition of a GnRH agonist (OR 1.8 95% CI 1.1 to 3.0). Data of three studies (n = 299) showed no convincing evidence of adding a GnRH antagonist to gonadotrophins (OR 1.5 95% CI 0.83 to 2.8). The results of two studies (n = 297) reported no evidence of benefit in doubling the dose of gonadotrophins (OR 1.2 95% 0.67 to 1.9) although the multiple pregnancy rates and OHSS rates were increased. For the remaining five comparisons only one or none studies were included. Robust evidence is lacking but based on the available results gonadotrophins might be the most effective drugs when IUI is combined with ovarian hyperstimulation. When gonadotrophins are applied it might be done on a daily basis. When gonadotrophins are used for ovarian stimulation low dose protocols are advised since pregnancy rates do not differ from pregnancy rates which result from high dose regimen, whereas the chances to encounter negative effects from ovarian stimulation such as multiples and OHSS are limited with low dose gonadotrophins. Further research is needed for each comparison made.
The searches found 130 citations, from which we could identify 22 possibly relevant studies. From these, we could only include one study. This study had a relatively small sample size of 17 participants who received lorazepam or oxazepam and were drug free for one week before the trial started. The only usable data reported by this study were clinically important change in symptoms of catatonia measured as 50% improvement on the Visual Analogue Scale (VAS). There was no difference in the numbers of participants showing a clinically important change in their catatonic symptoms (RR 0.95, 95% CI 0.42 to 2.16; participants = 17; studies = 1; very low quality evidence). No data were reported for other important outcomes of hospital stay, clinically important change in satisfaction with care, global state, adverse effects or general functioning We did find a few studies meeting our inclusion criteria but they reported no usable data. We had to exclude these. Although poorly reported, these studies do illustrate that relevant studies have been undertaken — they are not impossible to design and conduct. Analysis of the results from this review, which was a head-to-head comparison of two benzodiazepine monotherapies, does not show a clear difference in effect. No data were available for benzodiazepines compared to placebo or standard care. The lack of usable data and very low quality of data available makes it impossible to draw firm conclusions and further studies with a high-quality methodology and reporting are required in order to determine more definitively the outcomes associated with benzodiazepine use in the clinical management of catatonia in persons with schizophrenia and other SMI.
We included 19 trials (5839 randomised participants); seven compared penicillin with cephalosporins, six compared penicillin with macrolides, three compared penicillin with carbacephem, one trial compared penicillin with sulphonamides, one trial compared clindamycin with ampicillin, and one trial compared azithromycin with amoxicillin in children. All included trials reported clinical outcomes. Reporting of randomisation, allocation concealment, and blinding was poor in all trials. The overall quality of the evidence assessed using the GRADE tool was low for the outcome 'resolution of symptoms' in the intention-to-treat (ITT) analysis and very low for the outcomes 'resolution of symptoms' of evaluable participants and for adverse events. We downgraded the quality of evidence mainly due to lack of (or poor reporting of) randomisation or blinding, or both, heterogeneity, and wide confidence intervals (CIs). There was a difference in symptom resolution in favour of cephalosporins compared with penicillin (evaluable patients analysis odds ratio (OR) for absence of resolution of symptoms 0.51, 95% CI 0.27 to 0.97; number needed to treat to benefit (NNTB) 20, N = 5, n = 1660; very low quality evidence). However, this was not statistically significant in the ITT analysis (OR 0.79, 95% CI 0.55 to 1.12; N = 5, n = 2018; low quality evidence). Clinical relapse was lower for cephalosporins compared with penicillin (OR 0.55, 95% CI 0.30 to 0.99; NNTB 50, N = 4, n = 1386; low quality evidence), but this was found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33, N = 2, n = 770). There were no differences between macrolides and penicillin for any of the outcomes. One unpublished trial in children found a better cure rate for azithromycin in a single dose compared to amoxicillin for 10 days (OR 0.29, 95% CI 0.11 to 0.73; NNTB 18, N = 1, n = 482), but there was no difference between the groups in ITT analysis (OR 0.76, 95% CI 0.55 to 1.05; N = 1, n = 673) or at long-term follow-up (evaluable patients analysis OR 0.88, 95% CI 0.43 to 1.82; N = 1, n = 422). Children experienced more adverse events with azithromycin compared to amoxicillin (OR 2.67, 95% CI 1.78 to 3.99; N = 1, n = 673). Compared with penicillin carbacephem showed better symptom resolution post-treatment in adults and children combined (ITT analysis OR 0.70, 95% CI 0.49 to 0.99; NNTB 14, N = 3, n = 795), and in the subgroup analysis of children (OR 0.57, 95% CI 0.33 to 0.99; NNTB 8, N = 1, n = 233), but not in the subgroup analysis of adults (OR 0.75, 95% CI 0.46 to 1.22, N = 2, n = 562). Children experienced more adverse events with macrolides compared with penicillin (OR 2.33, 95% CI 1.06 to 5.15; N = 1, n = 489). Studies did not report on long-term complications so it was unclear if any class of antibiotics was better in preventing serious but rare complications. There were no clinically relevant differences in symptom resolution when comparing cephalosporins and macrolides with penicillin in the treatment of GABHS tonsillopharyngitis. Limited evidence in adults suggests cephalosporins are more effective than penicillin for relapse, but the NNTB is high. Limited evidence in children suggests carbacephem is more effective than penicillin for symptom resolution. Data on complications are too scarce to draw conclusions. Based on these results and considering the low cost and absence of resistance, penicillin can still be regarded as a first choice treatment for both adults and children. All studies were in high-income countries with low risk of streptococcal complications, so there is need for trials in low-income countries and Aboriginal communities where risk of complications remains high.
Two short-term studies involving 753 participants met the inclusion criteria. Only one study investigated the effects of pregabalin compared with lamotrigine in patients with newly diagnosed partial seizures, and the other study investigated the effects of pregabalin compared with gabapentin in hospitalised patients with refractory partial epilepsy. There were no studies on generalised-onset tonic-clonic seizures (with or without other generalised seizure types). We found that pregabalin was inferior in comparison to lamotrigine when measuring time to withdrawal due to inadequate seizure control after dose stabilisation from randomisation: hazard ratio (HR) 4.52; 95% confidence interval (CI) 1.93 to 10.60; time to achieve six-month remission after dose stabilisation from randomisation: HR 0.56; 95% CI 0.41 to 0.76; the proportion of participants who remained seizure-free for six or more continuous months: RR 0.76, 95% CI 0.67 to 0.87 (Europe: 0.83, 95% CI 0.69 to 0.99; Asia: RR 0.70, 95% CI 0.57 to 0.86; the Americas: RR 0.62, 95% CI 0.33 to 1.19); and time to first seizure after dose stabilisation from randomisation: HR 1.74; 95% CI 1.26 to 2.39. There was no significant difference in safety-related outcomes between pregabalin and lamotrigine, but more participants in the pregabalin group developed somnolence, weight increase and convulsion. Pregabalin was better than gabapentin when measuring time to withdrawal due to all reasons after randomisation: HR 0.25; 95% CI 0.11 to 0.57; and time to withdrawal due to inadequate seizure control after randomisation: HR 0.41; 95% CI 0.18 to 0.92. No significant difference was found in safety-related outcomes between pregabalin and gabapentin. But we found some limitations in the study design which may have had an influence on the results. Pregabalin seems to have similar tolerability but inferior efficacy in comparison to lamotrigine for newly diagnosed partial seizures. However, considering the limitations in the study design (such as the short-term follow-up and the low initial target dose selection), the results should be interpreted with caution. The available data were too limited to draw any conclusions between pregabalin and gabapentin. The result indicated that the treatment effects were influenced by the study regions. The clinical disadvantage of pregabalin was more prominent in Asia when compared with lamotrigine. We should determine whether pregabalin has ethnic differences in the treatment of epilepsy in the future. This review does not inform any treatment policy for patients with generalized onset tonic-clonic seizures. Further long-term trials are needed to investigate the genuine effectiveness of pregabalin as monotherapy.
We included 14 trials (17 comparisons) in the review; three trials involved multiple comparisons. Six trials, two of which had three comparison arms, (972 participants) compared hair removal (shaving, clipping, or depilatory cream) with no hair removal and found no statistically significant difference in SSI rates however the comparison is underpowered. Three trials (1343 participants) that compared shaving with clipping showed significantly more SSIs associated with shaving (RR 2.09, 95% CI 1.15 to 3.80). Seven trials (1213 participants) found no significant difference in SSI rates when hair removal by shaving was compared with depilatory cream (RR 1.53, 95% CI 0.73 to 3.21), however this comparison is also underpowered. One trial compared two groups that shaved or clipped hair on the day of surgery compared with the day before surgery; there was no statistically significant difference in the number of SSIs between groups however this comparison was also underpowered. We identified no trials that compared clipping with depilatory cream; or investigated application of depilatory cream at different pre-operative time points, or hair removal in different settings (e.g. ward, anaesthetic room). Whilst this review found no statistically significant effect on SSI rates of hair removal insufficient numbers of people have been involved in this research to allow confidence in a conclusion. When it is necessary to remove hair, the existing evidence suggests that clippers are associated with fewer SSIs than razors. There was no significant difference in SSI rates between depilatory creams and shaving, or between shaving or clipping the day before surgery or on the day of surgery however studies were small and more research is needed.
We included six RCTs (1539 participants) in this review. Trial sizes ranged from 50 to 703 participants. These six trials made four comparisons, namely: transparent dressings versus gauze; bordered transparent dressings versus a securement device; bordered transparent dressings versus tape; and transparent dressing versus sticking plaster. There is very low quality evidence of fewer catheter dislodgements or accidental removals with transparent dressings compared with gauze (two studies, 278 participants, RR 0.40; 95% CI 0.17 to 0.92, P = 0.03%). The relative effects of transparent dressings and gauze on phlebitis (RR 0.89; 95% CI 0.47 to 1.68) and infiltration (RR 0.80; 95% CI 0.48 to 1.33) are unclear. The relative effects on PVC failure of a bordered transparent dressing and a securement device have been assessed in only one small study and these were unclear. There was very low quality evidence from the same single study of less frequent dislodgement or accidental catheter removal with bordered transparent dressings than securement devices (RR 0.14, 95% CI 0.03 to 0.63) but more phlebitis with bordered dressings (RR 8.11, 95% CI 1.03 to 64.02) (very low quality evidence). A small single study compared bordered transparent dressings with tape and found very low quality evidence of more PVC failure with the bordered dressing (RR 1.84, 95% CI 1.08 to 3.11) but the relative effects on dislodgement were not clear (very low quality evidence). The relative effects of transparent dressings and a sticking plaster have only been compared in one small study and are unclear. More high quality RCTs are required to determine the relative effects of alternative PVC dressings and securement devices. It is not clear if any one dressing or securement device is better than any other in securing peripheral venous catheters. There is a need for further, independent high quality trials to evaluate the many traditional as well as the newer, high use products. Given the large cost differences between some different dressings and securement devices, future trials should include a robust cost-effectiveness analysis.
All four included studies were in Chinese; two of which were unpublished. Effect sizes were not clinically relevant and there was low quality evidence for all outcomes due to study limitations and sparse data (single studies). Two trials (680 participants) found that Compound Qishe Tablets relieved pain better in the short-term than either placebo or Jingfukang; one trial (60 participants) found than an oral herbal formula of Huangqi ((Radix Astragali)18 g, Dangshen (Radix Codonopsis) 9 g, Sanqi (Radix Notoginseng) 9 g, Chuanxiong (Rhizoma Chuanxiong)12 g, Lujiao (Cornu Cervi Pantotrichum) 12 g, and Zhimu (Rhizoma Anemarrhenae)12 g) relieved pain better than Mobicox or Methycobal and one trial (360 participants) showed that a topical herbal medicine, Compound Extractum Nucis Vomicae, relieved pain better than Diclofenac Diethylamine Emulgel. There is low quality evidence that an oral herbal medication, Compound Qishe Tablet, reduced pain more than placebo or Jingfukang and a topical herbal medicine, Compound Extractum Nucis Vomicae, reduced pain more than Diclofenac Diethylamine Emulgel. Further research is very likely to change both the effect size and our confidence in the results.
We identified 14 RCTs (2616 participants); nine studies were multi-centre and two studies involved children. The risk of bias was high in most studies; only three studies demonstrated adequate random sequence generation and only two studies were at low risk of bias for allocation concealment. Blinding of participants and personnel was at low risk of bias in one study. Blinding of outcome assessment was judged at low risk in 13 studies as the outcome measures were reported as laboratory results and therefore unlikely to be influenced by blinding. Attrition bias was at low risk of bias in eight studies while selective reporting was at low risk in six included studies. Four interventions were compared: epoetin alpha or beta at different frequencies using the same total dose (six studies); epoetin alpha at the same frequency and different total doses (two studies); epoetin alpha administered intravenously versus subcutaneous administration (one study); epoetin alpha or beta versus other epoetins or biosimilars (five studies). One study compared both different frequencies of epoetin alpha at the same total dose and at the same frequency using different total doses. Data from only 7/14 studies could be included in our meta-analyses. There were no significant differences in final haemoglobin (Hb) levels when dosing every two weeks was compared with weekly dosing (4 studies, 785 participants: MD -0.20 g/dL, 95% CI -0.33 to -0.07), when four weekly dosing was compared with two weekly dosing (three studies, 671 participants: MD -0.16 g/dL, 95% CI -0.43 to 0.10) or when different total doses were administered at the same frequency (four weekly administration: one study, 144 participants: MD 0.17 g/dL 95% CI -0.19 to 0.53). Five studies evaluated different interventions. One study compared epoetin theta with epoetin alpha and found no significant differences in Hb levels (288 participants: MD -0.02 g/dL, 95% CI -0.25 to 0.21). One study found significantly higher pain scores with subcutaneous epoetin alpha compared with epoetin beta. Two studies (165 participants) compared epoetin delta with epoetin alpha, with no results available since the pharmaceutical company withdrew epoetin delta for commercial reasons. The fifth study comparing the biosimilar HX575 with epoetin alpha was stopped after patients receiving HX575 subcutaneously developed anti-epoetin antibodies and no results were available. Adverse events were poorly reported in all studies and did not differ significantly within comparisons. Mortality was only detailed adequately in four studies and only one study included quality of life data. Epoetin alpha given at higher doses for extended intervals (two or four weekly) is non-inferior to more frequent dosing intervals in maintaining final Hb levels with no significant differences in adverse effects in non-dialysed CKD patients. However the data are of low methodological quality so that differences in efficacy and safety cannot be excluded. Further large, well designed, RCTs with patient-centred outcomes are required to assess the safety and efficacy of large doses of the shorter acting ESAs, including biosimilars of epoetin alpha, administered less frequently compared with more frequent administration of smaller doses in children and adults with CKD not on dialysis.
Four RCTs (307 participants) were included. Two studies compared clinical homeopathy (homeopathic remedy, asafoetida or asafoetida plus nux vomica) to placebo for IBS with constipation (IBS-C). One study compared individualised homeopathic treatment (consultation plus remedy) to usual care for the treatment of IBS in female patients. One study was a three armed RCT comparing individualised homeopathic treatment to supportive listening or usual care. The risk of bias in three studies (the two studies assessing clinical homeopathy and the study comparing individualised homeopathic treatment to usual care) was unclear on most criteria and high for selective reporting in one of the clinical homeopathy studies. The three armed study comparing individualised homeopathic treatment to usual care and supportive listening was at low risk of bias in four of the domains and high risk of bias in two (performance bias and detection bias). A meta-analysis of the studies assessing clinical homeopathy, (171 participants with IBS-C) was conducted. At short-term follow-up of two weeks, global improvement in symptoms was experienced by 73% (46/63) of asafoetida participants compared to 45% (30/66) of placebo participants (RR 1.61, 95% CI 1.18 to 2.18; 2 studies, very low certainty evidence). In the other clinical homeopathy study at two weeks, 68% (13/19) of those in the asafoetida plus nux vomica arm and 52% (12/23) of those in the placebo arm experienced a global improvement in symptoms (RR 1.31, 95% CI 0.80 to 2.15; very low certainty evidence). In the study comparing individualised homeopathic treatment to usual care (N = 20), the mean global improvement score (feeling unwell) at 12 weeks was 1.44 + 4.55 (n = 9) in the individualised homeopathic treatment arm compared to 1.41 + 1.97 (n=11) in the usual care arm (MD 0.03; 95% CI -3.16 to 3.22; very low certainty evidence). In the study comparing individualised homeopathic treatment to usual care, the mean IBS symptom severity score at 6 months was 210.44 + 112.4 (n = 16) in the individualised homeopathic treatment arm compared to 237.3 + 110.22 (n = 60) in the usual care arm (MD -26.86, 95% CI -88.59 to 34.87; low certainty evidence). The mean quality of life score (EQ-5D) at 6 months in homeopathy participants was 69.07 (SD 17.35) compared to 63.41 (SD 23.31) in usual care participants (MD 5.66, 95% CI -4.69 to 16.01; low certainty evidence). For In the study comparing individualised homeopathic treatment to supportive listening, the mean IBS symptom severity score at 6 months was 210.44 + 112.4 (n = 16) in the individualised homeopathic treatment arm compared to 262 + 120.72 (n = 18) in the supportive listening arm (MD -51.56, 95% CI -129.94 to 26.82; very low certainty evidence). The mean quality of life score at 6 months in homeopathy participants was 69.07 (SD 17.35) compared to 63.09 (SD 24.38) in supportive listening participants (MD 5.98, 95% CI -8.13 to 20.09; very low certainty evidence). None of the included studies reported on abdominal pain, stool frequency, stool consistency, or adverse events. The results for the outcomes assessed in this review are uncertain. Thus no firm conclusions regarding the effectiveness and safety of homeopathy for the treatment of IBS can be drawn. Further high quality, adequately powered RCTs are required to assess the efficacy and safety of clinical and individualised homeopathy for IBS compared to placebo or usual care.
We included seven randomised clinical trials. None of them had high quality. Plasma vaccine was significantly more effective than placebo in achieving hepatitis B antibodies (RR 23.0, 95% CI 14.39 to 36.76, 3 trials). We found no statistically significant difference between plasma vaccine or placebo regarding hepatitis B virus infections (RR 0.50, 95% CI 0.20 to 1.24). We found no statistically significant differences between recombinant vaccine and plasma vaccine in achieving hepatitis B antibodies (RR 0.65, 95% CI 0.28 to 1.53, 2 trials). Heterogeneity was significant and appeared to be attributable to the dose of vaccine. Two trials examined a reinforced recombinant vaccine strategy, which was not statistically more effective than three inoculations of recombinant vaccine regarding development of hepatitis B antibodies (RR 1.36, 95% CI 0.85 to 2.16). Plasma derived vaccines are more effective than placebo in achieving hepatitis B antibodies, while no statistically significant difference was found between recombinant and plasma vaccines. No statistically significant difference of effectiveness was observed between a reinforced vaccination series versus routine vaccinations of three inoculations of recombinant vaccine.
The review includes 16 studies (eight new studies included in this update) representing data from 556 participants. Studies are diverse in their design and their methods. They cover interventions with generic approaches, as well as interventions developed specifically to target disease-specific symptoms and problems in people with cystic fibrosis. These include cognitive behavioural interventions to improve adherence to nutrition or psychosocial adjustment, cognitive interventions to improve adherence or those associated with decision making in lung transplantation, a community-based support intervention and other interventions, such as self-hypnosis, respiratory muscle biofeedback, music therapy, dance and movement therapy, and a tele-medicine intervention to support patients awaiting transplantation. A substantial proportion of outcomes relate to adherence, changes in physical status or other specific treatment concerns during the chronic phase of the disease. There is some evidence that behavioural interventions targeting nutrition and growth in children (4 to 12 years) with cystic fibrosis are effective in the short term. Evidence was found that providing a structured decision-making tool for patients considering lung transplantation improves patients' knowledge of and expectations about the transplant, and reduces decisional conflict in the short term. One study about training in biofeedback-assisted breathing demonstrated some evidence that it improved some lung function measurements. Currently there is insufficient evidence for interventions aimed at other aspects of the disease process. Currently, insufficient evidence exists on psychological interventions or approaches to support people with cystic fibrosis and their caregivers, although some of the studies were promising. Due to the heterogeneity between studies, more of each type of intervention are needed to support preliminary evidence. Multicentre studies, with consequent funding implications, are needed to increase the sample size of these studies and enhance the statistical power and precision to detect important findings. In addition, multicentre studies could improve the generalisation of results by minimizing centre or therapist effects. Psychological interventions should be targeted to illness-specific symptoms or behaviours to demonstrate efficacy.
We included 12 trials involving 478 individuals. A number of trials showed a high risk of bias and others an unclear risk of bias due to poor reporting. The quality of the evidence was 'low' for most of the outcomes and 'moderate' for hand function, according to the GRADE system. In most of the studies, AO was followed by some form of physical activity. Primary outcome: the impact of AO on arm function showed a small significant effect (standardized mean difference (SMD) 0.36, 95% CI 0.13 to 0.60; 8 studies; 314 participants; low-quality evidence); and a large significant effect (mean difference (MD) 2.90, 95% CI 1.13 to 4.66; 3 studies; 132 participants; moderate-quality evidence) on hand function. Secondary outcomes: there was a large significant effect for ADL outcome (SMD 0.86, 95% CI 0.11 to 1.61; 4 studies, 226 participants; low-quality evidence). We were unable to pool other secondary outcomes to extract the evidence. Only two studies reported adverse effects without significant adverse AO events. We found evidence that AO is beneficial in improving upper limb motor function and dependence in activities of daily living (ADL) in people with stroke, when compared with any control group; however, we considered the quality of the evidence to be low. We considered the effect of AO on hand function to be large, but it does not appear to be clinically relevant, although we considered the quality of the evidence as moderate. As such, our confidence in the effect estimate is limited because it will likely change with future research.
72 RCTs met our inclusion criteria. The methodological quality of included studies varied. An organized system of regular review allied to vigorous antihypertensive drug therapy was shown to reduce systolic blood pressure (weighted mean difference (WMD) -8.0 mmHg, 95% CI: -8.8 to -7.2 mmHg) and diastolic blood pressure (WMD -4.3 mmHg, 95% CI: -4.7 to -3.9 mmHg) for three strata of entry blood pressure, and all-cause mortality at five years follow-up (6.4% versus 7.8%, difference 1.4%) in a single large RCT- the Hypertension Detection and Follow-Up study. Other interventions had variable effects. Self-monitoring was associated with moderate net reduction in systolic blood pressure (WMD -2.5 mmHg, 95% CI: -3.7 to -1.3 mmHg) and diastolic blood pressure (WMD -1.8 mmHg, 95% CI: -2.4 to -1.2 mmHg). RCTs of educational interventions directed at patients or health professionals were heterogeneous but appeared unlikely to be associated with large net reductions in blood pressure by themselves. Nurse or pharmacist led care may be a promising way forward, with the majority of RCTs being associated with improved blood pressure control and mean SBP and DBP but these interventions require further evaluation. Appointment reminder systems also require further evaluation due to heterogeneity and small trial numbers, but the majority of trials increased the proportion of individuals who attended for follow-up (odds ratio 0.41, 95% CI 0.32 to 0.51) and in two small trials also led to improved blood pressure control, odds ratio favouring intervention 0.54 (95% CI 0.41 to 0.73). Family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels. Self-monitoring and appointment reminders may be useful adjuncts to the above strategies to improve blood pressure control but require further evaluation.
We included 28 trials with 8487 participants on five SGAs: amisulpride, aripiprazole, olanzapine, quetiapine and risperidone. Three studies (1092 participants) provided data on aripiprazole augmentation in MDD. All efficacy data (response n = 1092, three RCTs, OR 0.48; 95% CI 0.37 to 0.63), (MADRS n = 1077, three RCTs, MD -3.04; 95% CI -4.09 to -2) indicated a benefit for aripiprazole but  more side effects (weight gain, EPS) . Seven trials (1754 participants) reported data on olanzapine. Compared to placebo fewer people discontinued treatment due to inefficacy; compared to antidepressants there were no efficacy differences, olanzapine augmentation showed symptom reduction (MADRS n = 808, five RCTs, MD -2.84; 95% CI -5.48 to -0.20), but also more weight or prolactin increase. Quetiapine data are based on seven trials (3414 participants). Compared to placebo, quetiapine monotherapy (response n = 1342, three RCTs, OR 0.52; 95% CI 0.41 to 0.66) and quetiapine augmentation (response n = 937, two RCTs, OR 0.68; 95% CI 0.52 to 0.90) showed symptom reduction, but quetiapine induced more sedation. Four trials (637 participants) presented data on risperidone augmentation, response data were better for risperidone (n = 371, two RCTs, OR 0.57; 95% CI 0.36 to 0.89) but augmentation showed more prolactin increase and weight gain. Five studies (1313 participants) presented data on amisulpride treatment for dysthymia. There were some beneficial effects compared to placebo or antidepressants but tolerability was worse. Quetiapine was more effective than placebo treatment. Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo. Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people. Most SGAs showed worse tolerability.
We included 15 studies, of which two were at low risk of bias, seven were at high risk of bias and six were unclear. Fixed appliances with mid-palatal expansion Nine studies tested fixed appliances with mid-palatal expansion against each other. No study reported a difference between any type of appliance. Fixed versus removable appliances Fixed quad-helix appliances may be 20% more likely to correct crossbites than removable expansion plates (RR 1.20; 95% CI 1.04 to 1.37; two studies; 96 participants; low-quality evidence). Quad-helix appliances may achieve 1.15 mm more molar expansion than expansion plates (MD 1.15 mm; 95% CI 0.40 to 1.90; two studies; 96 participants; moderate-quality evidence). There was insufficient evidence of a difference in canine expansion or the stability of crossbite correction. Very limited evidence showed that both fixed quad-helix appliances and removable expansion plates were superior to composite onlays in terms of crossbite correction, molar and canine expansion. Other comparisons Very limited evidence showed that treatments were superior to no treatment, but there was insufficient evidence of a difference between any active treatments. There is a very small body of low- to moderate-quality evidence to suggest that the quad-helix appliance may be more successful than removable expansion plates at correcting posterior crossbites and expanding the inter-molar width for children in the early mixed dentition (aged eight to 10 years). The remaining evidence we found was of very low quality and was insufficient to allow the conclusion that any one intervention is better than another for any of the outcomes in this review.
Three trials (of poor methodological quality) met the inclusion criteria. Complete remission of haemorrhoidal symptom was better with excisional haemorrhoidectomy (EH) (three studies, 202 patients, RR 1.68, 95% CI 1.00 to 2.83). There was significant heterogeneity between the studies (I2 = 90.5%; P = 0.0001). Similar analysis based on the grading of haemorrhoids revealed the superiority of EH over RBL for grade III haemorrhoids (prolapse that needs manual reduction) (two trials, 116 patients, RR 1.23, CI 1.04 to 1.45; P = 0.01). However, no significant difference was noticed in grade II haemorrhoids (prolapse that reduces spontaneously on cessation of straining) (one trial, 32 patients, RR 1.07, CI 0.94 to 1.21; P = 0.32) Fewer patients required re-treatment after EH (three trials, RR 0.20 CI 0.09 to 0.40; P < 0.00001). Patients undergoing EH were at significantly higher risk of postoperative pain (three trials, fixed effect; 212 patients, RR 1.94, 95% CI 1.62 to 2.33, P < 0.00001). The overall delayed complication rate showed significant difference (P = 0.03) (three trials, 204 patients, RR 6.32, CI 1.15 to 34.89) between the two interventions. The present systematic review confirms the long-term efficacy of EH, at least for grade III haemorrhoids, compared to the less invasive technique of RBL but at the expense of increased pain, higher complications and more time off work. However, despite these disadvantages of EH, patient satisfaction and patient's acceptance of the treatment modalities seems to be similar following both the techniques implying patient's preference for complete long-term cure of symptoms and possibly less concern for minor complications. So, RBL can be adopted as the choice of treatment for grade II haemorrhoids with similar results but with out the side effects of EH while reserving EH for grade III haemorrhoids or recurrence after RBL. More robust study is required to make definitive conclusions. One additional study was identified from the updated search (Ali 2005). However, after careful review and discussion among the authors, it was decided that this study did not meet the necessary criteria for including in the analysis. Hence, the results and conclusion remains the same.
Six studies met the inclusion criteria. One trial compared vas occlusion with clips versus a conventional vasectomy technique. No difference was found in failure to reach azoospermia (no sperm detected). Three trials examined vasectomy with vas irrigation. Two studies looked at irrigation with water versus no irrigation, while one examined irrigation with water versus the spermicide euflavine. None found a difference between the groups for time to azoospermia. However, one trial reported that the median number of ejaculations to azoospermia was lower in the euflavine group compared to the water irrigation group. One high-quality trial compared vasectomy with fascial interposition versus vasectomy without fascial interposition. The fascial interposition group was less likely to have vasectomy failure. Fascial interposition had more surgical difficulties, but the groups were similar in side effects. Lastly, one trial found that an intra-vas was less likely to produce azoospermia than was no-scalpel vasectomy. More men were satisfied with the intra-vas device, however. For vas occlusion with clips or vasectomy with vas irrigation, no conclusions can be made as those studies were of low quality and underpowered. Fascial interposition reduced vasectomy failure. An intra-vas device was less effective in reducing sperm count than was no-scalpel vasectomy. RCTs examining other vasectomy techniques were not available. More and better quality research is needed to examine vasectomy techniques.
This review included two trials, involving 103 participants, one comparing titanium with resorbable plates and screws and the other titanium with resorbable screws. Both studies were at high risk of bias and provided very limited data for the primary outcomes of this review. All participants in one trial suffered mild to moderate postoperative discomfort with no statistically significant difference between the two plating groups at different follow-up times. Mean scores of patient satisfaction were 7.43 to 8.63 (range 0 to 10) with no statistically significant difference between the two groups throughout follow-up. Adverse effects reported in one study were two plate exposures in each group occurring between the third and ninth months. Plate exposures occurred mainly in the posterior maxillary region, except for one titanium plate exposure in the mandibular premolar region. Known causes of infection were associated with loosened screws and wound dehiscence with no statistically significant difference in the infection rate between titanium (3/196), and resorbable (3/165) plates. We do not have sufficient evidence to determine if titanium plates or resorbable plates are superior for fixation of bones after orthognathic surgery. This review provides insufficient evidence to show any difference in postoperative pain and discomfort, level of patient satisfaction, plate exposure or infection for plate and screw fixation using either titanium or resorbable materials.
Ninety two trials evaluated the dose-related trough BP lowering efficacy of 14 different ACE inhibitors in 12 954 participants with a baseline BP of 157/101 mm Hg. The data do not suggest that any one ACE inhibitor is better or worse at lowering BP. A dose of 1/8 or 1/4 of the manufacturer's maximum recommended daily dose (Max) achieved a BP lowering effect that was 60 to 70% of the BP lowering effect of Max. A dose of 1/2 Max achieved a BP lowering effect that was 90% of Max. ACE inhibitor doses above Max did not significantly lower BP more than Max. Combining the effects of 1/2 Max and higher doses gives an estimate of the average trough BP lowering efficacy for ACE inhibitors as a class of drugs of -8 mm Hg for SBP and -5 mm Hg for DBP. ACE inhibitors reduced BP measured 1 to 12 hours after the dose by about 11/6 mm Hg. There are no clinically meaningful BP lowering differences between different ACE inhibitors. The BP lowering effect of ACE inhibitors is modest; the magnitude of trough BP lowering at one-half the manufacturers' maximum recommended dose and above is -8/-5 mm Hg. Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses. The review did not provide a good estimate of the incidence of harms associated with ACE inhibitors because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.
No new trials were included in this 2014 update. We included six studies: two prophylaxis trials (327 young to middle-aged adults in Russia) and four treatment trials (1196 teenagers and adults in France and Germany). The overall standard of trial reporting was poor and hence many important methodological aspects of the trials had unclear risk of bias. There was no statistically significant difference between the effects of Oscillococcinum® and placebo in the prevention of influenza-like illness: risk ratio (RR) 0.48, 95% confidence interval (CI) 0.17 to 1.34, P value = 0.16. Two treatment trials (judged as 'low quality') reported sufficient information to allow full data extraction: 48 hours after commencing treatment, there was an absolute risk reduction of 7.7% in the frequency of symptom relief with Oscillococcinum® compared with that of placebo (risk difference (RD) 0.077, 95% CI 0.03 to 0.12); the RR was 1.86 (95% CI 1.27 to 2.73; P value = 0.001). A significant but lesser effect was observed at three days (RR 1.27, 95% CI 1.03 to 1.56; P value = 0.03), and no significant difference between the groups was noted at four days (RR 1.11, 95% CI 0.98 to 1.27; P value = 0.10) or at five days (RR 1.06, 95% CI 0.96 to 1.16; P value = 0.25). One of the six studies reported one patient who suffered an adverse effect (headache) from taking Oscillococcinum®. There is insufficient good evidence to enable robust conclusions to be made about Oscillococcinum® in the prevention or treatment of influenza and influenza-like illness. Our findings do not rule out the possibility that Oscillococcinum® could have a clinically useful treatment effect but, given the low quality of the eligible studies, the evidence is not compelling. There was no evidence of clinically important harms due to Oscillococcinum®.
Thirty-six articles reporting a total of eighteen trials following 1467 participants were included. Dietary approaches assessed in this review were low-fat/high-carbohydrate diets, high-fat/low-carbohydrate diets, low-calorie (1000 kcal per day) and very-low-calorie (500 kcal per day) diets and modified fat diets. Two trials compared the American Diabetes Association exchange diet with a standard reduced fat diet and five studies assessed low-fat diets versus moderate fat or low-carbohydrate diets. Two studies assessed the effect of a very-low-calorie diet versus a low-calorie diet. Six studies compared dietary advice with dietary advice plus exercise and three other studies assessed dietary advice versus dietary advice plus behavioural approaches. The studies all measured weight and measures of glycaemic control although not all studies reported these in the articles published. Other outcomes which were measured in these studies included mortality, blood pressure, serum cholesterol (including LDL and HDL cholesterol), serum triglycerides, maximal exercise capacity and compliance. The results suggest that adoption of regular exercise is a good way to promote better glycaemic control in type 2 diabetic patients, however all of these studies were at high risk of bias. There are no high quality data on the efficacy of the dietary treatment of type 2 diabetes, however the data available indicate that the adoption of exercise appears to improve glycated haemoglobin at six and twelve months in people with type 2 diabetes. There is an urgent need for well-designed studies which examine a range of interventions, at various points during follow-up, although there is a promising study currently underway.
We included 67 studies with 10,509 participants overall. Of these, 15 studies with 5787 participants used a placebo. Stone clearance: Based on the overall analysis, treatment with an alpha-blocker may result in a large increase in stone clearance (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.36 to 1.55; low-quality evidence). A subset of higher-quality, placebo-controlled trials suggest that the likely effect is probably smaller (RR 1.16, 95% CI 1.07 to 1.25; moderate-quality evidence), corresponding to 116 more (95% CI 51 more to 182 more) stone clearances per 1000 participants. Major adverse events: Based on the overall analysis, treatment with an alpha-blocker may have little effect on major adverse events (RR 1.25, 95% CI 0.80 to 1.96; low-quality evidence). A subset of higher-quality, placebo-controlled trials suggest that alpha-blockers likely increase the risk of major adverse events slightly (RR 2.09, 95% CI 1.13 to 3.86), corresponding to 29 more (95% CI 3 more to 75 more) major adverse events per 1000 participants. Patients treated with alpha-blockers may experience shorter stone expulsion times (mean difference (MD) -3.40 days, 95% CI -4.17 to -2.63; low-quality evidence), may use less diclofenac (MD -82.41, 95% CI -122.51 to -42.31; low-quality evidence), and likely require fewer hospitalisations (RR 0.51, 95% CI 0.34 to 0.77; moderate-quality evidence), corresponding to 69 fewer hospitalisations (95% CI 93 fewer to 32 fewer) per 1000 participants. Meanwhile, the need for surgical intervention appears similar (RR 0.74, 95% CI 0.53 to 1.02; low-quality evidence), corresponding to 28 fewer surgical interventions (95% CI 51 fewer to 2 more) per 1000 participants. A predefined subgroup analysis (test for subgroup differences; P = 0.002) suggests that effects of alpha-blockers may vary with stone size, with RR of 1.06 (95% CI 0.98 to 1.15; P = 0.16; I² = 62%) for stones 5 mm or smaller versus 1.45 (95% CI 1.22 to 1.72; P < 0.0001; I² = 59%) for stones larger than 5 mm. We found no evidence suggesting possible subgroup effects based on stone location or alpha-blocker type. For patients with ureteral stones, alpha-blockers likely increase stone clearance but probably also slightly increase the risk of major adverse events. Subgroup analyses suggest that alpha-blockers may be less effective for smaller (5 mm or smaller) than for larger stones (greater than 5 mm).
We included two randomized controlled trials assessing very early, early, non-early (or a combination of these) discharge in children with cancer and febrile neutropenia. We graded the evidence as low quality; we downgraded for risk of bias and imprecision. One study, Santolaya 2004, consisted of 149 randomized low-risk episodes and compared early discharge (mean/median of less than five days) to non-early discharge (mean/median of five days or more). This study found no clear evidence of difference in treatment failure (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.24 to 3.50, P value = 0.89 for rehospitalization or adjustment of antimicrobial treatment, or both; Fischer's exact P value = 0.477 for death) or duration of treatment (mean difference -0.3 days, 95% CI -1.22 to 0.62, P value = 0.52 for any antimicrobial treatment; mean difference -0.5 days, 95% CI -1.36 to 0.36, P value = 0.25 for intravenous antimicrobial treatment; mean difference 0.2 days, 95% CI -0.51 to 0.91, P value = 0.58 for oral antimicrobial treatment). Costs were lower in the early discharge group (mean difference USD -265, 95% CI USD -403.14 to USD -126.86, P value = 0.0002). The second included study, Brack 2012, consisted of 62 randomized low-risk episodes and compared very early discharge (mean/median of less than 24 hours) to early discharge (mean/median of less than five days). This study also found no clear evidence of difference in treatment failure (RR 0.54, 95% CI 0.15 to 1.89, P value = 0.34 for rehospitalization or adjustment of antimicrobial treatment (or both); Fischer's exact P value = 0.557 for death). Regarding duration of treatment, median duration of intravenous antimicrobial treatment was shorter in the very early discharge group (Wilcoxon's P value ≤ 0.001, stated in the study) and median duration of oral antimicrobial treatment was shorter in the early discharge group (Wilcoxon's P ≤ 0.001, stated in the study) as compared to one another. However, there was no clear evidence of difference in median duration of any antimicrobial treatment (Wilcoxon's P value = 0.34, stated in the study). Costs were not assessed in this study. Neither of the included studies assessed quality of life. Meta-analysis was not possible as the included studies assessed different discharge moments and used different risk stratification models. Very limited data were available regarding the safety of early discharge compared to non-early discharge from in-hospital treatment in children with cancer and febrile neutropenia and a low risk for invasive infection. The absence of clear evidence of differences in both studies could be due to lack of power. Evidently, there are still profound gaps regarding very early and early discharge in children with cancer and febrile neutropenia. Future studies that assess this subject should have a large sample size and aim to establish uniform and objective criteria regarding the identification of a low-risk febrile neutropenic episode.
Four trials were included with a total of 220 participants (118 treated with atherectomy, 102 treated with balloon angioplasty) and 259 treated vessels (129 treated with atherectomy, 130 treated with balloon angioplasty). All studies compared atherectomy with angioplasty. No study was properly powered or assessors blinded to the procedures and there was a high risk of selection, attrition, detection and reporting biases. The estimated risk of success was similar between the treatment modalities although the confidence interval (CI) was compatible with small benefits of either treatment for the initial procedural success rate (Mantel-Haenszel risk ratio (RR) 0.92, 95% CI 0.44 to 1.91, P = 0.82), patency at six months (Mantel-Haenszel RR 0.92, 95% CI 0.51 to 1.66, P = 0.79) and patency at 12 months (Mantel-Haenszel RR 1.17, 95% CI 0.72 to 1.90, P = 0.53) following the procedure. The reduction in all-cause mortality with atherectomy was most likely due to an unexpectedly high mortality in the balloon angioplasty group in one of the two trials that reported mortality (Mantel-Haenszel RR 0.24, 95% CI 0.06 to 0.91, P = 0.04). Cardiovascular events were not reported in any study. There was a reduction in the rate of bailout stenting following atherectomy (Mantel-Haenszel RR 0.45, 95% CI 0.24 to 0.84, P = 0.01), and balloon inflation pressures were lower following atherectomy (mean difference -2.73 mmHg, 95% CI -3.48 to -1.98, P < 0.00001). Complications such as embolisation and vessel dissection were reported in two trials indicating more embolisations in the atherectomy group and more vessel dissections in the angioplasty group, but the data could not be pooled. From the limited data available, there was no clear evidence of different rates of adverse events between the atherectomy and balloon angioplasty groups for target vessel revascularisation and above-knee amputation. Quality of life and clinical and symptomatic outcomes such as walking distance or symptom relief were not reported in the studies. This review has identified poor quality evidence to support atherectomy as an alternative to balloon angioplasty in maintaining primary patency at any time interval. There was no evidence for superiority of atherectomy over angioplasty on any outcome, and distal embolisation was not reported in all trials of atherectomy. Properly powered trials are recommended.
Four RCTs (n = 607) of user-held records versus treatment as usual met the inclusion criteria. When the effect of user-held records on psychiatric hospital admissions was compared with treatment as usual in four studies, the pooled treatment effect showed no significant impact of the intervention and was of very low magnitude (n = 597, 4 RCTs, RR 0.99 CI 0.71 to 1.38, moderate quality evidence). Similarly, there was no significant effect of the intervention in three studies which investigated compulsory psychiatric hospital admissions (n = 507, 4 RCTs, RR 0.64 CI 0.37 to 1.10, moderate quality evidence). Other outcomes including satisfaction and mental state were investigated but pooled estimates were not obtainable due to skewed or poorly reported data, or only being investigated by one study. Two outcomes (violence and death) were not investigated by the included studies. Two important randomised studies are ongoing. The evidence gap remains regarding user-held, personalised, accessible clinical information for people with psychotic illnesses for many of the outcomes of interest. However, based on moderate quality evidence, this review suggests that there is no effect of the intervention on hospital or outpatient appointment use for individuals with psychotic disorders. The number of studies is low, however, and further evidence is required to ascertain whether these results are mediated by the type of intervention, such as involvement of a clinical team or the type of information included.
We included four randomised controlled trials in this review. A total of 868 participants with a clinical or radiological diagnosis of RAAA were randomised to receive either eEVAR or open surgical repair. Overall risk of bias was low, but we considered one study that performed randomisation in blocks by week and performed no allocation concealment and no blinding to be at high risk of selection bias. Another study did not adequately report random sequence generation, putting it at risk of selection bias, and two studies were underpowered. There was no clear evidence to support a difference between the two interventions for 30-day (or in-hospital) mortality (OR 0.88, 95% CI 0.66 to 1.16; moderate-quality evidence). There were a total of 44 endoleak events in 128 participants from three studies (low-quality evidence). Thirty-day complication outcomes (myocardial infarction, stroke, composite cardiac complications, renal complications, severe bowel ischaemia, spinal cord ischaemia, reoperation, amputation, and respiratory failure) were reported in between one and three studies, therefore we were unable to draw a robust conclusion. We downgraded the quality of the evidence for myocardial infarction, renal complications, and respiratory failure due to imprecision, inconsistency, and risk of bias. Odds ratios for complications outcomes were OR 2.38 (95% CI 0.34 to 16.53; 139 participants; 2 studies; low-quality evidence) for myocardial infarction; OR 1.07 (95% CI 0.21 to 5.42; 255 participants; 3 studies; low-quality evidence) for renal complications; and OR 3.62 (95% CI 0.14 to 95.78; 32 participants; 1 study; low-quality evidence) for respiratory failure. There was low-quality evidence of a reduction in bowel ischaemia in the eEVAR treatment group, but very few events were reported (OR 0.37, 95% CI 0.14 to 0.94), and we downgraded the evidence due to imprecision and risk of bias. Six-month and one-year outcomes were evaluated in three studies, but only results from a single study could be used for each outcome, which showed no clear evidence of a difference between the interventions. We rated six-month mortality evidence as of moderate quality due to imprecision (OR 0.89, 95% CI 0.40 to 1.98; 116 participants). The conclusions of this review are currently limited by the paucity of data. We found from the data available moderate-quality evidence suggesting there is no difference in 30-day mortality between eEVAR and open repair. Not enough information was provided for complications for us to make a well-informed conclusion, although it is possible that eEVAR is associated with a reduction in bowel ischaemia. Long-term data were lacking for both survival and late complications. More high-quality randomised controlled trials comparing eEVAR and open repair for the treatment of RAAA are needed to better understand if one method is superior to the other, or if there is no difference between the methods on relevant outcomes.
We found one randomised controlled trial with a low risk of bias which was carried out in a tertiary neonatal care centre in Australia. The study involved 36 women (18 received intravaginal prostaglandin E 2 gel and 18 received placebo). There was one case of neonatal respiratory distress in the control group, which the trialist reported as transient tachypnoea of the newborn (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.68, one study, n = 36). None of the neonates required mechanical ventilation and the trial authors reported median Apgar scores at one and five minutes as being similar in both groups. There were no treatment-related side effects in either group. Noradrenaline concentrations (median values (range)) were reported as being significantly higher in the cord blood samples of the intervention group compared to the control group. Although the trial authors reported a significant increase in catecholamine levels in the intervention group, there was no significant difference in the respiratory outcomes between intervention and control groups. The quality of evidence was graded as low because the sample size was small and there were few events. No definite conclusions can thus be drawn on the effects of prostaglandins on neonatal respiratory outcomes from this review.
We identified 26 new trials in this update, of which 9 await classification due to insufficient data for eligibility assessment, and 17 trials (N = 3105) met the inclusion criteria. We included a total of 28 trials involving 4195 infants with acute bronchiolitis, of whom 2222 infants received hypertonic saline. Hospitalised infants treated with nebulised hypertonic saline had a statistically significant shorter mean length of hospital stay compared to those treated with nebulised 0.9% saline (MD -0.41 days, 95% CI -0.75 to -0.07; P = 0.02, I² = 79%; 17 trials; 1867 infants) (GRADE quality of evidence: low). Infants who received hypertonic saline also had statistically significant lower post-inhalation clinical scores than infants who received 0.9% saline in the first three days of treatment (day 1: MD -0.77, 95% CI -1.18 to -0.36, P < 0.001; day 2: MD -1.28, 95% CI -1.91 to -0.65, P < 0.001; day 3: MD -1.43, 95% CI -1.82 to -1.04, P < 0.001) (GRADE quality of evidence: low). Nebulised hypertonic saline reduced the risk of hospitalisation by 14% compared with nebulised 0.9% saline among infants who were outpatients and those treated in the emergency department (RR 0.86, 95% CI 0.76 to 0.98; P = 0.02, I² = 7%; 8 trials; 1723 infants) (GRADE quality of evidence: moderate). Twenty-four trials presented safety data: 13 trials (1363 infants, 703 treated with hypertonic saline) did not report any adverse events, and 11 trials (2360 infants, 1265 treated with hypertonic saline) reported at least one adverse event, most of which were mild and resolved spontaneously. Nebulised hypertonic saline may modestly reduce length of stay among infants hospitalised with acute bronchiolitis and improve clinical severity score. Treatment with nebulised hypertonic saline may also reduce the risk of hospitalisation among outpatients and emergency department patients. However, we assessed the quality of the evidence as low to moderate.
One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias. Oral supplements versus control The change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants. Inhaled supplements versus control Two studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups. With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.
Eight RCTs with a total of 660 participants met review inclusion criteria. Duration of the included trials varied from 12 weeks to 18 months. Only one trial used an inactive control. Most studies were at unclear or high risk of bias in several domains. Overall, our ability to draw conclusions was hampered by very low-quality evidence. Almost all results were very imprecise; there were also problems related to risk of bias, inconsistency between trials, and indirectness of the evidence. No trial provided data on incident dementia. For comparisons of CCT with both active and inactive controls, the quality of evidence on our other primary outcome of global cognitive function immediately after the intervention period was very low. Therefore, we were unable to draw any conclusions about this outcome. Due to very low quality of evidence, we were also unable to determine whether there was any effect of CCT compared to active control on our secondary outcomes of episodic memory, working memory, executive function, depression, functional performance, and mortality. We found low-quality evidence suggesting that there is probably no effect on speed of processing (SMD 0.20, 95% confidence interval (CI) -0.16 to 0.56; 2 studies; 119 participants), verbal fluency (SMD -0.16, 95% CI -0.76 to 0.44; 3 studies; 150 participants), or quality of life (mean difference (MD) 0.40, 95% CI -1.85 to 2.65; 1 study; 19 participants). When CCT was compared with inactive control, we obtained data on five secondary outcomes, including episodic memory, executive function, verbal fluency, depression, and functional performance. We found very low-quality evidence; therefore, we were unable to draw any conclusions about these outcomes. Currently available evidence does not allow us to determine whether or not computerised cognitive training will prevent clinical dementia or improve or maintain cognitive function in those who already have evidence of cognitive impairment. Small numbers of trials, small samples, risk of bias, inconsistency between trials, and highly imprecise results mean that it is not possible to derive any implications for clinical practice, despite some observed large effect sizes from individual studies. Direct adverse events are unlikely to occur, although the time and sometimes the money involved in computerised cognitive training programmes may represent significant burdens. Further research is necessary and should concentrate on improving methodological rigour, selecting suitable outcomes measures, and assessing generalisability and persistence of any effects. Trials with long-term follow-up are needed to determine the potential of this intervention to reduce the risk of dementia.
This systematic review attempted to summarise evidence from randomised clinical trials on the treatment of spontaneous bacterial peritonitis. Thirteen studies were included; each one of them compared different antibiotics in their experimental and control groups. No meta-analyses could be performed, though data on the main outcomes were collected and analysed separately for each included trial. Currently, the evidence showing that lower dosage or short-term treatment with third generation cephalosporins is as effective as higher dosage or long-term treatment is weak. Oral quinolones could be considered an option for those with less severe manifestations of the disease. This review provides no clear evidence for the treatment of cirrhotic patients with spontaneous bacterial peritonitis. In practice, third generation cephalosporins have already been established as the standard treatment of spontaneous bacterial peritonitis, and it is clear, that empirical antibiotic therapy should be provided in any case. However, until large, well-conducted trials provide more information, practice will remain based on impression, not evidence.
Of 35 studies considered potentially relevant, 14 studies enrolling 1025 subjects met the entry criteria. Scopolamine was administered via transdermal patches, tablets or capsules, oral solutions or intravenously. Scopolamine was compared against placebo, calcium channel antagonists, antihistamine, methscopolamine or a combination of scopolamine and ephedrine. Studies were generally small in size and of varying quality. Scopolamine was more effective than placebo in the prevention of symptoms. Comparisons between scopolamine and other agents were few and suggested that scopolamine was superior (versus methscopolamine) or equivalent (versus antihistamines) as a preventative agent. Evidence comparing scopolamine to cinnarizine or combinations of scopolamine and ephedrine is equivocal or minimal. Although sample sizes were small, scopolamine was no more likely to induce drowsiness, blurring of vision or dizziness compared to other agents. Dry mouth was more likely with scopolamine than with methscopolamine or cinnarizine. No studies were available relating to the therapeutic effectiveness of scopolamine in the management of established symptoms of motion sickness. The use of scopolamine versus placebo in preventing motion sickness has been shown to be effective. No conclusions can be made on the comparative effectiveness of scopolamine and other agents such as antihistamines and calcium channel antagonists. In addition, we identified no randomised controlled trials that examined the effectiveness of scopolamine in the treatment of established symptoms of motion sickness.
We included four trials with a total of 4663 participants. All four trials reported short PRT courses, with three trials using 25 Gy in five fractions, and one trial using 20 Gy in four fractions. Only one study specifically required TME surgery for inclusion, whereas in another study 90% of participants received TME surgery. Preoperative radiotherapy probably reduces overall mortality at 4 to 12 years' follow-up (4 trials, 4663 participants; Peto OR 0.90, 95% CI 0.83 to 0.98; moderate-quality evidence). For every 1000 people who undergo surgery alone, 454 would die compared with 45 fewer (the true effect may lie between 77 fewer to 9 fewer) in the PRT group. There was some evidence from subgroup analyses that in trials using TME no or little effect of PRT on survival (P = 0.03 for the difference between subgroups). Preoperative radiotherapy may have little or no effect in reducing cause-specific mortality for rectal cancer (2 trials, 2145 participants; Peto OR 0.89, 95% CI 0.77 to 1.03; low-quality evidence). We found moderate-quality evidence that PRT reduces local recurrence (4 trials, 4663 participants; Peto OR 0.48, 95% CI 0.40 to 0.57). In absolute terms, 161 out of 1000 patients receiving surgery alone would experience local recurrence compared with 83 fewer with PRT. The results were consistent in TME and non-TME studies. There may be little or no difference in curative resection (4 trials, 4673 participants; RR 1.00, 95% CI 0.97 to 1.02; low-quality evidence) or in the need for sphincter-sparing surgery (3 trials, 4379 participants; RR 0.99, 95% CI 0.94 to 1.04; I2 = 0%; low-quality evidence) between PRT and surgery alone. Low-quality evidence suggests that PRT may increase the risk of sepsis from 13% to 16% (2 trials, 2698 participants; RR 1.25, 95% CI 1.04 to 1.52) and surgical complications from 25% to 30% (2 trials, 2698 participants; RR 1.20, 95% CI 1.01 to 1.42) compared to surgery alone. Two trials evaluated quality of life using different scales. Both studies concluded that sexual dysfunction occurred more in the PRT group. Mixed results were found for faecal incontinence, and irradiated participants tended to resume work later than non-irradiated participants between 6 and 12 months, but this effect had attenuated after 18 months (low-quality evidence). We found moderate-quality evidence that PRT reduces overall mortality. Subgroup analysis did not confirm this effect in people undergoing TME surgery. We found consistent evidence that PRT reduces local recurrence. Risk of sepsis and postsurgical complications may be higher with PRT. The main limitation of the findings of the present review concerns their applicability. The included trials only assessed short-course radiotherapy and did not use chemotherapy, which is widely used in the contemporary management of rectal cancer disease. The differences between the trials regarding the criteria used to define rectal cancer, staging, radiotherapy delivered, the time between radiotherapy and surgery, and the use of adjuvant or postoperative therapy did not appear to influence the size of effect across the studies. Future trials should focus on identifying participants that are most likely to benefit from PRT especially in terms of improving local control, sphincter preservation, and overall survival while reducing acute and late toxicities (especially rectal and sexual function), as well as determining the effect of radiotherapy when chemotherapy is used and the optimal timing of surgery following radiotherapy.
The review included 12 studies (reported in 22 publications). The included studies assigned 24,846 participants aged one to six months to vitamin A supplementation or control group. There was no effect of vitamin A supplementation for the primary outcome of all-cause mortality based on seven studies that included 21,339 (85%) participants (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.25; I2 = 0%; test for heterogeneity: P = 0.79; quality of evidence: moderate). Also, there was no effect of vitamin A supplementation on mortality or morbidity due to diarrhoea and respiratory tract infection. There was an increased risk of bulging fontanelle within 24 to 72 hours of supplementation in the vitamin A group compared to control (RR 3.10, 95% CI 1.89 to 5.09; I2 = 9%, test for heterogeneity: P = 0.36; quality of evidence: high). There was no reported subsequent increased risk of death, convulsions or irritability in infants who developed bulging fontanelle after vitamin A supplementation, and it resolved in most cases within 72 hours. There was no increased risk of other adverse effects such as vomiting, irritability, diarrhoea, fever and convulsions in the vitamin A supplementation group compared to control. Vitamin A supplementation did not have any statistically significant effect on vitamin A deficiency (RR 0.86, 95% CI 0.70 to 1.06; I2 = 27%; test for heterogeneity: P = 0.25; quality of evidence: moderate). There is no convincing evidence that vitamin A supplementation for infants one to six months of age results in a reduction in infant mortality or morbidity in low- and middle-income countries. There is an increased risk of bulging fontanelle with vitamin A supplementation in this age group; however, there were no reported subsequent complications because of this adverse effect.
We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections. We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.
Twenty-three trials (total of 912 patients) met the inclusion criteria (22 in RA; one in a mixed population of RA and osteoarthritis); all except one were published before 1990. Most study populations were not taking DMARDs (e.g. methotrexate, sulphasalazine, hydroxychloroquine and leflunomide) and all studies were performed prior to the introduction of biologic therapies (e.g. etanercept, infliximab and adalimumab). All trials were at high risk of bias, heterogeneity precluded meta-analysis, and we were only able to report a general description of results. The majority (18 studies, 78%) found no differences between the combination and monotherapy treatments they studied, while five (22%) reported conflicting results, favouring either the combination or monotherapy arms. From the 12 trials on NSAID + analgesic vs NSAID, nine reported no significant difference between the interventions, while three did: in two, the combination therapy achieved better pain control; and the third trial compared combination therapy with two different dosages of monotherapy (NSAID alone) and reported that a high dose phenylbutazone was superior to combination therapy (paracetamol + aspirin), which was superior to low dose phenylbutazone. From the five studies on the combination of two NSAIDS vs one NSAID, four reported no significant differences between interventions, and one reported significantly better pain control with combination therapy. The single trial comparing a combination of opioid + neuromodulator vs opioid reported better pain control with monotherapy. The remaining trials (NSAID + neuromodulator vs NSAID (3 trials); opioid + NSAID vs NSAID (1 trial); and opioid + analgesic vs analgesic (1 trial)) found no significant difference between combination therapy and monotherapy. Information regarding withdrawals due to inadequate analgesia and safety was incompletely reported, but in general there were no differences between combination therapy and monotherapy. No data were available that addressed the value of combination pain therapy or monotherapy for people with IA who have optimal disease suppression. There were no studies that included patients with AS, PsA or SpA. Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed trials are needed to address this question.
In this update, we found an additional 42 trials and added them to the original 254 studies. The update consists of 296 trials that evaluated dose-related efficacy of atorvastatin in 38,817 participants. Included are 242 before-and-after trials and 54 placebo-controlled RCTs. Log dose-response data from both trial designs revealed linear dose-related effects on blood total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides. The Summary of findings table 1 documents the effect of atorvastatin on LDL-cholesterol over the dose range of 10 to 80 mg/d, which is the range for which this systematic review acquired the greatest quantity of data. Over this range, blood LDL-cholesterol is decreased by 37.1% to 51.7% (Summary of findings table 1). The slope of dose-related effects on cholesterol and LDL-cholesterol was similar for atorvastatin and rosuvastatin, but rosuvastatin is about three-fold more potent. Subgroup analyses suggested that the atorvastatin effect was greater in females than in males and was greater in non-familial than in familial hypercholesterolaemia. Risk of bias for the outcome of withdrawals due to adverse effects (WDAEs) was high, but the mostly unclear risk of bias was judged unlikely to affect lipid measurements. Withdrawals due to adverse effects were not statistically significantly different between atorvastatin and placebo groups in these short-term trials (risk ratio 0.98, 95% confidence interval 0.68 to 1.40). This update resulted in no change to the main conclusions of the review but significantly increases the strength of the evidence. Studies show that atorvastatin decreases blood total cholesterol and LDL-cholesterol in a linear dose-related manner over the commonly prescribed dose range. New findings include that atorvastatin is more than three-fold less potent than rosuvastatin, and that the cholesterol-lowering effects of atorvastatin are greater in females than in males and greater in non-familial than in familial hypercholesterolaemia. This review update does not provide a good estimate of the incidence of harms associated with atorvastatin because included trials were of short duration and adverse effects were not reported in 37% of placebo-controlled trials.
Five trials, including 1476 participants, were included in the review. Two trials compared interferon with observation alone and three trials compared interferon plus chemotherapy with chemotherapy alone. A meta-analysis of two trials involving 370 participants found no significant difference in both overall survival (HR 1.14, 95% CI 0.84 to 1.55) and progression free survival (HR 0.99, 95% CI 0.79 to 1.24) between the interferon and observation alone groups in post-surgical women who had undergone first-line chemotherapy for advanced EOC. One trial with 293 participants found that while no significant difference was observed in incidence of nausea or vomiting between the two treatment groups, significantly more flu-like symptoms (RR 2.25, 95% CI 1.73 to 2.91) and fatigue (RR 1.54, 95% CI 1.27 to 1.88) were reported in the interferon group. For the second comparison, a meta-analysis of two trials comprising 244 participants found that although there was no significant difference in overall survival between the interferon plus chemotherapy and the chemotherapy alone group (HR 1.14, 95% CI 0.74 to 1.76), women in the interferon plus chemotherapy group had worse progression free survival than those in the chemotherapy alone group (HR 1.43, 95% CI 1.02 to 2.00). Compared to chemotherapy alone, adding interferon to chemotherapy did not alter the incidence of adverse events in post-surgical women with advanced EOC. Implications for practice Based on low quality evidence, the addition of interferon to first-line chemotherapy did not alter the overall survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is low quality evidence to suggest that interferon in combination with chemotherapy worsened the progression free survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is not enough evidence that interferon therapy alone alters overall survival or progression free survival compared to observation alone in post-surgical women who have undergone first-line chemotherapy. Implications for research Three of the five trials included in this review were stopped early and were, therefore, underpowered to detect any true effect of the intervention. The trials did not report the results of important outcomes in a uniform manner, preventing statistical aggregation of the results. Trial methodology was poorly reported resulting in unclear risk of bias. For clear recommendations to be made regarding the effectiveness of interferon in the treatment of advanced EOC, long-term, well conducted and adequately powered RCTs would be needed. However, the available data do not suggest that interferon has an adequately advantageous effect to warrant further investigation.
We included 16 randomized controlled trials of dihydropyridine calcium channel blockers in this systematic review, with 2768 randomized participants. Drugs studied included amlodipine, lercanidipine, mandipine, nifedipine, and felodipine (all administered once daily) and nicardipine (administered twice daily). We analyzed and presented data by hour post dose. The blood pressure-lowering effect was stable over time; there were no clinically important differences in blood pressure-lowering effect of calcium channel blockers between each hour for either systolic blood pressure (estimated mean hourly differences ranged between 9.45 mmHg and 13.2 mmHg) or diastolic blood pressure (estimated mean hourly differences ranged between 5.85 mmHg and 8.5 mmHg). However, there was a moderate risk of bias for this finding. Once-daily dihydropyridine calcium channel blockers appeared to lower blood pressure by a relatively constant amount throughout the 24-hour dosing interval. Six dihydropyridine calcium channel blockers studied in this review lowered blood pressure by a relatively similar amount each hour over the course of 24 hours. The benefits and harms of this pattern of blood pressure lowering are unknown. Further trials are needed with accurate recording of time of drug intake and with reporting of standard deviation of blood pressure at each hour. We did not attempt to assess adverse effects in this review due to the lack of reporting and the short duration of follow-up.
Four trials involving a total of 300 adults with SMI and PTSD are included. These trials evaluated three active intervention therapies: trauma-focused cognitive behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing (EMDR), and brief psychoeducation for PTSD, all delivered via individual sessions. Our main outcomes of interest were PTSD symptoms, quality of life/well-being, symptoms of co-morbid psychosis, anxiety symptoms, depressive symptoms, adverse events and health economic outcomes. 1. TF-CBT versus usual care/waiting list Three trials provided data for this comparison, however, continuous outcome data available were more often found to be skewed than unskewed, leading to the necessity of conducting analyses separately for the two types of continuous data. Using the unskewed data only, results showed no significant differences between TF-CBT and usual care in reducing clinician-rated PTSD symptoms at short term (1 RCT, n =13, MD 13.15, 95% CI -4.09 to 30.39,low-quality evidence). Limited unskewed data showed equivocal results between groups in terms of general quality of life (1 RCT, n = 39, MD -0.60, 95% CI -4.47 to 3.27, low-quality evidence), symptoms of psychosis (1 RCT, n = 9, MD -6.93, 95% CI -34.17 to 20.31, low-quality evidence), and anxiety (1 RCT, n = 9, MD 12.57, 95% CI -5.54 to 30.68, very low-quality evidence), at medium term. The only available data on depression symptoms were skewed and were equivocal across groups at medium term (2 RCTs, n = 48, MD 3.26, 95% CI -3.66 to 10.18, very low-quality evidence). TF-CBT was not associated with more adverse events (1 RCT, n = 100, RR 0.44, 95% CI 0.09 to 2.31, low-quality evidence) at medium term. No data were available for health economic outcomes. Very limited data for PTSD and other symptoms were available over the long term. 2. EMDR versus waiting list One trial provided data for this comparison. Favourable effects were found for EMDR in terms of PTSD symptom severity at medium term but data were skewed (1 RCT, n = 83, MD -12.31, 95% CI -22.72 to -1.90, very low-quality evidence). EMDR was not associated with more adverse events (1 RCT, n = 102, RR 0.21, 95% CI 0.02 to 1.85, low-quality evidence). No data were available for quality of life, symptoms of co-morbid psychosis, depression, anxiety and health economics. 3. TF-CBT versus EMDR One trial compared TF-CBT with EMDR. PTSD symptom severity, based on skewed data (1 RCT, n = 88, MD -1.69, 95% CI -12.63 to 9.23, very low-quality evidence) was similar between treatment groups. No data were available for the other main outcomes. 4. TF-CBT versus psychoeducation One trial compared TF-CBT with psychoeducation. Results were equivocal for PTSD symptom severity (1 RCT, n = 52, MD 0.23, 95% CI -14.66 to 15.12, low-quality evidence) and general quality of life (1 RCT, n = 49, MD 0.11, 95% CI -0.74 to 0.95, low-quality evidence) by medium term. No data were available for the other outcomes of interest. Very few trials have investigated TFPIs for individuals with SMI and PTSD. Results from trials of TF-CBT are limited and inconclusive regarding its effectiveness on PTSD, or on psychotic symptoms or other symptoms of psychological distress. Only one trial evaluated EMDR and provided limited preliminary evidence favouring EMDR compared to waiting list. Comparing TF-CBT head-to-head with EMDR and brief psychoeducation respectively, showed no clear effect for either therapy. Both TF-CBT and EMDR do not appear to cause more (or less) adverse effects, compared to waiting list or usual care; these findings however, are mostly based on low to very low-quality evidence. Further larger scale trials are now needed to provide high-quality evidence to confirm or refute these preliminary findings, and to establish which intervention modalities and techniques are associated with improved outcomes, especially in the long term.
The 2012 update search identified 19 further relevant studies, most of which were from China. Thus the review currently includes 26 studies with a total of 2184 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With the exception of two studies, the studies were small, the participants and personnel were not blinded (neither was outcome assessment), and most were short-term and incompletely reported. For this update we prespecified seven main outcomes of interest: clinical response (clinically significant response, aggression/agitation), leaving the study early (acceptability of treatment, overall tolerability), adverse events (sedation, weight gain) and quality of life. Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (14 RCTs, n = 1049, RR 1.31, 95% CI 1.16 to 1.47, I2 = 12%, low-quality evidence). However, this effect was removed after excluding open RCTs in a sensitivity analysis. In terms of acceptability of treatment (measured by the number of participants leaving the study early due to any reason) valproate was just as acceptable as placebo (11 RCTs, n = 951, RR 0.76, 95% CI 0.47 to 1.24, I2 = 55%). Also overall tolerability (measured by the number of participants leaving the study early for adverse events) between valproate and placebo was similar (6 RCTs, n = 974, RR 1.33, 95% CI 0.90 to 1.97, I2 = 0). Participants in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (3 RCTs, n = 186, MD -2.55, 95% CI -3.92 to -1.19, I2 = 82%, very low-quality evidence). Participants receiving valproate more frequently experienced sedation (8 RCTs, n = 770, RR 1.38, 95% CI 1.07 to 1.79, I2 = 0, low-quality evidence) but were no more likely to gain weight than those receiving placebo (4 RCTs, n = 427, RR 1.17, 95% CI 0.76 to 1.82, I2 = 0, low-quality evidence). No study reported on the important outcome of quality of life. There is limited evidence, based on a number of trials, that the augmentation of antipsychotics with valproate may be effective for overall clinical response, and also for specific symptoms, especially in terms of excitement and aggression. However, this evidence was entirely based on open RCTs. Moreover, valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups. Further randomised studies which are blinded are necessary before any clear recommendation can be made. Ideally these would focus on people with schizophrenia and aggression, on those with treatment-resistant forms of the illness and on those with schizoaffective disorders.
Twenty-one studies met our inclusion criteria (N = 457,202 participants). Nineteen studies provided data for the primary analysis (oxygen saturation threshold < 95% or ≤ 95%; N = 436,758 participants). The overall sensitivity of pulse oximetry for detection of CCHD was 76.3% (95% confidence interval [CI] 69.5 to 82.0) (low certainty of the evidence). Specificity was 99.9% (95% CI 99.7 to 99.9), with a false-positive rate of 0.14% (95% CI 0.07 to 0.22) (high certainty of the evidence). Summary positive and negative likelihood ratios were 535.6 (95% CI 280.3 to 1023.4) and 0.24 (95% CI 0.18 to 0.31), respectively. These results showed that out of 10,000 apparently healthy late preterm or full-term newborn infants, six will have CCHD (median prevalence in our review). Screening by pulse oximetry will detect five of these infants as having CCHD and will miss one case. In addition, screening by pulse oximetry will falsely identify another 14 infants out of the 10,000 as having suspected CCHD when they do not have it. The false-positive rate for detection of CCHD was lower when newborn pulse oximetry was performed longer than 24 hours after birth than when it was performed within 24 hours (0.06%, 95% CI 0.03 to 0.13, vs 0.42%, 95% CI 0.20 to 0.89; P = 0.027). Forest and ROC plots showed greater variability in estimated sensitivity than specificity across studies. We explored heterogeneity by conducting subgroup analyses and meta-regression of inclusion or exclusion of antenatally detected congenital heart defects, timing of testing, and risk of bias for the "flow and timing" domain of QUADAS-2, and we did not find an explanation for the heterogeneity in sensitivity. Pulse oximetry is a highly specific and moderately sensitive test for detection of CCHD with very low false-positive rates. Current evidence supports the introduction of routine screening for CCHD in asymptomatic newborns before discharge from the well-baby nursery.
The review included one trial involving 200 women and was at moderate to high risk of bias.The trial compared a daily dose of nitrofurantoin and close surveillance (regular clinic visit, urine cultures and antibiotics when a positive culture was found) with close surveillance only. No significant differences were found for the primary outcomes: recurrent pyelonephritis (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.31 to 2.53; one study, 167 women), RUTI before birth (RR 0.30, 95% CI 0.06 to 1.38; one study, 167 women), and preterm birth (before 37 weeks) (RR 1.18, 95% CI 0.42 to 3.35; one study, 147 women). The overall quality of evidence for these outcomes as assessed using GRADE was very low. There were no significant differences between the two comparison groups for any of the following secondary outcomes, birthweight less than 2500 (g) (RR 2.03, 95% CI 0.53 to 7.80; one study, 147 infants), birthweight (mean difference (MD) -113.00, 95% CI -327.20 to 101.20; one study, 147 infants), five-minute Apgar score less than seven (RR 2.03, 95% CI 0.19 to 21.87; one study, 147 infants) and miscarriages (RR 3.11, 95% CI 0.33 to 29.29; one study, 167 women). The evidence for these secondary outcomes was also of very low quality. The incidence of asymptomatic bacteriuria (ASB) (at least 103 colonies per mL) (secondary outcome), only reported in women with a clinic attendance rate of more than 90% (RR 0.55, 95% CI 0.34 to 0.89; one study, 102 women), was significantly reduced in women who received nitrofurantoin and close surveillance. Data on total mortality and small-for-gestational-age babies were not reported. A daily dose of nitrofurantoin and close surveillance has not been shown to prevent RUTI compared with close surveillance alone. A significant reduction of ASB was found in women with a high clinic attendance rate and who received nitrofurantoin and close surveillance. There was limited reporting of both primary and secondary outcomes for both women and infants. No conclusions can be drawn regarding the optimal intervention to prevent RUTI in women who are pregnant. Randomised controlled trials comparing different pharmacological and non-pharmacological interventions are necessary to investigate potentially effective interventions to prevent RUTI in women who are pregnant.
We included one trial of 167 women and their babies. This trial was a pilot study recruiting alongside another study, therefore, a separate sample size was not calculated. The trial compared a twice-weekly surveillance regimen (biophysical profile, nonstress tests, umbilical artery and middle cerebral artery Doppler and uterine artery Doppler) with the same regimen applied fortnightly (both groups had growth assessed fortnightly). There were insufficient data to assess this review's primary infant outcome of composite perinatal mortality and serious morbidity (although there were no perinatal deaths) and no difference was seen in the primary maternal outcome of emergency caesarean section for fetal distress (risk ratio (RR) 0.96; 95% confidence interval (CI) 0.35 to 2.63). In keeping with the more frequent monitoring, mean gestational age at birth was four days less for the twice-weekly surveillance group compared with the fortnightly surveillance group (mean difference (MD) -4.00; 95% CI -7.79 to -0.21). Women in the twice-weekly surveillance group were 25% more likely to have induction of labour than those in the fortnightly surveillance group (RR 1.25; 95% CI 1.04 to 1.50). There is limited evidence from randomised controlled trials to inform best practice for fetal surveillance regimens when caring for women with pregnancies affected by impaired fetal growth. More studies are needed to evaluate the effects of currently used fetal surveillance regimens in impaired fetal growth.
We included 22 studies in this updated analysis, including six new trials with 584 additional participants, resulting in a total of 1428 participants. The risk of bias was low in 11 studies, high in one study and unclear in the remaining studies, due primarily to failure to report methodology for randomisation, and allocation concealment or blinding, or both. Fourteen studies examined intraoperative core temperatures among heated and humidified insufflation cohorts and core temperatures were higher compared to cold gas insufflation (MD 0.31 °C, 95% CI, 0.09 to 0.53, I2 = 88%, P = 0.005) (low-quality evidence). If the analysis was limited to the eight studies at low risk of bias, this result became non-significant but remained heterogeneous (MD 0.18 °C, 95% CI, -0.04 to 0.39, I2= 81%, P = 0.10) (moderate-quality evidence). In comparison to the cold CO2 group, the meta-analysis of the heated, non-humidified group also showed no statistically significant difference between groups. Core temperature was statistically, significantly higher in the heated, humidified CO2 with external warming groups (MD 0.29 °C, 95% CI, 0.05 to 0.52, I2 = 84%, P = 0.02) (moderate-quality evidence). Despite the small difference in temperature of 0.31 °C with heated CO2, this is unlikely to be of clinical significance. For postoperative pain scores, there were no statistically significant differences between heated and cold CO2, either overall, or for any of the subgroups assessed. Interestingly, morphine-equivalent use was homogeneous and higher in heated, non-humidified insufflation compared to cold insufflation for postoperative day one (MD 11.93 mg, 95% CI 0.92 to 22.94, I2 = 0%, P = 0.03) (low-quality evidence) and day two (MD 9.79 mg, 95% CI 1.58 to 18.00, I2 = 0%, P = 0.02) (low-quality evidence). However, morphine use was not significantly different six hours postoperatively or in any humidified insufflation groups. There was no apparent effect on length of hospitalisation, lens fogging or length of operation with heated compared to cold gas insufflation, with or without humidification. Recovery room time was shorter in the heated cohort (MD -26.79 minutes, 95% CI -51.34 to -2.25, I2 = 95%, P = 0.03) (low-quality evidence). When the one and only unclear-risk study was removed from the analysis, the difference in recovery-room time became non-significant and the studies were statistically homogeneous (MD -1.22 minutes, 95% CI, -6.62 to 4.17, I2 = 12%, P = 0.66) (moderate-quality evidence). There were also no differences in the frequency of major adverse events that occurred in the cold or heated cohorts. These results should be interpreted with caution due to some limitations. Heterogeneity of core temperature remained significant despite subgroup analysis, likely due to variations in the study design of the individual trials, as the trials had variations in insufflation gas temperatures (35 ºC to 37 ºC), humidity ranges (88% to 100%), gas volumes and location of the temperature probes. Additionally, some of the trials lacked specific study design information making evaluation difficult. While heated, humidified gas leads to mildly smaller decreases in core body temperatures, clinically this does not account for improved patient outcomes, therefore, there is no clear evidence for the use of heated gas insufflation, with or without humidification, compared to cold gas insufflation in laparoscopic abdominal surgery.
Five studies treated 177 participants with painful diabetic neuropathy (104) or postherpetic neuralgia (73). The mean or median ages in the studies were 55 to 72 years. Four studies used a cross-over, and one a parallel group design; 145 participants were randomised to receive desipramine 12.5 mg to 250 mg daily, with most taking 100 mg to 150 mg daily following titration. Comparators were placebo in three studies (an 'active placebo' in two studies), fluoxetine, clomipramine (one study each), and amitriptyline (two studies), and treatment was for two to six weeks. All studies had one or more sources of potential major bias. No study provided first or second tier evidence for any outcome. No data were available on the proportion of people with at least 50% or 30% reduction in pain, but data were available from three studies for our other primary outcome of Patient Global Impression of Change, reported as patient evaluation of pain relief that was 'complete' or 'a lot'. No pooling of data was possible, but third tier evidence in individual studies indicated some improvement in pain relief with desipramine compared with placebo, although this was very low quality evidence, derived mainly from group mean data and completer analyses in small, short duration studies where major bias was possible. There were too few participants in comparisons of desipramine with another active treatment to draw any conclusions. All studies reported some information about adverse events, but reporting was inconsistent and fragmented. Participants taking desipramine experienced more adverse events, and a higher rate of withdrawal due to adverse events, than did participants taking placebo (very low quality evidence). This review found little evidence to support the use of desipramine to treat neuropathic pain. There was very low quality evidence of benefit and harm, but this came from studies that were methodologically flawed and potentially subject to major bias. Effective medicines with much greater supportive evidence are available. There may be a role for desipramine in patients who have not obtained pain relief from other treatments.
Twenty-three randomised controlled trials were identified. A total of 3872 and 2915 participants in the intervention and in the control group, respectively, were analysed. The weighted mean difference (WMD) for the level of glycosylated haemoglobin was -0.08 (95% confidence interval (CI) -0.12 to -0.04) in favour of the long acting insulin arm. The WMD between the groups in fasting plasma and blood glucose levels was -0.63 (95% CI -0.86 to -0.40) and -0.86 (95% CI -1.00 to -0.72) in favour of the long acting insulins. The odds ratio for a patient on long acting insulin to develop any type of hypoglycaemia was 0.93 (95% CI 0.8 to 1.08) compared to that of a patient on intermediate acting insulins. The OR for severe hypoglycaemic episodes was 0.73 (95% CI 0.61 to 0.87), and 0.70 (95% CI of 0.63 to 0.79) for nocturnal episodes. The WMD between the long and intermediate insulin groups for hypoglycaemic events per 100 patient follow up days was -0.77 (95% CI -0.89 to -0.65), -0.0 (95% CI -0.02 to 0.02) and -0.40 (95% CI -0.45 to -0.34) for overall, severe, and nocturnal hypoglycaemic episodes. Weight gain was more prominent in the control group. No difference was noted in the quantity or quality of severe adverse events or deaths. Long acting insulin preparations seem to exert a beneficial effect on nocturnal glucose levels. Their effect on the overall diabetes control is clinically unremarkable. Their use as a basal insulin regimen for type 1 diabetes mellitus warrants further substantiation.
Intra-arterial delivery of thrombolytic agents appeared to be more effective than intravenous administration. Thrombolysis was more effective when the angiographic catheter was placed within the thrombus. Although 'high dose' and 'forced infusion' techniques achieved vessel patency in less time than 'low dose infusion', there were more bleeding complications, and no increase in patency rates or improvement in limb salvage at 30 days. Implications for practice Thrombolysis should be reserved for patients with limb threatening ischaemia, due to the high risk of haemorrhage or death.  Greater benefit is seen when the thrombolytic agent is delivered into the thrombus. Systemic intravenous thrombolysis is less effective than intra-arterial thrombolysis and is associated with an increase in bleeding complications.  'High dose' and 'forced infusion' techniques, or adjunctive agents such as platelet glycoprotein IIb/IIIa inhibitors may speed up thrombolysis, but these are not accompanied by lower amputation rates or a decreased need for adjunctive endovascular or surgical procedures.  'Low dose continuous infusion', following initial lacing of the thrombus with a high dose of the thrombolytic agent, is the least labour intensive technique. Implications for research Only large multicentre trials with carefully controlled inclusion criteria will be sufficiently powerful to demonstrate genuine benefit for a particular thrombolytic regime.
A total of 59 RCTs with 8924 participants were included. The mean age of included participants ranged from 59.0 to 74.1 years. Mean prostate volume ranged from 39 mL to 82.6 mL. Primary outcomes BTURP probably results in little to no difference in urological symptoms, as measured by the International Prostate Symptom Score (IPSS) at 12 months on a scale of 0 to 35, with higher scores reflecting worse symptoms (mean difference (MD) -0.24, 95% confidence interval (CI) -0.39 to -0.09; participants = 2531; RCTs = 16; I² = 0%; moderate certainty of evidence (CoE), downgraded for study limitations), compared to MTURP. BTURP probably results in little to no difference in bother, as measured by health-related quality of life (HRQoL) score at 12 months on a scale of 0 to 6, with higher scores reflecting greater bother (MD -0.12, 95% CI -0.25 to 0.02; participants = 2004; RCTs = 11; I² = 53%; moderate CoE, downgraded for study limitations), compared to MTURP. BTURP probably reduces transurethral resection (TUR) syndrome events slightly (risk ratio (RR) 0.17, 95% CI 0.09 to 0.30; participants = 6745; RCTs = 44; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 20 fewer TUR syndrome events per 1000 participants (95% CI 22 fewer to 17 fewer). Secondary outcomes BTURP may carry a similar risk of urinary incontinence at 12 months (RR 0.20, 95% CI 0.01 to 4.06; participants = 751; RCTs = 4; I² = 0%; low CoE, downgraded for study limitations and imprecision), compared to MTURP. This corresponds to four fewer events of urinary incontinence per 1000 participants (95% CI five fewer to 16 more). BTURP probably slightly reduces blood transfusions (RR 0.42, 95% CI 0.30 to 0.59; participants = 5727; RCTs = 38; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 28 fewer events of blood transfusion per 1000 participants (95% CI 34 fewer to 20 fewer). BTURP may result in similar rates of re-TURP (RR 1.02, 95% CI 0.44 to 2.40; participants = 652; RCTs = 6; I² = 0%; low CoE, downgraded for study limitations and imprecision). This corresponds to one more re-TURP per 1000 participants (95% CI 19 fewer to 48 more). Erectile function as measured by the International Index of Erectile Function score (IIEF-5) at 12 months on a scale from 5 to 25, with higher scores reflecting better erectile function, appears to be similar (MD 0.88, 95% CI -0.56 to 2.32; RCTs = 3; I² = 68%; moderate CoE, downgraded for study limitations) for the two approaches. BTURP and MTURP probably improve urological symptoms, both to a similar degree. BTURP probably reduces both TUR syndrome and postoperative blood transfusion slightly compared to MTURP. The impact of both procedures on erectile function is probably similar. The moderate certainty of evidence available for the primary outcomes of this review suggests that there is no need for further RCTs comparing BTURP and MTURP.
Seven RCTs were included in the review, totalling 1385 patients. Four of these trials met the criteria for good quality studies. For any antiplatelet agent there were reductions of a poor outcome (RR 0.79, 95% confidence interval (CI) 0.62 to 1.01) and secondary brain ischaemia (RR 0.79, 95% CI 0.56 to 1.22) and more intracranial haemorrhagic complications (RR 1.36, 95% CI 0.59 to 3.12), but none of these differences were statistically significant. There was no effect on case fatality (RR 1.01, 95% CI 0.74 to 1.37) or aneurysmal rebleeding (RR 0.98, 95% CI 0.78 to 1.38). For individual antiplatelet agents, only ticlopidine was associated with statistically significant fewer occurrences of a poor outcome (RR 0.37, 95% CI 95% CI 0.14 to 0.98) but this estimate was based on only one small RCT. This review shows a trend towards better outcome in patients treated with antiplatelet agents, possibly due to a reduction in secondary ischaemia. However, results were not statistically significant, thus no definite conclusions can be drawn. Also, antiplatelet agents could increase the risk of haemorrhagic complications. On the basis of the current evidence treatment with antiplatelet agents in order to prevent secondary ischaemia or poor outcome cannot be recommended.
Three RCTs, with a total of 154 participants were included in this review. None of the studies reported data on prostate cancer mortality. All of the included studies differed with respect to design, participants included and allocation of lycopene. This clinical heterogeneity limits the value on the pooled estimated of the meta-analyses. The methodological quality of two of the three included studies was assessed as posing a 'high' risk of bias. Meta-analysis indicated no statistical difference in PSA levels between men randomised to receive lycopene and the comparison group (MD (mean difference) -0.34, 95% CI (confidence interval) -2.01 to 1.32). Only one study reported incidence of prostate cancer (10% in the lycopene group versus 30% in control group). The level of lycopene was also not statistically different in men randomised to receive lycopene and the comparison group (MD 0.39 µg/mL (micrograms/millilitre), 95% CI -0.19 to 0.98). No other meta-analyses were possible since other outcomes assessed only had one study contributing data. Given that only three RCTs were included in this systematic review, and the high risk of bias in two of the three studies, there is insufficient evidence to either support, or refute, the use of lycopene for the prevention of prostate cancer. Similarly, there is no robust evidence from RCTs to identify the impact of lycopene consumption upon the incidence of prostate cancer, prostate symptoms, PSA levels or adverse events.
We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials. We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome. There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference. DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result. Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score). There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.
Only one study met the criteria of inclusion in the review. This study compared oral zinc with placebo. Oral zinc was administered in a dose of 5 mL twice daily from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon. Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) ≥ 15 mg/dL, was similar between groups (N = 286; risk ratio (RR) 0.94, 95% confidence interval (CI) 0.58 to 1.52). Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (N = 286; mean difference (MD) -0.20; 95% CI -1.03 to 0.63). Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (N = 286; MD -12.80, 95% CI -16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (N = 286; RR 1.20; 95% CI 0.66 to 2.18). Incidences of side effects like vomiting (N = 286; RR 0.65, 95% CI 0.19 to 2.25), diarrhoea (N = 286; RR 2.92, 95% CI 0.31 to 27.71), and rash (N = 286; RR 2.92, 95% CI 0.12 to 71.03) were found to be rare and statistically comparable between groups. The limited evidence available has not shown that oral zinc supplementation given to infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.
We identified 22 studies (3465 participants); 17 studies (3282 participants) compared statin with placebo or no treatment, and five studies (183 participants) compared two different statin regimens. From data generally derived from a single high-quality study, it was found that statins may reduce major cardiovascular events (1 study, 2102 participants: RR 0.84, CI 0.66 to 1.06), cardiovascular mortality (4 studies, 2322 participants: RR 0.68, CI 0.45 to 1.01), and fatal or non-fatal myocardial infarction (1 study, 2102 participants: RR 0.70, CI 0.48 to 1.01); although effect estimates lack precision and include the possibility of no effect. Statins had uncertain effects on all-cause mortality (6 studies, 2760 participants: RR 1.08, CI 0.63 to 1.83); fatal or non-fatal stroke (1 study, 2102 participants: RR 1.18, CI 0.85 to 1.63); creatine kinase elevation (3 studies, 2233 participants: RR 0.86, CI 0.39 to 1.89); liver enzyme elevation (4 studies, 608 participants: RR 0.62, CI 0.33 to 1.19); withdrawal due to adverse events (9 studies, 2810 participants: RR 0.89, CI 0.74 to 1.06); and cancer (1 study, 2094 participants: RR 0.94, CI 0.82 to 1.07). Statins significantly reduced serum total cholesterol (12 studies, 3070 participants: MD -42.43 mg/dL, CI -51.22 to -33.65); low-density lipoprotein cholesterol (11 studies, 3004 participants: MD -43.19 mg/dL, CI -52.59 to -33.78); serum triglycerides (11 studies, 3012 participants: MD -27.28 mg/dL, CI -34.29 to -20.27); and lowered high-density lipoprotein cholesterol (11 studies, 3005 participants: MD -5.69 mg/dL, CI -10.35 to -1.03). Statins had uncertain effects on kidney function: ESKD (6 studies, 2740 participants: RR 1.14, CI 0.94 to 1.37); proteinuria (2 studies, 136 participants: MD -0.04 g/24 h, CI -0.17 to 0.25); acute allograft rejection (4 studies, 582 participants: RR 0.88, CI 0.61 to 1.28); and GFR (1 study, 62 participants: MD -1.00 mL/min, CI -9.96 to 7.96). Due to heterogeneity in comparisons, data directly comparing differing statin regimens could not be meta-analysed. Evidence for statins in people who have had a kidney transplant were sparse and lower quality due to imprecise effect estimates and provided limited systematic evaluation of treatment harm. Statins may reduce cardiovascular events in kidney transplant recipients, although treatment effects are imprecise. Statin treatment has uncertain effects on overall mortality, stroke, kidney function, and toxicity outcomes in kidney transplant recipients. Additional studies would improve our confidence in the treatment benefits and harms of statins on cardiovascular events in this clinical setting.
We included three trials (2804 children), comparing cuffed with uncuffed ETTs. We rated the risks of bias in all three trials as high. Outcome data were limited. The largest trial was supported by Microcuff GmbH, who provided the cuffed tubes used. The other two trials were small, and should be interpreted with caution. Based on the GRADE approach, we rated the quality of evidence as low to very low. Two trials comparing cuffed versus uncuffed ETTs found no difference between the groups for postextubation stridor (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.65 to 1.33; 2734 children; quality of evidence very low). However, those two trials demonstrated a statistically significantly lower rate of endotracheal tube exchange in the cuffed ETT group (RR 0.07, 95% CI 0.05 to 0.10; 2734 children; quality of evidence very low). One trial with 70 participants found that costs per case were lower in the cuffed ETT group (mean difference (MD) EUR 19.0 lower; 95% CI 24.23 to 13.77 lower; quality of evidence low), since the higher cost of the cuffed tubes may be offset by the savings made with anaesthetic gases. No clear evidence emerged to suggest any difference between cuffed and uncuffed tubes for outcomes such as the need to treat postextubation stridor with tracheal re-intubation (RR 1.85, 95% CI 0.17 to 19.76; 115 children; 2 trials; quality of evidence very low), epinephrine (RR 0.70, 95% CI 0.38 to 1.28; 115 children; 2 trials; quality of evidence very low) or corticosteroid (RR 0.87, 95% CI 0.51 to 1.49; 102 children; 1 trial; quality of evidence very low), or need for intensive care unit (ICU) admission to treat postextubation stridor (RR 2.77, 95% CI 0.30 to 25.78; 102 children; 1 trial; quality of evidence very low). None of the trials included in this review evaluated the ability to deliver appropriate tidal volume. Implications for practice We are unable to draw definitive conclusions about the comparative effects of cuffed or non-cuffed endotracheal tubes in children undergoing general anaesthesia. Our confidence is limited by risks of bias, imprecision and indirectness. The lower requirement for exchange of tubes with cuffed ETTs was very low-quality evidence, and the requirement for less medical gas used and consequent lower cost was low-quality evidence. In some cases, tracheal re-intubation is required to guarantee an open airway when adequate oxygenation is difficult after removal of the tube, for a variety of reasons including stridor, muscle weakness or obstruction. No data were available to permit evaluation of whether appropriate tidal volumes were delivered. Implications for research Large randomized controlled trials of high methodological quality should be conducted to help clarify the risks and benefits of cuffed ETTs for children. Such trials should investigate the capacity to deliver appropriate tidal volume. Future trials should also address cost effectiveness and respiratory complications. Such studies should correlate the age of the child with the duration of intubation, and with possible complications. Studies should also be conducted in newborn babies. Future research should be conducted to compare the effects of the different types or brands of cuffed tubes used worldwide. Finally, trials should be designed to perform more accurate assessments and to diagnose the complications encountered with cuffed compared to uncuffed ETTs.
There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials which met our inclusion criteria, three comparing NicVAX to placebo and one comparing NIC002 (formerly NicQbeta) to placebo. All were smoking cessation trials conducted by pharmaceutical companies as part of the drug development process, and all trials were judged to be at high or unclear risk of bias in at least one domain. Overall, 2642 smokers participated in the included studies in this review. None of the four included studies detected a statistically significant difference in long-term cessation between participants receiving vaccine and those receiving placebo. The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) in the trial of NIC002 and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups. In the two studies with full results available, post hoc analyses detected higher cessation rates in participants with higher levels of nicotine antibodies, but these findings are not readily generalisable. The two studies with full results showed nicotine vaccines to be well tolerated, with the majority of adverse events classified as mild or moderate. In the study of NIC002, participants receiving the vaccine were more likely to report mild to moderate adverse events, most commonly flu-like symptoms, whereas in the study of NicVAX there was no significant difference between the two arms. Information on adverse events was not available for the large Phase III trials of NicVAX. Vaccine candidates are likely to undergo significant changes before becoming available to the general public, and those included in this review may not be the first to reach market; this limits the external validity of the results reported in this review in terms of both effectiveness and tolerability. There is currently no evidence that nicotine vaccines enhance long-term smoking cessation. Rates of serious adverse events recorded in the two trials with full data available were low, and the majority of adverse events reported were at mild to moderate levels. The evidence available suggests nicotine vaccines do not induce compensatory smoking or affect withdrawal symptoms. No nicotine vaccines are currently licensed for use in any country but a number are under development. Further trials of nicotine vaccines are needed, comparing vaccines with placebo for smoking cessation. Further trials are also needed to explore the potential of nicotine vaccines to prevent relapse. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported.
We included nine industry-sponsored randomised controlled trials (3327 participants) in the review. Seven trials compared pregabalin to placebo. For the primary outcome, participants randomised to pregabalin were significantly more likely to attain a 50% or greater reduction in seizure frequency compared to placebo (RR 2.28, 95% CI 1.52 to 3.42, 7 trials, 2193 participants, low-certainty evidence). The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 1.99, 95% CI 1.74 to 2.28), indicating a dose-response relationship. Pregabalin was significantly associated with seizure freedom (RR 3.94, 95% CI 1.50 to 10.37, 4 trials, 1125 participants, moderate-certainty evidence). Participants were significantly more likely to withdraw from pregabalin treatment than placebo for any reason (RR 1.35, 95% CI 1.11 to 1.65, 7 trials, 2193 participants, moderate-certainty evidence) and for adverse effects (RR 2.65, 95% CI 1.88 to 3.74, 7 trials, 2193 participants, moderate-certainty evidence). Three trials compared pregabalin to three active-control drugs: lamotrigine, levetiracetam, and gabapentin. Participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency than those allocated to lamotrigine (RR 1.47, 95% CI 1.03 to 2.12, 1 trial, 293 participants) but not those allocated to levetiracetam (RR 0.94, 95% CI 0.80 to 1.11, 1 trial, 509 participants) or gabapentin (RR 0.96, 95% CI 0.82 to 1.12, 1 trial, 484 participants). We found no significant differences between pregabalin and lamotrigine (RR 1.39, 95% CI 0.40 to 4.83) for seizure freedom, however, significantly fewer participants achieved seizure freedom with add-on pregabalin compared to levetiracetam (RR 0.50, 95% CI 0.30 to 0.85). No data were reported for this outcome for pregabalin versus gabapentin. We found no significant differences between pregabalin and lamotrigine (RR 1.07, 95% CI 0.75 to 1.52), levetiracetam (RR 1.03, 95% CI 0.71 to 1.49), or gabapentin (RR 0.78, 95% CI 0.57 to 1.07) for treatment withdrawal due to any reason or due to adverse effects (pregabalin versus lamotrigine: RR 0.89, 95% CI 0.53 to 1.48; versus levetiracetam: RR 1.29, 95% CI 0.66 to 2.54; versus gabapentin: RR 1.07, 95% CI 0.54 to 2.11). Ataxia, dizziness, somnolence, weight gain, and fatigue were significantly associated with pregabalin. We rated the overall risk of bias in the included studies as low or unclear due to the possibility of publication bias and lack of methodological details provided. We rated the certainty of the evidence as very low to moderate using the GRADE approach. Pregabalin, when used as an add-on drug for treatment-resistant focal epilepsy, is significantly more effective than placebo at producing a 50% or greater seizure reduction and seizure freedom. Results demonstrated efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses, however issues with tolerability were noted at higher doses. The trials included in this review were of short duration, and longer-term trials are needed to inform clinical decision making.
There were no new included studies for this update. Eight studies (3118 participants) were included in this review. We found no evidence for difference in overall mortality between the groups treated with heparin and placebo (risk ratio (RR) = 0.84, 95% confidence interval (CI) 0.36 to 1.98). Heparins compared with placebo, reduced the occurrence of myocardial infarction in patients with unstable angina and NSTEMI (RR = 0.40, 95% CI 0.25 to 0.63, number needed to benefit (NNTB) = 33). There was a trend towards more major bleeds in the heparin studies compared to control studies (RR = 2.05, 95% CI 0.91 to 4.60). From a limited data set, there appeared to be no difference between patients treated with heparins compared to control in the occurrence of thrombocytopenia (RR = 0.20, 95% CI 0.01 to 4.24). Assessment of overall risk of bias in these studies was limited as most of the studies did not give sufficient detail to allow assessment of potential risk of bias. Compared with placebo, patients treated with heparins had a similar risk of mortality, revascularization, recurrent angina, and thrombocytopenia. However, those treated with heparins had a decreased risk of myocardial infarction and a higher incidence of minor bleeding. Overall, the evidence assessed in this review was classified as low quality according to the GRADE approach. The results presented in this review must therefore be interpreted with caution.
We included 38 trials that involved a total of 7924 children; seven trials were new for this update (1693 participants). Fifteen trials evaluated the effects of resin-based sealant versus no sealant (3620 participants in 14 studies plus 575 tooth pairs in one study); three trials with evaluated glass ionomer sealant versus no sealant (905 participants); and 24 trials evaluated one type of sealant versus another (4146 participants). Children were aged from 5 to 16 years. Trials rarely reported background exposure to fluoride of trial participants or baseline caries prevalence. Resin-based sealant versus no sealant: second-, third- and fourth-generation resin-based sealants prevented caries in first permanent molars in children aged 5 to 10 years (at 24 months follow-up: OR 0.12, 95% CI 0.08 to 0.19, 7 trials (5 published in the 1970s; 2 in the 2010s), 1548 children randomised, 1322 children evaluated; moderate-quality evidence). If we were to assume that 16% of the control tooth surfaces were decayed during 24 months of follow-up (160 carious teeth per 1000), then applying a resin-based sealant would reduce the proportion of carious surfaces to 5.2% (95% CI 3.13% to 7.37%). Similarly, assuming that 40% of control tooth surfaces were decayed (400 carious teeth per 1000), then applying a resin-based sealant would reduce the proportion of carious surfaces to 6.25% (95% CI 3.84% to 9.63%). If 70% of control tooth surfaces were decayed, there would be 19% decayed surfaces in the sealant group (95% CI 12.3% to 27.2%). This caries-preventive effect was maintained at longer follow-up but evidence quality and quantity was reduced (e.g. at 48 to 54 months of follow-up: OR 0.21, 95% CI 0.16 to 0.28, 4 trials, 482 children evaluated; RR 0.24, 95% CI 0.12 to 0.45, 203 children evaluated). Although studies were generally well conducted, we assessed blinding of outcome assessment for caries at high risk of bias for all trials (blinding of outcome assessment is not possible in sealant studies because outcome assessors can see and identify sealant). Glass ionomer sealant versus no sealant: was evaluated by three studies. Results at 24 months were inconclusive (very low-quality evidence). One sealant versus another sealant: the relative effectiveness of different types of sealants is unknown (very low-quality evidence). We included 24 trials that directly compared two different sealant materials. Comparisons varied in terms of types of sealant assessed, outcome measures chosen and duration of follow-up. Adverse events: only four trials assessed adverse events. No adverse events were reported. Resin-based sealants applied on occlusal surfaces of permanent molars are effective for preventing caries in children and adolescents. Our review found moderate-quality evidence that resin-based sealants reduced caries by between 11% and 51% compared to no sealant, when measured at 24 months. Similar benefit was seen at timepoints up to 48 months; after longer follow-up, the quantity and quality of evidence was reduced. There was insufficient evidence to judge the effectiveness of glass ionomer sealant or the relative effectiveness of different types of sealants. Information on adverse effects was limited but none occurred where this was reported. Further research with long follow-up is needed.
This review includes 15 trials with a total of 791 participants that have evaluated Pycnogenol® for the treatment of seven different chronic disorders. These included asthma (two studies; N = 86), attention deficit hyperactivity disorder (one study; N = 61), chronic venous insufficiency (two studies; N = 60), diabetes mellitus (four studies; N = 201), erectile dysfunction (one study; N = 21), hypertension (two studies; N = 69) and osteoarthritis (three studies; N = 293). Two of the studies were conducted exclusively in children; the others involved adults. Due to small sample size, limited numbers of trials per condition, variation in outcomes evaluated and outcome measures used, as well as the risk of bias in the included studies, no definitive conclusions regarding the efficacy or safety of Pycnogenol® are possible. Current evidence is insufficient to support Pycnogenol® use for the treatment of any chronic disorder. Well-designed, adequately powered trials are needed to establish the value of this treatment.
We included three trials, involving 496 participants, and defined four trials as waiting assessment. All three included trials were of edaravone plus another treatment compared with the other treatment alone. The dose of edaravone injections in the three trials was the same at 60 mg per day. The course of treatment in all three trials is 14 days. None of the included trials reported the pre-specified primary outcome of death or dependency defined using the modified Rankin scale during the follow-up period. The three trials evaluated the effect of edaravone at different times and using different methods. All three trials reported adverse events; there were no differences between the treatment group and the control group. Overall, edaravone appeared to increase the proportion of participants with marked neurological improvement compared with the control group, and the difference was significant (risk ratio (RR) 1.99, 95% confidence interval (CI) 1.60 to 2.49). The risk of bias in the included trials was moderate and the sample was small. Hence, although the data in this review show an effective treatment trend of edaravone for acute ischaemic stroke, further large, high-quality trials are required to confirm this trend.
Three randomised controlled trials and one quasi-randomised controlled trial were included. These involved a total of 292 participants with ankle fractures. All studies were at high risk of bias from lack of blinding. Additionally, loss to follow-up or inappropriate exclusion of participants put two trials at high risk of attrition bias. The trials used different and incompatible outcome measures for assessing function and pain. Only limited meta-analysis was possible for early treatment failure, some adverse events and radiological signs of arthritis. One trial, following up 92 of 111 randomised participants, found no statistically significant differences between surgery and conservative treatment in patient-reported symptoms (self assessed ankle "troubles": 11/43 versus 14/49; risk ratio (RR) 0.90, 95% CI 0.46 to 1.76) or walking difficulties at seven years follow-up. One trial, reporting data for 31 of 43 randomised participants, found a statistically significantly better mean Olerud score in the surgically treated group but no difference between the two groups in pain scores after a mean follow-up of 27 months. A third trial, reporting data for 49 of 96 randomised participants at 3.5 years follow-up, reported no difference between the two groups in a non-validated clinical score. Early treatment failure, generally reflecting the failure of closed reduction (criteria not reported in two trials) probably or explicitly leading to surgery in patients allocated conservative treatment, was significantly higher in the conservative treatment group (2/116 versus 19/129; RR 0.18, 95% CI 0.06 to 0.54). Otherwise, there were no statistically significant differences between the two groups in any of the reported complications. Pooled results from two trials of participants with radiological signs of osteoarthritis at averages of 3.5 and 7.0 years follow-up showed no between-group differences (44/66 versus 50/75; RR 1.05, 95% CI 0.83 to 1.31). There is currently insufficient evidence to conclude whether surgical or conservative treatment produces superior long-term outcomes for ankle fractures in adults. The identification of several ongoing randomised trials means that better evidence to inform this question is likely to be available in future.
We included two RCTs, enrolling a total of 102 participants. Both trials evaluated the effect of DBS on the internal globus pallidus nucleus, and assessed outcomes after three and six months of stimulation. One of the studies included participants with generalised and segmental dystonia; the other included participants with focal (cervical) dystonia. We assessed both studies at high risk for performance and for-profit bias. One study was retrospectively registered with a clinical trial register, we judged the second at high risk of detection bias. Low-quality evidence suggests that DBS of the internal globus pallidus nucleus may improve overall cervical dystonia-related symptoms (mean difference (MD) 9.8 units, 95% CI 3.52 to 16.08 units; 1 RCT, 59 participants), cervical dystonia-related functional capacity (MD 3.8 units, 95% CI 1.41 to 6.19; 1 RCT, 61 participants), and mood at three months (MD 3.1 units, 95% CI 0.73 to 5.47; 1 RCT, 61 participants). Low-quality evidence suggests that In people with cervical dystonia, DBS may slightly improve the overall clinical status (MD 2.3 units, 95% CI 1.15 to 3.45; 1 RCT, 61 participants). We are uncertain whether DBS improves quality of life in cervical dystonia (MD 3 units, 95% CI -7.71 to 13.71; 1 RCT, 57 participants; very low-quality evidence), or emotional state (MD 2.4 units, 95% CI -6.2 to 11.00; 1 RCT, 56 participants; very low-quality evidence). Low-quality evidence suggests that DBS of the internal globus pallidus nucleus may improve generalised or segmental dystonia-related symptoms (MD 14.4 units, 95% CI 8.0 to 20.8; 1 RCT, 40 participants), overall clinical status (MD 3.5 units, 95% CI 2.33 to 4.67; 1 RCT, 37 participants), physical functioning-related quality of life (MD 6.3 units, 95% CI 1.06 to 11.54; 1 RCT, 33 participants), and overall dystonia-related functional capacity at three months (MD 3.1 units, 95% CI 1.71 to 4.48; 1 RCT, 39 participants). We are uncertain whether DBS improves physical functioning-related quality of life (MD 5.0 units, 95% CI -2.14 to 12.14, 1 RCT, 33 participants; very low-quality evidence), or mental health-related quality of life (MD -4.6 units, 95% CI -11.26 to 2.06; 1 RCT, 30 participants; very low-quality evidence) in generalised or segmental dystonia. We pooled outcomes related to safety and tolerability, since both trials used the same intervention and comparison. We found very low-quality evidence of inconclusive results for risk of adverse events (relative risk (RR) 1.58, 95% 0.98 to 2.54; 2 RCTs, 102 participants), and tolerability (RR 1.86, 95% CI 0.16 to 21.57; 2 RCTs,102 participants). DBS of the internal globus pallidus nucleus may reduce symptom severity and improve functional capacity in adults with cervical, segmental or generalised moderate to severe dystonia (low-quality evidence), and may improve quality of life in adults with generalised or segmental dystonia (low-quality evidence). We are uncertain whether the procedure improves quality of life in cervical dystonia (very low-quality evidence). We are also uncertain about the safety and tolerability of the procedure in adults with either cervical and generalised, or segmental dystonia (very-low quality evidence). We could draw no conclusions for other populations with dystonia (i.e. children and adolescents, and adults with other types of dystonia), or for other DBS protocols (i.e. other target nuclei or stimulation paradigms). Further research is needed to establish the long-term efficacy and safety of DBS of the internal globus pallidus nucleus.
Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias. One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months. Combining the trial results suggests that patients with PFAPA likely experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution) (moderate-certainty evidence). Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Surgery probably results in a large overall reduction in the average number of episodes over the total length of follow-up (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years (moderate-certainty evidence). Surgery also likely reduces severity, as indicated by the length of PFAPA symptoms during these episodes. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group (moderate-certainty evidence). The evidence suggests that the proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92) (low-certainty evidence). Other outcomes such as absence from school and quality of life were not measured or reported. The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate certainty (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.
Of 2332 publications obtained through the search strategy, seven studies met the inclusion criteria; one study was ongoing and six studies of 435 participants were eligible for inclusion in the updated review. Data show a significant difference in immediate success rates of procedures favouring tube drainage over simple aspiration for management of primary spontaneous pneumothorax (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69 to 0.89; 435 participants, 6 studies; moderate-quality evidence). Duration of hospitalization however was significantly less for patients treated by simple aspiration (mean difference (MD) -1.66, 95% CI -2.28 to -1.04; 387 participants, 5 studies; moderate-quality evidence). A narrative synthesis of evidence revealed that simple aspiration led to fewer adverse events (245 participants, 3 studies; low-quality evidence), but data suggest no differences between groups in terms of one-year success rate (RR 1.07, 95% CI 0.96 to 1.18; 318 participants, 4 studies; moderate-quality evidence), hospitalization rate (RR 0.60, 95% CI 0.25 to 1.47; 245 participants, 3 studies; very low-quality evidence), and patient satisfaction (median between-group difference of 0.5 on a scale from 1 to 10; 48 participants, 1 study; low-quality evidence). No studies provided data on cost-effectiveness. Available trials showed low to moderate-quality evidence that intercostal tube drainage produced higher rates of immediate success, while simple aspiration resulted in a shorter duration of hospitalization. Although adverse events were reported more commonly for patients treated with tube drainage, the low quality of the evidence warrants caution in interpreting these findings. Similarly, although this review observed no differences between groups when early failure rate, one-year success rate, or hospital admission rate was evaluated, this too needs to be put into the perspective of the quality of evidence, specifically, for evidence of very low and low quality for hospitalization rate and patient satisfaction, respectively. Future adequately powered research is needed to strengthen the evidence presented in this review.
Five trials that randomly assigned 144 participants with overt hepatic encephalopathy that were published during 1979 to 1982 were included. Three trials assessed levodopa, and two trials assessed bromocriptine. The mean daily dose was 4 grams for levodopa and 15 grams for bromocriptine. The median duration of treatment was 14 days (range seven to 56 days). None of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy in the primary analyses (15/80 (19%) versus 14/80 (18%); odds ratio (OR) 2.99, 95% confidence interval (CI) 0.09 to 100.55; two trials) or when paired data from cross-over trials were included (OR 1.04, 95% CI 0.75 to 1.43). Clear evidence of intertrial heterogeneity was identified both in the primary analysis (I2 = 65%) and when paired data from cross-over trials were included (I2 = 40%). Dopamine agents had no beneficial or harmful effect on mortality (42/144 (29%) versus 38/144 (26%); OR 1.11, 95% CI 0.35 to 3.54; five trials). Trial sequential analyses demonstrated that we lacked information to refute or recommend the interventions for all outcomes. Dopamine agonists did not seem to increase the risk of adverse events. This review found no evidence to recommend or refute the use of dopamine agents for hepatic encephalopathy. More randomised placebo-controlled clinical trials without risks of systematic errors and risks of random errors seem necessary to permit firm decisions on dopamine agents for patients with hepatic encephalopathy.
We identified 14 studies (1390 participants), nine enrolled adults without a known access stenosis (primary prophylaxis; three studies including people using fistulas) and five enrolled adults with a documented stenosis in a non-dysfunctional access (secondary prophylaxis; three studies in people using fistulas). Study follow-up ranged from 6 to 38 months, and study size ranged from 58 to 189 participants. In low- to moderate-quality evidence (based on GRADE criteria) in adults treated with haemodialysis, relative to no surveillance and deferred correction, surveillance with pre-emptive correction of an AV stenosis reduced the risk of thrombosis (RR 0.79, 95% CI 0.65 to 0.97; I² = 30%; 18 study comparisons, 1212 participants), and probably improves the longevity of AV access (RR 0.80, 95% CI 0.64 to 0.99; I² = 0%; 11 study comparisons, 972 participants). In analyses subgrouped by access type, pre-emptive stenosis correction did not reduce the risk of thrombosis (RR 0.95, 95% CI 0.8 to 1.12; I² = 0%; 11 study comparisons, 697 participants) or access loss in grafts (RR 0.87, 95% CI 0.69 to 1.11; I² = 0%; 7 study comparisons; 662 participants), but did reduce the risk of thrombosis (RR 0.5, 95% CI 0.35 to 0.71; I² = 0%; 7 study comparisons, 515 participants) and the risk of access loss in fistulas (RR 0.5, 95% CI 0.29 to 0.86; I² = 0%; 4 studies; 310 participants). Three of the four studies reporting access loss data in fistulas (199 participants) were conducted in the same centre. Insufficient data were available to assess whether benefits vary by prophylaxis aim in fistulas (i.e. primary and secondary prophylaxis). Although the magnitude of the effects of pre-emptive stenosis correction was considerable for patient-centred outcomes, results were either heterogeneous or imprecise. While pre-emptive stenosis correction may reduce the rates of hospitalisation (IRR 0.54, 95% CI 0.31 to 0.93; I² = 67%; 4 study comparisons, 219 participants) and use of catheters (IRR 0.58, 95% CI 0.35 to 0.98; I² = 53%; 6 study comparisons, 394 participants), it may also increase the rates of diagnostic procedures (IRR 1.78, 95% CI 1.18 to 2.67; I² = 62%; 7 study comparisons, 539 participants), infection (IRR 1.74, 95% CI 0.78 to 3.91; I² = 0%; 3 studies, 248 participants) and mortality (RR 1.38, 95% CI 0.91 to 2.11; I² = 0%; 5 studies, 386 participants). In general, risk of bias was high or unclear in most studies for many domains we assessed. Four studies were published after 2005 and only one had evidence of registration within a trial registry. No study reported information on authorship and/or involvement of the study sponsor in data collection, analysis, and interpretation. Pre-emptive correction of a newly identified or known stenosis in a functional AV access does not improve access longevity. Although pre-emptive stenosis correction may be promising in fistulas existing evidence is insufficient to guide clinical practice and health policy. While pre-emptive stenosis correction may reduce the risk of hospitalisation, this benefit is uncertain whereas there may be a substantial increase (i.e. 80%) in the use of access-related procedures and procedure-related adverse events (e.g. infection, mortality). The net effects of pre-emptive correction on harms and resource use are thus unclear.
We included seven trials randomising 556 patients. The comparisons include CUSA (cavitron ultrasound surgical aspirator) versus clamp-crush (two trials); radiofrequency dissecting sealer (RFDS) versus clamp-crush (two trials); sharp dissection versus clamp-crush technique (one trial); and hydrojet versus CUSA (one trial). One trial compared CUSA, RFDS, hydrojet, and clamp-crush technique. The infective complications and transection blood loss were greater in the RFDS than clamp-crush. There was no difference in the blood transfusion requirements, intensive therapy unit (ITU) stay, or hospital stay in this comparison. There was no significant differences in the mortality, morbidity, markers of liver parenchymal injury or liver dysfunction, ITU, or hospital stay in the other comparisons. The blood transfusion requirements were lower in the clamp-crush technique than CUSA and hydrojet. There was no difference in the transfusion requirements of clamp-crush technique and sharp dissection. Clamp-crush technique is quicker than CUSA, hydrojet, and RFDS. The transection speed of sharp dissection and clamp-crush technique was not compared. There was no clinically or statistically significant difference in the operating time between sharp dissection and clamp-crush techniques. Clamp-crush technique is two to six times cheaper than the other methods depending upon the number of surgeries performed each year. Clamp-crush technique is advocated as the method of choice in liver parenchymal transection because it avoids special equipment, whereas the newer methods do not seem to offer any benefit in decreasing the morbidity or transfusion requirement.
This review now includes 73 randomised studies, with 4870 participants. Overall, the quality of the evidence is low to very low. Compared with placebo, use of fluphenazine decanoate does not result in any significant differences in death, nor does it reduce relapse over six months to one year, but one longer-term study found that relapse was significantly reduced in the fluphenazine arm (n = 54, 1 RCT, RR 0.35, CI 0.19 to 0.64, very low quality evidence). A very similar number of people left the medium-term studies (six months to one year) early in the fluphenazine decanoate (24%) and placebo (19%) groups, however, a two-year study significantly favoured fluphenazine decanoate (n = 54, 1 RCT, RR 0.47, CI 0.23 to 0.96, very low quality evidence). No significant differences were found in mental state measured on the Brief Psychiatric Rating Scale (BPRS) or in extrapyramidal adverse effects, although these outcomes were only reported in one small study each. No study comparing fluphenazine decanoate with placebo reported clinically significant changes in global state or hospital admissions. Fluphenazine decanoate does not reduce relapse more than oral neuroleptics in the medium term (n = 419, 6 RCTs, RR 1.46 CI 0.75 to 2.83, very low quality evidence). A small study found no difference in clinically significant changes in global state. No difference in the number of participants leaving the study early was found between fluphenazine decanoate (17%) and oral neuroleptics (18%), and no significant differences were found in mental state measured on the BPRS. Extrapyramidal adverse effects were significantly less for people receiving fluphenazine decanoate compared with oral neuroleptics (n = 259, 3 RCTs, RR 0.47 CI 0.24 to 0.91, very low quality evidence). No study comparing fluphenazine decanoate with oral neuroleptics reported death or hospital admissions. No significant difference in relapse rates in the medium term between fluphenazine decanoate and fluphenazine enanthate was found (n = 49, 1 RCT, RR 2.43, CI 0.71 to 8.32, very low quality evidence), immediate- and short-term studies were also equivocal. One small study reported the number of participants leaving the study early (29% versus 12%) and mental state measured on the BPRS and found no significant difference for either outcome. No significant difference was found in extrapyramidal adverse effects between fluphenazine decanoate and fluphenazine enanthate. No study comparing fluphenazine decanoate with fluphenazine enanthate reported death, clinically significant changes in global state or hospital admissions. There are more data for fluphenazine decanoate than for the enanthate ester. Both are effective antipsychotic preparations. Fluphenazine decanoate produced fewer movement disorder effects than other oral antipsychotics but data were of low quality, and overall, adverse effect data were equivocal. In the context of trials, there is little advantage of these depots over oral medications in terms of compliance but this is unlikely to be applicable to everyday clinical practice.
We included five trials in the review, with 190 participants in total. We did not identify any new studies for inclusion from the updated search in January 2016. Three trials were related to dental treatment, i.e. restorative and extraction treatments; two trials related to orthodontic treatment. We did not judge any of the included trials to be at low risk of bias. Three of the included trials compared paracetamol with placebo, only two of which provided data for analysis (presence or absence of parent-reported postoperative pain behaviour). Meta-analysis of the two trials gave arisk ratio (RR) for postoperative pain of 0.81 (95% confidence interval (CI) 0.53 to 1.22; two trials, 100 participants; P = 0.31), which showed no evidence of a benefit in taking paracetamol preoperatively (52% reporting pain in the placebo group versus 42% in the paracetamol group). One of these trials was at unclear risk of bias, and the other was at high risk. The quality of the evidence is low. One study did not have any adverse events; the other two trials did not mention adverse events. Four of the included trials compared ibuprofen with placebo. Three of these trials provided useable data. One trial reported no statistical difference in postoperative pain experienced by the ibuprofen group and the control group for children undergoing dental treatment. We pooled the data from the other two trials, which included participants who were having orthodontic separator replacement without a general anaesthetic, to determine the effect of preoperative ibuprofen on the severity of postoperative pain. There was a statistically significant mean difference in severity of postoperative pain of -13.44 (95% CI -23.01 to -3.88; two trials, 85 participants; P = 0.006) on a visual analogue scale (0 to 100), which indicated a probable benefit for preoperative ibuprofen before this orthodontic procedure. However, both trials were at high risk of bias. The quality of the evidence is low. Only one of the trials reported adverse events (one participant from the ibuprofen group and one from the placebo group reporting a lip or cheek biting injury). From the available evidence, we cannot determine whether or not preoperative analgesics are of benefit in paediatric dentistry for procedures under local anaesthetic. There is probably a benefit in using preoperative analgesics prior to orthodontic separator placement. The quality of the evidence is low. Further randomised clinical trials should be completed with appropriate sample sizes and well defined outcome measures.
We identified a single cross-over RCT (enrolling 9 participants) that compared home haemodialysis (long hours: 6 to 8 hours, 3 times/week) with in-centre haemodialysis (short hours: 3.5 to 4.5 hours, 3 times/weeks) for 8 weeks in prevalent home haemodialysis patients. Outcome data were limited and not available for the end of the first phase of treatment in this cross-over study which was at risk of bias due to differences in dialysate composition between the two treatment comparisons. Overall, home haemodialysis reduced 24 hour ambulatory blood pressure and improved uraemic symptoms, but increased treatment-related burden of disease and interference in social activities. Insufficient data were available for mortality, hospitalisation or dialysis vascular access complications or treatment durability. Insufficient randomised data were available to determine the effects of home haemodialysis on survival, hospitalisation, and quality of life compared with in-centre haemodialysis. Given the consistently observed benefits of home haemodialysis on quality of life and survival in uncontrolled studies, and the low prevalence of home haemodialysis globally, randomised studies evaluating home haemodialysis would help inform clinical practice and policy.
Ten RCTs were included. One trial reported near final height in girls and found that girls treated with GH were 7.5 cm taller than untreated controls (GH group, 155.3 cm ± 6.4; control, 147.8 cm ± 2.6; P = 0.003); another trial which reported adult height standard deviation score found that children treated with GH were 3.7 cm taller than children in a placebo-treated group (95% confidence intervals 0.03 to 1.10; P < 0.04). The other trials reported short term outcomes. Results suggest that short-term height gains can range from none to approximately 0.7 SD over one year. One study reported health related quality of life and showed no significant improvement in GH treated children compared with those in the control group, whilst another found no significant evidence that GH treatment impacts psychological adaptation or self-perception in children with ISS. No serious adverse effects of treatment were reported. GH therapy can increase short-term growth and improve (near) final height. Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature. Large, multicentre RCTs are required which should focus on final height and address quality of life and cost issues.
Twelve studies involving 27,482 participants met the inclusion criteria. Interventions were either mandatory or voluntary and included up to 10 discrete components in varying combinations. All but one study took place in North America. Although we searched for parental health outcomes, the vast majority of the sample in all included studies were female. Therefore, we describe adult health outcomes as 'maternal' throughout the results section. We downgraded the quality of all evidence at least one level because outcome assessors were not blinded. Follow-up ranged from 18 months to six years. The effects of welfare-to-work interventions on health were generally positive but of a magnitude unlikely to have any tangible effects. At T1 there was moderate-quality evidence of a very small negative impact on maternal mental health (standardised mean difference (SMD) 0.07, 95% Confidence Interval (CI) 0.00 to 0.14; N = 3352; studies = 2)); at T2, moderate-quality evidence of no effect (SMD 0.00, 95% CI 0.05 to 0.05; N = 7091; studies = 3); and at T3, low-quality evidence of a very small positive effect (SMD −0.07, 95% CI −0.15 to 0.00; N = 8873; studies = 4). There was evidence of very small positive effects on maternal physical health at T1 (risk ratio (RR) 0.85, 95% CI 0.54 to 1.36; N = 311; 1 study, low quality) and T2 (RR 1.06, 95% CI 0.95 to 1.18; N = 2551; 2 studies, moderate quality), and of a very small negative effect at T3 (RR 0.97, 95% CI 0.91 to 1.04; N = 1854; 1 study, low quality). At T1, there was moderate-quality evidence of a very small negative impact on child mental health (SMD 0.01, 95% CI −0.06 to 0.09; N = 2762; studies = 1); at T2, of a very small positive effect (SMD −0.04, 95% CI −0.08 to 0.01; N = 7560; studies = 5), and at T3, there was low-quality evidence of a very small positive effect (SMD −0.05, 95% CI −0.16 to 0.05; N = 3643; studies = 3). Moderate-quality evidence for effects on child physical health showed a very small negative effect at T1 (SMD −0.05, 95% CI −0.12 to 0.03; N = 2762; studies = 1), a very small positive effect at T2 (SMD 0.07, 95% CI 0.01 to 0.12; N = 7195; studies = 3), and a very small positive effect at T3 (SMD 0.01, 95% CI −0.04 to 0.06; N = 8083; studies = 5). There was some evidence of larger negative effects on health, but this was of low or very low quality. There were small positive effects on employment and income at 18 to 48 months (moderate-quality evidence), but these were largely absent at 49 to 72 months (very low to moderate-quality evidence), often due to control group members moving into work independently. Since the majority of the studies were conducted in North America before the year 2000, generalisabilty may be limited. However, all study sites were similar in that they were high-income countries with developed social welfare systems. The effects of WtW on health are largely of a magnitude that is unlikely to have tangible impacts. Since income and employment are hypothesised to mediate effects on health, it is possible that these negligible health impacts result from the small effects on economic outcomes. Even where employment and income were higher for the lone parents in WtW, poverty was still high for the majority of the lone parents in many of the studies. Perhaps because of this, depression also remained very high for lone parents whether they were in WtW or not. There is a lack of robust evidence on the health effects of WtW for lone parents outside North America.
For early mortality where there was evidence of heterogeneity, a fixed-effect meta-analysis showed no difference between magensium and placebo groups (OR 0.99, 95%CI 0.94 to 1.04), while a random-effects meta-analysis showed a significant reduction comparing magnesium with placebo (OR 0.66, 95% CI 0.53 to 0.82). Stratification by timing of treatment (< 6 hrs, 6+ hrs) reduced heterogeneity, and in both fixed-effect and random-effects models no significant effect of magnesium was found. In stratified analyses, early mortality was reduced for patients not treated with thrombolysis (OR=0.73, 95% CI 0.56 to 0.94 by random-effects model) and for those treated with less than 75 mmol of magnesium (OR=0.59, 95% CI 0.49 to 0.70) in the magnesium compared with placebo groups. Meta-analysis for the secondary outcomes where there was no evidence of heterogeneity showed reductions in the odds of ventricular fibrillation (OR=0.88, 95% CI 0.81 to 0.96), but increases in the odds of profound hypotension (OR=1.13, 95% CI 1.09 to 1.19) and bradycardia (OR=1.49, 95% CI 1.26 to 1.77) comparing magnesium with placebo. No difference was observed for heart block (OR=1.05, 95% CI 0.97-1.14). For those outcomes where there was evidence of heterogeneity, meta-analysis with both fixed-effect and random-effects models showed that magnesium could decrease ventricular tachycardia (OR=0.45, 95% CI 0.31 to 0.66 by fixed-effect model; OR=0.40, 95% CI 0.19 to 0.84 by random-effects model) and severe arrhythmia needing treatment or Lown 2-5 (OR=0.72, 95% CI 0.60 to 0.85 by fixed-effect model; OR=0.51, 95% CI 0.33 to 0.79 by random-effects model) compared with placebo. There was no difference on the effect of cardiogenic shock between the two groups. Owing to the likelihood of publication bias and marked heterogeneity of treatment effects, it is essential that the findings are interpreted cautiously. From the evidence reviewed here, we consider that: (1) it is unlikely that magnesium is beneficial in reducing mortality both in patients treated early and in patients treated late, and in patients already receiving thrombolytic therapy; (2) it is unlikely that magnesium will reduce mortality when used at high dose (>=75 mmol); (3) magnesium treatment may reduce the incidence of ventricular fibrillation, ventricular tachycardia, severe arrhythmia needing treatment or Lown 2-5, but it may increase the incidence of profound hypotension, bradycardia and flushing; and (4) the areas of uncertainty regarding the effect of magnesium on mortality remain the effect of low dose treatment (< 75 mmol) and in patients not treated with thrombolysis.
Four studies enrolling 318 infants were included. All studies enrolled preterm infants on the basis of gestational age criteria. All studies commenced treatment in the first 48 hours, but used different regimens, dose and durations of treatment. All four studies used thyroxine (T4). Valerio 2004 incorporated one arm with an early short course of T3, then T4 for 6 weeks. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997; Vanhole 1997). All studies were small with the largest (van Wassenaer 1997) enrolling 200 infants. No significant difference was found in neonatal morbidity, mortality or neurodevelopmental outcome in infants who received thyroid hormones compared to control. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99) or cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley MDI (WMD -1.14, 95% CI -5.46, 3.19) and PDI (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months. van Wassenaer 1997 reported no significant difference in the Bayley MDI (MD -3.50, 95% CI -11.21, 4.21) and PDI (MD 3.10, 95% CI -3.31, 9.51) at 24 months, IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71) and children in special schooling at 10 years (RR 0.88, 95% CI 0.43, 1.83). Meta-analysis of all four trials found no significant difference in mortality to discharge (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14). No significant differences were reported for neonatal morbidities, including the need for mechanical ventilation, duration of mechanical ventilation, air leak, CLD in survivors at 28 days or 36 weeks, intraventricular haemorrhage, severe intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis, necrotising enterocolitis or retinopathy of prematurity. This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required.
Two RCTs (123 participants), both using amitriptyline, met the pre-specified inclusion criteria. These studies provided mixed findings on the efficacy of amitriptyline for the treatment of abdominal pain-related FGIDs. The larger, publicly-funded study reported no statistically significant difference in efficacy between amitriptyline and placebo in 90 children and adolescents with FGIDs after 4 weeks of treatment. On intention-to-treat (ITT)- analysis, 59% of the children reported feeling better in the amitriptyline group compared with 53% in the placebo group (RR 1.12; 95% CI: 0.77 to 1.63; P = 0.54). The risk of bias for this study was rated as low. The second RCT enrolled 33 adolescents with irritable bowel syndrome. Patients receiving amitriptyline experienced greater improvements in the primary outcome, overall quality of life, at weeks 6, 10, and 13 compared with those on placebo (P= 0.019, 0.004, and 0.013, respectively). No effect estimates were calculated for the quality of life outcome because mean quality of life scores and standard deviations were not reported. For most secondary outcomes no statistically significant differences between amitriptyline and placebo could be detected. The risk of bias for this study was rated as unclear for most items. However, it was rated as high for other bias due to multiple testing. The results of this study should be interpreted with caution due to the small number of patients and multiple testing. The larger study reported mild adverse events including fatigue, rash and headache and dizziness. On ITT analysis, 4% of the amitriptyline group experienced at least one adverse event compared to 2% of the placebo group. There was no statistically significant difference in the proportion of patients who experienced at least one adverse event (RR 1.91; 95% CI 0.18 to 20.35; P = 0.59). The smaller study reported no adverse events. The methods of adverse effects assessment was poorly reported in both studies and no clear conclusions on the risks of harms of amitriptyline can be drawn. Clinicians must be aware that for the majority of antidepressant medications no evidence exists that supports their use for the treatment of abdominal pain-related FGIDs in children and adolescents. The existing randomised controlled evidence is limited to studies on amitriptyline and revealed no statistically significant differences between amitriptyline and placebo for most efficacy outcomes. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. Studies in children with depressive disorders have shown that antidepressants can lead to substantial, sometimes life-threatening adverse effects. Until better evidence evolves, clinicians should weigh the potential benefits of antidepressant treatment against known risks of antidepressants in paediatric patients.
We included five RCTs (285 participants). Three studies were included in the original review and two more in the update. The authors of the included studies reported benefits of acupuncture in managing pancreatic cancer pain; no difference between real and sham electroacupuncture for pain associated with ovarian cancer; benefits of acupuncture over conventional medication for late stage unspecified cancer; benefits for auricular (ear) acupuncture over placebo for chronic neuropathic pain related to cancer; and no differences between conventional analgesia and acupuncture within the first 10 days of treatment for stomach carcinoma. All studies had a high risk of bias from inadequate sample size and a low risk of bias associated with random sequence generation. Only three studies had low risk of bias associated with incomplete outcome data, while two studies had low risk of bias associated with allocation concealment and one study had low risk of bias associated with inadequate blinding. The heterogeneity of methodologies, cancer populations and techniques used in the included studies precluded pooling of data and therefore meta-analysis was not carried out. A subgroup analysis on acupuncture for cancer-induced bone pain was not conducted because none of the studies made any reference to bone pain. Studies either reported that there were no adverse events as a result of treatment, or did not report adverse events at all. There is insufficient evidence to judge whether acupuncture is effective in treating cancer pain in adults.
We did not identify any new trials for inclusion in this 2017 update. We included 17 trials with 5099 participants in the primary analysis. The quality of trials was generally good. At follow-up there was no difference in participants described as being clinically improved between the antibiotic and placebo groups (11 studies with 3841 participants, risk ratio (RR) 1.07, 95% confidence interval (CI) 0.99 to 1.15). Participants given antibiotics were less likely to have a cough (4 studies with 275 participants, RR 0.64, 95% CI 0.49 to 0.85; number needed to treat for an additional beneficial outcome (NNTB) 6) and a night cough (4 studies with 538 participants, RR 0.67, 95% CI 0.54 to 0.83; NNTB 7). Participants given antibiotics had a shorter mean cough duration (7 studies with 2776 participants, mean difference (MD) -0.46 days, 95% CI -0.87 to -0.04). The differences in presence of a productive cough at follow-up and MD of productive cough did not reach statistical significance. Antibiotic-treated participants were more likely to be improved according to clinician's global assessment (6 studies with 891 participants, RR 0.61, 95% CI 0.48 to 0.79; NNTB 11) and were less likely to have an abnormal lung exam (5 studies with 613 participants, RR 0.54, 95% CI 0.41 to 0.70; NNTB 6). Antibiotic-treated participants also had a reduction in days feeling ill (5 studies with 809 participants, MD -0.64 days, 95% CI -1.16 to -0.13) and days with impaired activity (6 studies with 767 participants, MD -0.49 days, 95% CI -0.94 to -0.04). The differences in proportions with activity limitations at follow-up did not reach statistical significance. There was a significant trend towards an increase in adverse effects in the antibiotic group (12 studies with 3496 participants, RR 1.20, 95% CI 1.05 to 1.36; NNT for an additional harmful outcome 24). There is limited evidence of clinical benefit to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest beneficial effect in some patients such as frail, elderly people with multimorbidity who may not have been included in trials to date. However, the magnitude of this benefit needs to be considered in the broader context of potential side effects, medicalisation for a self limiting condition, increased resistance to respiratory pathogens, and cost of antibiotic treatment.
There was one trial with 20 participants (16 females) included in the review. The mean age of participants was 13.1 years. The trial was a double-blinded, randomised cross-over trial which had a duration of 12 months in total and compared high-dose and low-dose pancreatic enzyme therapy. As only the abstract of the trial was available, the overall risk of bias was judged to be unclear. The trial did not address either of our primary outcomes (time until resolution of DIOS and treatment failure rate), but reported episodes of acute DIOS, presence of abdominal mass and abdominal pain. There were no numerical data available for these outcomes, but the authors stated that there was no difference between treatment with high-dose or low-dose pancreatic enzymes. The overall quality of the evidence was found to be very low. There is a clear lack of evidence for the treatment of DIOS in people with cystic fibrosis. The included abstract did not address our primary outcome measures and did not provide numerical data for the two secondary outcomes it did address. Therefore, we cannot justify the use of high-dose pancreatic enzymes for treating DIOS, nor can we comment on the efficacy and safety of other laxative agents. From our findings, it is clear that more randomised controlled trials need to be conducted in this area.
We included two cluster-randomised trials that compared interventions aimed at communities to routine immunisation practices. In one study from India, families, teachers, children and village leaders were encouraged to attend information meetings where they received information about childhood vaccination and could ask questions. In the second study from Pakistan, people who were considered to be trusted in the community were invited to meetings to discuss vaccine coverage rates in their community and the costs and benefits of childhood vaccination. They were asked to develop local action plans and to share the information they had been given and continue the discussions in their communities. The trials show low certainty evidence that interventions aimed at communities to inform and educate about childhood vaccination may improve knowledge of vaccines or vaccine-preventable diseases among intervention participants (adjusted mean difference 0.121, 95% confidence interval (CI) 0.055 to 0.189). These interventions probably increase the number of children who are vaccinated. The study from India showed that the intervention probably increased the number of children who received vaccinations (risk ratio (RR) 1.67, 95% CI 1.21 to 2.31; moderate certainty evidence). The study from Pakistan showed that there is probably an increase in the uptake of both measles (RR 1.63, 95% CI 1.03 to 2.58) and DPT (diptheria, pertussis and tetanus) (RR 2.17, 95% CI 1.43 to 3.29) vaccines (both moderate certainty evidence), but there may be little or no difference in the number of children who received polio vaccine (RR 1.01, 95% CI 0.97 to 1.05; low certainty evidence). There is also low certainty evidence that these interventions may change attitudes in favour of vaccination among parents with young children (adjusted mean difference 0.054, 95% CI 0.013 to 0.105), but they may make little or no difference to the involvement of mothers in decision-making regarding childhood vaccination (adjusted mean difference 0.043, 95% CI -0.009 to 0.097). The studies did not assess knowledge among participants of vaccine service delivery; participant confidence in the vaccination decision; intervention costs; or any unintended harms as a consequence of the intervention. We did not identify any studies that compared interventions aimed at communities to inform and/or educate with interventions directed to individual parents or caregivers, or studies that compared two interventions aimed at communities to inform and/or educate about childhood vaccination. This review provides limited evidence that interventions aimed at communities to inform and educate about early childhood vaccination may improve attitudes towards vaccination and probably increase vaccination uptake under some circumstances. However, some of these interventions may be resource intensive when implemented on a large scale and further rigorous evaluations are needed. These interventions may achieve most benefit when targeted to areas or groups that have low childhood vaccination rates.’
We included one study that met our selection criteria; a double-masked, placebo-controlled, randomised trial of high dose intravenous steroids in patients with indirect TON diagnosed within seven days of the initial injury. A total of 31 eligible participants were randomised to receive either high dose intravenous steroids (n = 16) or placebo (n = 15), and they were all followed-up for three months. Mean final best corrected visual acuity (BCVA) was 1.78±1.23 Logarithm of the Minimum Angle of Resolution (LogMAR) in the placebo group, and 1.11±1.14 LogMAR in the steroid group. The mean difference in BCVA between the placebo and steroid groups was 0.67 LogMAR (95% confidence interval -1.54 to 0.20), and this difference was not statistically significant (P = 0.13). At three months follow-up, an improvement in BCVA of 0.40 LogMAR occurred in eight eyes (8/15, 53.3%) in the placebo group, and in 11 eyes (11/16, 68.8%) in the treatment group. This difference was not statistically significant (P = 0.38). There is a relatively high rate of spontaneous visual recovery in TON and there is no convincing data that steroids provide any additional visual benefit over observation alone. Recent evidence also suggests a possible detrimental effect of steroids in TON and further studies are urgently needed to clarify this important issue. Each case therefore needs to be assessed on an individual basis and proper informed consent is paramount.
Fifty-three double-blind RCTs evaluating a thiazide in 15129 hypertensive patients (baseline BP of 156/101 mmHg) were included. Hydrochlorothiazide was the thiazide used in 49/53 (92%) of the included studies. The additional BP reduction caused by the thiazide as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. Thiazides as a second-line drug reduced BP by 6/3 and 8/4 mmHg at doses of 1 and 2 times the manufacturer's recommended starting dose respectively. The BP lowering effect was dose related. The effect was similar to that obtained when thiazides are used as a single agent. Only 3 double-blind RCTs evaluating loop diuretics were identified. These RCTs showed a BP lowering effect of a starting dose of about 6/3 mmHg. Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug. This means that the BP lowering effect of thiazides is additive. Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose. Because of the short duration of the trials and lack of reporting of adverse events, this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug.
This review included three studies. However, data for progestogen-releasing intrauterine systems were available from only one study that compared 29 women with a levonorgestrel (LNG)-IUS versus 29 women with a combined oral contraceptive (COC) for treating uterine fibroids. There was a significant reduction of menstrual blood loss (MBL) in women receiving the LNG-IUS compared to the COC using the alkaline hematin test (mean difference (MD) 77.5%, 95% CI 71.3% to 83.67%, 58 women) and a pictorial assessment chart (PBAC) (MD 34.5%, 95% CI 14.9% to 54.1%, 58 women). The reduction in uterine fibroid size was significantly greater in the leuprorelin group at 16 weeks compared to the progestogen lynestrenol group (MD -15.93 mm, 95% CI -18.02 to -13.84 mm, 46 women). There was no RCT evaluating the effect of DMPA on uterine fibroids. Progestogen-releasing intrauterine systems appear to reduce menstrual blood loss in premenopausal women with uterine fibroids. Oral progestogens did not reduce fibroid size or fibroid- related symptoms. However, there was a methodological limitation and the one included study with data had a small sample size. This evidence is insufficient to support the use of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids.
Nine randomised controlled trials were identified as meeting the inclusion criteria. The nine trials enrolled 2,159 participants but looked at a multiplicity of drug combinations. Despite this, a reasonably robust literature suggests no statistically significant difference between the two drug combinations, including severe adverse events and adherence/tolerance/retention. The quality of the literature was found overall to be low to very low for all key outcomes. Only one study reported on drug resistance, and no studies reported on sexual transmission of HIV. The length of follow-up time and study settings varied greatly. While ideally future research would focus on direct comparison of standard therapeutic combinations of d4T+3TC+an NNRTI and AZT+3TC+an NNRTI to compare these regimens more directly, it is unlikely that additional trials will be mounted. Observational studies should focus on understanding outcomes, including toxicity and tolerability, in low- and middle-income countries.
We included eight randomized controlled trials (four of which were cross-over trials) with 510 participants (443 boys, 67 girls) in this review. Participants in these studies were children with both ADHD and a chronic tic disorder. All studies took place in the USA and ranged from three to 22 weeks in duration. Five of the eight studies were funded by charitable organizations or government agencies, or both. One study was funded by the drug manufacturer. The other two studies did not specify the source of funding. Risk of bias of included studies was low for blinding; low or unclear for random sequence generation, allocation concealment, and attrition bias; and low or high for selective outcome reporting. We were unable to combine any of the studies in a meta-analysis due to important clinical heterogeneity and unit-of-analysis issues. Several of the trials assessed multiple agents. Medications assessed included methylphenidate, clonidine, desipramine, dextroamphetamine, guanfacine, atomoxetine, and deprenyl. There was low-quality evidence for methylphenidate, atomoxetine, and clonidine, and very low-quality evidence for desipramine, dextroamphetamine, guanfacine and deprenyl in the treatment of ADHD in children with tics. All studies, with the exception of a study using deprenyl, reported improvement in symptoms of ADHD. Tic symptoms also improved in children treated with guanfacine, desipramine, methylphenidate, clonidine, and a combination of methylphenidate and clonidine. In one study, tics limited further dosage increases of methylphenidate. High-dose dextroamphetamine appeared to worsen tics in one study, although the length of this study was limited to three weeks. There was appetite suppression or weight loss in association with methylphenidate, dextroamphetamine, atomoxetine, and desipramine. There was insomnia associated with methylphenidate and dextroamphetamine, and sedation associated with clonidine. Following an updated search of potentially relevant studies, we found no new studies that matched our inclusion criteria and thus our conclusions have not changed. Methylphenidate, clonidine, guanfacine, desipramine, and atomoxetine appear to reduce ADHD symptoms in children with tics though the quality of the available evidence was low to very low. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may, nonetheless, exacerbate tics in individual cases. In these instances, treatment with alpha agonists or atomoxetine may be an alternative. Although there is evidence that desipramine may improve tics and ADHD in children, safety concerns will likely continue to limit its use in this population.
We identified seven randomized studies involving 450 European participants with LNB for inclusion in this systematic review. We found no trials conducted in the United States. Marked heterogeneity among these studies prevented meta-analysis. None of the studies included a placebo control on the initial antibiotic treatment, and only one was blinded. None were delayed-start studies. All were active comparator studies, and most were not adequately powered for non-inferiority comparison. The trials investigated four antibiotics: penicillin G and ceftriaxone in four studies, doxycycline in three studies, and cefotaxime in two studies. One study tested a three-month course of oral amoxicillin versus placebo following initial treatment with intravenous ceftriaxone. One study was limited to children. The trials measured efficacy using heterogeneous physician- or patient-reported outcomes, or both. In some cases cerebrospinal fluid analysis was included as an indirect biomarker of disease and outcome. None of the studies reported on our proposed primary outcome, 'Improvement in a measure of overall disability in the long term (three or more months).' None of the trials revealed any between-group differences in symptom resolution in response to active treatment. In general, treatment was tolerated well. The quality of adverse event reporting, however, was low. There is mostly low- to very low-quality clinical evidence from a limited number of mostly small, heterogeneous trials with diverse outcome measures, comparing the relative efficacy of central nervous system-penetrant antibiotics for the treatment of LNB. The few existing randomized studies have limited power and lack consistent and well-defined entry criteria and efficacy endpoints. It is not possible to draw firm conclusions on the relative efficacy of accepted antibiotic drug regimens for the treatment of LNB. The majority of people are reported to have good outcomes, and symptoms resolve by 12 months regardless of the antibiotic used. A minority of participants did not improve sufficiently, and some were retreated. These randomized studies provide some evidence that doxycycline, penicillin G, ceftriaxone, and cefotaxime are efficacious in the treatment of European LNB. No evidence of additional efficacy was observed when, in one study, an initial antibiotic treatment with intravenous ceftriaxone was followed by additional longer treatment with oral amoxicillin. There is a lack of evidence identified through our high-quality search strategy on the efficacy of antibiotics for treatment of LNB in the United States.
Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV1 predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16). Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline.
Six trials involving 907 patients were identified. For 'death (all causes)' the Peto odds ratio of 0.77 with a 95% confidence interval (CI) of 0.48 to 1.24 did not show a statistically significant difference between both treatment groups. For 'stroke (any)' the Peto odds ratio of 0.58 (95% CI: 0.34 to 0.98) indicated a statistically significant benefit in favour of antiplatelet drugs (P = 0.04). For 'vascular death', 'stroke or vascular death', 'serious vascular events', 'death or dependency', 'myocardial infarction', 'major extracranial haemorrhage', 'local haemorrhage requiring surgery', 'restenosis', 'TIA or amaurosis fugax', neither any benefit nor any hazard of antiplatelet drugs could be shown. For the outcome events 'intracranial haemorrhage', 'ischaemic stroke' and 'occurrence or progression of contralateral stenosis', data were either too sparse for meaningful analyses, or not available at all. Our results may indicate that antiplatelet drugs did not significantly change the odds of death but reduce the outcome 'stroke of any cause' in patients undergoing carotid endarterectomy. However, it can not be excluded that the beneficial effect in reducing stroke is due to chance. There is a suggestion that antiplatelets may increase the odds of haemorrhage, but there are currently too few data to quantify this effect.
We included ten studies with a total of 1592 patients. Eight included studies reported sufficiently detailed results to enter into analyses related to antidepressant efficacy. We split one study which included two different antidepressants and therefore had nine groups of patients treated with antidepressants compared with nine groups receiving placebo treatment. Information needed to make 'Risk of bias' judgements was often missing. We found high-quality evidence of little or no difference in scores on depression symptom rating scales between the antidepressant and placebo treated groups after 6 to 13 weeks (standardised mean difference (SMD) -0.10, 95% confidence interval (CI) -0.26 to 0.06; 614 participants; 8 studies). There was probably also little or no difference between groups after six to nine months (mean difference (MD) 0.59 point, 95% CI -1.12 to 2.3, 357 participants; 2 studies; moderate-quality evidence). The evidence on response rates at 12 weeks was of low quality, and imprecision in the result meant we were uncertain of any effect of antidepressants (antidepressant: 49.1%, placebo: 37.7%; odds ratio (OR) 1.71, 95% CI 0.80 to 3.67; 116 participants; 3 studies). However, the remission rate was probably higher in the antidepressant group than the placebo group (antidepressant: 40%, placebo: 21.7%; OR 2.57, 95% CI 1.44 to 4.59; 240 participants; 4 studies; moderate-quality evidence). The largest of these studies continued for another 12 weeks, but because of imprecision of the result we could not be sure of any effect of antidepressants on remission rates after 24 weeks. There was evidence of no effect of antidepressants on performance of activities of daily living at weeks 6 to 13 (SMD -0.05, 95% CI -0.36 to 0.25; 173 participants; 4 studies; high-quality evidence) and probably also little or no effect on cognition (MD 0.33 point on the Mini-Mental State Examination, 95% CI -1.31 to 1.96; 194 participants; 6 studies; moderate-quality evidence). Participants on antidepressants were probably more likely to drop out of treatment than those on placebo over 6 to 13 weeks (OR 1.51, 95% CI 1.07 to 2.14; 836 participants; 9 studies). The meta-analysis of the number of participants suffering at least one adverse event showed a significant difference in favour of placebo (antidepressant: 49.2%, placebo: 38.4%; OR 1.55, 95% CI 1.21 to 1.98, 1073 participants; 3 studies), as did the analyses for participants suffering one event of dry mouth (antidepressant: 19.6%, placebo: 13.3%; OR 1.80, 95% CI 1.23 to 2.63, 1044 participants; 5 studies), and one event of dizziness (antidepressant: 19.2%, placebo: 12.5%; OR 2.00, 95% CI 1.34 to 2.98, 1044 participants; 5 studies). Heterogeneity in the way adverse events were reported in studies presented a major difficulty for meta-analysis, but there was some evidence that antidepressant treatment causes more adverse effects than placebo treatment does. The available evidence is of variable quality and does not provide strong support for the efficacy of antidepressants for treating depression in dementia, especially beyond 12 weeks. On the only measure of efficacy for which we had high-quality evidence (depression rating scale scores), antidepressants showed little or no effect. The evidence on remission rates favoured antidepressants but was of moderate quality, so future research may find a different result. There was insufficient evidence to draw conclusions about individual antidepressant drugs or about subtypes of dementia or depression. There is some evidence that antidepressant treatment may cause adverse events.
We included four studies (five publications) involving 302 participants with idiopathic non-allergic rhinitis. All the included studies described patients with moderately severe, idiopathic non-allergic rhinitis who were between the ages of 16 and 65. Studies had follow-up periods ranging from four to 38 weeks. The overall risk of bias in the studies was either high or unclear (two studies had overall high risk of bias, while two others had low to unclear risk of bias). Using the GRADE system we assessed the evidence as being of low to moderate quality. A meta-analysis was not possible, given lack of similarity of the reported outcomes. Two studies compared capsaicin with placebo. One study reported that capsaicin resulted in an improvement of overall nasal symptoms (a primary outcome) measured on a visual analogue scale (VAS) of 0 to 10. There was a mean difference (MD) of -3.34 (95% confidence interval (CI) -5.24 to -1.44), MD -3.73 (95% CI -5.45 to -2.01) and MD -3.52 (95% CI -5.55 to -1.48) at two, 12 and 36 weeks post-treatment, respectively. Another study reported that, compared to placebo, capsaicin (at 4 µg/puff) was more likely to produce overall symptom resolution (reduction in nasal blockage, sneezing/itching/coughing and nasal secretion measured with a daily record chart) at four weeks post-treatment (a primary outcome). The risk ratio (RR) was 3.17 (95% CI 1.38 to 7.29). One study compared capsaicin to budesonide (an intranasal corticosteroid). This study found that patients treated with capsaicin had a better overall symptom score compared to those treated with budesonide (MD 2.50, 95% CI 1.06 to 3.94, VAS of 0 to 10). However, there were no differences in the individual symptom scores for headache, postnasal drip, rhinorrhoea, nasal blockage, sneezing and sore throat assessed during the last three days of a four-week treatment. One study compared two different regimens of capsaicin administration: five treatments in one day versus five treatments given every two to three days during two weeks. Using daily record charts, the study reported significant improvement of individual symptom scores for rhinorrhoea in patients treated five times per day, however numerical data were not presented. There were no improvements in the other outcomes: rhinorrhoea, nasal obstruction, sneezing and overall nasal symptoms, measured on a VAS. Finally, one of these studies also compared three doses of capsaicin (to placebo). Patients treated with a 1 µg versus 4 µg per puff dose of capsaicin had a worse daily record chart overall symptom score resolution (RR 0.63, 95% CI 0.34 to 1.16). Only one study attempted to measure adverse effects (a primary outcome), however due to methodological issues with the assessment we are unable to draw any conclusions. We sought to include other secondary outcomes (e.g. quality of life measures, treatment dropouts, endoscopic scores, turbinate or mucosal size, cost of therapy), but none of these were measured or reported in the included studies. Capsaicin may be an option in the treatment of idiopathic non-allergic rhinitis. It is given in the form of brief treatments, usually during the same day. It appears to have beneficial effects on overall nasal symptoms up to 36 weeks after treatment, based on a few, small studies (low-quality evidence). Well-conducted randomised controlled trials are required to further advance our understanding of the effectiveness of capsaicin in non-allergic rhinitis, especially in patients with non-allergic rhinitis of different types and severity, and using different methods of capsaicin application.
Thirteen trials performed between the years 1974 and 2008 were included, involving 1412 patients. Four trials included 520 children with acute lymphoblastic leukemia and the remaining trials included adults with acute leukemia, solid organ transplantation or autologous bone marrow transplantation. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was an 85% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR of 0.15 (95% CI 0.04 to 0.62; 10 trials, 1000 patients). The evidence was graded as moderate due to possible risk of bias. PCP-related mortality was also significantly reduced, RR of 0.17 (95% CI 0.03 to 0.94; nine trials, 886 patients) (low quality of evidence due to possible risk of bias and imprecision), but in trials comparing PCP prophylaxis against placebo or no treatment there was no significant effect on all-cause mortality (low quality of evidence due to imprecision). Occurrence of leukopenia or neutropenia and their duration were not reported consistently. No significant differences in overall adverse events or events requiring discontinuation were seen comparing trimethoprim/sulfamethoxazole to no treatment or placebo (four trials, 470 patients, moderate quality evidence). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients). Given an event rate of 6.2% in the control groups of the included trials, prophylaxis for PCP using trimethoprim/sulfamethoxazole is highly effective among non-HIV immunocompromised patients, with a number needed to treat to prevent PCP of 19 patients (95% CI 17 to 42). Prophylaxis should be considered for patients with a similar baseline risk of PCP.
We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail. Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52). Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006). Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia). This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.
Four randomised trials were eligible for inclusion in this systematic review - two studies with 83 adults comparing fluoroquinolones with β-lactams and two studies with 55 adults comparing aminoglycosides with polymyxins. None of the included studies reported information on exacerbations - one of our primary outcomes. Included studies reported no serious adverse events - another of our primary outcomes - and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and β-lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low-quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low-quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low-quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV₁). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low-quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low-quality evidence). The evidence for changes in FEV₁ was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. Limited low-quality evidence favours short-term oral fluoroquinolones over beta-lactam antibiotics for patients hospitalised with exacerbations. Very low-quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head-to-head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short-term or long-term therapy. More research on this topic is needed.
Ten studies were included in the review but only five reported data that could be used. Three of the ten studies were related to exercise-based psychological interventions. Seven were related to psychological interventions. No meta-analyses were possible due to diversity of participants, interventions and outcomes. Two studies compared a psychosocial intervention versus another intervention. Three studies compared a psychosocial intervention to a control group. Only one primary prevention trial reported data for the primary outcomes and, although this study found a significant difference in depression in favour of the intervention at endpoint, this difference was no longer evident at 18 months. No studies of primary prevention comparing different interventions and reporting primary outcomes of interest were identified. The methodological quality of the included studies was summarised. No study met our full quality criteria and one was regarded as low-quality. The remainder could not be rated because of incomplete data in the published reports and inadequate responses from the trialists. There is evidence only from individual small and low quality trials with minimal data suggesting that police officers benefit from psychosocial interventions, in terms of physical symptoms and psychological symptoms such as anxiety, depression, sleep problems, cynicism, anger, PTSD, marital problems and distress. No data on adverse effects were available. Meta-analyses of the available data were not possible. Further well-designed trials of psychosocial interventions are required. Research is needed on organization-based interventions to enhance psychological health among police officers.
The curves for the life-table cumulative pregnancy rates for the Prentif cap and the diaphragm did not differ. However, the Kaplan-Meier six-month cumulative pregnancy rates for the FemCap and the diaphragm were not clinically equivalent. The Prentif cap had more Class I to Class III cervical cytologic conversions than the diaphragm (OR 2.31; 95% CI 1.04 to 5.11). The FemCap trial did not find differences in Papanicolaou smear results between the groups. Fewer Prentif cap users had vaginal ulcerations or lacerations (OR 0.31; 95% CI 0.14 to 0.71) than diaphragm users. Fewer FemCap users had blood in the device (OR 2.29; 95% CI 1.27 to 4.14), but more had urinary tract infections (OR 0.59; 95% CI 0.39 to 0.95). In the FemCap trial, similar proportions of women reported liking their device. However, FemCap users were less likely to use the device alone after the trial (OR 0.47; 95% CI 0.31 to 0.71) or recommend it to a friend (OR 0.48; 95% CI 0.29 to 0.81). The Prentif cap was as effective as its comparison diaphragm in preventing pregnancy, but the FemCap was not. Both cervical caps appear to be medically safe.
We found one RCT, which included 13 women, that met our inclusion criteria and this trial reported data on LARVH versus RAH. Women who underwent LARVH for treatment of early-stage cervical cancer appeared to have less blood loss compared with those who underwent RAH. The trial reported a borderline significant difference between the two types of surgery (median blood loss 400 mL (interquartile range (IQR): 325 to 1050) and 1000 mL (IQR: 800 to 1025) for LARVH and RAH, respectively, P value = 0.05). RAH was associated with significantly shorter operation time compared with LARVH (median: 180 minutes with LARVH versus 138 minutes with RAH, P value = 0.05). There was no statistically significant difference in the risk of perioperative complications in women who underwent LARVH and RAH. The trial reported two (29%) and four (57%) cases of intraoperative and postoperative complications, respectively, in the LARVH group and no (0%) reported cases of intraoperative complications and five (83%) cases of postoperative complications in the RAH group. There were no reported cases of severe perioperative complications. Bladder and bowel dysfunction of either a transient or chronic nature remain major morbidities after radical hysterectomy, and the one included study showed that there may be significantly less after LARVH. The included trial lacked statistical power due to the small number of women in each group and the low number of observed events. Therefore, the absence of reliable evidence, regarding the effectiveness and safety of the two surgical techniques for the management of early-stage cervical cancer, precludes any definitive guidance or recommendations for clinical practice. The trial did not report data on long-term outcomes, but was at moderate risk of bias due to very low numbers of included women.
No immediate mortality was reported. There was no significant difference in serious cardio-respiratory complications suffered by patients in either sedation group. Failure to complete the procedure due to sedation-related problems was reported in one study. Three studies found faster and better recovery in patients receiving propofol for their ERCP procedures. Study protocols regarding use of supplemental oxygen, intravenous fluid administration and capnography monitoring varied considerably. The studies showed either moderate or high risk of bias. Results from individual studies suggested that patients have a better recovery profile after propofol sedation for ERCP procedures than after midazolam and meperidine sedation. As there was no difference between the two sedation techniques as regards safety, propofol sedation is probably preferred for patients undergoing ERCP procedures. However, in all of the studies that were identified only non-anaesthesia personnel were involved in administering the sedation. It would be helpful if further research was conducted where anaesthesia personnel were involved in the administration of sedation for ERCP procedures. This would clarify the extent to which anaesthesia personnel should be involved in the administration of propofol sedation.
We identified 37 randomised controlled trials involving 11,948 participants. These trials compared lidocaine versus placebo or no intervention, disopyramide, mexiletine, tocainide, propafenone, amiodarone, dimethylammonium chloride, aprindine and pirmenol. Overall, trials were underpowered and had high risk of bias. Ninety-seven per cent of trials (36/37) were conducted without an a priori sample size estimation. Ten trials were sponsored by the pharmaceutical industry. Trials were conducted in 17 countries, and intravenous intervention was the most frequent route of administration. In trials involving participants with proven or non-proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences regarding all-cause mortality (213/5879 (3.62%) vs 199/5848 (3.40%); RR 1.02, 95% CI 0.82 to 1.27; participants = 11727; studies = 18; I2 = 15%); low-quality evidence), cardiac mortality (69/4184 (1.65%) vs 62/4093 (1.51%); RR 1.03, 95% CI 0.70 to 1.50; participants = 8277; studies = 12; I2 = 12%; low-quality evidence) and prophylaxis of ventricular fibrillation (76/5128 (1.48%) vs 103/4987 (2.01%); RR 0.78, 95% CI 0.55 to 1.12; participants = 10115; studies = 16; I2 = 18%; low-quality evidence). In terms of sinus bradycardia, lidocaine effect is imprecise compared with effects of placebo or no intervention (55/1346 (4.08%) vs 49/1203 (4.07%); RR 1.09, 95% CI 0.66 to 1.80; participants = 2549; studies = 8; I2 = 21%; very low-quality evidence). In trials involving only participants with proven acute myocardial infarction, lidocaine versus placebo or no intervention showed no significant differences in all-cause mortality (148/2747 (5.39%) vs 135/2506 (5.39%); RR 1.01, 95% CI 0.79 to 1.30; participants = 5253; studies = 16; I2 = 9%; low-quality evidence). No significant differences were noted between lidocaine and any other antiarrhythmic drug in terms of all-cause mortality and ventricular fibrillation. Data on overall survival 30 days after myocardial infarction were not reported. Lidocaine compared with placebo or no intervention increased risk of asystole (35/3393 (1.03%) vs 14/3443 (0.41%); RR 2.32, 95% CI 1.26 to 4.26; participants = 6826; studies = 4; I2 = 0%; very low-quality evidence) and dizziness/drowsiness (74/1259 (5.88%) vs 16/1274 (1.26%); RR 3.85, 95% CI 2.29 to 6.47; participants = 2533; studies = 6; I2 = 0%; low-quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. Trial sequential analyses suggest that additional trials may not be needed for reliable conclusions to be drawn regarding these outcomes. This Cochrane review found evidence of low quality to suggest that prophylactic lidocaine has very little or no effect on mortality or ventricular fibrillation in people with acute myocardial infarction. The safety profile is unclear. This conclusion is based on randomised controlled trials with high risk of bias. However (disregarding the risk of bias), trial sequential analysis suggests that additional trials may not be needed to disprove an intervention effect of 20% relative risk reduction. Smaller risk reductions might require additional higher trials.
Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype. Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI −44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80). Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD −2.77 mmHg, 95% CI −4.96 to −0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD −3.50, 95% CI −5.54 to −1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1). It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only. Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials.
Three trials including 255 patients qualified for this review. In two of the trial, a total of 150 patients were randomised to absorbable clips (n = 75) and non-absorbable clips (n = 75). In the third trial, a total of 105 patients were randomised to absorbable ligatures (n = 53) and non-absorbable clips (n = 52). All three trials were of high risk of bias. There was no difference in the morbidity between the groups. There was statistically significant longer operating time (MD 12.00 minutes, 95% CI 1.59 to 22.41) in the absorbable ligature group than non-absorbable clips. The duration and method of follow-up were not adequate to determine the incidence of long-term complications. We are unable to determine the benefits and harms of different methods of cystic duct occlusion because of the small sample size, short period of follow-up, and lack of reporting of important outcomes in the included trials. Adequately powered randomised trials with low risk of bias and with long periods of follow-up and assessing all of the important outcomes for patients and professionals are necessary.
We found two randomised clinical trials including 154 adult participants, aged between 18 years and 65 years, diagnosed with hepatosplenic schistosomiasis. One of the trials randomised participants to proximal splenorenal shunt versus distal splenorenal shunt versus oesophagogastric devascularisation with splenectomy, and the other randomised participants to distal splenorenal shunt versus oesophagogastric devascularisation with splenectomy. In both trials the diagnosis of hepatosplenic schistosomiasis was made based on clinical and biochemical assessments. The trials were conducted in Brazil and Egypt. Both trials were at high risk of bias. We are uncertain as to whether surgical portosystemic shunts improved all-cause mortality compared with oesophagogastric devascularisation with splenectomy due to imprecision in the trials (risk ratio (RR) 2.35, 95% confidence interval (CI) 0.55 to 9.92; participants = 154; studies = 2). We are uncertain whether serious adverse events differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy (RR 2.26, 95% CI 0.44 to 11.70; participants = 154; studies = 2). None of the trials reported on health-related quality of life. We are uncertain whether variceal rebleeding differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy (RR 0.39, 95% CI 0.13 to 1.23; participants = 154; studies = 2). We found evidence suggesting an increase in encephalopathy in the shunts group versus the devascularisation with splenectomy group (RR 7.51, 95% CI 1.45 to 38.89; participants = 154; studies = 2). We are uncertain whether ascites and re-interventions differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy. We computed Trial Sequential Analysis for all outcomes, but the trial sequential monitoring boundaries could not be drawn because of insufficient sample size and events. We downgraded the overall certainty of the body of evidence for all outcomes to very low due to risk of bias and imprecision. Given the very low certainty of the available body of evidence and the low number of clinical trials, we could not determine an overall benefit or harm of surgical portosystemic shunts compared with oesophagogastric devascularisation with splenectomy. Future randomised clinical trials should be designed with sufficient statistical power to assess the benefits and harms of surgical portosystemic shunts versus oesophagogastric devascularisations with or without splenectomy and with or without oesophageal transection.
The review currently includes eleven RCTs with 4144 participants on three second-generation antipsychotics (olanzapine, quetiapine, risperidone). Nine studies investigated the effects of second-generation antipsychotics in generalised anxiety disorder, only two studies investigated the effects in social phobia. There were no studies on panic disorder or any other primary anxiety disorder. Seven studies investigated the effects of quetiapine. Participants with generalised anxiety disorder responded significantly better to quetiapine than to placebo (4 RCTs, N = 2265, OR = 2.21, 95% CI 1.10 to 4.45). However, they were more likely to drop out due to adverse events, to gain weight, to suffer from sedation or to suffer from extrapyramidal side effects. When quetiapine was compared with antidepressants, there was no significant difference in efficacy-related outcomes, but more participants in the quetiapine groups dropped out due to adverse events, gained weight and feeling sedated. Only two very small studies with a total of 36 participants examined olanzapine and found no difference in response to treatment. Two trials compared adjunctive treatment with risperidone with placebo and found no difference in response to treatment. We identified eligible trials on quetiapine, risperidone and olanzapine. The available data on olanzapine and risperidone are too limited to draw any conclusions. Monotherapy with quetiapine seems to be efficacious in reducing symptoms of generalised anxiety disorder and this effect may be similar to that of antidepressants. However, quetiapine's efficacy must be weighed against its lower tolerability.
Overall 16 studies were identified and included. MR1: three trials (n=145). Some evidence of effectiveness of cognitive rehabilitation on cognitive outcomes, although this was difficult to interpret because of the large number of outcome measures used. MR2: three trials (n=80). One small trial suggesting psychotherapy may help with depression. MR3: seven studies (n=688). Some evidence that cognitive behavioural therapy may help people adjust to, and cope with, having MS (three trials). The other trials were diverse in nature and some difficult to interpret because of multiple outcome measures. MR4: three trials (n=93). Two small studies of cognitive behavioural therapy showed significant improvements in depression. The diversity of psychological interventions identified indicates the many ways in which they can potentially help people with MS. No definite conclusions can be made from this review. However there is reasonable evidence that cognitive behavioural approaches are beneficial in the treatment of depression, and in helping people adjust to, and cope with, having MS.
Three randomised clinical trials were included in this review. All of them had a high risk of bias. One trial was conducted in Shanghai, China. There are several published reports on this trial, in which data were presented differently. According to the 2004 trial report, participants were randomised to screening every six months with alpha-foetoprotein and ultrasonography (n = 9373) versus no screening (n = 9443). We could not draw any definite conclusions from it. A second trial was conducted in Toronto, Canada. In this trial, there were 1069 participants with chronic hepatitis B. The trial compared screening every six months with alpha-foetoprotein alone (n = 532) versus alpha-foetoprotein and ultrasound (n = 538) over a period of five years. This trial was designed as a pilot trial; the small number of participants and the rare events did not allow an effective comparison between the two modes of screening that were studied. The remaining trial, conducted in Taiwan and published as an abstract, was designed as a cluster randomised trial to determine the optimal interval for screening using alpha foetoprotein and ultrasound. Screening intervals of four months and 12 months were compared in the two groups. Further details about the screening strategy were not available. The trial reported on cumulative four-year survival, cumulative three-year incidence of hepatocellular carcinoma, and mean tumour size. The cumulative four-year survival was not significantly different between the two screening intervals. The incidence of hepatocellular cancer was higher in the four-monthly screening group. The included trials did not report on adverse events. It appears that the sensitivity and specificity of the screening modes were poor, accounting for a substantial number of false-positive and false-negative screening results. There is not enough evidence to support or refute the value of alpha-foetoprotein or ultrasound screening, or both, of hepatitis B surface antigen (HBsAg) positive patients for hepatocellular carcinoma. More and better designed randomised trials are required to compare screening against no screening.
Ten studies (1785 participants) met the inclusion criteria. The two new studies in this update had been identified in the earlier update, but data were not available. There remain three potentially relevant unpublished studies for which data are not available at this time. The NNT for celecoxib 200 mg and 400 mg compared with placebo for at least 50% of maximum pain relief over four to six hours was 4.2 (95% confidence interval (CI) 3.4 to 5.6) and 2.6 (95% CI 2.3 to 3.0) respectively. The median time to use of rescue medication was 6.6 hours with celecoxib 200 mg, 8.4 hours with celecoxib 400 mg, and 2.3 hours with placebo. The proportion of participants requiring rescue medication over 24 hours was 74% with celecoxib 200 mg, 63% for celecoxib 400 mg, and 91% for placebo. The NNT to prevent one patient using rescue medication was 4.8 (95% CI 3.5 to 7.7) and 3.5 (95% CI 2.9 to 4.6) for celecoxib 200 mg and 400 mg respectively. Adverse events were generally mild to moderate in severity, and were experienced by a similar proportion of participants in the celecoxib and placebo groups. One serious adverse event that was probably related to celecoxib was reported. Single-dose oral celecoxib is an effective analgesic for postoperative pain relief. Indirect comparison suggests that the 400 mg dose has similar efficacy to ibuprofen 400 mg.
One trial, involving 393 women undergoing either vacuum or forceps deliveries, was included. The trial compared the antibiotic intravenous cefotetan after cord clamping compared with no treatment. This trial reported only two out of the nine outcomes specified in this review. Seven women in the group given no antibiotics had endomyometritis and none in prophylactic antibiotic group, the risk reduction was 93% (risk ratio (RR) 0.07; 95% confidence interval (CI) 0.00 to 1.21; low-quality evidence). There was no difference in the length of hospital stay between the two groups (mean difference (MD) 0.09 days; 95% CI -0.23 to 0.41; low-quality evidence). Overall, the risk of bias was judged to be unclear. The quality of the evidence using GRADE was low for both endometritis and maternal length of stay. One small trial was identified reporting only two outcomes. Evidence from this single trial suggests that antibiotic prophylaxis may lead to little or no difference in endometritis or maternal length of stay. There were no data on any other outcomes to evaluate the impact of antibiotic prophylaxis after operative vaginal delivery. Future research on antibiotic prophylaxis for operative vaginal delivery is needed to conclude whether it is useful for reducing postpartum morbidity.
Four trials involving 229 participants were included. The studies were clinically heterogeneous, which precluded a meta-analysis. One trial (48 participants with burn wounds undergoing split skin grafts) compared HBOT with usual care and reported a significantly higher complete graft survival associated with HBOT (95% healthy graft area risk ratio (RR) 3.50; 95% confidence interval (CI) 1.35 to 9.11). A second trial (10 participants in free flap surgery) reported no significant difference between graft survival (no data available). A third trial (36 participants with crush injuries) reported significantly more wounds healed (RR 1.70; 95% CI 1.11 to 2.61), and significantly less tissue necrosis (RR 0.13; 95% CI 0.02 to 0.90) with HBOT compared to sham HBOT. The fourth trial (135 people undergoing flap grafting) reported no significant differences in complete graft survival with HBOT compared with dexamethasone (RR 1.14; 95% CI 0.95 to 1.38) or heparin (RR 1.21; 95% CI 0.99 to 1.49). Many of the predefined secondary outcomes of the review were not reported. All four trials were at unclear or high risk of bias. There is a lack of high quality, valid research evidence regarding the effects of HBOT on wound healing. Whilst two small trials suggested that HBOT may improve the outcomes of skin grafting and trauma, these trials were at risk of bias. Further evaluation by means of high quality RCTs is needed.
The updated review included data from 72 studies, comprising a total of 4378 participants. Of these, 2291 received some form of treatment and 2087 acted as controls. The interventions consisted most often of different pharmaceutical agents, such as dopamine and its analogues, diuretics, calcium channel blockers, ACE inhibitors, NAC, ANP, sodium bicarbonate, antioxidants and EPO or selected hydration fluids. Some clinical heterogeneity and varying risk of bias were noted amongst the studies, although we were able to meaningfully interpret the data. Results showed significant heterogeneity and indicated that most interventions provided no benefit. Data on perioperative mortality were reported in 41 studies and data on acute renal injury in 44 studies (all interventions combined). Because of considerable clinical heterogeneity (different clinical scenarios, as well as considerable methodological variability amongst the studies), we did not perform a meta-analysis on the combined data. Subgroup analysis of major interventions and surgical procedures showed no significant influence of interventions on reported mortality and acute renal injury. For the subgroup of participants who had pre-existing renal damage, the risk of mortality from 10 trials (959 participants) was estimated as odds ratio (OR) 0.76, 95% confidence interval (CI) 0.38 to 1.52; the risk of acute renal injury (as reported in the trials) was estimated from 11 trials (979 participants) as OR 0.43, 95% CI 0.23 to 0.80. Subgroup analysis of studies that were rated as having low risk of bias revealed that 19 studies reported mortality numbers (1604 participants); OR was 1.01, 95% CI 0.54 to 1.90. Fifteen studies reported data on acute renal injury (criteria chosen by the individual studies; 1600 participants); OR was 1.03, 95% CI 0.54 to 1.97. No reliable evidence from the available literature suggests that interventions during surgery can protect the kidneys from damage. However, the criteria used to diagnose acute renal damage varied in many of the older studies selected for inclusion in this review, many of which suffered from poor methodological quality such as insufficient participant numbers and poor definitions of end points such as acute renal failure and acute renal injury. Recent methods of detecting renal damage such as the use of specific biomarkers and better defined criteria for identifying renal damage (RIFLE (risk, injury, failure, loss of kidney function and end-stage renal failure) or AKI (acute kidney injury)) may have to be explored further to determine any possible benefit derived from interventions used to protect the kidneys during the perioperative period.
Six studies involving over 1345 TBAs, more than 32,000 women and approximately 57,000 births that examined the effects of TBA training for trained versus untrained TBAs (one study) and additionally trained TBA training versus trained TBAs (five studies) are included in this review. These studies consist of individual randomised trials (two studies) and cluster-randomised trials (four studies). The primary outcomes across the sample of studies were perinatal deaths, stillbirths and neonatal deaths (early, late and overall). Trained TBAs versus untrained TBAs: one cluster-randomised trial found a significantly lower perinatal death rate in the trained versus untrained TBA clusters (adjusted odds ratio (OR) 0.70, 95% confidence interval (CI) 0.59 to 0.83), lower stillbirth rate (adjusted OR 0.69, 95% CI 0.57 to 0.83) and lower neonatal death rate (adjusted OR 0.71, 95% CI 0.61 to 0.82). This study also found the maternal death rate was lower but not significant (adjusted OR 0.74, 95% CI 0.45 to 1.22). Additionally trained TBAs versus trained TBAs: three large cluster-randomised trials compared TBAs who received additional training in initial steps of resuscitation, including bag-valve-mask ventilation, with TBAs who had received basic training in safe, clean delivery and immediate newborn care. Basic training included mouth-to-mouth resuscitation (two studies) or bag-valve-mask resuscitation (one study). There was no significant difference in the perinatal death rate between the intervention and control clusters (one study, adjusted OR 0.79, 95% CI 0.61 to 1.02) and no significant difference in late neonatal death rate between intervention and control clusters (one study, adjusted risk ratio (RR) 0.47, 95% CI 0.20 to 1.11). The neonatal death rate, however, was 45% lower in intervention compared with the control clusters (one study, 22.8% versus 40.2%, adjusted RR 0.54, 95% CI 0.32 to 0.92). We conducted a meta-analysis on two outcomes: stillbirths and early neonatal death. There was no significant difference between the additionally trained TBAs versus trained TBAs for stillbirths (two studies, mean weighted adjusted RR 0.99, 95% CI 0.76 to 1.28) or early neonatal death rate (three studies, mean weighted adjusted RR 0.83, 95% CI 0.68 to 1.01). The results are promising for some outcomes (perinatal death, stillbirth and neonatal death). However, most outcomes are reported in only one study. A lack of contrast in training in the intervention and control clusters may have contributed to the null result for stillbirths and an insufficient number of studies may have contributed to the failure to achieve significance for early neonatal deaths. Despite the additional studies included in this updated systematic review, there remains insufficient evidence to establish the potential of TBA training to improve peri-neonatal mortality.
Sixty-one observational studies were selected of varying quality. Despite methodological differences there was a remarkable consistency in results, particularly for death and head injury outcomes. Motorcycle helmets were found to reduce the risk of death and head injury in motorcyclists who crashed. From four higher quality studies helmets were estimated to reduce the risk of death by 42% (OR 0.58, 95% CI 0.50 to 0.68) and from six higher quality studies helmets were estimated to reduce the risk of head injury by 69% (OR 0.31, 95% CI 0.25 to 0.38). Insufficient evidence was found to estimate the effect of motorcycle helmets compared with no helmet on facial or neck injuries. However, studies of poorer quality suggest that helmets have no effect on the risk of neck injuries and are protective for facial injury. There was insufficient evidence to demonstrate whether differences in helmet type confer more or less advantage in injury reduction. Motorcycle helmets reduce the risk of death and head injury in motorcycle riders who crash. Further well-conducted research is required to determine the effects of helmets and different helmet types on mortality, head, neck and facial injuries. However, the findings suggest that global efforts to reduce road traffic injuries may be facilitated by increasing helmet use by motorcyclists.
Twelve studies were included in the review. This update incorporated two new studies. One of the new trials was a large field-based trial that included 2377 participants, 1220 of whom were allocated stretching. All other 11 studies were small, with between 10 and 30 participants receiving the stretch condition. Ten studies were laboratory-based and other two were field-based. All studies were exposed to either a moderate or high risk of bias. The quality of evidence was low to moderate. There was a high degree of consistency of results across studies. The pooled estimate showed that pre-exercise stretching reduced soreness at one day after exercise by, on average, half a point on a 100-point scale (mean difference -0.52, 95% CI -11.30 to 10.26; 3 studies). Post-exercise stretching reduced soreness at one day after exercise by, on average, one point on a 100-point scale (mean difference -1.04, 95% CI -6.88 to 4.79; 4 studies). Similar effects were evident between half a day and three days after exercise. One large study showed that stretching before and after exercise reduced peak soreness over a one week period by, on average, four points on a 100-point scale (mean difference -3.80, 95% CI -5.17 to -2.43). This effect, though statistically significant, is very small. The evidence from randomised studies suggests that muscle stretching, whether conducted before, after, or before and after exercise, does not produce clinically important reductions in delayed-onset muscle soreness in healthy adults.
One small, short-term trial was eligible for inclusion. We included this study of 25 adults with chronic lung disease (only 32% of people included in the trial had bronchiectasis), as the other conditions were linked to development of bronchiectasis, and all were characterised by chronic sputum production. We were not able to obtain separate data for people with a diagnosis of bronchiectasis. We judged that the study was at a high risk of selection bias. The primary outcome (mean difference in control of bronchiectasis severity, quality of life (Qol), cough scores) was not reported in the included study. The single trial in adults reported a significant reduction in sputum production over 14 days for the treatment group (inhaled indomethacin) compared with the placebo group (mean difference (MD) -75.00 g/day; 95% confidence interval (CI) -134.61 to -15.39) and a significant improvement in the Borg Dyspnoea Scale score (MD -1.90, 95% CI -3.15 to -0.65). We noted no significant differences between groups in lung function or blood indices and no reported adverse events. No new studies of adults or children have been conducted since the last version of this review was published. Therefore, final conclusions have not changed. Current evidence is insufficient to support or refute the use of inhaled NSAIDs for the management of bronchiectasis in adults or children. One small trial reported a reduction in sputum production and improved dyspnoea among adults with chronic lung disease who were treated with inhaled indomethacin, indicating that additional studies on the efficacy of NSAIDs for treatment of patients with bronchiectasis are warranted.
We included six single-site trials in rehabilitation settings, involving 338 participants. Four trials included people with only stroke. All studies provided sensory stimulation, sometimes with another intervention. Sensory stimulation typically involved practising tasks that required visuo-perceptual processing with occupational therapist assistance. Repetition was never used and only one study included functional training. No trials provided data on longer term improvement in ADL scores. Only three trials provided any data suitable for analysis. Two of these trials compared active to placebo intervention. There was no evidence of a difference in ADL scores at the scheduled end of intervention: mean difference (95% confidence interval (CI)) was 0.9 (-1.6 to 3.5) points on a self-care ADL scale in one study and odds ratio (95% CI) was 1.3 (0.56 to 3.1) for passing a driving test in the other, both in favour of active intervention. The trial that compared two active interventions did not find evidence of difference in any of the review outcomes. There is insufficient evidence to support or refute the view that perceptual interventions are effective. Future studies should be sufficiently large, include a standard care comparison and measure longer term functional outcomes. People with impaired perception problems should continue to receive neurorehabilitation according to clinical guidelines.
Thirty-eight studies fulfilled the inclusion criteria. Rectal 5-ASA was superior to placebo for inducing symptomatic, endoscopic and histological improvement and remission, with POR for symptomatic improvement 8.87 (8 trials, 95% CI: 5.30 to 14.83; P < 0.00001), endoscopic improvement 11.18 (5 trials, 95% CI 5.99 to 20.88; P < 0.00001), histologic improvement 7.69 (6 trials, 95% CI 3.26 to 18.12; P < 0.00001), symptomatic remission 8.30 (8 trials, 95% CI 4.28 to 16.12; P < 0.00001), endoscopic remission 5.31 (7 trials, 95% CI 3.15 to 8.92; P < 0.00001), and histologic remission 6.28 (5 trials, 95% CI 2.74 to 14.40; P < 0.0001). Rectal 5-ASA was superior to rectal corticosteroids for inducing symptomatic improvement and remission with POR 1.56 (6 trials, 95% CI 1.15 to 2.11; P = 0.004) and 1.65 (6 trials, 95% CI 1.11 to 2.45; P = 0.01), respectively. Rectal 5-ASA was not superior to oral 5-ASA for symptomatic improvement (POR 2.25; 95% CI 0.53 to 19.54; P = 0.27). Neither total daily dose nor 5-ASA formulation affected treatment response. Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus standardization of outcome measurements for clinical trials in ulcerative colitis.
Twenty-one trials (n = 3286) were included in the review. Seventeen trials (n = 2617) were included in the meta-analysis. Antispasmodics used included valethamate bromide, hyoscine butyl-bromide, drotaverine hydrochloride, rociverine and camylofin dihydrochloride. Most studies included antispasmodics as part of their package of active management of labour. Overall, the quality of studies was poor, as only four trials were assessed as low risk of bias. Thirteen trials (n = 1995) reported on the duration of first stage of labour, which was significantly reduced by an average of 74.34 minutes when antispasmodics were administered (mean difference (MD) -74.34 minutes; 95% confidence Interval (CI) -98.76 to -49.93). Seven studies (n = 797) reported on the total duration of labour, which was significantly reduced by an average of 85.51 minutes (MD -85.51 minutes; 95% CI -121.81 to -49.20). Six studies (n = 820) had data for the outcome: rate of cervical dilatation. Administration of antispasmodics significantly increased the rate of cervical dilatation by an average of 0.61 cm/hour (MD 0.61 cm/hour; 95% CI 0.34 to 0.88). Antispasmodics did not affect the duration of second and third stage of labour. The rate of normal vertex deliveries was not affected either. Only one study explored pain relief following administration of antispasmodics and no conclusions can be drawn on this outcome. There was significant heterogeneity for most outcomes and therefore, we undertook random-effects meta-analysis. Subgroup analysis was undertaken to explore heterogeneity, but remained largely unexplained. Maternal and neonatal adverse events were reported inconsistently. The main maternal adverse event reported was tachycardia. No serious neonatal adverse events were reported. There is low quality evidence that antispasmodics reduce the duration of first stage of labour and increase the cervical dilatation rate. There is very low quality evidence that antispasmodics reduce the total duration of labour. There is moderate quality evidence that antispasmodics do not affect the rate of normal vertex deliveries. There is insufficient evidence to make any conclusions regarding the safety of these drugs for both mother and baby. Large, rigorous randomised controlled trials are needed to evaluate the effect of antispasmodics on prolonged labour and to evaluate their effect on labour in a context of expectant management of labour.
Two studies with a combined total of 288 participants met the inclusion criteria for this review. One study compared low molecular weight heparin with unfractionated heparin and found no difference between the treatments in the prevention of DVT (odds ratio (OR) 1.23, 95% confidence interval (CI) 0.28 to 5.35). No bleeding events or deaths occurred. This study was open label and therefore at a high risk of performance bias. Additionally, the method of randomisation was not reported and therefore the risk of selection bias was unclear. In the second study heparin did not significantly improve prevention of pulmonary embolism (OR 1.02, 95% CI 0.44 to 2.37) when compared to placebo. Furthermore, when the level of amputation was considered, the incidence of pulmonary embolism was similar between the two treatment groups: above knee amputation (OR 0.79, 95% CI 0.31 to 1.97) and below knee amputation (OR 1.53, 95% CI 0.09 to 26.43). Ten participants died during the study; five underwent a post-mortem and three were found to have had a recent pulmonary embolism, all of whom had been on placebo. Bleeding events were reported in less than 10% of participants in both treatment groups but specific data were not presented. This study did not report the methods used to conceal allocation of treatment and therefore it was unclear if selection bias occurred. However, this study appeared to be free from all other sources of bias. No study looked at mechanical prophylaxis. As only two studies were included in this review, each comparing different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in patients undergoing lower limb amputation. Further large-scale studies that are of good quality are required.
In this updated review, one new ongoing study was found but no new eligible completed studies were identified. This update was therefore conducted using the same four studies included in the original review. These studies included a total of 1219 participants, mean age 40 to 54 years. All included studies were reported as RCTs. Two were multicentred, together including a total of 1114 patients who underwent cerebral aneurysm clipping, and were judged to have an overall low risk of bias. The other two studies were single centred. One included 80 patients who had a craniotomy following severe traumatic brain injury and was judged to have an unclear or low risk of bias. The other study included 25 patients who underwent hemicranicectomy to relieve oedema following cerebral infarction and was judged to have an unclear or high risk of bias. All studies assessed hypothermia versus normothermia. Overall 608 participants received hypothermia with target temperatures ranging from 32.5 °C to 35 °C, and 611 were assigned to normothermia with the actual temperatures recorded in this group ranging form 36.5 °C to 38 °C. For those who were cooled, 556 had cooling commenced immediately after induction of anaesthesia that was continued until the surgical objective of aneurysm clipping was achieved, and 52 had cooling commenced immediately after surgery and continued for 48 to 96 hours. Pooled estimates of effect were calculated for the outcomes mortality during treatment or follow-up (ranging from in-hospital to one year); neurological outcome measured in terms of the Glasgow Outcome Score (GOS) of 3 or less; and adverse events of infections, myocardial infarction, ischaemic stroke and congestive cardiac failure. With regards to mortality, the risk of dying if allocated to hypothermia compared to normothermia was not statistically significantly different (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.59 to 1.27, P = 0.47). There was no indication that the time at which cooling was started affected the risk of dying (RR with intraoperative cooling 0.95, 95% CI 0.60 to 1.51, P = 0.83; RR for cooling postoperatively 0.67, 95% CI 0.34 to 1.35, P = 0.26). For the neurological outcome, the risk of having a poor outcome with a GOS of 3 or less was not statistically different in those who received hypothermia versus normothermia (RR 0.80, 95% CI 0.61 to 1.04, P = 0.09). Again there was no indication that the time at which cooling was started affected this result. Regarding adverse events, there was no statistically significant difference in the incidence in those allocated to hypothermia versus normothermia for risk of surgical infection (RR 1.20, 95% CI 0.73 to 1.97, P = 0.48), myocardial infarction (RR 1.86, 95% CI 0.69 to 4.98, P = 0.22), ischaemic stroke (RR 0.93, 95% CI 0.82 to 1.05, P = 0.24) or congestive heart failure (RR 0.85, 95% CI 0.60 to 1.21, P = 0.38). In contrast to other outcomes, where time of application of cooling did not change the statistical significance of the effect estimates, there was a weak statistically significant increased risk of infection in those who were cooled postoperatively versus those who were not cooled (RR 1.77, 95% CI 1.05 to 2.98, P = 0.03). Overall, as in the original review, no evidence was found that the use of induced hypothermia was either beneficial or harmful in patients undergoing neurosurgery. We found no evidence that the use of induced hypothermia was associated with a significant reduction in mortality or severe neurological disability, or an increase in harm in patients undergoing neurosurgery.
The 2012 update identified 13 studies classified as ongoing or awaiting classification (yet to report allergy outcomes). Forty-three studies were excluded, primarily as no allergy data were reported, although none of these enrolled infants were at high risk of allergy. Four studies enrolling 1428 infants were eligible for inclusion. All studies were at high risk of attrition bias. Allergy outcomes were reported from four months to two years of age. Meta-analysis of two studies (226 infants) found no significant difference in infant asthma although significant heterogeneity was found between studies. Meta-analysis of four studies found a significant reduction in eczema (1218 infants, typical risk ratio 0.68, 95% CI 0.48 to 0.97; typical risk difference -0.04, 95% CI -0.07 to -0.00; number needed to treat to benefit (NNTB) 25, 95% CI 14 to > 100; P = 0.03). No statistically significant heterogeneity was found between studies. One study reported no significant difference in urticaria. No statistically significant subgroup differences were found according to infant risk of allergy or type of infant feed. However, individual studies reported a significant reduction in asthma and eczema from supplementation with a mixture of galacto- and fructo-oligosaccharide (GOS/FOS 9:1 ratio) (8 g/L) in infants at high risk of allergy; and in eczema from supplementation with GOS/FOS (9:1) (6.8 g/L) and acidic oligosacccharide (1.2 g/L) in infants not selected for allergy risk. Further research is needed before routine use of prebiotics can be recommended for prevention of allergy in formula fed infants. There is some evidence that a prebiotic supplement added to infant feeds may prevent eczema. It is unclear whether the use of prebiotic should be restricted to infants at high risk of allergy or may have an effect in low risk populations; or whether it may have an effect on other allergic diseases including asthma.
We identified 10 published reports of nine original RCTs (one report was a long-term follow-up of the original trial) in over 1100 primary care doctors and around 492,000 patients. The main risk of bias came from participants in most studies knowing whether they had received the intervention or not, and we downgraded the rating of the quality of evidence because of this. We meta-analysed data using a random-effects model on the primary and key secondary outcomes and formally assessed heterogeneity. Remaining outcomes are presented narratively. There is moderate quality evidence that interventions that aim to facilitate shared decision making reduce antibiotic use for ARIs in primary care (immediately after or within six weeks of the consultation), compared with usual care, from 47% to 29%: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55 to 0.68. Reduction in antibiotic prescribing occurred without an increase in patient-initiated re-consultations (RR 0.87, 95% CI 0.74 to 1.03, moderate quality evidence) or a decrease in patient satisfaction with the consultation (OR 0.86, 95% CI 0.57 to 1.30, low quality evidence). There were insufficient data to assess the effects of the intervention on sustained reduction in antibiotic prescribing, adverse clinical outcomes (such as hospital admission, incidence of pneumonia and mortality), or measures of patient and caregiver involvement in shared decision making (such as satisfaction with the consultation; regret or conflict with the decision made; or treatment compliance following the decision). No studies assessed antibiotic resistance in colonising or infective organisms. Interventions that aim to facilitate shared decision making reduce antibiotic prescribing in primary care in the short term. Effects on longer-term rates of prescribing are uncertain and more evidence is needed to determine how any sustained reduction in antibiotic prescribing affects hospital admission, pneumonia and death.
We included five RCTs with a total of 827 participants. Outcomes were available for 730 participants (384 participants randomised to continuous sutures and 346 participants to interrupted sutures). All the trials were of unclear or high risk of bias. The participants underwent abdominal or groin operations. The only outcomes reported in the trials were superficial surgical site infection, superficial wound dehiscence (breakdown) and length of hospital stay. Other important outcomes such as quality of life, long-term patient outcomes and use of healthcare resources were not reported in these trials. Overall, 6.5% (39/602 participants, four trials) developed superficial surgical site infections. There was no significant difference between the groups in the proportion of participants who developed superficial surgical site infections (RR 0.73; 95% CI 0.40 to 1.33). A total of 23 participants (23/625 (3.7%), four trials) developed superficial wound dehiscence. Twenty-two of the 23 participants belonged to the interrupted suture group.The proportion of participants who developed superficial wound dehiscence was statistically significantly lower in the continuous suture group compared to the interrupted suture group (RR 0.08; 95% CI 0.02 to 0.35). Most of these wound dehiscences were reported in two recent trials in which the continuous skin suture groups received absorbable subcuticular sutures while the interrupted skin suture groups received non-absorbable transcutaneous sutures. The non-absorbable sutures were removed seven to nine days after surgery in the interrupted sutures groups whilst sutures in the comparator groups were not removed, being absorbable. The continuous suture technique with absorbable suture does not require suture removal and provides support for the wound for a longer period of time. This may have contributed to the difference between the two groups in the proportion of participants who developed superficial wound dehiscence. There was no significant difference in the length of the hospital stay between the two groups (MD -1.40 days; 95% CI -7.14 to 4.34). Superficial wound dehiscence may be reduced by using continuous subcuticular sutures. However, there is uncertainty about this because of the quality of the evidence. Besides, the nature of the suture material used may have led to this observation, as the continuous suturing technique used suture material that did not need to be removed, whereas the comparator used interrupted (non-absorbable) sutures that did need to be removed. Differences in the methods of skin closure have the potential to affect patient outcomes and use of healthcare resources. Further well-designed trials at low risk of bias are necessary to determine which type of suturing is better.
Six studies (271 patients) were included. Five studies investigated PGE1 with or without fosinopril/losartan versus fosinopril/losartan or no treatment and one compared PGE1 versus Xueshuantong (a Chinese medicinal herb). There was a significant decrease in urinary albumin excretion rate (UAER) in patients treated with PGE1 (MD -48.28 µg/min, 95% CI -75.29 to -21.28), other outcomes also showed a significant decrease in the patients with PGE1 (albuminuria: MD -143.66 mg/24 h, 95% CI -221.48 to -65.84; proteinuria: MD -300 g/24 h, 95% CI -518.34 to -81.66). PGE1 had a positive effect on albuminuria (MD -660 mg/24 h, 95% CI -867.07 to -452.93) in clinical DKD (CDN, III stage of DN) compared with Xueshuantong. No data on incidence of ESKD, all-cause mortality or quality of life were available. PGE1 may have positive effects on DKD by reducing UAER, decreasing albuminuria and lessening proteinuria, with no obvious serious adverse events. However, limited by the poor methodological quality of the included studies and the small number of participants, there is currently insufficient evidence for determining if PGE1 could be used for preventing the progression of DKD. Large, properly randomised, placebo-controlled, double-blind studies are urgently needed.
The search found 17 studies that assessed the effect of higher versus lower intake of PUFAs on allergic outcomes in infants. Only nine studies enrolling 2704 infants reported allergy outcomes that could be used in meta-analyses. Of these, there were methodological concerns for eight. In infants up to two years of age, meta-analyses found no difference in incidence of all allergy (1 study, 323 infants; RR 0.96, 95% CI 0.73 to 1.26; risk difference (RD) -0.02, 95% CI -0.12 to 0.09; heterogeneity not applicable), asthma (3 studies, 1162 infants; RR 1.04, 95% CI 0.80 to 1.35, I2 = 0%; RD 0.01, 95% CI -0.04 to 0.05, I2 = 0%), dermatitis/eczema (7 studies, 1906 infants; RR 0.93, 95% CI 0.82 to 1.06, I2 = 0%; RD -0.02, 95% CI -0.06 to 0.02, I2 = 0%) or food allergy (3 studies, 915 infants; RR 0.81, 95% CI 0.56 to 1.19, I2 = 63%; RD -0.02, 95% CI -0.06 to 0.02, I2 = 74%). There was a reduction in allergic rhinitis (2 studies, 594 infants; RR 0.47, 95% CI 0.23 to 0.96, I2 = 6%; RD -0.04, 95% CI -0.08 to -0.00, I2 = 54%; number needed to treat for an additional beneficial outcome (NNTB) 25, 95% CI 13 to ∞). In children aged two to five years, meta-analysis found no difference in incidence of all allergic disease (2 studies, 154 infants; RR 0.69, 95% CI 0.47 to 1.02, I2 = 43%; RD -0.16, 95% CI -0.31 to -0.00, I2 = 63%; NNTB 6, 95% CI 3 to ∞), asthma (1 study, 89 infants; RR 0.45, 95% CI 0.20 to 1.02; RD -0.20, 95% CI -0.37 to -0.02; heterogeneity not applicable; NNTB 5, 95% CI 3 to 50), dermatitis/eczema (2 studies, 154 infants; RR 0.65, 95% CI 0.34 to 1.24, I2 = 0%; RD -0.09 95% CI -0.22 to 0.04, I2 = 24%) or food allergy (1 study, 65 infants; RR 2.27, 95% CI 0.25 to 20.68; RD 0.05, 95% CI -0.07 to 0.16; heterogeneity not applicable). In children aged two to five years, meta-analysis found no difference in prevalence of all allergic disease (2 studies, 633 infants; RR 0.98, 95% CI 0.81 to 1.19, I2 = 36%; RD -0.01, 95% CI -0.08 to 0.07, I2 = 0%), asthma (2 studies, 635 infants; RR 1.12, 95% CI 0.82 to 1.53, I2 = 0%; RD 0.02, 95% CI -0.04 to 0.09, I2 = 0%), dermatitis/eczema (2 studies, 635 infants; RR 0.81, 95% CI 0.59 to 1.09, I2 = 0%; RD -0.04 95% CI -0.11 to 0.02, I2 = 0%), allergic rhinitis (2 studies, 635 infants; RR 1.02, 95% CI 0.83 to 1.25, I2 = 0%; RD 0.01, 95% CI -0.06 to 0.08, I2 = 0%) or food allergy (1 study, 119 infants; RR 0.27, 95% CI 0.06 to 1.19; RD -0.10, 95% CI -0.20 to -0.00; heterogeneity not applicable; NNTB 10, 95% CI 5 to ∞). There is no evidence that PUFA supplementation in infancy has an effect on infant or childhood allergy, asthma, dermatitis/eczema or food allergy. However, the quality of evidence was very low. There was insufficient evidence to determine an effect on allergic rhinitis.
We identified 12 studies of patients commencing warfarin for inclusion in the review. The overall risk of bias was found to be variable, with most studies reporting adequate methods for randomisation but only two studies reporting adequate data on allocation concealment. Four studies (355 patients) compared 5 mg versus 10 mg loading doses. All four studies reported INR in-range by day five. Although there was notable heterogeneity, pooling of these four studies showed no overall difference between 5 mg versus 10 mg loading doses (RR 1.17, 95% CI 0.77 to 1.77, P = 0.46, I2 = 83%). Two of these studies used two consecutive INRs in-range as the outcome and showed no difference between a 5 mg and 10 mg dose by day five (RR 0.86, 95% CI 0.62 to 1.19, P = 0.37, I2 = 22%); two other studies used a single INR in-range as the outcome and showed a benefit for the 10 mg initiation dose by day 5 (RR 1.49, 95% CI 1.01 to 2.21, P = 0.05, I2 = 72%). Two studies compared a 5 mg dose to other doses: a 2.5 mg initiation dose took longer to achieve the therapeutic range (2.7 versus 2.0 days; P < 0.0001), but those receiving a calculated initiation dose achieved a target range quicker (4.2 days versus 5 days, P = 0.007). Two studies compared age adjusted doses to 10 mg initiation doses. More elderly patients receiving an age adjusted dose achieved a stable INR compared to those receiving a 10 mg initial dose (and Fennerty regimen). Four studies used genotype guided dosing in one arm of each trial. Three studies reported no overall differences; the fourth study, which reported that the genotype group spent significantly more time in-range (P < 0.001), had a control group whose INRs were significantly lower than expected. No clear impacts from adverse events were found in either arm to make an overall conclusion. The studies in this review compared loading doses in several different situations. There is still considerable uncertainty between the use of a 5 mg and a 10 mg loading dose for the initiation of warfarin. In the elderly, there is some evidence that lower initiation doses or age adjusted doses are more appropriate, leading to fewer high INRs. However, there is insufficient evidence to warrant genotype guided initiation.
This review includes two studies. The previous review included one RCT with a parallel-group design, which was conducted in a dental hospital setting in the United Kingdom; our new search for this update identified one prospective cohort study conducted in the private sector in the USA. Primary outcome No eligible studies in this review reported the effects of removal compared with retention of asymptomatic disease-free impacted wisdom teeth on health-related quality of life Secondary outcomes We found only low to very low quality evidence of the effects of removal compared with retention of asymptomatic disease-free impacted wisdom teeth for a limited number of secondary outcome measures. One prospective cohort study, reporting data from a subgroup of 416 healthy male participants, aged 24 to 84 years, compared the effect of the absence (previous removal or agenesis) against the presence of asymptomatic disease-free impacted wisdom teeth on periodontitis and caries associated with the distal of the adjacent second molar during a follow-up period of three to over 25 years. Very low quality evidence suggests that the presence of asymptomatic disease-free impacted wisdom teeth may be associated with increased risk of periodontitis affecting the adjacent second molar in the long term. In the same study, which is at serious risk of bias, there is insufficient evidence to demonstrate a difference in caries risk associated with the presence or absence of impacted wisdom teeth. One RCT with 164 randomised and 77 analysed adolescent participants compared the effect of extraction with retention of asymptomatic disease-free impacted wisdom teeth on dimensional changes in the dental arch after five years. Participants (55% female) had previously undergone orthodontic treatment and had 'crowded' wisdom teeth. No evidence from this study, which was at high risk of bias, was found to suggest that removal of asymptomatic disease-free impacted wisdom teeth has a clinically significant effect on dimensional changes in the dental arch. The included studies did not measure our other secondary outcomes: costs, other adverse events associated with retention of asymptomatic disease-free impacted wisdom teeth (pericoronitis, root resorption, cyst formation, tumour formation, inflammation/infection) and adverse effects associated with their removal (alveolar osteitis/postoperative infection, nerve injury, damage to adjacent teeth during surgery, bleeding, osteonecrosis related to medication/radiotherapy, inflammation/infection). Insufficient evidence is available to determine whether or not asymptomatic disease-free impacted wisdom teeth should be removed. Although asymptomatic disease-free impacted wisdom teeth may be associated with increased risk of periodontitis affecting adjacent second molars in the long term, the evidence is of very low quality. Well-designed RCTs investigating long-term and rare effects of retention and removal of asymptomatic disease-free impacted wisdom teeth, in a representative group of individuals, are unlikely to be feasible. In their continuing absence, high quality, long-term prospective cohort studies may provide valuable evidence in the future. Given the lack of available evidence, patient values should be considered and clinical expertise used to guide shared decision making with patients who have asymptomatic disease-free impacted wisdom teeth. If the decision is made to retain asymptomatic disease-free impacted wisdom teeth, clinical assessment at regular intervals to prevent undesirable outcomes is advisable.
We included 32 studies involving a total of 748 participants aged above 18 with acute, postacute or chronic ischaemic or haemorrhagic stroke. We also identified 55 ongoing studies. The risk of bias did not differ substantially for different comparisons and outcomes. We found nine studies with 396 participants examining the effects of tDCS versus sham tDCS (or any other passive intervention) on our primary outcome measure, ADLs after stroke. We found evidence of effect regarding ADL performance at the end of the intervention period (standardised mean difference (SMD) 0.24, 95% confidence interval (CI) 0.03 to 0.44; inverse variance method with random-effects model; moderate quality evidence). Six studies with 269 participants assessed the effects of tDCS on ADLs at the end of follow-up, and found improved ADL performance (SMD 0.31, 95% CI 0.01 to 0.62; inverse variance method with random-effects model; moderate quality evidence). However, the results did not persist in a sensitivity analysis including only trials of good methodological quality. One of our secondary outcome measures was upper extremity function: 12 trials with a total of 431 participants measured upper extremity function at the end of the intervention period, revealing no evidence of an effect in favour of tDCS (SMD 0.01, 95% CI -0.48 to 0.50 for studies presenting absolute values (low quality evidence) and SMD 0.32, 95% CI -0.51 to 1.15 (low quality evidence) for studies presenting change values; inverse variance method with random-effects model). Regarding the effects of tDCS on upper extremity function at the end of follow-up, we identified four studies with a total of 187 participants (absolute values) that showed no evidence of an effect (SMD 0.01, 95% CI -0.48 to 0.50; inverse variance method with random-effects model; low quality evidence). Ten studies with 313 participants reported outcome data for muscle strength at the end of the intervention period, but in the corresponding meta-analysis there was no evidence of an effect. Three studies with 156 participants reported outcome data on muscle strength at follow-up, but there was no evidence of an effect. In six of 23 studies (26%), dropouts, adverse events or deaths that occurred during the intervention period were reported, and the proportions of dropouts and adverse events were comparable between groups (risk difference (RD) 0.01, 95% CI -0.02 to 0.03; Mantel-Haenszel method with random-effects model; low quality evidence; analysis based only on studies that reported either on dropouts, or on adverse events, or on both). However, this effect may be underestimated due to reporting bias. At the moment, evidence of very low to moderate quality is available on the effectiveness of tDCS (anodal/cathodal/dual) versus control (sham/any other intervention) for improving ADL performance after stroke. However, there are many ongoing randomised trials that could change the quality of evidence in the future. Future studies should particularly engage those who may benefit most from tDCS after stroke and in the effects of tDCS on upper and lower limb function, muscle strength and cognitive abilities (including spatial neglect). Dropouts and adverse events should be routinely monitored and presented as secondary outcomes. They should also address methodological issues by adhering to the Consolidated Standards of Reporting Trials (CONSORT) statement.
Thirteen studies (2032 participants) were included. Six studies (654 patients) reported symptomatic UTI and eight studies (796 patients) reported bacteriuria. Overall, study quality was mixed. The overall pooled estimates for the major outcome measures were not interpretable because of underlying heterogeneity. Subgroup analyses suggested that methenamine hippurate may have some benefit in patients without renal tract abnormalities (symptomatic UTI: RR 0.24, 95% CI 0.07 to 0.89; bacteriuria: RR 0.56, 95% CI 0.37 to 0.83), but not in patients with known renal tract abnormalities (symptomatic UTI: RR 1.54, 95% CI 0.38 to 6.20; bacteriuria: RR 1.29, 95% CI 0.54 to 3.07). For short-term treatment duration (1 week or less) there was a significant reduction in symptomatic UTI in those without renal tract abnormalities (RR 0.14, 95% CI 0.05 to 0.38). The rate of adverse events was low. Methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, particularly when used for short-term prophylaxis. It does not appear to work in patients with neuropathic bladder or in patients who have renal tract abnormalities. The rate of adverse events was low, but poorly described. There is a need for further large well-conducted RCTs to clarify this question, particularly for longer term use for people without neuropathic bladder.
All three studies fulfilling the entry criteria had limitations, including possible or definite bias. There was substantial heterogeneity among studies.  Furosemide administration did not significantly increase the risk of failure of ductal closure; however, sample size was insufficient to rule out even a 31% increase. In the subset with initial BUN/creatinine ratio > 20 mg/mg, two of 18 patients receiving furosemide could not complete a three-dose course of indomethacin because of toxicity. Minimal or no information was available about any of the other main outcome variables. Furosemide increased urine output regardless of the initial BUN/creatinine ratio, leading to a 5% weight loss during a three-dose course, an undesired effect in patients with initial BUN/creatinine ratio > 20 mg/mg. Furosemide increased creatinine clearance only in patients with initial BUN/creatinine ratio < 20 mg/mg. There is not enough evidence to support the administration of furosemide to premature infants treated with indomethacin for symptomatic patent ductus arteriosus. Furosemide appears to be contraindicated in the presence of dehydration in those infants.
All 61 included studies were observational studies with some methodological limitations; randomized trials were absent. The studies presented data on 15,077 women with a wide range of risk factors for breast cancer, who underwent RRM. Twenty-one BRRM studies looking at the incidence of breast cancer or disease-specific mortality, or both, reported reductions after BRRM, particularly for those women with BRCA1/2 mutations. Twenty-six CRRM studies consistently reported reductions in incidence of contralateral breast cancer but were inconsistent about improvements in disease-specific survival. Seven studies attempted to control for multiple differences between intervention groups and showed no overall survival advantage for CRRM. Another study showed significantly improved survival following CRRM, but after adjusting for bilateral risk-reducing salpingo-oophorectomy (BRRSO), the CRRM effect on all-cause mortality was no longer significant. Twenty studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have RRM but greater variation in satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BRRM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BRRM, but there was diminished satisfaction with body image and sexual feelings. Seventeen case series reporting on adverse events from RRM with or without reconstruction reported rates of unanticipated reoperations from 4% in those without reconstruction to 64% in participants with reconstruction. In women who have had cancer in one breast, removing the other breast may reduce the incidence of cancer in that other breast, but there is insufficient evidence that this improves survival because of the continuing risk of recurrence or metastases from the original cancer. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention, when considering RRM. While published observational studies demonstrated that BRRM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies are suggested. BRRM should be considered only among those at high risk of disease, for example, BRCA1/2 carriers. CRRM was shown to reduce the incidence of contralateral breast cancer, but there is insufficient evidence that CRRM improves survival, and studies that control for multiple confounding variables are recommended. It is possible that selection bias in terms of healthier, younger women being recommended for or choosing CRRM produces better overall survival numbers for CRRM. Given the number of women who may be over-treated with BRRM/CRRM, it is critical that women and clinicians understand the true risk for each individual woman before considering surgery. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention when considering RRM.
We included and analysed 140 studies for this review. In the main analyses, a total of 108 comparisons from 70 studies compared any intervention in which audit and feedback was a core, essential component to usual care and evaluated effects on professional practice. After excluding studies at high risk of bias, there were 82 comparisons from 49 studies featuring dichotomous outcomes, and the weighted median adjusted RD was a 4.3% (interquartile range (IQR) 0.5% to 16%) absolute increase in healthcare professionals' compliance with desired practice. Across 26 comparisons from 21 studies with continuous outcomes, the weighted median adjusted percent change relative to control was 1.3% (IQR = 1.3% to 28.9%). For patient outcomes, the weighted median RD was -0.4% (IQR -1.3% to 1.6%) for 12 comparisons from six studies reporting dichotomous outcomes and the weighted median percentage change was 17% (IQR 1.5% to 17%) for eight comparisons from five studies reporting continuous outcomes. Multivariable meta-regression indicated that feedback may be more effective when baseline performance is low, the source is a supervisor or colleague, it is provided more than once, it is delivered in both verbal and written formats, and when it includes both explicit targets and an action plan. In addition, the effect size varied based on the clinical behaviour targeted by the intervention. Audit and feedback generally leads to small but potentially important improvements in professional practice. The effectiveness of audit and feedback seems to depend on baseline performance and how the feedback is provided. Future studies of audit and feedback should directly compare different ways of providing feedback.
Combining data from 425 reports (307,028 abstracts) resulted in an overall full publication proportion of 37.3% (95% confidence interval (CI), 35.3% to 39.3%) with varying lengths of follow-up. This is significantly lower than that found in our 2007 review (44.5%. 95% CI, 43.9% to 45.1%). Using a survival analyses to estimate the proportion of abstracts that would be published in full by 10 years produced proportions of 46.4% for all studies; 68.7% for randomized and controlled trials and 44.9% for other studies. Three hundred and fifty-three reports were at high risk of bias on one or more items, but only 32 reports were considered at high risk of bias overall. Forty-five reports (15,783 abstracts) with 'positive' results (defined as any 'significant' result) showed an association with full publication (RR = 1.31; 95% CI 1.23 to 1.40), as did 'positive' results defined as a result favoring the experimental treatment (RR =1.17; 95% CI 1.07 to 1.28) in 34 reports (8794 abstracts). Results emanating from randomized or controlled trials showed the same pattern for both definitions (RR = 1.21; 95% CI 1.10 to 1.32 (15 reports and 2616 abstracts) and RR = 1.17; 95% CI, 1.04 to 1.32 (13 reports and 2307 abstracts), respectively. Other factors associated with full publication include oral presentation (RR = 1.46; 95% CI 1.40 to 1.52; studied in 143 reports with 115,910 abstracts); acceptance for meeting presentation (RR = 1.65; 95% CI 1.48 to 1.85; 22 reports with 22,319 abstracts); randomized trial design (RR = 1.51; 95% CI 1.36 to 1.67; 47 reports with 28,928 abstracts); and basic research (RR = 0.78; 95% CI 0.74 to 0.82; 92 reports with 97,372 abstracts). Abstracts originating at an academic setting were associated with full publication (RR = 1.60; 95% CI 1.34 to 1.92; 34 reports with 16,913 abstracts), as were those considered to be of higher quality (RR = 1.46; 95% CI 1.23 to 1.73; 12 reports with 3364 abstracts), or having high impact (RR = 1.60; 95% CI 1.41 to 1.82; 11 reports with 6982 abstracts). Sensitivity analyses excluding reports that were abstracts themselves or classified as having a high risk of bias did not change these findings in any important way. In considering the reports of the methodology research that we included in this review, we found that reports published in English or from a native English-speaking country found significantly higher proportions of studies published in full, but that there was no association with year of report publication. The findings correspond to a proportion of abstracts published in full of 31.9% for all reports, 40.5% for reports in English, 42.9% for reports from native English-speaking countries, and 52.2% for both these covariates combined. More than half of results from abstracts, and almost a third of randomized trial results initially presented as abstracts fail to be published in full and this problem does not appear to be decreasing over time. Publication bias is present in that 'positive' results were more frequently published than 'not positive' results. Reports of methodology research written in English showed that a higher proportion of abstracts had been published in full, as did those from native English-speaking countries, suggesting that studies from non-native English-speaking countries may be underrepresented in the scientific literature. After the considerable work involved in adding in the more than 300 additional studies found by the February 2016 searches, we chose not to update the search again because additional searches are unlikely to change these overall conclusions in any important way.
We included one RCT (56 eyes of 55 participants) in this review. The study compared two types of topical biguanides for the treatment of AK: chlorhexidine 0.02% and polyhexamethylene biguanide (PHMB) 0.02%. All participants were contact lens wearers with a median age of 31 years. Treatment duration ranged from 51 to 145 days. The study, conducted in the UK, was well-designed and had low risk of bias overall. Outcome data were available for 51 (91%) of 56 eyes. Follow-up times for outcome measurements in the study were not reported. Resolution of infection, defined as control of ocular inflammation, relief of pain and photosensitivity, and recovery of vision, was 86% in the chlorhexidine group compared with 78% in the PHMB group (relative risk (RR) 1.10, 95% confidence intervals (CI) 0.84 to 1.42). In the chlorhexidine group, 20 of 28 eyes (71%) had better visual acuity compared with 13 of 23 eyes (57%) in the PHMB group at final follow-up (RR 1.26, 95% CI 0.82 to 1.94). Five participants required therapeutic keratoplasty: 2 in the chlorhexidine group compared with 3 in the PHMB group (RR 0.55, 95% CI 0.10 to 3.00). No serious adverse event related to drug toxicity was observed in the study. There is insufficient evidence to evaluate the relative effectiveness and safety of medical therapy for the treatment of AK. Results from the one included study yielded no difference with respect to outcomes reported between chlorhexidine and PHMB. However, the sample size was inadequate to detect clinically meaningful differences between the two groups as indicated by the wide confidence intervals of effect estimates.
We identified one study, which was set in Australia, that met the inclusion criteria. This was a randomised, double-blind, placebo-controlled, cross-over trial in 16 children (10 boys and 6 girls) with predominant dystonic cerebral palsy and a mean age of 9 years (standard deviation 4.3 years, range 2 to 17 years). We considered the trial to be at low risk of selection, performance, detection, attrition, reporting and other sources of bias. We rated the GRADE quality of the evidence as low. We found no difference in mean follow-up scores for change in dystonia as measured by the Barry Albright Dystonia Scale (BADS), which assesses eight body regions for dystonia on a 5-point scale (0 = none to 4 = severe), resulting in a total score of 0 to 32. The BADS score was 2.67 points higher (95% confidence interval (CI) −2.55 to 7.90; low-quality evidence), that is, worse dystonia, in the treated group. Trihexyphenidyl may be associated with an increased risk of adverse effects (risk ratio 2.54, 95% CI 1.38 to 4.67; low-quality evidence). There was no difference in mean follow-up scores for upper limb function as measured by the Quality of Upper Extremity Skills Test, which has four domains that collectively assess 36 items (each scored 1 or 2) and produces a total score of 0 to 100. The score in the treated group was 4.62 points lower (95% CI −10.98 to 20.22; low-quality evidence), corresponding to worse function, than in the control group. We found low-quality evidence for improved participation (as represented by higher scores) in the treated group in activities of daily living, as measured by three tools: 18.86 points higher (95% CI 5.68 to 32.03) for the Goal Attainment Scale (up to five functional goals scored on 5-point scale (−2 = much less than expected to +2 = much more than expected)), 2.91 points higher (95% CI 1.01 to 4.82) for the satisfaction subscale of the Canadian Occupational Performance Measure (COPM; satisfaction with performance in up to five problem areas scored on a 10-point scale (1 = not satisfied at all to 10 = extremely satisfied)), and 2.24 points higher (95% CI 0.64 to 3.84) for performance subscale of the COPM (performance in up to five problem areas scored on a 10-point scale (1 = not able to do to; 10 = able to do extremely well)). The study did not report on pain or quality of life. At present, there is insufficient evidence regarding the effectiveness of trihexyphenidyl for people with cerebral palsy for the outcomes of: change in dystonia, adverse effects, increased upper limb function and improved participation in activities of daily living. The study did not measure pain or quality of life. There is a need for larger randomised, controlled, multicentre trials that also examine the effect on pain and quality of life in order to determine the effectiveness of trihexyphenidyl for people with cerebral palsy.
One new trial was identified and included in this update bringing the total to eight trials involving 787 women. Three small trials compared a mechanical device with no treatment and although they suggested that use of a mechanical device might be better than no treatment, the evidence for this was inconclusive. Four trials compared one mechanical device with another. Quantitative synthesis of data from these trials was not possible because different mechanical devices were compared in each trial using different outcome measures. Data from the individual trials showed no clear difference between devices, but with wide confidence intervals. One trial compared three groups: a mechanical device alone, behavioural therapy (pelvic floor muscle training) alone and behavioural therapy combined with a mechanical device. While at three months there were more withdrawals from the device-only group, at 12 months differences between the groups were not sustained on any measure. The place of mechanical devices in the management of urinary incontinence remains in question. Currently there is little evidence from controlled trials on which to judge whether their use is better than no treatment and large well-conducted trials are required for clarification. There was also insufficient evidence in favour of one device over another and little evidence to compare mechanical devices with other forms of treatment.
We included four studies (152 participants), with a follow-up duration ranging from three months to 12 months. In two studies patients acted as self-controls, i.e. one side of the nose underwent debridement and the other side did not ('split-nose' studies). The risk of bias in all studies was high, mostly due to the inability to blind the patients to the debridement procedure. Primary outcomes Disease-specific health-related quality of life scores Only one study (58 participants) provided data for disease-specific health-related quality of life. At six months follow-up, lower disease-specific health-related quality of life scores, measured using the Sino-Nasal Outcome Test-22 (SNOT-22, range 0 to 110), were noted in the debridement group but the difference was not statistically significant (9.7 in the debridement group versus 10.3 in the control group, P = 0.47) (low-quality evidence). Disease severity (patient-reported symptom score) Only one study (60 participants) provided data for disease severity measured by visual analogue scale (VAS) score. No significant differences in total symptom score were observed between groups postoperatively (low-quality evidence). Significant adverse effects Significant adverse effects related to the debridement procedure were not reported in any of the included studies, however it is not clear whether data regarding adverse effects were not collected or if none were indeed observed in any of the included studies. Secondary outcomes All four studies assessed thepostoperative endoscopic appearance of the sinonasal cavities using the Lund-Kennedy score (range 0 to 10). A pooled analysis of endoscopic scores in the two non 'split-nose' studies revealed better endoscopic scores in the debridement group, however this was not a statistically significant difference (mean difference -0.31, 95% confidence interval (CI) -1.35 to 0.72; I² = 0%; two studies; 118 participants) (low-quality evidence). A sub-analysis of the adhesion formation component of the endoscopic score was available for all four studies and revealed a significantly lower adhesion rate in the debridement group (risk ratio 0.43, 95% CI 0.28 to 0.68; I² = 29%; four studies; 152 participants). Analysis of the number needed to treat to benefit revealed that for every three patients undergoing debridement, the endoscopic score would be decreased by one point in one patient. For every five patients undergoing debridement adhesion formation would be prevented in one patient. Use of postoperative medical treatment was reported in all studies, all of which recommended nasal douching. Steroids (systemic or nasal) were administered in two studies. However, the data were very limited and heterogeneous, therefore we could not analyse the impact of concomitant postoperative medical treatment. The rate of revision surgery was not reported in any of the included studies, however it is not clear whether these data were not recorded or if there were no revision surgeries in any of the included studies. We are uncertain about the effects of postoperative sinonasal debridement due to high risk of bias in the included studies and the low quality of the evidence. Sinonasal debridement may make little or no difference to disease-specific health-related quality of life or disease severity. Low-quality evidence suggests that postoperative debridement is associated with a significantly lower risk of adhesions at three months follow-up. Whether this has any impact on longer-term outcomes is unknown.
We reviewed 106 reports of 35 trials, published between 1931 and 2015. We included 19 trials including over 310,000 women, excluded 15 trials and one is ongoing. Overall, seven trials were judged to be of low risk of bias, three were high risk of bias and for nine it was unclear. 1) Vitamin A alone versus placebo or no treatment Overall, when trial results are pooled, vitamin A supplementation does not affect the risk of maternal mortality (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.65 to 1.20; four trials Ghana, Nepal, Bangladesh, UK, high quality evidence), perinatal mortality (RR 1.01, 95% CI 0.95 to 1.07; one study, high quality evidence), neonatal mortality, stillbirth, neonatal anaemia, preterm birth (RR 0.98, 95% CI 0.94 to 1.01, five studies, high quality evidence), or the risk of having a low birthweight baby. Vitamin A supplementation reduces the risk of maternal night blindness (RR 0.79, 95% CI 0.64 to 0.98; two trials). There is evidence that vitamin A supplements may reduce maternal clinical infection (RR 0.45, 95% CI 0.20 to 0.99, five trials; South Africa, Nepal, Indonesia, Tanzania, UK, low quality evidence) and maternal anaemia (RR 0.64, 95% CI 0.43 to 0.94; three studies, moderate quality evidence). 2) Vitamin A alone versus micronutrient supplements without vitamin A Vitamin A alone compared to micronutrient supplements without vitamin A does not decrease maternal clinical infection (RR 0.99, 95% CI 0.83 to 1.18, two trials, 591 women). No other primary or secondary outcomes were reported 3) Vitamin A with other micronutrients versus micronutrient supplements without vitamin A Vitamin A supplementation (with other micronutrients) does not decrease perinatal mortality (RR 0.51, 95% CI 0.10 to 2.69; one study, low quality evidence), maternal anaemia (RR 0.86, 95% CI 0.68 to 1.09; three studies, low quality evidence), maternal clinical infection (RR 0.95, 95% CI 0.80 to 1.13; I² = 45%, two studies, low quality evidence) or preterm birth (RR 0.39, 95% CI 0.08 to 1.93; one study, low quality evidence). In HIV-positive women vitamin A supplementation given with other micronutrients was associated with fewer low birthweight babies (< 2.5 kg) in the supplemented group in one study (RR 0.67, 95% CI 0.47 to 0.96; one study, 594 women). The pooled results of three large trials in Nepal, Ghana and Bangladesh (with over 153,500 women) do not currently suggest a role for antenatal vitamin A supplementation to reduce maternal or perinatal mortality. However, the populations studied were probably different with regard to baseline vitamin A status and there were problems with follow-up of women. There is good evidence that antenatal vitamin A supplementation reduces maternal night blindness, maternal anaemia for women who live in areas where vitamin A deficiency is common or who are HIV-positive. In addition the available evidence suggests a reduction in maternal infection, but these data are not of a high quality.
We identified seven studies that met inclusion criteria for this review. Three were recorded as completed (or terminated) but no results were published. Of the remaining four studies (299 participants): two investigated liposomal bupivacaine transversus abdominis plane (TAP) block, one liposomal bupivacaine dorsal penile nerve block, and one ankle block. The study investigating liposomal bupivacaine ankle block was a Phase II dose-escalating/de-escalating trial presenting pooled data that we could not use in our analysis. The studies did not report our primary outcome, cumulative pain score between 0 and 72 hours, and secondary outcomes, mean pain score at 12, 24, 48, 72, or 96 hours. One study reported no difference in mean pain score during the first, second, and third postoperative 24-hour periods in participants receiving liposomal bupivacaine TAP block compared to no TAP block. Two studies, both in people undergoing laparoscopic surgery under TAP block, investigated cumulative postoperative opioid dose, reported opposing findings. One found a lower cumulative opioid consumption between 0 and 72 hours compared to bupivacaine hydrochloride TAP block and one found no difference during the first, second, and third postoperative 24-hour periods compared to no TAP block. No studies reported time to first postoperative opioid or percentage not requiring opioids over the initial 72 hours. No studies reported a health economic analysis or patient-reported outcome measures (outside of pain). The review authors sought data regarding adverse events but none were available, however there were no withdrawals reported to be due to adverse events. Using GRADE, we considered the quality of evidence to be very low with any estimate of effect very uncertain and further research very likely to have an important impact on our confidence in the estimate of effect. All studies were at high risk of bias due to their small sample size (fewer than 50 participants per arm) leading to uncertainty around effect estimates. Additionally, inconsistency of results and sparseness of data resulted in further downgrading of the quality of the data. A lack of evidence has prevented an assessment of the efficacy of liposomal bupivacaine administered as a peripheral nerve block. At present there is a lack of data to support or refute the use of liposomal bupivacaine administered as a peripheral nerve block for the management of postoperative pain. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Two studies (67 participants) were included in the review. Based on the published reports, both studies had potential for bias in several domains. There is some evidence that long intravenous lines are superior to short intravenous lines. One study of 20 participants found that the lifespan of a long intravenous line is longer than that of a short intravenous line, and that participants preferred the long intravenous lines to short intravenous lines. A further study of 47 participants found no difference in lifespan, or participant preference when comparing two different long intravenous lines (the Hydrocath and Vygon EC). Neither study was powered to detect differences in serious complications of the devices. There is some evidence to support the use of long intravenous lines rather than short intravenous lines, in terms of lifespan of the line and patient satisfaction. There is no evidence to suggest that any one type of long intravenous line is superior, and currently choice of line should be determined by operator and patient preference. There are numerous devices available which are used in cystic fibrosis. Further research is required to identify clinically important differences between these devices.
We included in the review seven trials with 542 participants. One trial randomised limbs to undergo PTA alone or PTA with stent placement, and the remaining studies randomised participants. Five trials with 476 participants show that the technical success rate was greater in the stent group than in the angioplasty group (odds ratio (OR) 3.00, 95% confidence interval (CI) 1.14 to 7.93; 476 lesions; 5 studies; I² = 23%). Meta-analysis of three eligible trials with 456 participants did not show a clear difference in short-term (within six months) patency between infrapopliteal arterial lesions treated with PTA and those treated with PTA and stenting (OR 0.88, 95% CI 0.37 to 2.11; 456 lesions; 3 studies; I² = 77%). Results also did not show clear differences between treatment groups in procedure complication rate (OR 0.87, 95% CI 0.01 to 53.60; 360 participants; 5 studies; I² = 85%), rate of major amputations at 12 months (OR 1.34, 95% CI 0.56 to 3.22; 306 participants; 4 studies; I² = 0%), and rate of mortality at 12 months (OR 0.71, 95% CI 0.43 to 1.17; 497 participants; 6 studies; I² = 0%). Heterogeneity between studies was high for the outcomes procedure complications and primary patency. The overall methodological quality of the trials included in this review was moderate due to selection and performance bias. Studies used different regimens for pretreatment and post-treatment antiplatelet/anticoagulant medication. We downgraded the certainty of the overall evidence for all outcomes by one level to moderate due to inconsistency of results across studies and large confidence intervals (small numbers of trials and participants). Trials show that the immediate technical success rate of restoring luminal patency is higher in the stent group but reveal no clear differences in short-term patency at six months between infrapopliteal arterial lesions treated with PTA with stenting versus those treated with PTA without stenting. We ascertained no clear differences between groups in periprocedural complications, major amputation, and mortality. However, use of different regimens for pretreatment and post-treatment antiplatelet/anticoagulant medication and the duration of its use within and between trials may have influenced the outcomes. Limited currently available data suggest that high-quality evidence is insufficient to show that PTA with stent insertion is superior to use of standard PTA alone without stenting for treatment of infrapopliteal arterial lesions. Further studies should standardise the use of antiplatelets/anticoagulants before and after the intervention to improve the comparability of the two treatments.
We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I2= 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting. Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented. For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.
Seven small studies were identified and varied according to probiotics tested, methodological quality and medication regimen. No studies were pooled for statistical analysis. There was no statistically significant benefit of E. coli Nissle for reducing the risk of relapse compared to placebo (RR 0.43, 95% CI 0.15 to 1.20), or Lactobacillus GG after surgically-induced remission (RR 1.58, 95% CI 0.30 to 8.40) or medically-induced remission (RR 0.83, 95% CI 0.25 to 2.80). There was no statistically significant benefit of probiotics for reducing the risk of relapse compared to maintenance therapy employing aminosalicylates or azathioprine (RR 0.67, 95% CI 0.13 to 3.30), and in this study the probiotic Lactobacillus GG was associated with adverse events. In children, there was there was no statistically significant difference between Lactobacillus GG and placebo for reducing the risk of relapse (RR 1.85, 95% CI 0.77 to 4.40).   A small study using the yeast Saccharomyces boulardii demonstrated a difference that was not statistically significant in favour of probiotic combined with a reduced level of maintenance therapy over standard maintenance treatment alone (RR 0.17, 95% CI 0.02 to 1.23). There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in CD. All of the included studies enrolled small numbers of patients and may have lacked statistical power to show differences should they exist. Larger trials are required to determine if probiotics are of benefit in Crohn's disease.
We included three randomised controlled trials (RCTs) with 175 women. The three published RCTs compared NTG alone versus placebo. The detachment status of retained placenta was unknown in all three RCTs. Collectively, among the three included trials, two were judged to be at low risk of bias and the third trial was judged to be at high risk of bias for two domains: incomplete outcome data and selective reporting. The three trials reported seven out of 23 of the review's pre-specified outcomes. The primary outcome "manual removal of the placenta" was reported in all three studies. No differences were seen between NTG and placebo for manual removal of the placenta (average risk ratio (RR) 0.83, 95% confidence interval (CI) 0.47 to 1.46; women = 175; I² = 81%). A random-effects model was used because of evidence of substantial heterogeneity in the analysis. There were also no differences between groups for risk of severe postpartum haemorrhage (RR 0.93, 95% CI 0.62 to 1.39; women = 150; studies = two; I² = 0%). Blood transfusion was only reported in one study (40 women) and again there was no difference between groups (RR 1.00, 95% CI 0.07 to 14.90; women = 40; I² = 0%). Mean blood loss (mL) was reported in the three studies and no differences were observed (mean difference (MD) -115.31, 95% CI -306.25 to 75.63; women = 169; I² = 83%). Nitroglycerin administration was not associated with an increase in headaches (RR 1.09, 95% CI 0.80 to 1.47; women = 174; studies = three; I² = 0%). However, nitroglycerin administration was associated with a significant, though mild, decrease in systolic and diastolic blood pressure and a significant increase in pulse rate (MD -3.75, 95% CI -7.47 to -0.03) for systolic blood pressure, and (MD 6.00, 95% CI 3.07 to 8.93) for pulse rate (beats per minute) respectively (reported by only one study including 24 participants). Maternal mortality and addition of therapeutic uterotonics were not reported in any study. In cases of retained placenta, currently available data showed that the use of NTG alone did not reduce the need for manual removal of placenta. This intervention did not increase the incidence of severe postpartum haemorrhage nor the need for blood transfusion. Haemodynamically, NTG had a significant though mild effect on both pulse rate and blood pressure.
Twelve trials were eligible. All had high risk of bias and reporting was inconsistent. Hepatitis B vaccine did not show a clear effect on the risk of developing HBsAg (RR 0.96, 95% CI 0.89 to 1.03, 4 trials, 1230 participants) and anti-HBc (RR 0.81, 95% CI 0.61 to 1.07; 4 trials, 1230 participants, random-effects) when data were analysed using intention-to-treat analysis assuming an unfavourable event for missing data. Analysis based on data of available participants showed reduced risk of developing HBsAg (RR 0.12, 95% CI 0.03 to 0.44, 4 trials, 576 participants) and anti-HBc (RR 0.36, 95% CI 0.17 to 0.76, 4 trials, 576 participants, random-effects). Intention-to-treat analysis assuming favourable outcome for missing data showed similar reduction in risk. Hepatitis B vaccination had an unclear effect on the risk of lacking protective antibody levels (RR 0.57, 95% CI 0.26 to 1.27, 3 trials, 1210 participants, random-effects). Development of adverse events was sparsely reported. In people not previously exposed to hepatitis B, vaccination has unclear effect on the risk of developing infection, as compared to no vaccination. The risk of lacking protective antibody levels as well as serious and non-serious adverse events appear comparable among recipients and non-recipients of hepatitis B vaccine.
We retrieved a total of 10 studies (885 participants), seven of which contributed to the meta-analysis for the primary outcome. Four of these compared antidepressants and placebo, two compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update we included one additional unpublished study. These new data contributed to the secondary analysis, while the results of the primary analysis remained unchanged. For acute-phase treatment response (6 to 12 weeks), we found no difference between antidepressants as a class and placebo on symptoms of depression measured both as a continuous outcome (standardised mean difference (SMD) −0.45, 95% confidence interval (CI) −1.01 to 0.11, five RCTs, 266 participants; very low certainty evidence) and as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.82, 95% CI 0.62 to 1.08, five RCTs, 417 participants; very low certainty evidence). No trials reported data on follow-up response (more than 12 weeks). In head-to-head comparisons we only retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants, showing no difference between these two classes (SMD −0.08, 95% CI −0.34 to 0.18, three RCTs, 237 participants; very low certainty evidence). No clear evidence of a beneficial effect of antidepressants versus either placebo or other antidepressants emerged from our analyses of the secondary efficacy outcomes (dichotomous outcome, response at 6 to 12 weeks, very low certainty evidence). In terms of dropouts due to any cause, we found no difference between antidepressants as a class compared with placebo (RR 0.85, 95% CI 0.52 to 1.38, seven RCTs, 479 participants; very low certainty evidence), and between SSRIs and tricyclic antidepressants (RR 0.83, 95% CI 0.53 to 1.30, three RCTs, 237 participants). We downgraded the certainty (quality) of the evidence because the included studies were at an unclear or high risk of bias due to poor reporting, imprecision arising from small sample sizes and wide confidence intervals, and inconsistency due to statistical or clinical heterogeneity. Despite the impact of depression on people with cancer, the available studies were very few and of low quality. This review found very low certainty evidence for the effects of these drugs compared with placebo. On the basis of these results, clear implications for practice cannot be deduced. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which agent to prescribe may be based on the data on antidepressant efficacy in the general population of individuals with major depression, also taking into account that data on medically ill patients suggest a positive safety profile for the SSRIs. To better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.
Of the nine hundred and seventy titles initially identified through the search strategy, eight trials met the inclusion criteria. A total of 749 children and their families were randomised to receive a family and parenting intervention or to be in a control group. In seven of these studies the participants were juvenile delinquents and their families and in only one the participants were children/adolescents with conduct disorder who had not yet had contact with the juvenile justice system. At follow up, family and parenting interventions significantly reduced the time spent by juvenile delinquents in institutions (WMD 51.34 days, 95%CI 72.52 to 30.16). There was also a significant reduction in the risk of a juvenile delinquent being re arrested (RR 0.66, 95%CI 0.44 to 0.98) and in their rate of subsequent arrests at 1-3 years (SMD -0.56, 95% CI -1.100 to - 0.03). For both of these outcomes there was substantial heterogeneity in the results suggesting a need for caution in interpretation. At present there is insufficient evidence that family and parenting interventions reduce the risk of being incarcerated (RR=0.50, 95% CI 0.20 to 1.21). No significant difference was found for psychosocial outcomes such as family functioning, and child/adolescent behaviour. The evidence suggests that family and parenting interventions for juvenile delinquents and their families have beneficial effects on reducing time spent in institutions. This has an obvious benefit to the participant and their family and may result in a cost saving for society. These interventions may also reduce rates of subsequent arrest but at present these results need to be interpreted with caution due to the heterogeneity of the results.
We identified 10 studies (545 participants and 560 tube insertions) which met our inclusion criteria. No study was assigned low risk of bias or low concern in every QUADAS-2 domain. We judged only three (30%) studies to have low risk of bias in the participant selection domain because they performed ultrasound after they confirmed correct position by other methods. Few data (43 participants) were available for misplacement detection (specificity) due to the low incidence of misplacement. We did not perform a meta-analysis because of considerable heterogeneity of the index test such as the difference of echo window, the combination of ultrasound with other confirmation methods (e.g. saline flush visualization by ultrasound) and ultrasound during the insertion of the tube. For all settings, sensitivity estimates for individual studies ranged from 0.50 to 1.00 and specificity estimates from 0.17 to 1.00. For settings where X-ray was not readily available and participants underwent gastric tube insertion for drainage (four studies, 305 participants), sensitivity estimates of ultrasound in combination with other confirmatory tests ranged from 0.86 to 0.98 and specificity estimates of 1.00 with wide confidence intervals. For the studies using ultrasound alone (four studies, 314 participants), sensitivity estimates ranged from 0.91 to 0.98 and specificity estimates from 0.67 to 1.00. Of 10 studies that assessed the diagnostic accuracy of gastric tube placement, few studies had a low risk of bias. Based on limited evidence, ultrasound does not have sufficient accuracy as a single test to confirm gastric tube placement. However, in settings where X-ray is not readily available, ultrasound may be useful to detect misplaced gastric tubes. Larger studies are needed to determine the possibility of adverse events when ultrasound is used to confirm tube placement.
The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies. In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%. In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I2 = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I2 = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%. Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine. We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.
We included one trial with relevant and available data (n=56, duration 2 years) comparing compliance therapy with non-specific counseling. The primary outcome 'non-compliance with treatment' showed no significant difference between compliance therapy and non-specific counseling (n=56, RR 1.23 CI 0.74 to 2.05). The compliance therapy did not substantially effect attitudes to treatment (n=50, WMD DAI score -2.10 CI -6.11 to 1.91). Very few people (˜10%) left the study by one year (n=56, RR 0.5 CI 0.1 to 2.51). Mental state seemed unaffected by the therapy (n=50, WMD PANSS score 6.1 CI -4.54 to 16.74) as was insight (n=50, WMD SAI -0.5 CI -2.43 to 1.43), global functioning (n=50, WMD GAF -4.20 CI -16.42 to 8.02) and quality of life (n=50, WMD QLS -3.40 CI -16.25 to 9.45). At both one and two years the average number of days in hospital was non-significantly reduced for those allocated to the compliance therapy. There is no clear evidence to suggest that compliance therapy is beneficial for people with schizophrenia and related syndromes but more randomised studies are justified and needed in order for this intervention to be fully examined.
One randomised controlled trial of 100 IBD patients receiving a specialist nurse delivered counselling package (n = 50) or routine outpatient clinic follow-up (n = 50), with assessments at entry and six and 12 months, was included in this review. This study was of low methodological quality. Disease remission, patient compliance, clinical improvement, utilisation of nurse-led services, patient satisfaction, hospital admission, outpatient attendance, progression to surgery, length of hospital stay and cost effectiveness data were not reported. Pooled mean mental health scores at 6 months were higher in patients who received nurse-led counselling compared to patients who received routine follow-up. However, this difference was not statistically significant (WMD 3.67; 95% CI -0.44 to 7.77; P = 0.08). Other pooled assessments of physical and psychological well-being showed no statistically significant differences. Although specialist nurse counselling interventions might provide benefit for IBD patients the one included study was of low quality and the results of this study should be interpreted with caution. Higher quality trials of gastroenterology and IBD specialist nursing interventions are needed to assess the impact of specialist nursing interventions on the care and management of patients with inflammatory bowel disease.
Our initial search yielded 4406 unique references. Fifteen reviews met our inclusion criteria; 14 of which were included in the quantitative analysis. The included reviews analyzed data from 1583 meta-analyses that covered 228 different medical conditions. The mean number of included studies per paper was 178 (range 19 to 530). Eleven (73%) reviews had low risk of bias for explicit criteria for study selection, nine (60%) were low risk of bias for investigators' agreement for study selection, five (33%) included a complete sample of studies, seven (47%) assessed the risk of bias of their included studies, Seven (47%) reviews controlled for methodological differences between studies, Eight (53%) reviews controlled for heterogeneity among studies, nine (60%) analyzed similar outcome measures, and four (27%) were judged to be at low risk of reporting bias. Our primary quantitative analysis, including 14 reviews, showed that the pooled ROR comparing effects from RCTs with effects from observational studies was 1.08 (95% confidence interval (CI) 0.96 to 1.22). Of 14 reviews included in this analysis, 11 (79%) found no significant difference between observational studies and RCTs. One review suggested observational studies had larger effects of interest, and two reviews suggested observational studies had smaller effects of interest. Similar to the effect across all included reviews, effects from reviews comparing RCTs with cohort studies had a pooled ROR of 1.04 (95% CI 0.89 to 1.21), with substantial heterogeneity (I2 = 68%). Three reviews compared effects of RCTs and case-control designs (pooled ROR: 1.11 (95% CI 0.91 to 1.35)). No significant difference in point estimates across heterogeneity, pharmacological intervention, or propensity score adjustment subgroups were noted. No reviews had compared RCTs with observational studies that used two of the most common causal inference methods, instrumental variables and marginal structural models. Our results across all reviews (pooled ROR 1.08) are very similar to results reported by similarly conducted reviews. As such, we have reached similar conclusions; on average, there is little evidence for significant effect estimate differences between observational studies and RCTs, regardless of specific observational study design, heterogeneity, or inclusion of studies of pharmacological interventions. Factors other than study design per se need to be considered when exploring reasons for a lack of agreement between results of RCTs and observational studies. Our results underscore that it is important for review authors to consider not only study design, but the level of heterogeneity in meta-analyses of RCTs or observational studies. A better understanding of how these factors influence study effects might yield estimates reflective of true effectiveness.
This review included two randomised controlled trials. The first trial included 200 women who were randomised to receive uterine massage or no massage following delivery of the placenta, after active management of the third stage of labour including use of oxytocin. The numbers of women with blood loss more than 500 mL was small, with no statistically significant difference (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.16 to 1.67). There were no cases of retained placenta in either group. The mean blood loss was significantly less in the uterine massage group at 30 minutes (mean difference (MD) -41.60 mL, 95% CI -75.16 to -8.04) and 60 minutes after trial entry (MD -77.40 mL, 95% CI -118.71 to -36.09). The need for additional uterotonics was significantly reduced in the uterine massage group (RR 0.20, 95% CI 0.08 to 0.50). For use of uterine massage before and after delivery of the placenta, one trial recruited 1964 women in Egypt and South Africa. Women were assigned to receive oxytocin, uterine massage or both after delivery of the baby but before delivery of the placenta. There was no added benefit for uterine massage plus oxytocin over oxytocin alone as regards blood loss greater than or equal to 500 mL (average RR 1.56, 95% CI 0.44, 5.49; random-effects) or need for additional use of uterotonics (RR 1.02, 95% CI 0.56 to 1.85). The two trials were combined to examine the effect of uterine massage commenced either before or after delivery of the placenta. There was substantial heterogeneity with respect to the blood loss 500 mL or more after trial entry. The average effect using a random-effects model found no statistically significant differences between groups (average RR 1.14, 95% CI 0.39 to 3.32; random-effects). The results of this review are inconclusive, and should not be interpreted as a reason to change current practice. Due to the limitations of the included trials, more trials with sufficient numbers of women are needed in order to estimate the effects of sustained uterine massage. All the women compared in this review received oxytocin as part of the active management of labour. Recent research suggests that once an oxytocic has been given, there is limited scope for further reduction in postpartum blood loss. Trials of uterine massage in settings where uterotonics are not available, and which measure women's experience of the procedure, are needed.
Eleven studies met the inclusion criteria. Six studies (440 participants) compared dextropropoxyphene with placebo, four studies (325 participants) and one individual patient meta-analysis (638 participant) compared dextropropoxyphene plus paracetamol 650 mg with placebo. For a single dose of dextropropoxyphene 65 mg in postoperative pain the NNT for at least 50% pain relief was 7.7 (95% confidence interval (CI) 4.6 to 22) when compared with placebo over four to six hours. There was no significant difference between the proportion of participants remedicating within four to eight hours with dextroporpoxyphene 65 mg (35%) and placebo (43%), relative risk 0.8 (0.7 to 1.03). For the equivalent dose of dextropropoxyphene combined with paracetamol 650 mg the NNT was 4.4 (3.5 to 5.6) when compared with placebo. These results were compared with those for other analgesics obtained from equivalent systematic reviews. Significantly fewer participants remedicated within four to eight hours with dextropropoxyphene 65 mg combined with paracetamol 650 mg (34%) than with placebo (57%), relative risk 0.7 (0.5 to 0.8). Pooled data showed increased incidence of central nervous system adverse effects for dextropropoxyphene plus paracetamol compared with placebo. Since the last version of this review no new relevant studies have been identified. The combination of dextropropoxyphene 65 mg with paracetamol 650 mg shows similar efficacy to tramadol 100 mg for single dose studies in postoperative pain but with a lower incidence of adverse effects. The same dose of paracetamol combined with 60 mg codeine appears more effective but, with the slight overlap in the 95% CI, this conclusion is not robust. Adverse effects of both combinations were similar. Ibuprofen 400 mg has a lower (better) NNT than both dextropropoxyphene 65 mg plus paracetamol 650 mg and tramadol 100 mg.
Eleven trials that randomized 1838 participants met the study inclusion criteria. Seven of the trials included femoropopliteal arterial lesions, three included tibial arterial lesions, and one included both. The trials were carried out in Europe and in the USA and all used the taxane drug paclitaxel in the DEB arm. Nine of the 11 trials were industry-sponsored. Four companies manufactured the DEB devices (Bard, Bavaria Medizin, Biotronik, and Medtronic). The trials examined both anatomic and clinical endpoints. There was heterogeneity in the frequency of stent deployment and the type and duration of antiplatelet therapy between trials. Using GRADE assessment criteria, the quality of the evidence presented was moderate for the outcomes of target lesion revascularization and change in Rutherford category, and high for amputation, primary vessel patency, binary restenosis, death, and change in ankle-brachial index (ABI). Most participants were followed up for 12 months, but one trial reported outcomes at five years. There were better outcomes for DEBs for up to two years in primary vessel patency (odds ratio (OR) 1.47, 95% confidence interval (CI) 0.22 to 9.57 at six months; OR 1.92, 95% CI 1.45 to 2.56 at 12 months; OR 3.51, 95% CI 2.26 to 5.46 at two years) and at six months and two years for late lumen loss (mean difference (MD) -0.64 mm, 95% CI -1.00 to -0.28 at six months; MD -0.80 mm, 95% CI -1.44 to -0.16 at two years). DEB were also superior to uncoated balloon angioplasty for up to five years in target lesion revascularization (OR 0.28, 95% CI 0.17 to 0.47 at six months; OR 0.40, 95% CI 0.31 to 0.51 at 12 months; OR 0.28, 95% CI 0.18 to 0.44 at two years; OR 0.21, 95% CI 0.09 to 0.51 at five years) and binary restenosis rate (OR 0.44, 95% CI 0.29 to 0.67 at six months; OR 0.38, 95% CI 0.15 to 0.98 at 12 months; OR 0.26, 95% CI 0.10 to 0.66 at two years; OR 0.12, 95% CI 0.05 to 0.30 at five years). There was no significant difference between DEB and uncoated angioplasty in amputation, death, change in ABI, change in Rutherford category and quality of life (QoL) scores, or functional walking ability, although none of the trials were powered to detect a significant difference in these clinical endpoints. We carried out two subgroup analyses to examine outcomes in femoropopliteal and tibial interventions as well as in people with CLI (4 or greater Rutherford class), and showed no advantage for DEBs in tibial vessels at six and 12 months compared with uncoated balloon angioplasty. There was also no advantage for DEBs in CLI compared with uncoated balloon angioplasty at 12 months. Based on a meta-analysis of 11 trials with 1838 participants, there is evidence of an advantage for DEBs compared with uncoated balloon angioplasty in several anatomic endpoints such as primary vessel patency (high-quality evidence), binary restenosis rate (moderate-quality evidence), and target lesion revascularization (low-quality evidence) for up to 12 months. Conversely, there is no evidence of an advantage for DEBs in clinical endpoints such as amputation, death, or change in ABI, or change in Rutherford category during 12 months' follow-up. Well-designed randomized trials with long-term follow-up are needed to compare DEBs with uncoated balloon angioplasties adequately for both anatomic and clinical study endpoints before the widespread use of this expensive technology can be justified.
24 RCTs with 6915 participants fulfilled the criteria of inclusion and were included in the review. Compared to placebo, acamprosate was shown to significantly reduce the risk of any drinking RR 0.86 (95% CI 0.81 to 0.91); NNT 9.09 (95% CI 6.66 to 14.28) and to significantly increase the cumulative abstinence duration MD 10.94 (95% CI 5.08 to 16.81), while secondary outcomes (gamma-glutamyltransferase, heavy drinking) did not reach statistical significance. Diarrhea was the only side effect that was more frequently reported under acamprosate than placebo RD 0.11 (95% 0.09 to 0.13); NNTB 9.09 (95% CI 7.69 to 11.11). Effects of industry-sponsored trials RR 0.88 (95% 0.80 to 0.97) did not significantly differ from those of non-profit funded trials RR 0.88 (95% CI 0.81 to 0.96). In addition, the linear regression test did not indicate a significant risk of publication bias (p = 0.861). Acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients. Even though the sizes of treatment effects appear to be rather moderate in their magnitude, they should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment.
We included 67 studies including randomised controlled trials and observational studies with a mixed risk of bias. A total number of participants is not included as the total would be made up of a heterogenous set of observations (participant people, observations on participants and countries (object of some studies)). The risk of bias for five RCTs and most cluster-RCTs was high. Observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis. The highest quality cluster-RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Benefit from reduced transmission from children to household members is broadly supported also in other study designs where the potential for confounding is greater. Nine case-control studies suggested implementing transmission barriers, isolation and hygienic measures are effective at containing respiratory virus epidemics. Surgical masks or N95 respirators were the most consistent and comprehensive supportive measures. N95 respirators were non-inferior to simple surgical masks but more expensive, uncomfortable and irritating to skin. Adding virucidals or antiseptics to normal handwashing to decrease respiratory disease transmission remains uncertain. Global measures, such as screening at entry ports, led to a non-significant marginal delay in spread. There was limited evidence that social distancing was effective, especially if related to the risk of exposure. Simple and low-cost interventions would be useful for reducing transmission of epidemic respiratory viruses. Routine long-term implementation of some measures assessed might be difficult without the threat of an epidemic.
We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias. Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I² = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02). Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV₁) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I² = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I² = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I² = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I² = 0%; moderate quality of evidence) than participants receiving SABA alone. Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I² = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone. Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild-moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone.
Fifty-three studies (8548 patients) were included. The majority of included studies were rated as low risk of bias. 5-ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy-one per cent of 5-ASA patients failed to enter clinical remission compared to 83% of placebo patients (RR 0.86, 95% CI 0.82 to 0.89). A dose-response trend for 5-ASA was also observed. No statistically significant differences in efficacy were found between 5-ASA and SASP. Fifty-four per cent of 5-ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Forty-five per cent of once daily patients failed to enter clinical remission compared to 48% of conventionally dosed patients (RR 0.94, 95% CI 0.83 to 1.07). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Fifty per cent of patients in the 5-ASA group failed to enter remission compared to 52% of patients in the 5-ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02). A pooled analysis of 3 studies (n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty-seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty-five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulation and 5-ASA dose ranging (high dose versus low dose) studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. SASP was not as well tolerated as 5-ASA. Twenty-nine percent of SASP patients experienced an adverse event compared to 15% of 5-ASA patients (RR 0.48, 95% CI 0.37 to 0.63). 5-ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5-ASA in place of SASP appears unlikely. 5-ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5-ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5-ASA improves adherence in a community-based setting. There do not appear to be any differences in efficacy or safety among the various 5-ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.
The search identified one study of 125 children (72 boys and 53 girls) with calcium-containing idiopathic nephrolithiasis and normal renal morphology following initial treatment with shockwave lithotripsy (SWL). Patients were randomized to oral potassium citrate 1 mEq/kg per day for 12 months versus no specific medication or preventive measure with results reported for a total of 96 patients (48 per group). This included children who were stone-free (n = 52) or had residual stone fragments (n = 44) following SWL. Primary outcomes: Medical therapy may lower rates of stone recurrence with a risk ratio (RR) of 0.19 (95% confidence interval (CI) 0.06 to 0.60; low quality evidence). This corresponds to 270 fewer stone recurrences per 1000 (133 fewer to 313 fewer) children. We downgraded the quality of evidence by two levels for very serious study limitations related to unclear allocation concealment (selection bias) and a high risk of performance, detection and attrition bias. While the data for adverse events were incomplete, they reported that six of 48 (12.5%) children receiving potassium citrate left the trial because of adverse effects. This corresponds to a RR of 13.0 (95% CI 0.75 to 224.53; very low quality evidence); an absolute effect size estimate could not be generated. We downgraded the quality of evidence for study limitations and imprecision. We found no information on retreatment rates. Secondary outcomes: We found no evidence on serum electrolytes, 24-hour urine collection parameters or time to new stone formation. We were unable to perform any preplanned secondary analyses. Oral potassium citrate supplementation may reduce recurrent calcium urinary stone formation in children following SWL; however, our confidence in this finding is limited. A substantial number of children stopped the medication due to adverse events. There is no trial evidence on retreatment rates. There is a critical need for additional well-designed trials in children with nephrolithiasis.
We included four RCTs (a total of 690 participants), in this review. Participants were adults who were mechanically ventilated in a general, medical or surgical ICU, with mean or median age in the studies ranging from 56 to 62 years. Admitting diagnoses in three of the four studies were indicative of critical illness, while participants in the fourth study had undergone cardiac surgery. Three studies included range-of-motion exercises, bed mobility activities, transfers and ambulation. The fourth study involved only upper limb exercises. Included studies were at high risk of performance bias, as they were not blinded to participants and personnel, and two of four did not blind outcome assessors. Three of four studies reported only on those participants who completed the study, with high rates of dropout. The description of intervention type, dose, intensity and frequency in the standard care control group was poor in two of four studies. Three studies (a total of 454 participants) reported at least one measure of physical function. One study (104 participants) reported low-quality evidence of beneficial effects in the intervention group on return to independent functional status at hospital discharge (59% versus 35%, risk ratio (RR) 1.71, 95% confidence interval (CI) 1.11 to 2.64); the absolute effect is that 246 more people (95% CI 38 to 567) per 1000 would attain independent functional status when provided with early mobilization. The effects on physical functioning are uncertain for a range measures: Barthel Index scores (early mobilization: median 75 control: versus 55, low quality evidence), number of ADLs achieved at ICU (median of 3 versus 0, low quality evidence) or at hospital discharge (median of 6 versus 4, low quality evidence). The effects of early mobilization on physical function measured at ICU discharge are uncertain, as measured by the Acute Care Index of Function (ACIF) (early mobilization mean: 61.1 versus control: 55, mean difference (MD) 6.10, 95% CI -11.85 to 24.05, low quality evidence) and the Physical Function ICU Test (PFIT) score (5.6 versus 5.4, MD 0.20, 95% CI -0.98 to 1.38, low quality evidence). There is low quality evidence that early mobilization may have little or no effect on physical function measured by the Short Physical Performance Battery score at ICU discharge from one study of 184 participants (mean 1.6 in the intervention group versus 1.9 in usual care, MD -0.30, 95% CI -1.10 to 0.50), or at hospital discharge (MD 0, 95% CI -1.00 to 0.90). The fourth study, which examined postoperative cardiac surgery patients did not measure physical function as an outcome. Adverse effects were reported across the four studies but we could not combine the data. Our certainty in the risk of adverse events with either mobilization strategy is low due to the low rate of events. One study reported that in the intervention group one out of 49 participants (2%) experienced oxygen desaturation less than 80% and one of 49 (2%) had accidental dislodgement of the radial catheter. This study also found cessation of therapy due to participant instability occurred in 19 of 498 (4%) of the intervention sessions. In another study five of 101 (5%) participants in the intervention group and five of 109 (4.6%) participants in the control group had postoperative pulmonary complications deemed to be unrelated to intervention. A third study found one of 150 participants in the intervention group had an episode of asymptomatic bradycardia, but completed the exercise session. The fourth study reported no adverse events. There is insufficient evidence on the effect of early mobilization of critically ill people in the ICU on physical function or performance, adverse events, muscle strength and health-related quality of life at this time. The four studies awaiting classification, and the three ongoing studies may alter the conclusions of the review once these results are available. We assessed that there is currently low-quality evidence for the effect of early mobilization of critically ill adults in the ICU due to small sample sizes, lack of blinding of participants and personnel, variation in the interventions and outcomes used to measure their effect and inadequate descriptions of the interventions delivered as usual care in the studies included in this Cochrane Review.
We included nine studies involving 1118 women. We identified four comparisons. One comparison included six studies (which randomised 394 women) comparing umbilical vein injection of normal saline plus oxytocin versus that of normal saline, as well as three other comparisons, each of which includes one study. Comparing intraumbilical injection of normal saline plus oxytocin with intraumbilical injection of saline only, there was no evidence of difference in any of the relevant outcomes reported namely the number of women who required blood transfusion, the incidence of manual removal of placenta, blood loss, and length of the third stage of labour. Subgroup analyses by both total amount of solution administered and dose of oxytocin showed no evidence of difference. Other comparisons included only one study for each, and there was no relevant information available. Routine use of oxytocin or any other uterotonics with normal saline via umbilical vein injection is not recommended until new evidence is available. Further research should be conducted to show effectiveness of oxytocin with normal saline via umbilical vein injection.
Forty-four eligible trials, involving 8436 participants were identified. Compared to placebo, adjuvant therapy significantly reduced off-time (-1.05 hours/day, 95% confidence interval (CI) -1.19 to -0.90; P<0.00001), the required levodopa dose (-55.65 mg/day, CI -62.67 to -48.62; P<0.00001) and improved UPDRS scores (UPDRS ADL score: -1.31 points, CI -1.62 to -0.99; P<0.00001; UPDRS motor score: -2.84 points, CI -3.36 to -2.32; P<0.00001; UPDRS total score: -3.26 points, CI -4.52 to -2.00; P<0.00001). However, dyskinesia (odds ratio (OR) 2.50, CI 2.21 to 2.84; P<0.00001) and side-effects including constipation (OR 3.19, CI 2.17 to 4.68; P<0.00001), dizziness (OR 1.57, CI 1.30 to 1.90; P<0.00001), dry mouth (OR 2.33, CI 1.22 to 4.47; P=0.01), hallucinations (OR 2.16, CI 1.70 to 2.74; P<0.00001), hypotension (OR 1.47, CI 1.18 to 1.83; P=0.0007), insomnia (OR 1.38, CI 1.09 to 1.74; P=0.007), nausea (OR 1.78, CI 1.53 to 2.07; P<0.00001), somnolence (OR 1.87, CI 1.40 to 2.51; P<0.0001) and vomiting (OR 2.56, CI 1.67 to 3.93; P<0.0001) were all increased with adjuvant therapy. Indirect comparisons of the three drug classes suggested that dopamine agonists were more efficacious in reducing off-time (dopamine agonist: -1.54 hours/day; COMTI: -0.83 hours/day; MAOBI: -0.93 hours/day; test for heterogeneity between drug classes P=0.0003) and levodopa dose (dopamine agonist: -116 mg/day; COMTI: -52 mg/day; MAOBI: -29 mg/day; test for heterogeneity between drug classes P<0.00001). UPDRS scores also improved more with dopamine agonists than with COMTI or MAOBI (UPDRS total scores - dopamine agonist: -10.01 points versus COMTI: -1.46 points versus MAOBI: -2.20 points; test for heterogeneity between drug classes P<0.00001), although more dyskinesia were seen with dopamine agonists (OR 2.70) and COMTI (OR 2.50) than with MAOBI (OR 0.94) (test for heterogeneity between drug classes P=0.009). Although the increase in the overall incidence of side-effects was generally more marked with dopamine agonists (OR 1.52) and COMTI (OR 2.0) than with MAOBI (OR 1.32), heterogeneity between drug classes was only of borderline significance (P=0.07). Compared to placebo, adjuvant therapy reduces off-time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other side-effects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head-to-head randomised trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed.
Our search identified 1999 titles, of which 53 trials (57 articles) fulfilled our inclusion criteria. The 53 included studies enrolled a total of 4671 participants with critical illness or undergoing elective major surgery. We analysed seven domains of potential risk of bias. In 10 studies the risk of bias was evaluated as low in all of the domains. Thirty-three trials (2303 patients) provided data on nosocomial infectious complications; pooling of these data suggested that glutamine supplementation reduced the infectious complications rate in adults with critical illness or undergoing elective major surgery (RR 0.79, 95% CI 0.71 to 0.87, P ＜ 0.00001, I² = 8%, moderate quality evidence). Thirty-six studies reported short-term (hospital or less than one month) mortality. The combined rate of mortality from these studies was not statistically different between the groups receiving glutamine supplement and those receiving no supplement (RR 0.89, 95% CI 0.78 to 1.02, P = 0.10, I² = 22%, low quality evidence). Eleven studies reported long-term (more than six months) mortality; meta-analysis of these studies (2277 participants) yielded a RR of 1.00 (95% CI 0.89 to 1.12, P = 0.94, I² = 30%, moderate quality evidence). Subgroup analysis of infectious complications and mortality outcomes did not find any statistically significant differences between the predefined groups. Hospital length of stay was reported in 36 studies. We found that the length of hospital stay was shorter in the intervention group than in the control group (MD -3.46 days, 95% CI -4.61 to -2.32, P < 0.0001, I² = 63%, low quality evidence). Slightly prolonged intensive care unit (ICU) stay was found in the glutamine supplemented group from 22 studies (2285 participants) (MD 0.18 days, 95% CI 0.07 to 0.29, P = 0.002, I² = 11%, moderate quality evidence). Days on mechanical ventilation (14 studies, 1297 participants) was found to be slightly shorter in the intervention group than in the control group (MD - 0.69 days, 95% CI -1.37 to -0.02, P = 0.04, I² = 18%, moderate quality evidence). There was no clear evidence of a difference between the groups for side effects and quality of life, however results were imprecise for serious adverse events and few studies reported on quality of life. Sensitivity analysis including only low risk of bias studies found that glutamine supplementation had beneficial effects in reducing the length of hospital stay (MD -2.9 days, 95% CI -5.3 to -0.5, P = 0.02, I² = 58%, eight studies) while there was no statistically significant difference between the groups for all of the other outcomes. This review found moderate evidence that glutamine supplementation reduced the infection rate and days on mechanical ventilation, and low quality evidence that glutamine supplementation reduced length of hospital stay in critically ill or surgical patients. It seems to have little or no effect on the risk of mortality and length of ICU stay, however. The effects on the risk of serious side effects were imprecise. The strength of evidence in this review was impaired by a high risk of overall bias, suspected publication bias, and moderate to substantial heterogeneity within the included studies.
We identified 15 studies for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), non-humidified HFNC, models for delivering HFNC), the gas flows used and the indications for respiratory support (primary support from soon after birth, post-extubation support, weaning from CPAP support). When used as primary respiratory support after birth compared to CPAP (4 studies, 439 infants), there were no differences in the primary outcomes of death (typical risk ratio (RR) 0.36, 95% CI 0.01 to 8.73; 4 studies, 439 infants) or chronic lung disease (CLD) (typical RR 2.07, 95% CI 0.64 to 6.64; 4 studies, 439 infants). HFNC use resulted in longer duration of respiratory support, but there were no differences in other secondary outcomes. One study (75 infants) showed no differences between HFNC and NIPPV as primary support. Following extubation (total 6 studies, 934 infants), there were no differences between HFNC and CPAP in the primary outcomes of death (typical RR 0.77, 95% CI 0.43 to 1.36; 5 studies, 896 infants) or CLD (typical RR 0.96, 95% CI 0.78 to 1.18; 5 studies, 893 infants). There was no difference in the rate of treatment failure (typical RR 1.21, 95% CI 0.95 to 1.55; 5 studies, 786 infants) or reintubation (typical RR 0.91, 95% CI 0.68 to 1.20; 6 studies, 934 infants). Infants randomised to HFNC had reduced nasal trauma (typical RR 0.64, 95% CI 0.51 to 0.79; typical risk difference (RD) −0.14, 95% CI −0.20 to −0.08; 4 studies, 645 infants). There was a small reduction in the rate of pneumothorax (typical RR 0.35, 95% CI 0.11 to 1.06; typical RD −0.02, 95% CI −0.03 to −0.00; 5 studies 896 infants) in infants treated with HFNC. Subgroup analysis found no difference in the rate of the primary outcomes between HFNC and CPAP in preterm infants in different gestational age subgroups, though there were only small numbers of extremely preterm and late preterm infants. One trial (28 infants) found similar rates of reintubation for humidified and non-humidified HFNC, and two other trials (100 infants) found no difference between different models of equipment used to deliver humidified HFNC. For infants weaning from non-invasive respiratory support (CPAP), two studies (149 infants) found that preterm infants randomised to HFNC had a reduced duration of hospitalisation compared with infants who remained on CPAP. HFNC has similar rates of efficacy to other forms of non-invasive respiratory support in preterm infants for preventing treatment failure, death and CLD. Most evidence is available for the use of HFNC as post-extubation support. Following extubation, HFNC is associated with less nasal trauma, and may be associated with reduced pneumothorax compared with nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with other forms of primary non-invasive support after birth and for weaning from non-invasive support. Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely preterm and mildly preterm subgroups, and for comparing different HFNC devices.
A total of 30 RCTs are included in this review. Overall both the quality of trial reporting and trial conduct were generally poor and meta analysis was largely precluded due to study heterogeneity or poor data reporting. In the context of this poor quality evidence, silver sulphadiazine (SSD) was consistently associated with poorer healing outcomes than biosynthetic (skin substitute) dressings, silver-containing dressings and silicon-coated dressings. Burns treated with hydrogel dressings appear to heal more quickly than those treated with usual care. There is a paucity of high-quality evidence regarding the effect of different dressings on the healing of superficial and partial thickness burn injuries. The studies summarised in this review evaluated a variety of interventions, comparators and clinical endpoints and all were at risk of bias. It is impossible to draw firm and confident conclusions about the effectiveness of specific dressings, however silver sulphadiazine was consistently associated with poorer healing outcomes than biosynthetic, silicon-coated and silver dressings whilst hydrogel-treated burns had better healing outcomes than those treated with usual care.
Thirty-nine trials (2326 participants) fulfilled our inclusion criteria, of which 37 provided data for meta-analyses. There were multiple sources of bias in many of the trials; randomisation was adequately concealed in 14 studies, 15 used intention-to-treat analyses and 12 used blinded outcome assessors. For the 35 trials (1356 participants) comparing exercise with no treatment or a control intervention, the pooled SMD for the primary outcome of depression at the end of treatment was -0.62 (95% confidence interval (CI) -0.81 to -0.42), indicating a moderate clinical effect. There was moderate heterogeneity (I² = 63%). When we included only the six trials (464 participants) with adequate allocation concealment, intention-to-treat analysis and blinded outcome assessment, the pooled SMD for this outcome was not statistically significant (-0.18, 95% CI -0.47 to 0.11). Pooled data from the eight trials (377 participants) providing long-term follow-up data on mood found a small effect in favour of exercise (SMD -0.33, 95% CI -0.63 to -0.03). Twenty-nine trials reported acceptability of treatment, three trials reported quality of life, none reported cost, and six reported adverse events. For acceptability of treatment (assessed by number of drop-outs during the intervention), the risk ratio was 1.00 (95% CI 0.97 to 1.04). Seven trials compared exercise with psychological therapy (189 participants), and found no significant difference (SMD -0.03, 95% CI -0.32 to 0.26). Four trials (n = 300) compared exercise with pharmacological treatment and found no significant difference (SMD -0.11, -0.34, 0.12). One trial (n = 18) reported that exercise was more effective than bright light therapy (MD -6.40, 95% CI -10.20 to -2.60). For each trial that was included, two authors independently assessed for sources of bias in accordance with the Cochrane Collaboration 'Risk of bias' tool. In exercise trials, there are inherent difficulties in blinding both those receiving the intervention and those delivering the intervention. Many trials used participant self-report rating scales as a method for post-intervention analysis, which also has the potential to bias findings. Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.
We included nine studies in this review which involved 134 participants with TBI. Only five studies reported between-group differences, yielding outcome data for 105 participants with TBI. These five studies assessed the effects of a range of pharmacological (baclofen, botulinum toxin A) and non-pharmacological (casting, physiotherapy, splints, tilt table standing and electrical stimulation) interventions, often in combination. The studies which tested the effect of baclofen and tizanidine did not report their results adequately. Where outcome data were available, spasticity and adverse events were reported, in addition to some secondary outcome measures. Of the five studies with results, three were funded by governments, charities or health services and two were funded by a pharmaceutical or medical technology company. The four studies without useable results were funded by pharmaceutical or medical technology companies. It was difficult to draw conclusions about the effectiveness of these interventions due to poor reporting, small study size and the fact that participants with TBI were usually only a proportion of the overall total. Meta-analysis was not feasible due to the paucity of data and heterogeneity of interventions and comparator groups. Some studies concluded that the intervention they tested had beneficial effects on spasticity, and others found no difference between certain treatments. The most common adverse event was minor skin damage in people who received casting. We believe it would be misleading to provide any further description of study results given the quality of the evidence was very low for all outcomes. The very low quality and limited amount of evidence about the management of spasticity in people with TBI means that we are uncertain about the effectiveness or harms of these interventions. Well-designed and adequately powered studies using functional outcome measures to test the interventions used in clinical practice are needed.
Five small trials comparing dynamic compression plates with locked intramedullary nailing were included in this review. These involved a total of 260 participants undergoing surgery for either acute fractures or after early failure of conservative treatment. All five trials had methodological flaws, such as the lack of assessor blinding, that could have influenced their findings. There was no significant difference in fracture union between plating and nailing (five trials, RR 1.05; 95% CI 0.97 to 1.13). There was a statistically significant increase in shoulder impingement following nailing when compared with plating (five trials, RR 0.12; 95% CI 0.04 to 0.38). Intramedullary nails were removed significantly more frequently than plates (three trials, RR 0.17; 95% CI 0.04 to 0.76). There was no statistically significant difference between plating and nailing in operating time, blood loss during surgery, iatrogenic radial nerve injury, return to pre-injury occupation by six months or American Shoulder and Elbow Surgeons (ASES) scores. Two further small trials are awaiting classification. The available evidence shows that intramedullary nailing is associated with an increased risk of shoulder impingement, with a related increase in restriction of shoulder movement and need for removal of metalwork. There was insufficient evidence to determine if there were any other important differences, including in functional outcome, between dynamic compression plating and locked intramedullary nailing for humeral shaft fractures.
We included 30 trials (35 data sets) representing 1992 infants with bronchiolitis. In 11 inpatient and 10 outpatient studies, oxygen saturation did not improve with bronchodilators (mean difference (MD) -0.43, 95% confidence interval (CI) -0.92 to 0.06, n = 1242). Outpatient bronchodilator treatment did not reduce the rate of hospitalization (11.9% in bronchodilator group versus 15.9% in placebo group, odds ratio (OR) 0.75, 95% CI 0.46 to 1.21, n = 710). Inpatient bronchodilator treatment did not reduce the duration of hospitalization (MD 0.06, 95% CI -0.27 to 0.39, n = 349). Effect estimates for inpatients (MD -0.62, 95% CI -1.40 to 0.16) were slightly larger than for outpatients (MD -0.25, 95% CI -0.61 to 0.11) for oximetry. Oximetry outcomes showed significant heterogeneity (I2 statistic = 81%). Including only studies with low risk of bias had little impact on the overall effect size of oximetry (MD -0.38, 95% CI -0.75 to 0.00) but results were close to statistical significance. In eight inpatient studies, there was no change in average clinical score (standardized MD (SMD) -0.14, 95% CI -0.41 to 0.12) with bronchodilators. In nine outpatient studies, the average clinical score decreased slightly with bronchodilators (SMD -0.42, 95% CI -0.79 to -0.06), a statistically significant finding of questionable clinical importance. The clinical score outcome showed significant heterogeneity (I2 statistic = 73%). Including only studies with low risk of bias reduced the heterogeneity but had little impact on the overall effect size of average clinical score (SMD -0.22, 95% CI -0.41 to -0.03). Sub-analyses limited to nebulized albuterol or salbutamol among outpatients (nine studies) showed no effect on oxygen saturation (MD -0.19, 95% CI -0.59 to 0.21, n = 572), average clinical score (SMD -0.36, 95% CI -0.83 to 0.11, n = 532) or hospital admission after treatment (OR 0.77, 95% CI 0.44 to 1.33, n = 404). Adverse effects included tachycardia, oxygen desaturation and tremors. Bronchodilators such as albuterol or salbutamol do not improve oxygen saturation, do not reduce hospital admission after outpatient treatment, do not shorten the duration of hospitalization and do not reduce the time to resolution of illness at home. Given the adverse side effects and the expense associated with these treatments, bronchodilators are not effective in the routine management of bronchiolitis. This meta-analysis continues to be limited by the small sample sizes and the lack of standardized study design and validated outcomes across the studies. Future trials with large sample sizes, standardized methodology across clinical sites and consistent assessment methods are needed to answer completely the question of efficacy.
One small trial at high risk of bias met the inclusion criteria. The trial randomised 49 participants, most of whom had cancer. It compared standard care (defined as surgery, antibiotics and oral rinses at the discretion of the oral-maxillofacial surgeon) to standard care plus hyperbaric oxygen therapy (2 atmospheres twice a day for 40 treatments). The trial measured the percentage of participants who improved or healed at three, six, 12 and 18 months and last contact. It also measured mean weekly pain scores. At three months, the study found that the participants in intervention group were more likely to have an improvement in their osteonecrosis than the standard care group participants (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.01 to 3.74). There was no clear difference between the groups for the outcome 'healed' at three months (RR 3.60, 95% CI 0.87 to 14.82). There was no clear difference between the groups for improvement or healing when they were evaluated at six, 12 and 18 months and last contact. The study did not give any information on adverse events. Although the findings suggest adjunctive hyperbaric oxygen improved BRONJ, the quality of the evidence is very low since the only study was underpowered and was at high risk of bias due to lack of blinding, cross-over of participants between groups and very high attrition (50% at 12 months and 80% at 18 months in this study, which was designed for an intended follow-up of 24 months). There is a lack of evidence from randomised controlled trials to guide treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ). One small trial at high risk of bias evaluated hyperbaric oxygen therapy (HBO) as an adjunct to "standard" care and could not confirm or refute the effectiveness of HBO. There are two ongoing trials of teriparatide treatment for BRONJ. We found no randomised controlled trials of any other BRONJ treatments. High quality randomised controlled trials are needed. We provide recommendations for their focus and design.
Two randomised controlled trials recruiting a total of 413 patients met the criteria for inclusion in our review; one study had a low risk of bias and the other study had a high risk of bias. Ear plugs versus control One study recruited 201 children (aged six months to six years) who underwent myringotomy and ventilation tube insertion. The study compared an intervention group who were instructed to swim and bathe with ear plugs with a control group; the participants were followed up at one-month intervals for one year. This study, with low risk of bias, showed that the use of ear plugs results in a small but statistically significant reduction in the rate of otorrhoea from 1.2 episodes to 0.84 episodes in the year of follow-up (mean difference (MD) -0.36 episodes per year, 95% confidence interval (CI) -0.45 to -0.27). There was no significant difference in ventilation tube extrusion or hearing outcomes between the two study arms. No child required surgical intervention to remove ventilation tubes and no adverse events were reported. Water avoidance versus control Another study recruited 212 children (aged three months to 12 years) who underwent myringotomy and ventilation tube insertion. The study compared an intervention group who were instructed not to swim or submerge their heads while bathing with a control group; the participants were followed up at three-month intervals for one year. This study, with high risk of bias, did not show any evidence of a reduction or increase in the rate of otorrhoea (1.17 episodes per year in both groups; MD 0 episodes, 95% CI -0.14 to 0.14). No other outcomes were reported for this study and no adverse events were reported. Quality of evidence The overall quality (GRADE) of the body of evidence for the effect of ear plugs on the rate of otorrhoea and the effect of water avoidance on the rate of otorrhoea are low and very low respectively. The baseline rate of ventilation tube otorrhoea and the morbidity associated with it is usually low and therefore careful prior consideration must be given to the efficacy, costs and burdens of any intervention aimed at reducing this rate. While there is some evidence to suggest that wearing ear plugs reduces the rate of otorrhoea in children with ventilation tubes, clinicians and parents should understand that the absolute reduction in the number of episodes of otorrhoea appears to be very small and is unlikely to be clinically significant. Based on the data available, an average child would have to wear ear plugs for 2.8 years to prevent one episode of otorrhoea. Some evidence suggests that advising children to avoid swimming or head immersion during bathing does not affect rates of otorrhoea, although good quality data are lacking in this area. Currently, consensus guidelines therefore recommend against the routine use of water precautions on the basis that the limited clinical benefit is outweighed by the associated cost, inconvenience and anxiety. Future high-quality studies could be undertaken but may not be thought necessary. It is uncertain whether further trials in this area would change the findings of this review or have an impact on practice. Any future high-quality research should focus on determining whether particular groups of children benefit more from water precautions than others, as well as on developing clinical guidelines and their implementation.
We identified no studies for inclusion in the original review or for this update. However, we felt that some studies that were excluded warranted discussion. These included one randomised trial (RCT), which showed no improvement in sexual scores associated with encouraging women to practise dilation therapy; a recent small RCT that did not show any advantage to dilation over vibration therapy during radiotherapy; two non-randomised comparative studies; and five correlation studies. One of these showed that objective measurements of vaginal elasticity and length were not linked to dilation during radiotherapy, but the study lacked power. One study showed that women who dilated tolerated a larger dilator, but the risk of objectivity and bias with historical controls was high. Another study showed that the vaginal measurements increased in length by a mean of 3 cm after dilation was introduced 6 to 10 weeks after radiotherapy, but there was no control group; another case series showed the opposite. Three recent studies showed less stenosis associated with prophylactic dilation after radiotherapy. One small case series suggested that dilation years after radiotherapy might restore the vagina to a functional length. There is no reliable evidence to show that routine, regular vaginal dilation during radiotherapy treatment prevents stenosis or improves quality of life. Several observational studies have examined the effect of dilation therapy after radiotherapy. They suggest that frequent dilation practice is associated with lower rates of self reported stenosis. This could be because dilation is effective or because women with a healthy vagina are more likely to comply with dilation therapy instructions compared to women with strictures. We would normally suggest that a RCT is needed to distinguish between a casual and causative link, but pilot studies highlight many reasons why RCT methodology is challenging in this area.
We included eight studies (490 adult participants). The presence of nasal polyps on examination was an inclusion criterion in three studies, an exclusion criterion in one study and the remaining studies included a mixed population. No studies specifically investigated the effect of antifungals in patients with AFRS. Topical antifungal treatment versus placebo or no intervention We included seven studies (437 participants) that used amphotericin B (six studies; 383 participants) and one that used fluconazole (54 participants). Different delivery methods, volumes and concentrations were used. Four studies reported disease-specific health-related quality of life  using a range of instruments. We did not meta-analyse the results due to differences in the instruments used, and measurement and reporting methods. At the end of treatment (one to six months) none of the studies reported statistically significant differences between the groups (low-quality evidence - we are uncertain about the result). Two studies reported disease severity  using patient-reported symptom scores. Meta-analysis was not possible. At the end of treatment (8 to 13 weeks) one study showed no difference and the second found that patients in the placebo group had less severe symptoms (very low-quality evidence - we are very uncertain about the result). In terms of adverse effects , topical antifungals may lead to more local irritation compared with placebo (risk ratio (RR) 2.29, 95% confidence interval (CI) 0.61 to 8.62; 312 participants; 5 studies; low-quality evidence) but little or no difference in epistaxis (RR 0.97, 95% CI 0.14 to 6.63; 225 participants; 4 studies, low-quality evidence) or headache (RR 1.26, 95% CI 0.60 to 2.63; 195 participants; 3 studies; very low-quality evidence). None of the studies found a difference in generic health-related quality of life  (one study) or endoscopic score  (five studies) between the treatment groups. Three studies investigated CT scan ; two found no difference between the groups and one found a significant decrease in the mean percentage of air space occluded, favouring the antifungal group. Systemic antifungal treatment versus placebo or no treatment One study (53 participants) comparing terbinafine tablets against placebo reported that there may be little or no difference between the groups in disease-specific health-related quality of life  or disease severity score  (both low-quality evidence). Systemic antifungals may lead to more hepatic toxicity events (RR 3.35, 95% CI 0.14 to 78.60) but fewer gastrointestinal disturbances (RR 0.37, 95% CI 0.04 to 3.36), compared to placebo, although the evidence was of low quality. This study did not find a difference in CT scan  score between the groups. Generic health-related quality of life  and endoscopic score  were not measured. Other comparisons We found no studies that compared antifungal agents against other treatments for chronic rhinosinusitis. Due to the very low quality of the evidence, it is uncertain whether or not the use of topical or systemic antifungals has an impact on patient outcomes in adults with chronic rhinosinusitis compared with placebo or no treatment. Studies including specific subgroups (i.e. AFRS) are lacking.
In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial. Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD] -1.49, 95% confidence interval [CI] -2.65 to -0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD -0.42, 95% CI -0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI -1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants. No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence). We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias. Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed.
We included a total of 27 reviews in this overview. The reviews were generally of high quality according to AMSTAR ratings, and included studies provided evidence that ranged from very low to high in quality. Ten reviews had not been updated in the past three years. Seven reviews described interventions that provided a beneficial effect in reducing OHSS rates, and we categorised one additional review as 'promising'. Of the effective interventions, all except one had no detrimental effect on pregnancy outcomes. Evidence of at least moderate quality indicates that clinicians should consider the following interventions in ART cycles to reduce OHSS rates. • Metformin treatment before and during an ART cycle for women with PCOS (moderate-quality evidence). • Gonadotrophin-releasing hormone (GnRH) antagonist protocol in ART cycles (moderate-quality evidence). • GnRH agonist (GnRHa) trigger in donor oocyte or 'freeze-all' programmes (moderate-quality evidence). Evidence of low or very low quality suggests that clinicians should consider the following interventions in ART cycles to reduce OHSS rates. • Clomiphene citrate for controlled ovarian stimulation in ART cycles (low-quality evidence). • Cabergoline around the time of human chorionic gonadotrophin (hCG) administration or oocyte pickup in ART cycles (low-quality evidence). • Intravenous fluids (plasma expanders) around the time of hCG administration or oocyte pickup in ART cycles (very low-quality evidence). • Progesterone for luteal phase support in ART cycles (low-quality evidence). • Coasting (withholding gonadotrophins) - a promising intervention that needs to be researched further for reduction of OHSS. On the basis of this overview, we must conclude that evidence is currently insufficient to support the widespread practice of embryo cryopreservation. Currently, 27 reviews in the Cochrane Library were conducted to report on or to try to report on OHSS in ART cycles. We identified four review protocols but no new registered titles that can potentially be included in this overview in the future. This overview provides the most up-to-date evidence on prevention of OHSS in ART cycles from all currently published Cochrane reviews on ART. Clinicians can use the evidence summarised in this overview to choose the best treatment regimen for individual patients - a regimen that not only reduces the chance of developing OHSS but does not compromise other outcomes such as pregnancy or live birth rate. Review results, however, are limited by the lack of recent primary studies or updated reviews. Furthermore, this overview can be used by policymakers in developing local and regional protocols or guidelines and can reveal knowledge gaps for future research.
We identified no new studies from the updated searches. We included in this review two RCTs for a total of 630 participants. Both RCTs included participants with an established diagnosis of polycythaemia vera and with no clear indication or contraindication to aspirin therapy. We judged both studies to be of moderate quality. Published data from both studies were insufficient for a time-to-event data analysis and for some of the primary and secondary outcomes that we planned. The use of low-dose aspirin, compared with placebo, was associated with a lower risk of fatal thrombotic events (although this benefit was not statistically significant (OR 0.20, 95% CI 0.03 to 1.14; P = 0.07). No data on mortality from bleeding episodes were available. A non-significant benefit of aspirin was shown for all-cause mortality (OR 0.46, 95% CI 0.21 to 1.01; P = 0.05). No increase in the risk of major bleeding was reported in participants taking aspirin compared with those given placebo (OR 0.99, 95% CI 0.23 to 4.36; P = 0.99), and a non-significant increase with aspirin treatment was shown for minor bleeding (OR 1.85, 95% CI 0.90 to 3.79; P = 0.09). No published studies have reported findings in participants with essential thrombocythaemia or in the study of other antiplatelet drugs. For patients with polycythaemia vera who have no clear indication or contraindication to aspirin therapy, available evidence suggests that the use of low-dose aspirin, when compared with no treatment, is associated with a statistically non-significant reduction in the risk of fatal thrombotic events and all-cause mortality, without an increased risk of major bleeding.
We found only one RCT meeting the selection criteria for the second objective (therapeutic potential) of this review. This study recruited nine participants. It compared the use of gastrografin versus placebo in adult patients with MBO with no indication for further intervention (surgery, endoscopy) apart from standardised conservative management. The overall risk of bias for the study was high due to issues with low numbers of participants, selective reporting of outcomes and a high attrition rate for the intervention arm. Primary outcomes The included trial was a pilot study whose primary outcome was to test the feasibility for a large study. The authors reported specifically on the number of patients screened, the number recruited and reasons for exclusion; this was not the focus of our review. Due to the low number of participants, the authors of the study decided not to report on our primary outcome of assessing the ability of OWSC to predict the likelihood of malignant small bowel obstruction resolving with conservative treatment alone (diagnostic effect). It also did not report on our primary outcome of rate of resolution of MBO in patients receiving OWSC compared with those not receiving it (therapeutic effect). The study reported that no issues regarding safety or tolerability of either gastrografin or placebo were identified. The overall quality of the evidence for the incidence of adverse events with OWSC was very low, downgraded twice for serious limitations to study quality (high risk of selective reporting and attrition bias) and downgraded once for imprecision (sparse data). Secondary outcomes The study planned to report on this review’s secondary outcome measures of length of hospital stay and time from administration of OWSC to resolution of MBO. However the authors of the study decided not to do so due to the low numbers of patients recruited. The study did not report on our secondary outcome measure of survival times from onset of inoperable MBO until death. There is insufficient evidence from RCTs to determine the place of OWSC in predicting which patients with inoperable MBO will respond with conservative treatment alone. There is also insufficient evidence from RCTs to determine the therapeutic effects and safety of OWSC in patients with malignant small bowel obstruction.
We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported. We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life. TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.
Out of 14 717 citations, 11 RCTs met the inclusion criteria (1381 participants). Six studies addressed outcomes relating to medication adherence, and there was some evidence from two studies that telephone interventions can improve adherence. A meta-analysis of three studies for which there was sufficient data showed no significant benefit (SMD 0.49, 95% CI -1.12 to 2.11). There was some evidence from a study of young substance abusing HIV positive persons of the efficacy of telephone interventions for reducing risky sexual behaviour, while a trial of older persons found no benefit. Three RCTs addressed virologic outcomes, and there is very little evidence that telephone interventions improved virologic outcomes. Five RCTs addressed outcomes relating to depressive and psychiatric symptoms, and showed some evidence that telephone interventions can be of benefit. Three of these studies which focussed on depressive symptoms were combined in a meta-analysis, which showed no significant benefit (SMD 0.02, 95% CI -0.18 to 0.21 95% CI). Telephone voice interventions may have a role in improving medication adherence, reducing risky sexual behaviour, and reducing depressive and psychiatric symptoms, but current evidence is sparse, and further research is needed.
The updated search resulted in the inclusion of one new study. This review now includes five RCTs with 366 participants. There were more female than male participants (70% were female); their ages ranged from 14 to 53 years. All trials involved ACL reconstructions performed by experienced surgeons. Assessing the studies' risk of bias was hampered by poor reporting of trial methods, and consequently several studies were judged to be 'unclear' for several types of bias. One trial presenting primary outcome data was at high risk of detection bias from lack of clinician blinding and attrition bias from an unaccounted loss to follow-up at two years. We found moderate quality evidence (three trials, 193 participants) of no clinically relevant difference between CAS and conventional surgery in International Knee Documentation Committee (IKDC) subjective scores (self-reported measure of knee function; scale of 0 to 100 where 100 was best function). Pooled data from two of these trials (120 participants) showed a small, but clinically irrelevant difference favouring CAS (MD 2.05, 95% CI -2.16 to 6.25). A third trial (73 participants) also found minimal difference in IKDC subjective scores (reported MD 0.2). We found low quality evidence (two trials, 120 participants) showing no difference between the two groups in Lysholm scores, also measured on a scale 0 to 100 where 100 is best function (MD 0.25, 95% CI -3.75 to 4.25). We found very low quality evidence (one trial, 40 participants) showing no difference between the two groups in Tegner scores. We found low quality evidence (three trials, 173 participants) showing the majority of participants in both groups were assessed as having normal or nearly normal knee function (86/87 with CAS versus 84/86 with no CAS; RR 1.01, 95% CI 0.96 to 1.06). Similarly, no differences were found for our secondary outcome measures of knee stability, loss in range of motion and tunnel placement. None of the trials reported on re-operation. No adverse post-surgical events were reported in two trials (133 participants); this outcome was not reported by the other three trials. CAS use was associated with longer operating times compared with conventional operating techniques: the mean difference in operating times reported in the studies ranged between 9 and 27 minutes. From the available evidence, we are unable to demonstrate or refute a favourable effect of CAS for cruciate ligament reconstructions of the knee compared with conventional reconstructions. However, the currently available evidence does not indicate that CAS in knee ligament reconstruction improves outcome. There is a need for improved reporting of future studies of this technology.
We included two cluster-RCTs, which provided data from 2447 participants. Both trials were conducted in areas endemic to trachoma: Northern Australia and Tanzania. The follow-up period was three months in one trial and 12 months in the other; both trials had about 90% participant follow-up at final visit. Overall the quality of the evidence is uncertain due to the trials not reporting many design methods and the differences in outcomes reported between trials. Face washing combined with topical tetracycline was compared with topical tetracycline alone in three pairs of villages in one trial. The trial found that face washing combined with topical tetracycline reduced 'severe' active trachoma compared with topical tetracycline alone at 12 months (adjusted odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.97); however, the trial did not find any important difference between the intervention and control villages in reducing other types of active trachoma (adjusted OR 0.81, 95% CI 0.42 to 1.59). Intervention villages had a higher prevalence of clean faces than the control villages among children with severe trachoma (adjusted OR 0.35, 95% CI 0.21 to 0.59) and any trachoma (adjusted OR 0.58, 95% CI 0.47 to 0.72) at 12 months follow-up. The second trial compared eye washing to no treatment or to topical tetracycline alone or to a combination of eye washing and tetracycline drops in children with follicular trachoma. At three months, the trial found no evidence of benefit of eye washing alone or in combination with tetracycline eye drops in reducing follicular trachoma amongst children with follicular trachoma (risk ratio (RR) 1.03, 95% CI 0.96 to 1.11; one trial, 1143 participants). There is evidence from one trial that face washing combined with topical tetracycline may be effective in reducing severe active trachoma and in increasing the prevalence of clean faces at one year follow-up. Current evidence is inconclusive as to the effectiveness of face washing alone or in combination with topical tetracycline in reducing active or severe trachoma.
One hundred and thirty-four studies involving 428,293 participants met the inclusion criteria. Some studies provided data for more than one group. Pure Prevention cohorts (Group 1) included 49 studies (N = 142,447). Pooled results at follow-up at one year or less found no overall effect of intervention curricula versus control (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). In a subgroup analysis, the combined social competence and social influences curricula (six RCTs) showed a statistically significant effect in preventing the onset of smoking (OR 0.49, 95% CI 0.28 to 0.87; seven arms); whereas significant effects were not detected in programmes involving information only (OR 0.12, 95% CI 0.00 to 14.87; one study), social influences only (OR 1.00, 95% CI 0.88 to 1.13; 25 studies), or multimodal interventions (OR 0.89, 95% CI 0.73 to 1.08; five studies). In contrast, pooled results at longest follow-up showed an overall significant effect favouring the intervention (OR 0.88, 95% CI 0.82 to 0.96). Subgroup analyses detected significant effects in programmes with social competence curricula (OR 0.52, 95% CI 0.30 to 0.88), and the combined social competence and social influences curricula (OR 0.50, 95% CI 0.28 to 0.87), but not in those programmes with information only, social influence only, and multimodal programmes. Change in Smoking Behaviour over time (Group 2) included 15 studies (N = 45,555). At one year or less there was a small but statistically significant effect favouring controls (standardised mean difference (SMD) 0.04, 95% CI 0.02 to 0.06). For follow-up longer than one year there was a statistically nonsignificant effect (SMD 0.02, 95% CI -0.00 to 0.02). Twenty-five studies reported data on the Point Prevalence of Smoking (Group 3), though heterogeneity in this group was too high for data to be pooled. We were unable to analyse data for 49 studies (N = 152,544). Subgroup analyses (Pure Prevention cohorts only) demonstrated that at longest follow-up for all curricula combined, there was a significant effect favouring adult presenters (OR 0.88, 95% CI 0.81 to 0.96). There were no differences between tobacco-only and multifocal interventions. For curricula with booster sessions there was a significant effect only for combined social competence and social influences interventions with follow-up of one year or less (OR 0.50, 95% CI 0.26 to 0.96) and at longest follow-up (OR 0.51, 95% CI 0.27 to 0.96). Limited data on gender differences suggested no overall effect, although one study found an effect of multimodal intervention at one year for male students. Sensitivity analyses for Pure Prevention cohorts and Change in Smoking Behaviour over time outcomes suggested that neither selection nor attrition bias affected the results. Pure Prevention cohorts showed a significant effect at longest follow-up, with an average 12% reduction in starting smoking compared to the control groups. However, no overall effect was detected at one year or less. The combined social competence and social influences interventions showed a significant effect at one year and at longest follow-up. Studies that deployed a social influences programme showed no overall effect at any time point; multimodal interventions and those with an information-only approach were similarly ineffective. Studies reporting Change in Smoking Behaviour over time did not show an overall effect, but at an intervention level there were positive findings for social competence and combined social competence and social influences interventions.
We included 24 studies (2664 participants) of adult participants (older than 18 years of age) with respiratory distress due to ACPE, not requiring immediate mechanical ventilation. People with ACPE presented either to an Emergency Department or were inpatients. ACPE treatment was provided in an intensive care or Emergency Department setting. There was a median follow-up of 13 days for hospital mortality, one day for endotracheal intubation, and three days for acute myocardial infarction. Compared with SMC, NPPV may reduce hospital mortality (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.51 to 0.82; participants = 2484; studies = 21; I2 = 6%; low quality of evidence) with a number needed to treat for an additional beneficial outcome (NNTB) of 17 (NNTB 12 to 32). NPPV probably reduces endotracheal intubation rates (RR 0.49, 95% CI 0.38 to 0.62; participants = 2449; studies = 20; I2 = 0%; moderate quality of evidence) with a NNTB of 13 (NNTB 11 to 18). There is probably little or no difference in acute myocardial infarction (AMI) incidence with NPPV compared to SMC for ACPE (RR 1.03, 95% CI 0.91 to 1.16; participants = 1313; studies = 5; I2 = 0%; moderate quality of evidence). We are uncertain as to whether NPPV increases hospital length of stay (mean difference (MD) −0.31 days, 95% CI −1.23 to 0.61; participants = 1714; studies = 11; I2 = 55%; very low quality of evidence). Adverse events were generally similar between NPPV and SMC groups, but evidence was of low quality. Our review provides support for continued clinical application of NPPV for ACPE, to improve outcomes such as hospital mortality and intubation rates. NPPV is a safe intervention with similar adverse event rates to SMC alone. Additional research is needed to determine if specific subgroups of people with ACPE have greater benefit of NPPV compared to SMC. Future research should explore the benefit of NPPV for ACPE patients with hypercapnia.
A single trial containing 22 patients, with a low risk of bias was included. This trial found that after 24 months, compared with placebo, the use of intratympanic dexamethasone demonstrated a statistically significant improvement in vertigo as defined by a respective improvement in functional level (90% versus 42%), class (82% versus 57%), change in Dizziness Handicap Inventory scores (60.4 versus 41.3) and mean vertigo subjective improvement (90% versus 57%). The treatment regime described by the authors involved daily injections of dexamethasone solution 4 mg/ml for five consecutive days. These results were clinically significant. No complications were reported. The results of a single trial provide limited evidence to support the effectiveness of intratympanic steroids in patients with Ménière's disease. This trial demonstrated a statistically and clinically significant improvement of the frequency and severity of vertigo measured 24 months after the treatment was administered. It is important to note that there were a few aspects of the study which we were unable to clarify with the study authors.
Fifty trials met the inclusion criteria, 45 in men after radical prostatectomy, four trials after TURP and one trial after either operation. The trials included 4717 men of whom 2736 had an active conservative intervention. There was considerable variation in the interventions, populations and outcome measures. Data were not available for many of the pre-stated outcomes. Men's symptoms improved over time irrespective of management. There was no evidence from eight trials that pelvic floor muscle training with or without biofeedback was better than control for men who had urinary incontinence up to 12 months after radical prostatectomy; the quality of the evidence was judged to be moderate (for example 57% with urinary incontinence in the intervention group versus 62% in the control group, risk ratio (RR) for incontinence after 12 months 0.85, 95% confidence interval (CI) 0.60 to 1.22). One large multi-centre trial of one-to-one therapy showed no difference in any urinary or quality of life outcome measures and had narrow CIs. It seems unlikely that men benefit from one-to-one PFMT therapy after TURP. Individual small trials provided data to suggest that electrical stimulation, external magnetic innervation, or combinations of treatments might be beneficial but the evidence was limited. Amongst trials of conservative treatment for all men after radical prostatectomy, aimed at both treatment and prevention, there was moderate evidence of an overall benefit from pelvic floor muscle training versus control management in terms of reduction of urinary incontinence (for example 10% with urinary incontinence after one year in the intervention groups versus 32% in the control groups, RR for urinary incontinence 0.32, 95% CI 0.20 to 0.51). However, this finding was not supported by other data from pad tests. The findings should be treated with caution because the risk of bias assessment showed methodological limitations. Men in one trial were more satisfied with one type of external compression device, which had the lowest urine loss, compared to two others or no treatment. The effect of other conservative interventions such as lifestyle changes remained undetermined as no trials involving these interventions were identified. The value of the various approaches to conservative management of postprostatectomy incontinence after radical prostatectomy remains uncertain. The evidence is conflicting and therefore rigorous, adequately powered randomised controlled trials (RCTs) which abide by the principles and recommendations of the CONSORT statement are still needed to obtain a definitive answer. The trials should be robustly designed to answer specific well constructed research questions and include outcomes which are important from the patient's perspective in decision making and are also relevant to the healthcare professionals. Long-term incontinence may be managed by an external penile clamp, but there are safety problems.
One trial involving 76 women who planned to have their babies delivered by caesarean section met the inclusion criteria, but data were available for only 64 women. This trial was of low quality with unclear allocation concealment and only a few main clinical outcomes reported for the women. The trial did not report any infant outcomes. It appears that music added to standard care during caesarean section under regional anaesthesia had some impact on pulse rate at the end of maternal contact with the neonate in the intra-operative period (MD -7.50 fewer beats per minute, 95% CI -14.08 to -0.92) and after completion of skin suture for the caesarean section (MD -7.37 fewer beats per minute, 95% CI -13.37 to -1.37). There was also an improvement in the birth satisfaction score (maximum possible score of 35) (MD of 3.38, 95%CI 1.59 to 5.17). Effects on other outcomes were either not significant or not reported in the one included trial. The findings indicate that music during planned caesarean section under regional anaesthesia may improve pulse rate and birth satisfaction score. However, the magnitude of these benefits is small and the methodological quality of the one included trial is questionable. Therefore, the clinical significance of music is unclear. More research is needed to investigate the effects of music during caesarean section under regional anaesthesia on both maternal and infant outcomes, in various ethnic pregnant women, and with adequate sample sizes.
Two randomised controlled trials comparing elective birth at 37 weeks for women with an uncomplicated twin pregnancy, with expectant management were included, involving 271 women and 542 infants. One trial was at an overall low risk of bias, and one trial was at unclear risk of selection bias, performance bias and detection bias. There were no statistically significant differences identified between a policy of elective birth at 37 weeks' gestation and expectant management with regards to birth by caesarean section (two studies; 271 participants; risk ratio (RR) 1.05; 95% confidence interval (CI) 0.83 to 1.32); perinatal death or serious perinatal morbidity (two studies; 542 infants; RR 0.34; 95% CI 0.01 to 8.35); or maternal death or serious maternal morbidity (one study; 235 women; RR 0.29; 95% CI 0.06 to 1.38). There were no statistically significant differences identified for the pre-specified secondary maternal and infant review outcomes reported by these two trials between the two treatment policies (including for: haemorrhage requiring blood transfusion; instrumental vaginal birth; meconium-stained liquor; Apgar score less than seven at five minutes; admission to neonatal intensive care; birthweight less than 2500 g; neonatal encephalopathy; and respiratory distress syndrome). While not a pre-specified review outcome, elective birth at 37 weeks, compared with expectant management, was shown to significantly reduce the risk of infants being born with a birthweight less than the third centile (one study; 470 infants; RR 0.30; 95% CI 0.13 to 0.68). Early birth at 37 weeks' gestation compared with ongoing expectant management for women with an uncomplicated twin pregnancy does not appear to be associated with an increased risk of harms, findings which are consistent with the United Kingdom's National Institute for Health and Care Excellence (NICE) recommendations which advocate birth for women with a dichorionic twin pregnancy at 37 + 0 weeks' gestation. It is unlikely that sufficient clinical equipoise exists to allow for the randomisation of women to a later gestational age at birth.
We found one small RCT, judged to be at low risk of bias, that enrolled 28 children aged 1 to 16 years with evidence of sensitisation to peanut and a clinical history of reaction to peanut within 60 minutes of exposure. The study did not include children who had moderate to severe asthma or who had a history of severe peanut anaphylaxis. Randomisation was in a 2:1 ratio resulting in 19 children being randomised to the intervention arm and nine to the placebo arm. Intervention arm children received OIT with peanut flour and control arm participants received placebo comprising of oat flour. The primary outcome was assessed using a double-blind, placebo controlled oral food challenge (OFC) at approximately one year. No data were available on longer term outcomes beyond the OFC conducted at the end of the study. Because of adverse events, three patients withdrew from the intervention arm before the completion of the study. Therefore, only 16 participants received the full course of peanut OIT, whereas all nine patients receiving placebo completed the trial. The per-protocol analysis found a significant increase in the threshold dose of peanut allergen required to trigger a reaction in those in the intervention arm with all 16 participants able to ingest the maximum cumulative dose of 5000 mg of peanut protein (which the authors equate as being equivalent to approximately 20 peanuts) without developing symptoms, whereas in the placebo group they were able to ingest a median cumulative dose of 280 mg (range: 0 to 1900 mg, P < 0.001) before experiencing symptoms.  Per-protocol analyses also demonstrated that peanut OIT resulted in reductions in skin prick test size (P < 0.001), interleukin-5 (P = 0.01), interleukin-13 (P = 0.02) and an increase in peanut-specific immunoglobulin G4 (IgG4) (P < 0.01). Children in the intervention arm experienced more adverse events during treatment than those in the placebo arm. In the initial day escalation phase, nine (47%) of the 19 participants initially enrolled in the OIT arm experienced clinically-relevant adverse events which required treatment with H1-antihistamines, two of which required additional treatment with epinephrine (adrenaline). The one small RCT we found showed that allergen-specific peanut OIT can result in desensitisation in children, and that this is associated with evidence of underlying immune-modulation. However, this treatment approach was associated with a substantial risk of adverse events, although the majority of these were mild.  In view of the risk of adverse events and the lack of evidence of long-term benefits, allergen-specific peanut OIT cannot currently be recommended as a treatment for the management of patients with IgE-mediated peanut allergy.  Larger RCTs are needed to investigate the acceptability, long-term effectiveness and cost-effectiveness of safer treatment regimens, particularly in relation to the induction of clinical and immunological tolerance.
Four trials were included in the review. Of these, two were randomised parallel studies, one was a crossover study and the other had a sequential design. A total of 84 patients were involved. Study quality was mixed and the studies were short (typically two weeks). All studies showed a similar direction and size of effect. In the randomised parallel studies, acetazolamide caused a metabolic acidosis and produced a non-significant fall in PCO2 (MD -0.41 kPa; 95% CI -0.91, 0.09; N=2) and a significant rise in PO2 (MD 1.54 kPa; 95% CI 0.97, 2.11; N=2). One study reported an improvement in sleep but there were no data concerning outcomes such as health status, symptoms, exacerbation rate, hospital admissions or deaths. Side effects were reported infrequently. An update search conducted in October 2005 did not identify any further studies. Acetazolamide can produce a small increase in arterial PO2 and fall in PCO2. These conclusions are drawn from a few small short studies that were not all of high quality. It is not known whether this physiological improvement is associated with clinical benefit.
The evidence favoured five active strategies for inviting women into community breast cancer screening services: letter of invitation (OR 1.66, 95% CI 1.43 to 1.92), mailed educational material (Odds Ratio(OR) 2.81, 95% Confidence Interval (CI) 1.96 to 4.02), letter of invitation plus phone call (OR 2.53, 95% CI 2.02 to 3.18), phone call (OR 1.94, 95% CI 1.70 to 2.23), and training activities plus direct reminders for the women (OR 2.46, 95% CI 1.72 to 3.50). Home visits did not prove to be effective (OR 1.06, 95 % CI 0.80 to 1.40) and letters of invitation to multiple examinations plus educational material favoured the control group (OR 0.62, 95 % CI 0.32 to 1.20). Most active recruitment strategies for breast cancer screening programs examined in this review were more effective than no intervention. Combinations of effective interventions can have an important effect. Some costly strategies, as a home visit and a letter of invitation to multiple screening examinations plus educational material, were not effective. Further reviews comparing the effective interventions and studies that include cost-effectiveness, women's satisfaction and equity issues are needed.
We included 13 trials that recruited 14,959 women from diverse healthcare settings (antenatal clinics, women's health clinics, emergency departments, primary care) predominantly located in high-income countries and urban settings. The majority of studies minimised selection bias; performance bias was the greatest threat to validity. The overall quality of the body of evidence was low to moderate, mainly due to heterogeneity, risk of bias, and imprecision. We excluded five of 13 studies from the primary analysis as they either did not report identification data, or the way in which they did was not consistent with clinical identification by healthcare providers. In the remaining eight studies (n = 10,074), screening increased clinical identification of victims/survivors (OR 2.95, 95% CI 1.79 to 4.87, moderate quality evidence). Subgroup analyses suggested increases in identification in antenatal care (OR 4.53, 95% CI 1.82 to 11.27, two studies, n = 663, moderate quality evidence); maternal health services (OR 2.36, 95% CI 1.14 to 4.87, one study, n = 829, moderate quality evidence); and emergency departments (OR 2.72, 95% CI 1.03 to 7.19, three studies, n = 2608, moderate quality evidence); but not in hospital-based primary care (OR 1.53, 95% CI 0.79 to 2.94, one study, n = 293, moderate quality evidence). Only two studies (n = 1298) measured referrals to domestic violence support services following clinical identification. We detected no evidence of an effect on referrals (OR 2.24, 95% CI 0.64 to 7.86, low quality evidence). Four of 13 studies (n = 2765) investigated prevalence (excluded from main analysis as rates were not clinically recorded); detection of IPV did not differ between face-to-face screening and computer/written-based assessment (OR 1.12, 95% CI 0.53 to 2.36, moderate quality evidence). Only two studies measured women's experience of violence (three to 18 months after screening) and found no evidence that screening decreased IPV. Only one study reported on women's health with no differences observable at 18 months. Although no study reported adverse effects from screening interventions, harm outcomes were only measured immediately afterwards and only one study reported outcomes at three months. There was insufficient evidence on which to judge whether screening increases uptake of specialist services, and no studies included an economic evaluation. The evidence shows that screening increases the identification of women experiencing IPV in healthcare settings. Overall, however, rates were low relative to best estimates of prevalence of IPV in women seeking healthcare. Pregnant women in antenatal settings may be more likely to disclose IPV when screened, however, rigorous research is needed to confirm this. There was no evidence of an effect for other outcomes (referral, re-exposure to violence, health measures, harm arising from screening). Thus, while screening increases identification, there is insufficient evidence to justify screening in healthcare settings. Furthermore, there remains a need for studies comparing universal screening to case-finding (with or without advocacy or therapeutic interventions) for women's long-term wellbeing in order to inform IPV identification policies in healthcare settings.
Only one trial (89 patients) fulfilled the inclusion criteria. This trial randomized 45 patients to curcumin and 44 patients to placebo. All patients received treatment with sulfasalazine or mesalamine. The study was rated as low risk of bias. Curcumin was administered orally in a dose of 2 g/day for six months. Fewer patients relapsed in the curcumin group than the placebo group at six months. Four per cent of patients in the curcumin group relapsed at six months compared to 18% of patients in the placebo group (RR 0.24, 95% CI 0.05 to 1.09; P = 0.06). There was no statistically significant difference in relapse rates at 12 months. Twenty-two per cent of curcumin patients relapsed at 12 months compared to 32% of placebo patients (RR 0.70, 95% CI 0.35 to 1.40; P = 0.31). A total of nine adverse events were reported in seven patients. These adverse events included sensation of abdominal bulging, nausea, transient hypertension, and transient increase in the number of stools. The authors did not report which treatment group the patients who experienced adverse events belonged to. The clinical activity index (CAI) at six months was significantly lower in the curcumin group compared to the placebo group (1.0 + 2.0 versus 2.2 + 2.3; MD -1.20, 95% CI -2.14 to -0.26). The endoscopic index (EI) at six months was significantly lower in the curcumin group than in the placebo group (0.8 + 0.6 versus 1.6 + 1.6; MD -0.80, 95% CI -1.33 to -0.27). Curcumin may be a safe and effective therapy for maintenance of remission in quiescent UC when given as adjunctive therapy along with mesalamine or sulfasalazine. However, further research in the form of a large scale methodologically rigorous randomized controlled trial is needed to confirm any possible benefit of curcumin in quiescent UC.
The review found seven trials, involving 1497 patients, which met the criteria to be included. The trials were generally of moderate methodological quality; two studies have not published their results on overall survival so the presence of selective outcome reporting bias cannot be ruled out. None of the studies used blinding to treatment allocation, though this is unlikely to have biased the results for overall survival. Studies varied in terms of co-administered regimen and in terms of treatment line. In four studies, trastuzumab was administered with a chemotherapy, such as a taxane-containing, anthracycline-containing or capecitabine-containing regimen. Two studies considered postmenopausal women and administered trastuzumab with hormone-blocking medications, such as an aromatase inhibitor. One study administered trastuzumab in addition to lapatinib. Five studies out of seven included women treated with trastuzumab administered until progression as first-line treatment and two studies considered trastuzumab beyond progression. The combined HRs for overall survival and progression-free survival favoured the trastuzumab-containing regimens (HR 0.82, 95% confidence interval (CI) 0.71 to 0.94, P = 0.004; and HR 0.61, 95% CI 0.54 to 0.70, P < 0.00001, respectively; moderate-quality evidence). Trastuzumab increased the risk of congestive heart failure (RR 3.49, 90% CI 1.88 to 6.47, P = 0.0009; moderate-quality evidence) and left ventricular ejection fraction (LVEF) decline (RR 2.65, 90% CI 1.48 to 4.74, P = 0.006). For haematological toxicities, such as neutropenic fever and anaemia, there was no clear evidence that risks differed between groups, while trastuzumab seemed to raise the risk of neutropenia. The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens. The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens, and patients treated as first-line or subsequent lines. Few data were collected on central nervous system progression. Similarly, few studies reported on quality of life and treatment-related deaths. Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer, but it also increased the risk of cardiac toxicities, such as congestive heart failure and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab as first-line treatment, or along with a taxane-based regimen, improved mortality outcomes. The evidence to support the use of trastuzumab beyond progression is limited. The recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at progression, making it more difficult to understand the real net benefit of trastuzumab. Trastuzumab is generally used for women with HER2-positive early breast cancer in clinical practice, while women enrolled in most of the trials in the metastatic setting were naive to trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is therefore still an open issue, although it is likely that the majority are being offered it again.
Fourteen studies (1805 patients) were included: Nine (779 patients) compared budesonide to conventional corticosteroids, three (535 patients) were placebo-controlled, and two (491 patients) compared budesonide to mesalamine. Ten studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to open label design. One study was judged to be at high risk of bias due to selective reporting. After eight weeks of treatment, 9 mg budesonide was significantly more effective than placebo for induction of clinical remission. Forty-seven per cent (115/246) of budesonide patients achieved remission at 8 weeks compared to 22% (29/133) of placebo patients (RR 1.93, 95% CI 1.37 to 2.73; 3 studies, 379 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (144 events). Budesonide was significantly less effective than conventional steroids for induction of remission at eight weeks. Fifty-two per cent of budesonide patients achieved remission at week 8 compared to 61% of patients who received conventional steroids (RR 0.85, 95% CI 0.75 to 0.97; 8 studies, 750 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to risk of bias. Budesonide was significantly less effective than conventional steroids among patients with severe disease (CDAI > 300) (RR 0.52, 95% CI 0.28 to 0.95). Studies comparing budesonide to mesalamine were not pooled due to heterogeneity (I2 = 81%). One study (n = 182) found budesonide to be superior to mesalamine for induction of remission at 8 weeks. Sixty-eight per cent (63/93) of budesonide patients were in remission at 8 weeks compared to 42% (37/89) of mesalamine patients (RR 1.63, 95% CI 1.23 to 2.16). The other study found no statistically significant difference in remission rates at eight weeks. Sixty-nine per cent (107/154) of budesonide patients were in remission at 8 weeks compared to 62% (132/242) of mesalamine patients (RR 1.12, 95% CI 0.95 to 1.32). Fewer adverse events occurred in those treated with budesonide compared to conventional steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better than conventional steroids in preserving adrenal function (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78). Budesonide is more effective than placebo for induction of remission in Crohn's disease. Although short-term efficacy with budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement, the likelihood of adverse events and adrenal suppression with budesonide is lower. The current evidence does not allow for a firm conclusion on the relative efficacy of budesonide compared to 5-ASA products.
We identified 15 studies (1550 patients). CRRT did not differ from IRRT with respect to in-hospital mortality (RR 1.01, 95% CI 0.92 to 1.12), ICU mortality (RR 1.06, 95% CI 0.90 to 1.26), number of surviving patients not requiring RRT (RR 0.99, 95% CI 0.92 to 1.07), haemodynamic instability (RR 0.48, 95% CI 0.10 to 2.28) or hypotension (RR 0.92, 95% CI 0.72 to 1.16) and need for escalation of pressor therapy (RR 0.53, 95% CI 0.26 to 1.08). Patients on CRRT were likely to have significantly higher mean arterial pressure (MAP) (MD 5.35, 95% CI 1.41 to 9.29) and higher risk of clotting dialysis filters (RR, 95% CI 8.50 CI 1.14 to 63.33). In patients who are haemodynamically stable, the RRT modality does not appear to influence important patient outcomes, and therefore the preference for CRRT over IRRT in such patients does not appear justified in the light of available evidence. CRRT was shown to achieve better haemodynamic parameters such as MAP. Future research should focus on factors such as the dose of dialysis and evaluation of newer promising hybrid technologies such as SLED. Triallists should follow the recommendations regarding clinical endpoints assessment in RCTs in ARF made by the Working Group of the Acute Dialysis Quality Initiative Working Group.
Four trials appeared to meet the inclusion criteria, but one was excluded because of poor methodology. The three remaining trials compared testosterone treatment with placebo in a total of 109 subjects with intermittent claudication or critical leg ischaemia. The most recent trial to meet the inclusion criteria dated from 1971. No trials were available which investigated the potentially beneficial effects of oestrogenic hormones in women with lower limb atherosclerosis. Testosterone therapy produced no significant improvement in tests of walking distance or in a variety of other objective tests for peripheral arterial disease, including venous filling time, muscle blood flow and plethysmography. The relative risk for subjective improvement in symptoms using the combined trial results was also non-significant (relative risk (RR) 1.10, 95% confidence interval (CI) 0.81 to 1.48). There is no evidence to date that short-term testosterone treatment is beneficial in subjects with lower limb atherosclerosis. However, this might reflect limited data rather than the lack of a real effect.
We included two RCTs with 297 participants comparing PUL to sham surgery or TURP. The mean age was 65.6 years and mean International Prostate Symptom Score was 22.7. Mean prostate volume was 42.2 mL. We considered review outcomes measured up to and including 12 months after randomization as short-term and later than 12 months as long-term. For patient-reported outcomes, lower scores indicate more urological symptom improvement and higher quality of life. In contrast, higher scores refers to better erectile and ejaculatory function. PUL versus sham: based on one study of 206 randomized participants with short follow-up (up to three months), PUL may lead to a clinically important improvement in urological symptom scores (mean difference (MD) –5.20, 95% confidence interval (CI) –7.44 to –2.96; low-certainty evidence) and likely improves quality of life (MD –1.20, 95% CI –1.67 to –0.73; moderate-certainty evidence). We are uncertain whether PUL increases major adverse events (very low-certainty evidence). There were no retreatments reported in either study group by three months. PUL likely results in little to no difference in erectile function (MD –1.40, 95% CI –3.24 to 0.44; moderate-certainty evidence) and ejaculatory function (MD 0.50, 95% CI –0.38 to 1.38; moderate-certainty evidence). PUL versus TURP: based on one study of 91 randomized participants with a short follow-up (up to 12 months), PUL may result in a substantially lesser improvement in urological symptom scores than TURP (MD 4.50, 95% CI 1.10 to 7.90; low-certainty evidence). PUL may result in a slightly reduced or similar quality of life (MD 0.30, 95% CI –0.49 to 1.09; low-certainty evidence). We are very uncertain whether PUL may cause fewer major adverse events but increased retreatments (both very low-certainty evidence). PUL probably results in little to no difference in erectile function (MD 0.80, 95% CI –1.50 to 3.10; moderate-certainty evidence), but probably results in substantially better ejaculatory function (MD 5.00, 95% CI 3.08 to 6.92; moderate-certainty evidence). With regards to longer term follow-up (up to 24 months) based on one study of 91 randomized participants, PUL may result in a substantially lesser improvement in urological symptom score (MD 6.10, 95% CI 2.16 to 10.04; low-certainty evidence) and result in little worse to no difference in quality of life (MD 0.80, 95% CI 0.00 to 1.60; low-certainty evidence). The study did not report on major adverse events. We are very uncertain whether PUL increases retreatment (very low-certainty evidence). PUL likely results in little to no difference in erectile function (MD 1.60, 95% CI –0.80 to 4.00; moderate-certainty evidence), but may result in substantially better ejaculatory function (MD 4.30, 95% CI 2.17 to 6.43; low-certainty evidence). We were unable to perform any of the predefined secondary analyses for either comparison. We found no evidence for other comparisons such as PUL versus laser ablation or enucleation. PUL appears less effective than TURP in improving urological symptoms both short-term and long term, while quality of life outcomes may be similar. The effect on erectile function appears similar but ejaculatory function may be better. We are uncertain about major adverse events short-term and found no long-term information. We are very uncertain about retreatment rates both short-term and long-term. We were unable to assess the effects of PUL in subgroups based on age, prostate size, or symptom severity and also could not assess how PUL compared to other surgical management approaches. Given the large numbers of alternative treatment modalities to treat men with LUTS secondary to BPH, this represents important information that should be shared with men considering surgical treatment.
In this update, no new trials were identified (08/2002).  Only one trial with 54 men lasting 240 days (with 330 days of follow up) met study inclusion criteria. There was a statistically significant change favoring allopurinol in patient-reported discomfort between the study and control groups at follow up. Between days 45 to 225, the mean score was -0.95 (SD 0.19) for the allopurinol group (seven men), compared with -0.47 (SD 0.21) for the placebo group (seven men). The weighted mean difference (WMD) was -0.48 (95% CI -0.690 to -0.270). The mean score between days 45-135 was -1.08 (SD 1.29) for the 25 men in the allopurinol group, compared with -0.21 (SD 0.97) for the 14 men in the control group. The WMD was -0.87 (95%CI -1.587 to -0.153). The allopurinol group had significantly less investigator graded prostate pain and had lower levels of serum urate, urine urate, and expressed prostatic secretion urate and xanthine. No significant differences between the two groups regarding leukocyte counts were found. No patient receiving allopurinol had any significant side effects. Three patients in the placebo group dropped out because of side effects. One small trial of allopurinol for treating chronic prostatitis showed improvements in patient-reported symptom improvement, investigator-graded prostate pain, and biochemical parameters. However, the data provided, the measures used, and the statistics presented do not make these findings convincing that changes in urine and prostatic secretion composition regarding purine and pyrimidine bases resulted in the relief of symptoms. Further studies of allopurinol treatment using standardized and validated outcomes measures and analyses are necessary to determine whether allopurinol is effective.
Based on a single trial and moderate-quality evidence, alvimopan reduced the time to reach a composite endpoint of tolerance of solid food and documented bowel movements (hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.41 to 2.23). This represents 165 more patients (109 more to 207 more) per 1000 meeting this endpoint within 10 days of surgery. Based on moderate-quality evidence, alvimopan reduced the time to hospital discharge (HR 1.67, 95% CI 1.38 to 2.01). This represents 138 more patients (82 more to 198 more) per 1000 being discharged within 10 days of surgery. Also based on moderate-quality evidence, alvimopan was associated with a reduced risk of major adverse events (risk ratio (RR) 0.28, 95% CI 0.18 to 0.44) representing 355 fewer patients (404 fewer to 276 fewer) with major adverse events per 1000. We downgraded this outcome for indirectness as it included adverse events that we did not consider major. In terms of secondary outcomes, alvimopan did not appear to alter the rate of readmission (RR 0.89, 95% CI 0.59 to 1.33), change the rate of any cardiovascular event (RR 0.54, 95% CI 0.27 to 1.05) or alter the mean narcotic pain medication use (mean difference 0, 95% CI 14.08 fewer to 14.08 more morphine equivalents). The quality of evidence was moderate for all three outcomes. Based on high-quality evidence, alvimopan reduced the rate of nasogastric tube replacement (RR 0.31, 95% CI 0.16 to 0.59). We did not find evidence for the drug's impact on rates of parenteral nutrition. All outcomes were short term and limited to a 30-day time horizon. Based on the existence of only one trial, we were unable to perform any subgroup or sensitivity analyses. In patients undergoing radical cystectomy and urinary diversion, the use of alvimopan administered as part of an enhanced recovery pathway for a limited duration (up to 15 doses for up to seven days) probably reduces the time to tolerance of solid food, time to hospital discharge and rates of major adverse events. Readmission rates, rates of cardiovascular events and narcotic pain requirements are probably similar. The need for reinsertion of nasogastric tubes is reduced. We found no evidence for the impact on rates of parenteral nutrition within 30 postoperative days.
We included 26 trials involving 17,011 participants (8497 participants were assigned active therapy and 8514 participants received placebo/control). Not all trials contributed to each outcome. Most data came from trials that had a wide time window for recruitment; four trials gave treatment within six hours and one trial within eight hours. The trials tested alpha-2 adrenergic agonists (A2AA), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARA), calcium channel blockers (CCBs), nitric oxide (NO) donors, thiazide-like diuretics, and target-driven blood pressure lowering. One trial tested phenylephrine. At 24 hours after randomisation oral ACEIs reduced systolic blood pressure (SBP, mean difference (MD) -8 mmHg, 95% confidence interval (CI) -17 to 1) and diastolic blood pressure (DBP, MD -3 mmHg, 95% CI -9 to 2), sublingual ACEIs reduced SBP (MD -12.00 mm Hg, 95% CI -26 to 2) and DBP (MD -2, 95%CI -10 to 6), oral ARA reduced SBP (MD -1 mm Hg, 95% CI -3 to 2) and DBP (MD -1 mm Hg, 95% CI -3 to 1), oral beta blockers reduced SBP (MD -14 mm Hg; 95% CI -27 to -1) and DBP (MD -1 mm Hg, 95% CI -9 to 7), intravenous (iv) beta blockers reduced SBP (MD -5 mm Hg, 95% CI -18 to 8) and DBP (-5 mm Hg, 95% CI -13 to 3), oral CCBs reduced SBP (MD -13 mmHg, 95% CI -43 to 17) and DBP (MD -6 mmHg, 95% CI -14 to 2), iv CCBs reduced SBP (MD -32 mmHg, 95% CI -65 to 1) and DBP (MD -13, 95% CI -31 to 6), NO donors reduced SBP (MD -12 mmHg, 95% CI -19 to -5) and DBP (MD -3, 95% CI -4 to -2) while phenylephrine, non-significantly increased SBP (MD 21 mmHg, 95% CI -13 to 55) and DBP (MD 1 mmHg, 95% CI -15 to 16). Blood pressure lowering did not reduce death or dependency either by drug class (OR 0.98, 95% CI 0.92 to 1.05), stroke type (OR 0.98, 95% CI 0.92 to 1.05) or time to treatment (OR 0.98, 95% CI 0.92 to 1.05). Treatment within six hours of stroke appeared effective in reducing death or dependency (OR 0.86, 95% CI 0.76 to 0.99) but not death (OR 0.70, 95% CI 0.38 to 1.26) at the end of the trial. Although death or dependency did not differ between people who continued pre-stroke antihypertensive treatment versus those who stopped it temporarily (worse outcome with continuing treatment, OR 1.06, 95% CI 0.91 to 1.24), disability scores at the end of the trial were worse in participants randomised to continue treatment (Barthel Index, MD -3.2, 95% CI -5.8, -0.6). There is insufficient evidence that lowering blood pressure during the acute phase of stroke improves functional outcome. It is reasonable to withhold blood pressure-lowering drugs until patients are medically and neurologically stable, and have suitable oral or enteral access, after which drugs can than be reintroduced. In people with acute stroke, CCBs, ACEI, ARA, beta blockers and NO donors each lower blood pressure while phenylephrine probably increases blood pressure. Further trials are needed to identify which people are most likely to benefit from early treatment, in particular whether treatment started very early is beneficial.
Two studies, involving a total of 147 participants with TransAtlantic Inter-Society Consensus (TASC)-II D femoropopliteal lesions, met our inclusion criteria and were included in the review. Both studies were small but otherwise of high methodological quality. However, the treatment techniques and control groups of the two studies differed, precluding the combining of study results and resulting in the evidence being less applicable. We therefore considered the quality of the evidence to be low. In one study, participants with TASC-II D lesions were randomized to receive either SIA with stenting of the superficial femoral artery or remote endarterectomy (RE) with stenting of the superficial femoral artery. Three-year follow-up results showed a Rutherford classification improvement of 64% in the SIA group compared to 80% in the RE group (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.61 to 1.03; 95 participants; P = 0.079). Postexercise ankle brachial index improvements (defined as an increased value of 0.2) were reported in 70% of participants in the SIA group compared to 82% in the RE group (RR 0.86, 95% CI 0.68 to 1.08; 95 participants; P = 0.18). The study reported the technical success rate was 93% for the SIA group and 96% for the RE group (RR 0.97, 95% CI 0.88 to 1.07; 95 participants; P = 0.91). Primary patency at 12 months was 59.1% in the SIA group compared to 78.4% in the RE group (RR 0.75, 95% CI 0.57 to 1.00; 95 participants; P = 0.05). Primary patency at 24 months was 56.8% in the SIA group compared to 76.5% in the RE group (RR 0.74, 95% CI 0.55 to 1.00; 95 participants; P = 0.05) and 47.7% in the SIA group and 62.7% in the RE group at 36 months (RR 0.76, 95% CI 0.52 to 1.11; 95 participants; P = 0.15). Assisted primary patency was 52.3% in the SIA group compared to 70.6% in the RE group (P = 0.01) at 36 months. Secondary patency was better for the RE group (P = 0.03) at 36 months. Limb salvage at three years' follow-up was 95% in the SIA group and 98% in the RE group (RR 0.97, 95% CI 0.90 to 1.05; 95 participants; P = 0.4). There were no perioperative deaths, but complications occurred in two SIA participants (femoral pseudoaneurysm and pulmonary edema) and in three RE participants (seroma, femoral pseudoaneurysm, superficial femoral artery acute occlusion). In the second study, the effects of the SIA OUTBACK re-entry catheter device in people affected by TASC-II D superficial femoral artery chronic total occlusion were compared with the SIA manual re-entry technique. This study did not report clinical improvement and limb salvage. Technical success was achieved in all cases in both the OUTBACK device and manual groups. The primary 6-month patency rate was 100% in the OUTBACK group (26 of 26 participants) compared to 96.2% in the manual group (25 of 26 participants) (RR 1.04, 95% CI 0.94 to 1.15). The primary 12-month patency rate was 92.3% in the OUTBACK group (24 of 26 participants) compared to 84.6% in the manual group (22 of 26 participants) (RR 1.09, 95% CI 0.90 to 1.33). Patency rates at 24 and 36 months were not reported. The study reported that there were no complications. Using the GRADE approach, we classified the quality of the evidence presented by both studies in this review as low due to small study size and the small number of studies. In addition, the two included trials differed from each other in the techniques and control used, and we were therefore unable to combine the data. Consequently there is currently insufficient evidence to support SIA over other techniques. Evidence from more randomized controlled trials is needed to assess the role of SIA in people with chronic lower limb arterial total occlusions.
We have included data from 27 randomised trials involving 12,256 women. All of the trials examined telephone support versus usual care (no additional telephone support). We did not identify any trials comparing different modes of telephone support (for example, text messaging versus one-to-one calls). All but one of the trials were carried out in high-resource settings. The majority of studies examined support provided via telephone conversations between women and health professionals although a small number of trials included telephone support from peers. In two trials women received automated text messages. Many of the interventions aimed to address specific health problems and collected data on behavioural outcomes such as smoking cessation and relapse (seven trials) or breastfeeding continuation (seven trials). Other studies examined support interventions aimed at women at high risk of postnatal depression (two trials) or preterm birth (two trials); the rest of the interventions were designed to offer women more general support and advice. For most of our pre-specified outcomes few studies contributed data, and many of the results described in the review are based on findings from only one or two studies. Overall, results were inconsistent and inconclusive although there was some evidence that telephone support may be a promising intervention. Results suggest that telephone support may increase women's overall satisfaction with their care during pregnancy and the postnatal period, although results for both periods were derived from only two studies. There was no consistent evidence confirming that telephone support reduces maternal anxiety during pregnancy or after the birth of the baby, although results on anxiety outcomes were not easy to interpret as data were collected at different time points using a variety of measurement tools. There was evidence from two trials that women at high risk of depression who received support had lower mean depression scores in the postnatal period, although there was no clear evidence that women who received support were less likely to have a diagnosis of depression. Results from trials offering breastfeeding telephone support were also inconsistent, although the evidence suggests that telephone support may increase the duration of breastfeeding. There was no strong evidence that women receiving telephone support were less likely to be smoking at the end of pregnancy or during the postnatal period. For infant outcomes, such as preterm birth and infant birthweight, overall, there was little evidence. Where evidence was available, there were no clear differences between groups. Results from two trials suggest that babies whose mothers received support may have been less likely to have been admitted to a neonatal intensive care unit (NICU), although it is not easy to understand the mechanisms underpinning this finding. Despite some encouraging findings, there is insufficient evidence to recommend routine telephone support for women accessing maternity services, as the evidence from included trials is neither strong nor consistent. Although benefits were found in terms of reduced depression scores, breastfeeding duration and increased overall satisfaction, the current trials do not provide strong enough evidence to warrant investment in resources.
Ten studies met the inclusion criteria. Nine of them were RCTs. All studies involved physicians as participants (including postgraduate trainees), and one study also included other participants. Only two studies measured patient outcomes. Searching skills and/or frequency of use of electronic databases, mainly MEDLINE, were targeted in eight studies. Use of Internet for audit and feedback, and email for provider-patient communication, were targeted in two studies. Four studies showed small to moderate positive effects of the intervention on ICT adoption. Four studies were unable to demonstrate significant positive effects, and the two others showed mixed effects. No studies looked at the long-term effect or sustainability of the intervention. There is very limited evidence on effective interventions promoting the adoption of ICTs by healthcare professionals. Small effects have been reported for interventions targeting the use of electronic databases and digital libraries. The effectiveness of interventions to promote ICT adoption in healthcare settings remains uncertain, and more well designed trials are needed.
Nine randomised and two quasi-randomised clinical trials, involving a total of 2093 participants with 2123 fractures, were included. The evidence was dominated by one large multicentre trial of 1319 participants. Both quasi-randomised trials were at high risk of selection bias. Otherwise, the trials were generally at low or unclear risk of bias. There were very few data on functional outcomes; and often incomplete data on re-operations. The trials evaluated five different comparisons of interventions: reamed versus unreamed intramedullary nailing (six trials); Ender nail versus interlocking nail (two trials); expandable nail versus interlocking nail (one trial); interlocking nail with one distal screw versus with two distal screws (one trial); and closed nailing via the transtendinous approach versus the paratendinous approach (one trial). No statistically significant differences were found between the reamed and unreamed nailing groups in 'major' re-operations (66/789 versus 72/756; risk ratio (RR) 0.88, 95% confidence interval (CI) 0.64 to 1.21; 5 trials), or in the secondary outcomes of nonunion, pain, deep infection, malunion and compartment syndrome. While inconclusive, the evidence from a subgroup analysis suggests that reamed nailing is more likely to reduce the incidence of major re-operations related to non-union in closed fractures than in open fractures. Implant failure, such as broken screws, occurred less often in the reamed nailing group (35/789 versus 79/756; RR 0.42, 95% CI 0.28 to 0.61). There was insufficient evidence established to determine the effects of interlocking nail with one distal screw versus with two distal screws, interlocking nail versus expandable nail and paratendinous approach versus transtendinous approach for treating tibial shaft fractures in adults. Ender nails when compared with an interlocking nail in two trials resulted in a higher re-operation rate (12/110 versus 3/128; RR 4.43, 95% CI 1.37 to 14.32) and more malunions. There were no statistically significant differences between the two devices in the other reported secondary outcomes of nonunion, deep infection, and implant failure. One trial found a lower re-operation rate for an expandable nail when compared with an interlocking nail (1/27 versus 9/26; RR 0.11, 95% CI 0.01 to 0.79). The differences between the two nails in the incidence of deep infection or neurological defects were not statistically significant. The trial comparing one distal screw versus two distal screws found no statistically significant difference in nonunion between the two groups. However, it found significantly more implant failures in the one distal screw group (13/22 versus 1/20; RR 11.82, 95% CI 1.70 to 82.38). One trial found no statistically significant differences in functional outcomes or anterior knee pain at three year follow-up between the transtendinous approach and the paratendinous approach for nail insertion. Overall, there is insufficient evidence to draw definitive conclusions on the best type of, or technique for, intramedullary nailing for tibial shaft fractures in adults. 'Moderate' quality evidence suggests that there is no clear difference in the rate of major re-operations and complications between reamed and unreamed intramedullary nailing. Reamed intramedullary nailing has, however, a lower incidence of implant failure than unreamed nailing. 'Low' quality evidence suggests that reamed nailing may reduce the incidence of major re-operations related to non-union in closed fractures rather than in open fractures. 'Low' quality evidence suggests that the Ender nail has poorer results in terms of re-operation and malunion than an interlocking nail.
According to GRADE the quality of the studies was moderate. Three additional trials are included in this update. The present review includes data analyses based on 10 qualifying trials that enrolled 1644 neonates. There was no significant difference in the incidence of CLD at 36 weeks' PMA in the inhaled steroid versus the placebo group (5 trials, 429 neonates) among all randomised (typical RR 0.97, 95% CI 0.62 to 1.52; typical RD −0.00, 95% CI −0.07 to 0.06). There was no heterogeneity for this outcome (typical RR I² = 11%; typical RD I² = 0%). There was a significant reduction in the incidence of CLD at 36 weeks' PMA among survivors (6 trials, 1088 neonates) (typical RR 0.76, 95% CI 0.63 to 0.93; typical RD −0.07, 95% CI −0.13 to −0.02; NNTB 14, 95% CI 8 to 50). There was a significant reduction in the combined outcome of death or CLD at 36 weeks' PMA among all randomised neonates (6 trials, 1285 neonates) (typical RR 0.86, 95% CI 0.75 to 0.99; typical RD −0.06, 95% CI −0.11 to −0.00) (P = 0.04); NNTB 17, 95% CI 9 to infinity). There was no significant heterogeneity for any of these analyses (I² = 0%). A lower rate of reintubation was noted in the inhaled steroid group compared with the control group in one study. There were no statistically significant differences in short-term complications between groups and no differences in adverse events at long-term follow-up reported. Long-term follow-up of infants enrolled in the study by Bassler 2015 is ongoing. Based on this updated review, there is increasing evidence from the trials reviewed that early administration of inhaled steroids to VLBW neonates is effective in reducing the incidence of death or CLD at 36 weeks' PMA among either all randomised infants or among survivors. Even though there is statistical significance, the clinical relevance is of question as the upper CI limit for the outcome of death or CLD at 36 weeks' PMA is infinity. The long-term follow-up results of the Bassler 2015 study may affect the conclusions of this review. Further studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short- and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.
The search of four standard electronic databases yielded 119 potentially relevant studies but only 18 RCTs involving 1252 people were found suitable for statistical analysis. There was significant heterogeneity among trials and the majority of trials were of poor quality. The use of FG under skin flaps following breast and axillary surgery failed to reduce the incidence of postoperative seroma (risk ratio (RR) 1.02; 95% Confidence Interval (CI) 0.90 to 1.16, P value = 0.73), mean volume of seroma (standardised mean difference (SMD) -0.25; 95% CI -0.92 to 0.42, P value = 0.46), wound infection (RR 1.05; 95% CI 0.63 to 1.77, P value = 0.84), postoperative complications (RR 1.13; 95% CI 0.63 to 2.04, P value = 0.68) and length of hospital stay (SMD -0.2; 95% CI -0.78 to 0.39, P value = 0.51). FG reduced the total volume of drained seroma (SMD -0.75, 95% CI -1.24 to -0.26, P value = 0.003) and duration of persistent seromas requiring frequent aspirations (SMD -0.59; CI 95% -0.95 to -0.23, P value = 0.001). FG did not influence the incidence of postoperative seroma, the mean volume of seroma, wound infections, complications and the length of hospital stays in people undergoing breast cancer surgery. Due to significant methodological and clinical diversity among the included studies this conclusion may be considered weak and biased. Therefore, a major multicentre and high-quality RCT is required to validate these findings.
Cabergoline has been compared with placebo in two phase II (6 - 12 weeks) and one phase III randomised controlled trials (24 weeks). These were double-blind, parallel group, multicentre studies including 268 patients with Parkinson's disease and motor complications. The reduction of 1.14 hours (WMD; 95% CI -0.06, 2.33; p = 0.06) in off time in favour of cabergoline was not statistically significant. Inadequate data on dyskinesia was collected either on rating scales or as adverse event reporting to allow a conclusion to be drawn. A small but statistically significant advantage of cabergoline over placebo was seen in one study for UPDRS ADL (part II) score and UPDRS motor score. No such advantage was seen in one other study due to small numbers of patients and the comparatively low doses of cabergoline used. No significant differences in Schwab and England scale were seen in two studies. Levodopa dose reduction was significantly greater with cabergoline (WMD 149.6 mg/d; 95% CI 94.1, 205.1; p < 0.00001). There was a trend towards more dopaminergic adverse events with cabergoline but this did not reach statistical significance at the p < 0.01 level. However, there was a trend towards fewer withdrawals from cabergoline. In the management of the motor complications seen in Parkinson's disease, cabergoline can be used to reduce levodopa dose and modestly improve motor impairment and disability with an acceptable adverse event profile. These conclusions are based on, at best, medium term evidence.
This review included six randomised controlled trials that enrolled a total of 564 adults undergoing elective midline laparotomy for colorectal resection comparing continuous wound infusion of a local anaesthetic to a normal saline placebo. Due to 23 post-randomisation exclusions, a total of 541 participants contributed data to the analysis of at least one outcome (local anaesthetic 268; control 273). Most participants were aged 55 to 65 years, with normal body mass index and low to moderate anaesthetic risk (American Society of Anesthesiologists class I-III). Random sequence generation, allocation concealment, and blinding were appropriately carried out in most trials. However, we had to downgrade the certainty of the evidence for most outcomes due to serious study limitations (risk of bias), inconsistency, indirectness, imprecision and reporting bias. Primary outcomes On postoperative day 1, pain at rest (mean difference (MD) −0.59 (from 3.1), 95% confidence interval (CI) −1.12 to −0.07; 5 studies, 511 participants; high-certainty evidence), pain on movement (MD −1.1 (from 6.1), 95% CI −2.3 to −0.01; 3 studies, 407 participants; low-certainty evidence) and opioid consumption via PCA (MD −12 mg (from 41 mg), 95% CI −20 to −4; 6 studies, 528 participants; moderate-certainty evidence) were reduced in the local anaesthetic group compared to the control group. Secondary outcomes There was a reduction in the time to first bowel movement (MD −0.67 from 4.4 days, 95% CI −1.17 to −0.17; 4 studies, 197 participants; moderate-certainty evidence) and the length of hospital stay (MD −1.2 from 7.4 days, 95% CI −2.0 to −0.3; 4 studies, 456 participants; high-certainty evidence) in the local anaesthetic group compared to the control group. There was no evidence of a difference in any serious postoperative adverse events until hospital discharge (RR 1.04, 95% CI 0.68 to 1.58; 6 studies, 541 participants; low-certainty evidence) between the two study groups. After elective midline laparotomy for colorectal resection, continuous wound infusion of a local anaesthetic compared to a normal saline placebo reduces postoperative pain at rest and the length of hospital stay, on the basis of high-certainty evidence. This means we are very confident that the effect estimates for these outcomes lie close to the true effects. There is moderate-certainty evidence to indicate that the intervention probably reduces opioid consumption via PCA and the time to first bowel movement. This means we are moderately confident that effect estimates for these outcomes are likely to be close to the true effects, but there is a possibility that they are substantially different. The intervention may reduce postoperative pain on movement, however, this conclusion is based on low-certainty evidence. This means our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. There is low-certainty evidence to indicate that the intervention may have little or no effect on the rates of any serious postoperative adverse events until hospital discharge. High-quality randomised controlled trials to evaluate the intervention with a focus on important clinical and patient-centred outcomes are needed.
Ten new studies were identified so a total of 34 studies (3033 total participants) were included in the 2015 review update. The risk of bias attributes were frequently poorly performed. Low risk of bias was reported in 18 studies for sequence generation, 16 studies for allocation concealment, seven for performance and detection bias, 15 for incomplete reporting and 16 for selective reporting. Three months or more of prednisone significantly reduced the risk of frequently relapsing nephrotic syndrome (FRNS) (6 studies, 582 children: RR 0.68, 95% CI 0.47 to 1.00) and of relapse by 12 to 24 months (8 studies, 741 children: RR 0.80, 95% CI 0.64 to 1.00) compared with two months. Five or six months of prednisone significantly reduced the risk of relapse (7 studies, 763 children: RR 0.62, 95% CI 0.45 to 0.85) but not FRNS (5 studies, 591 children: RR 0.78, 95% CI 0.50 to 1.22) compared with three months. However there was significant heterogeneity in the analyses. Subgroup analysis stratified by risk of bias for allocation concealment showed that the risk for FRNS did not differ significantly between two or three months of prednisone and three to six months among studies at low risk of bias but was significantly reduced in extended duration studies compared with two or three months in studies at high risk or unclear risk of bias. There were no significant differences in the risk of adverse effects between extended duration and two or three months of prednisone. Four studies found that in children with FRNS, daily prednisone during viral infections compared with alternate-day prednisone or no treatment significantly reduced the rate of relapse. In this 2015 update the addition of three well-designed studies has changed the conclusion of this review. Studies of long versus shorter duration of corticosteroids have heterogeneous treatment effects, with the older high risk of bias studies tending to over-estimate the effect of longer course therapy, compared with more recently published low risk of bias studies. Among studies at low risk of bias, there was no significant difference in the risk for FRNS between prednisone given for two or three months and longer durations or total dose of therapy indicating that there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS. The risk of relapse in children with FRNS is reduced by the administration of daily prednisone at onset of an upper respiratory tract or viral infection. Three additional studies have increased the evidence supporting this conclusion. This management strategy may be considered for children with FRNS. A paucity of data on prednisone use in relapsing nephrotic syndrome remains. In particular there are no data from RCTs evaluating the efficacy and safety of prolonged courses of low dose alternate-day prednisone although this management strategy is recommended in current guidelines.
Eleven trials including 5662 participants met the inclusion criteria. DOT was performed by a range of people (nurses, community health workers, family members or former TB patients) in a variety of settings (clinic, the patient's home or the home of a community volunteer). DOT versus self-administered Six trials from South Africa, Thailand, Taiwan, Pakistan and Australia compared DOT with self-administered therapy for treatment. Trials included DOT at home by family members, community health workers (who were usually supervised); DOT at home by health staff; and DOT at health facilities. TB cure was low with self-administration across all studies (range 41% to 67%), and direct observation did not substantially improve this (RR 1.08, 95% CI 0.91 to 1.27; five trials, 1645 participants, moderate quality evidence). In a subgroup analysis stratified by the frequency of contact between health services in the self-treatment arm, daily DOT may improve TB cure when compared to self-administered treatment where patients in the self-administered group only visited the clinic every month (RR 1.15, 95% CI 1.06 to 1.25; two trials, 900 participants); but with contact in the control becoming more frequent, this small effect was not apparent (every two weeks: RR 0.96, 95% CI 0.83 to 1.12; one trial, 497 participants; every week: RR 0.90, 95% CI 0.68 to 1.21; two trials, 248 participants). Treatment completion showed a similar pattern, ranging from 59% to 78% in the self-treatment groups, and direct observation did not improve this (RR 1.07, 95% CI 0.96 to 1.19; six trials, 1839 participants, moderate quality evidence). DOT at home versus DOT at health facility In four trials that compared DOT at home by family members, or community health workers, with DOT by health workers at a health facility there was little or no difference in cure or treatment completion (cure: RR 1.02, 95% CI 0.88 to 1.18, four trials, 1556 participants, moderate quality evidence; treatment completion: RR 1.04, 95% CI 0.91 to 1.17, three trials, 1029 participants, moderate quality evidence). DOT by family member versus DOT by community health worker Two trials compared DOT at home by family members with DOT at home by community health workers. There was also little or no difference in cure or treatment completion (cure: RR 1.02, 95% CI 0.86 to 1.21; two trials, 1493 participants, moderate quality evidence; completion: RR 1.05, 95% CI 0.90 to 1.22; two trials, 1493 participants, low quality evidence). Specific patient categories A trial of 300 intravenous drug users in the USA evaluated direct observation with no observation in TB prophylaxis to prevent active disease and showed little difference in treatment completion (RR 1.00, 95% CI 0.88 to 1.13; one trial, 300 participants, low quality evidence). From the existing trials, DOT did not provide a solution to poor adherence in TB treatment. Given the large resource and cost implications of DOT, policy makers might want to reconsider strategies that depend on direct observation. Other options might take into account financial and logistical barriers to care; approaches that motivate patients and staff; and defaulter follow-up.
We included seven RCTs (N = 923): one examined asymptomatic women with twin pregnancies; four included women with singleton pregnancies and symptoms of preterm labour (PTL); one included women with singleton pregnancies and symptoms of preterm premature rupture of membranes (PPROM); and one included asymptomatic singletons. All trials used TVU for screening. We assessed the risk of bias of the included studies as mixed, and the quality of the evidence for primary outcomes as very low for all populations. For asymptomatic women with twin pregnancies, it is uncertain whether knowledge of TVU-measured cervical length compared to no knowledge reduces PTB at less than 34 weeks (risk ratio (RR) 0.62, 95% confidence intervals (CI) 0.30 to 1.25; 1 study, 125 participants) because the quality of the evidence is very low. The results were also inconclusive for preterm birth at 36, 32, or 30 weeks; gestational age at birth, and other maternal and perinatal outcomes. Four trials examined knowledge of TVU-measured cervical length of singletons with symptoms of PTL versus no knowledge. We are uncertain of the effects because of inconclusive results and very low-quality evidence for: preterm births at less than 37 weeks (average RR 0.59, 95% CI 0.26 to 1.32; 2 studies, 242 participants; I² = 66%; Tau² = 0.23). Birth occurred about four days later in the knowledge groups (mean difference (MD) 0.64 weeks, 95% CI 0.03 to 1.25; 3 trials, 290 women). The results were inconclusive for the other outcomes for which there were available data: PTB at less than 34 or 28 weeks; birthweight less than 2500 g; perinatal death; maternal hospitalisation; tocolysis; and steroids for fetal lung maturity. The trial of singletons with PPROM (N = 92) evaluated safety of using TVU to measure cervical length in this population as its primary outcome, not its effect on management. The results were inconclusive for incidence of maternal and neonatal infections between the TVU and no ultrasound groups. In the trial of asymptomatic singletons (N = 296), in which women either received TVU or not, the results were inconclusive for preterm birth at less than 37 weeks (RR 1.27, 95% CI 0.61 to 2.61; I² = 0%), gestational age at birth, and other perinatal and maternal outcomes. We downgraded evidence for limitations in study design, inconsistency between the trials, and imprecision, due to small sample size and wide confidence intervals crossing the line of no effect. No trial compared the effect of knowledge of the CL with no knowledge of CL in other populations, such as asymptomatic women with singleton pregnancies, or symptomatic women with twin pregnancies. There are limited data on the effects of knowing the cervical length, measured by ultrasound, for preventing preterm births, which preclude us from drawing any conclusions for women with asymptomatic twin or singleton pregnancies, singleton pregnancies with PPROM, or other populations and clinical scenarios. Limited evidence suggests that knowledge of transvaginal ultrasound-measured cervical length, used to inform the management of women with singleton pregnancies and symptoms of preterm labour, appears to prolong pregnancy by about four days over women in the no knowledge groups. Future studies could look at specific populations separately (e.g. singleton versus twins; symptoms versus no symptoms of PTL), report on all pertinent maternal and perinatal outcomes, and include cost-effectiveness analyses. Most importantly, future studies should include a clear protocol for management of women based on TVU-measured cervical length.
We identified 30 new non-randomized cohort studies (45 comparisons): no new RCTs were found. This update now includes five RCTs (yielding 6 comparisons) and 80 non-randomized cohort studies (130 comparisons), with 86,640 patients treated in RCTs and 57,205 patients treated outside RCTs. In the randomised studies, patients were invited to participate in an RCT or not; these comparisons provided limited information because of small sample sizes (a total of 412 patients) and the nature of the questions they addressed. When the results of RCTs and non-randomized cohorts that reported dichotomous outcomes were combined, there were 98 comparisons; there was also heterogeneity (P < 0.00001, I2 = 42.2%) between studies. No statistical significant differences were found for 85 of the 98 comparisons. Eight comparisons reported statistically significant better outcomes for patients treated within RCTs, and five comparisons reported statistically significant worse outcomes for patients treated within RCTs. There was significant heterogeneity (P < 0.00001, I2 = 58.2%) among the 38 continuous outcome comparisons. No statistically significant differences were found for 30 of the 38 comparisons. Three comparisons reported statistically significant better outcomes for patients treated within RCTs, and five comparisons reported statistically significant worse outcomes for patients treated within RCTs. This review indicates that participation in RCTs is associated with similar outcomes to receiving the same treatment outside RCTs. These results challenge the assertion that the results of RCTs are not applicable to usual practice.
Fifteen trials were included in the review (2064 participants). Three types of photocoagulation were used in the trials: direct photocoagulation of the entire CNV (11 trials), perifoveal photocoagulation (one trial) and grid photocoagulation (three trials). In 12 trials the control group was observation only. One trial compared photocoagulation to submacular surgery and two trials compared different lasers. Data on the progression of visual loss could be extracted from five of the eight trials of direct photocoagulation of the CNV versus observation. The treatment effect was in the direction of harm in all studies at three months follow up (RR 1.41, 95% confidence intervals (CI) 1.08 to 1.82). After two years the treatment effect was in the direction of benefit (RR 0.67, 95% CI 0.53 to 0.83). These studies were clinically heterogenous with participants having CNV lesions in different locations and different baseline visual acuities. There was little evidence of statistical heterogeneity at three months but substantial statistical heterogeneity at two years. However, all treatment effects in the individual trials were in the direction of benefit. One study comparing perifoveal photocoagulation or observation of subfoveal CNV found benefits that were statistically significant only at two years (RR 0.36, 95% CI 0.18 to 0.72). Other comparisons did not demonstrate differences. In the medium to long term laser photocoagulation of CNV slows the progression of visual loss in people with neovascular AMD. However, it is associated with an increased risk of visual loss immediately after treatment and this period may be longer in people with subfoveal AMD. With the advent of modern pharmacological therapies, and concern for the impact of iatrogenic scotoma in subfoveal CNV, laser photocoagulation of subfoveal CNV is not recommended. No studies have compared photocoagulation with modern pharmacological agents for AMD for non-subfoveal CNV.
Twenty-two trials with 12,455 participants randomised (9595 used in analyses) were included. For the 13 that contributed data for the permanent tooth surfaces meta-analysis, the pooled D(M)FS prevented fraction estimate comparing fluoride varnish with placebo or no treatment was 43% (95% confidence interval (CI) 30% to 57%; P < 0.0001). There was substantial heterogeneity, confirmed statistically (P < 0.0001; I2 = 75%), however this body of evidence was assessed as of moderate quality. The pooled d(e/m)fs prevented fraction estimate was 37% (95% CI 24% to 51%; P < 0.0001) for the 10 trials that contributed data for the primary tooth surfaces meta-analysis, also with some heterogeneity (P = 0.009; I2 = 59%). Once again this body of evidence was assessed as of moderate quality. No significant association between estimates of D(M)FS or d(e/m)fs prevented fractions and the pre-specified factors of baseline caries severity, background exposure to fluorides, application features such as prior prophylaxis, concentration of fluoride, frequency of application were found. There was also no significant association between estimates of D(M)FS or d(e/m)fs prevented fractions and the post hoc factors: whether a placebo or no treatment control was used, length of follow-up, or whether individual or cluster randomisation was used, in the meta-regression models. A funnel plot of the trials in the main meta-analyses indicated no clear relationship between prevented fraction and study precision. In both methods, power is limited when few trials are included. There was little information concerning possible adverse effects or acceptability of treatment. The conclusions of this updated review remain the same as those when it was first published. The review suggests a substantial caries-inhibiting effect of fluoride varnish in both permanent and primary teeth, however the quality of the evidence was assessed as moderate, as it included mainly high risk of bias studies, with considerable heterogeneity.
We identified three randomised trials with 261 participants for inclusion. The risk of bias was low in one and high in two trials. Two of the randomised trials compared PEI versus PAI; we included 185 participants in the analysis. The overall survival (HR 1.47; 95% confidence interval (CI) 0.68 to 3.19) and recurrence-free survival (HR 1.42; 95% CI 0.68 to 2.94) were not statistically significantly different between the intervention groups of the two trials. Trial sequential analysis for the comparison PEI versus PAI including two trials revealed that the number of participants that were included in the trials were insufficient in order to judge a relative risk reduction of 20%. Data on the duration of hospital stay were available from one trial for the comparison PEI versus PAI showing a significantly shorter hospital stay for the participants treated with PEI (mean 1.7 days; range 2 to 3 days) versus PAI (mean 2.2 days; range 2 to 5 days). Quality of life was not reported. There were only mild adverse events in participants treated with either PEI or PAI such as transient fever, flushing, and local pain. One randomised trial compared PEI versus surgery; we included 76 participants in the analyses. There was no significant difference in the overall survival (HR 1.57; 95% CI 0.53 to 4.61) and recurrence-free survival (HR 1.35; 95% CI 0.69 to 2.63). No serious adverse events were reported in the PEI group while three postoperative deaths occurred in the surgery group. In addition to the three randomised trials, we identified one quasi-randomised study comparing PEI versus PAI. Due to methodological flaws of the study, we extracted only the data on adverse events and presented them in a narrative way. We found no randomised trials that compared PEI or PAI versus no intervention, best supportive care, sham intervention, or other percutaneous local ablative therapies excluding RFTA. We found also no randomised clinical trials that compared PAI versus other interventional treatments or surgery. We identified two ongoing randomised clinical trials. One of these two trials compares PEI versus surgery and the other PEI versus transarterial chemoembolization. To date, it is unclear whether the trials will be eligible for inclusion in this meta-analysis as the data are not yet available. This review will not be updated until new randomised clinical trials are published and can be used for analysis. PEI versus PAI did not differ significantly regarding benefits and harms in people with early HCC, but the two included trials had only a limited number of participants and one trial was judged a high risk of bias. Thus, the current evidence precludes us from making any firm conclusions. There was also insufficient evidence to determine whether PEI versus surgery (segmental liver resection) was more effective, because conclusions were based on a single randomised trial. While some data from this single trial suggested that PEI was safer, the high risk of bias and the lack of any confirmatory evidence make a reliable assessment impossible. We found no trials assessing PEI or PAI versus no intervention, best supportive care, or sham intervention. There is a need for more randomised clinical trials assessing interventions for people with early stage HCC. Such trials should be conducted with low risks of systematic errors and random errors.
We found 18 trials that met our inclusion criteria. Of six patch studies, five examined the marketed patch containing norelgestromin plus ethinyl estradiol (EE); one studied a patch in development that contains levonorgestrel (LNG) plus EE. Of 12 vaginal ring trials, 11 examined the same marketing ring containing etonogestrel plus EE; one studied a ring being developed that contains nesterone plus EE. Contraceptive effectiveness was not significantly different for the patch or ring versus the comparison COC. Compliance data were limited. Patch users showed better compliance than COC users in three trials. For the norelgestromin plus EE patch, ORs were 2.05 (95% CI 1.83 to 2.29) and 2.76 (95% CI 2.35 to 3.24). In the levonorgestrel plus EE patch report, patch users were less likely to have missed days of therapy (OR 0.36; 95% CI 0.25 to 0.51). Of four vaginal ring trials, one found ring users had more noncompliance (OR 3.99; 95% CI 1.87 to 8.52), while another showed more compliance with the regimen (OR 1.67; 95% CI 1.04 to 2.68). More patch users discontinued early than COC users. ORs from two meta-analyses were 1.59 (95% CI 1.26 to 2.00) and 1.56 (95% CI 1.18 to 2.06) and another trial showed OR 2.57 (95% CI 0.99 to 6.64). Patch users also had more discontinuation due to adverse events than COC users. Users of the norelgestromin-containing patch reported more breast discomfort, dysmenorrhea, nausea, and vomiting. In the levonorgestrel-containing patch trial, patch users reported less vomiting, headaches, and fatigue. Of 11 ring trials with discontinuation data, two showed the ring group discontinued less than the COC group: OR 0.32 (95% CI 0.16 to 0.66) and OR 0.52 (95% CI 0.31 to 0.88). Ring users were less likely to discontinue due to adverse events in one study (OR 0.32; 95% CI 0.15 to 0.70). Compared to the COC users, ring users had more vaginitis and leukorrhea but less vaginal dryness. Ring users also reported less nausea, acne, irritability, depression, and emotional lability than COC users. For cycle control, only one trial study showed a significant difference. Women in the patch group were less likely to have breakthrough bleeding and spotting. Seven ring studies had bleeding data; four trials showed the ring group generally had better cycle control than the COC group. Effectiveness was not significantly different for the methods compared. Pregnancy data were available from half of the patch trials but two-thirds of ring trials. The patch could lead to more discontinuation than the COC. The patch group had better compliance than the COC group. Compliance data came from half of the patch studies and one-third of the ring trials. Patch users had more side effects than the COC group. Ring users generally had fewer adverse events than COC users but more vaginal irritation and discharge. The quality of the evidence for this review was considered low for the patch and moderate for the ring. The main reasons for downgrading were lack of information on the randomization sequence generation or allocation concealment, the outcome assessment methods, high losses to follow up, and exclusions after randomization.
Thirty-three small studies ( 2267 patients) compared different fusion techniques. The major treatments were discectomy alone, addition of an interbody fusion procedure (autograft, allograft, cement, or cage), and addition of anterior plates. Eight studies had a low risk of bias. Few studies reported on pain, therefore, at best, there was very low quality evidence of little or no difference in pain relief between the different techniques. We found moderate quality evidence for these secondary outcomes: no statistically significant difference in Odom's criteria between iliac crest autograft and a metal cage (6 studies, RR 1.11 (95% CI 0.99 to1.24)); bone graft produced more effective fusion than discectomy alone (5 studies, RR 0.22 (95% CI 0.17 to 0.48)); no statistically significant difference in complication rates between discectomy alone and iliac crest autograft (7 studies, RR 1.56 (95% CI 0.71 to 3.43)); and low quality evidence that iliac crest autograft results in better fusion than a cage (5 studies, RR 1.87 (95% CI 1.10 to 3.17)); but more complications (7 studies, RR 0.33 (95% CI 0.12 to 0.92)). When the working mechanism for pain relief and functional improvement is fusion of the motion segment, there is low quality evidence that iliac crest autograft appears to be the better technique. When ignoring fusion rates and looking at complication rates, a cage has a weak evidence base over iliac crest autograft, but not over discectomy alone. Future research should compare additional instrumentation such as screws, plates, and cages against discectomy with or without autograft.
We included three studies involving 1879 participants: two RCTs and one cluster-RCT. Interventions consisted of: · patient workshop and individual coaching using behaviour change techniques; · individual patient coaching utilising cognitive-behavioural therapy and motivational interviewing; and · holistic patient review, multi-disciplinary practitioner training, and organisational change. No studies reported the primary outcome ‘patient involvement in decision-making’ or the primary adverse outcome ‘less patient involvement as a result of the intervention’. Comparing interventions (patient workshop and individual coaching, holistic patient review plus practitioner training, and organisational change) to usual care: we are uncertain whether interventions had any effect on patient reports of high self-rated health (risk ratio (RR) 1.40, 95% confidence interval (CI) 0.36 to 5.49; very low-certainty evidence) or on patient enablement (mean difference (MD) 0.60, 95% CI -9.23 to 10.43; very low-certainty evidence) compared with usual care. Interventions probably had no effect on health-related quality of life (adjusted difference in means 0.00, 95% CI -0.02 to 0.02; moderate-certainty evidence) or on medication adherence (MD 0.06, 95% CI -0.05 to 0.17; moderate-certainty evidence) but probably improved the number of patients discussing their priorities (adjusted odds ratio 1.85, 95% CI 1.44 to 2.38; moderate-certainty evidence) and probably increased the number of nurse consultations (incident rate ratio from adjusted multi-level Poisson model 1.37, 95% CI 1.17 to 1.61; moderate-certainty evidence) compared with usual care. Practitioner outcomes were not measured. Interventions were not reported to adversely affect rates of participant death or anxiety, emergency department attendance, or hospital admission compared with usual care. Comparing interventions (patient workshop and coaching, individual patient coaching) to attention-control conditions: we are uncertain whether interventions affect patient-reported high self-rated health (RR 0.38, 95% CI 0.15 to 1.00, favouring attention control, with very low-certainty evidence; RR 2.17, 95% CI 0.85 to 5.52, favouring the intervention, with very low-certainty evidence). We are uncertain whether interventions affect patient enablement and engagement by increasing either patient activation (MD 1.20, 95% CI -8.21 to 10.61; very low-certainty evidence) or self-efficacy (MD 0.29, 95% CI -0.21 to 0.79; very low-certainty evidence); or whether interventions affect the number of general practice visits (MD 0.51, 95% CI -0.34 to 1.36; very low-certainty evidence), compared to attention-control conditions. The intervention may however lead to more patient-reported changes in management of their health conditions (RR 1.82, 95% CI 1.35 to 2.44; low-certainty evidence). Practitioner outcomes were not measured. Interventions were not reported to adversely affect emergency department attendance nor hospital admission when compared with attention control. Comparing one form of intervention with another: not measured. There was 'unclear' risk across studies for performance bias, detection bias, and reporting bias; however, no aspects were 'high' risk. Evidence was downgraded via GRADE, most often because of 'small sample size' and 'evidence from a single study'. Limited available evidence does not allow a robust conclusion regarding the objectives of this review. Whilst patient involvement in decision-making is seen as a key mechanism for improving care, it is rarely examined as an intervention and was not measured by included studies. Consistency in design, analysis, and evaluation of interventions would enable a greater likelihood of robust conclusions in future reviews.
We included 15 studies. Fourteen studies reported data per woman (2894 women) and one study reported data per cycle (969 cycles). The quality of the evidence using the GRADE approach ranged from moderate quality to very low quality. The main reasons for downgrading evidence were poor methodological reporting, selective reporting, inconsistency and imprecision. Live birth per woman - Overall, there was no evidence of a difference in live birth rate between Day three and Day two embryo transfer (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.23; three studies, n = 1200 women; I2 = 63%; very low quality evidence). The data suggest that if 32% of women who underwent a Day two embryo transfer had a live birth, then between 28% to 39% of women undergoing a Day three embryo transfer would have a live birth. Ongoing pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for ongoing pregnancy (RR 0.98, 95% CI 0.85 to 1.12; six studies, n = 1740 women; I2 = 52%; very low quality of evidence). The data suggest that if 33% of women undergoing a Day two embryo transfer had an ongoing pregnancy then between 28% to 37% of women undergoing a Day three embryo transfer would have an ongoing pregnancy. Clinical pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the chance of a clinical pregnancy (RR 1.08, 95% CI 0.98 to 1.19; 12 studies, n = 2461, I2 = 51%; very low quality evidence). The data suggest that if 39% of women undergoing Day two embryo transfer had a clinical pregnancy, then between 38% to 46% of women undergoing a Day three embryo transfer would have a clinical pregnancy. Multiple pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of a multiple pregnancy (RR 1.12, 95% CI 0.86 to 1.44; eight studies, n = 1837; I2 = 0%; moderate quality evidence). The data suggest that if 11% of women undergoing Day two embryo transfer had a multiple pregnancy, then between 9% to 15% of women undergoing a Day three embryo transfer would have a multiple pregnancy. Miscarriage rate per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of miscarriage (RR 1.16, 95% CI 0.84 to 1.60; nine studies, n = 2153 women, I2 = 26%; moderate quality evidence). The data suggest that if 6% of women undergoing Day two embryo transfer had a miscarriage, then between 5% to 10% of women undergoing a Day three embryo transfer would have a miscarriage. Ectopic pregnancy rate per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of ectopic pregnancy (RR 0.99, 95% CI 0.29 to 3.40; six studies, n = 1531 women, I2 = 0%; low quality evidence). The data suggest that if 0.7% of women undergoing Day two embryo transfer have an ectopic pregnancy, then between 0.2% to 2% of women undergoing Day three embryo transfer would have an ectopic pregnancy. Subgroup analysis for pregnancy outcomes did not identify any differential effect between IVF and ICSI. None of the included studies prespecified complication rate (e.g. OHSS), fetal abnormality or women's evaluation of the procedure as outcomes in their studies. Twelve of 15 studies contributed data that could be included in meta-analyses. The quality of the evidence ranged from moderate to very low. Only three of the 15 studies reported data for live birth, although the data for ongoing pregnancy and clinical pregnancy are consistent with the live birth data, suggesting no difference between Day three and Day two embryo transfer for these outcomes. There was no evidence of a difference identified between Day three and Day two embryo transfer for multiple pregnancy, miscarriage or ectopic pregnancy per woman randomised. No data were reported for complication rate, fetal abnormality or woman's evaluation of the procedure. The current evidence has not identified any evidence of differences in pregnancy outcomes between Day two and Day three embryo transfers. Any further studies comparing these timings of embryo transfer are unlikely to alter the findings and we suggest that this review no longer be updated.
We included a total of 22 trials (9137 participants) of which 15 were randomized trials (7762 participants). The overall risk of bias was mostly unclear or high due to selection and performance bias. We used GRADE to assess the quality of the evidence and this was downgraded from high to moderate or very low due to the risk of bias, imprecision or indirectness. The rate of PE in the studies comparing IPC alone with combined IPC and pharmacological prophylaxis was low, underpowering the analyses. The incidence of symptomatic PE was 0.79% with IPC, but ranged between 0.1 to 1% with combined IPC and pharmacological prophylaxis (OR 0.49, 95% CI 0.18 to 1.34; 12 studies, 3017 participants, moderate quality evidence). The incidence of DVT was 4.10% in the IPC group and 2.19% in the combined group showing a reduced incidence of DVT in favour of the combined group (OR 0.52, 95% CI 0.33 to 0.82; 11 studies, 2934 participants, moderate quality evidence). The addition of an anticoagulant to IPC, however, increased the risk of any bleeding compared to IPC alone; 0.66% (7/1053) in the IPC group and 4.0% (44/1102) in the combined group (OR 5.04, 95% CI 2.36 to 10.77; 7 studies, 2155 participants, moderate quality evidence). Major bleeding followed a similar pattern; 0.1% (1/1053) in the IPC group to 1.5% (17/1102) in the combined group (OR 6.81, 95% CI 1.99 to 23.28; 7 studies, 2155 participants, moderate quality evidence). We detected no difference between the type of surgery subgroups such as orthopedic and non-orthopedic participants for DVT incidence (P = 0.16). Tests for differences between type of surgery subgroups were not possible for PE incidence. Compared with pharmacological prophylaxis alone, the use of combined IPC and pharmacological prophylaxis modalities reduced the incidence of symptomatic PE from 2.92% to 1.20% (OR 0.39, 95% CI 0.23 to 0.64; 10 studies, 3544 participants, moderate quality evidence). The incidence of DVT was 6.2% in the pharmacological prophylaxis group and 2.9% in the combined group showing no difference between the combined and pharmacological prophylaxis groups (OR 0.42, 95% CI 0.18 to 1.03; 11 studies, 2866 participants, moderate quality evidence). Increased bleeding side effects were not observed for IPC when it was added to anticoagulation (bleeding: OR 0.80, 95% CI 0.30 to 2.14, very low quality evidence; major bleeding: OR 1.21, 95% CI 0.35 to 4.18, very low quality evidence, 3 studies, 244 participants). No difference was detected between the type of surgery subgroups for PE incidence (P = 0.68) or for DVT incidence (P = 0.10). Moderate quality evidence suggests that combining IPC and pharmacological prophylaxis, compared with IPC or pharmacological prophylaxis alone, decreases the incidence of DVT when compared to compression, and incidence of PE when compared to anticoagulation. Moderate quality evidence suggests that there is no difference between combined and single modalities in the incidence of PE when compared with compression alone and DVT when compared with anticoagulation alone. The quality of evidence for PE or DVT was downgraded to moderate due to imprecision or risk of bias in study methodology, highlighting the need for further research. Moderate quality evidence suggests the addition of pharmacological prophylaxis to IPC, increased the risk of bleeding compared to IPC alone, a side effect not observed for IPC when added to pharmacological prophylaxis (very low quality evidence), as expected for a physical method of thromboprophylaxis. The quality of evidence for bleeding was downgraded to moderate due to indirectness or very low due to risk of bias in study methodology, indirectness and imprecision highlighting the need for further research. Nevertheless, the results of the current review agree with current guideline recommendations, which support the use of combined modalities in hospitalised patients (limited to those with trauma or undergoing surgery) at risk of developing VTE. More studies on the role of combined modalities in VTE prevention are needed.
Three trials with 144 participants met the inclusion criteria. Two of the trials had a randomised cross-over design, one was a cross-over trial which we classified as quasi-randomised. Participants in the included studies were people with dementia living in nursing homes. They were predominantly women and had a mean age of over 80 years. SPT was performed using an audio or video recording prepared by family members or surrogates. It varied in its content, frequency of administration and duration. All the studies compared multiple treatments. In one study, SPT was compared with two other interventions; in the other two studies, it was compared with three other interventions. Specifically, SPT was compared to usual care, personalised music (two studies), a 'placebo' audiotape containing the voice of a person (two studies), and one-to-one social interaction performed by trained research assistants (one study). In terms of outcomes evaluated, one study considered agitation and withdrawn behaviour (both assessed with three methods); the second study evaluated verbal disruptive behaviour (assessed with three methods); and the third study evaluated physically agitated behaviour and verbally agitated behaviour (the method used was not clearly described). According to the GRADE criteria, the overall quality of the evidence was very low due to very small numbers of participants and risk of bias in the included studies; (none of the trials was at low risk of selection bias; all the trials were at high risk of performance bias; one trial was at high risk of attrition bias; and all had unclear selective reporting). Because of variation in the participants, the format of SPT, the comparison interventions, and the measures used to assess outcomes, we judged the results unsuitable for a meta-analysis. Within each trial, the effect of SPT on behaviour, compared to usual care, was mixed and depended on the measure used. Two trials which included a personalised music intervention reported no significant differences between simulated presence and music on behavioural outcomes. Because the overall quality of the evidence was very low, we were very uncertain regarding all the results None of the studies evaluated quality of life or any of our secondary outcome measures (performance of activities of daily living, dropout and carer burden). We were unable to draw any conclusions about the efficacy of SPT for treating behavioural and psychological symptoms and improving quality of life of people with dementia. New high-quality studies are needed to investigate the effect of SPT.
We included 28 studies, comprising 17 RCTs, 5 Q-RCTs and 6 ITS studies. Most (21/28) took place in the USA, and 19 took place in university settings, 14 of which mainly involved university students or staff. Most (20/28) studies assessed the impact of labelling on menus or menu boards, or nutritional labelling placed on, or adjacent to, a range of foods or drinks from which participants could choose. Eight studies provided participants with only one labelled food or drink option (in which labelling was present on a container or packaging, adjacent to the food or on a display board) and measured the amount consumed. The most frequently assessed labelling type was energy (i.e. calorie) information (12/28). Eleven studies assessed the impact of nutritional labelling on purchasing food or drink options in real-world settings, including purchases from vending machines (one cluster-RCT), grocery stores (one ITS), or restaurants, cafeterias or coffee shops (three RCTs, one Q-RCT and five ITS). Findings on vending machines and grocery stores were not interpretable, and were rated as very low quality. A meta-analysis of the three RCTs, all of which assessed energy labelling on menus in restaurants, demonstrated a statistically significant reduction of 47 kcal in energy purchased (MD −46.72 kcal, 95% CI −78.35, −15.10, N = 1877). Assuming an average meal of 600 kcal, energy labelling on menus would reduce energy purchased per meal by 7.8% (95% CI 2.5% to 13.1%). The quality of the evidence for these three studies was rated as low, so our confidence in the effect estimate is limited and may change with further studies. Of the remaining six studies, only two (both ITS studies involving energy labels on menus or menus boards in a coffee shop or cafeteria) were at low risk of bias, and their results support the meta-analysis. The results of the other four studies which were conducted in a restaurant, cafeterias (2 studies) or a coffee shop, were not clearly reported and were at high risk of bias. Seventeen studies assessed the impact of nutritional labels on consumption in artificial settings or scenarios (henceforth referred to as laboratory studies or settings). Of these, eight (all RCTs) assessed the effect of labels on menus or placed on a range of food options. A meta-analysis of these studies did not conclusively demonstrate a reduction in energy consumed during a meal (MD −50 kcal, 95% CI −104.41, 3.88, N = 1705). We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies. Six laboratory studies (four RCTs and two Q-RCTs) assessed the impact of labelling a single food or drink option (such as chocolate, pasta or soft drinks) on energy consumed during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant difference in energy (kcal) consumed (SMD 0.05, 95% CI −0.17 to 0.27, N = 732). However, the confidence intervals were wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies. There was no evidence that nutritional labelling had the unintended harm of increasing energy purchased or consumed. Indirect evidence came from five laboratory studies that involved mislabelling single nutrient content (i.e. placing low energy or low fat labels on high-energy foods) during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant increase in energy (kcal) consumed (SMD 0.19, 95% CI −0.14to 0.51, N = 718). The effect was small and the confidence intervals wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence from these studies as very low, providing very little confidence in the effect estimate. Findings from a small body of low-quality evidence suggest that nutritional labelling comprising energy information on menus may reduce energy purchased in restaurants. The evidence assessing the impact on consumption of energy information on menus or on a range of food options in laboratory settings suggests a similar effect to that observed for purchasing, although the evidence is less definite and also of low quality. Accordingly, and in the absence of observed harms, we tentatively suggest that nutritional labelling on menus in restaurants could be used as part of a wider set of measures to tackle obesity. Additional high-quality research in real-world settings is needed to enable more certain conclusions. Further high-quality research is also needed to address the dearth of evidence from grocery stores and vending machines and to assess potential moderators of the intervention effect, including socioeconomic status.
We included 20 studies with 1401 surgical participants comparing an α-2 agonist against a control. Thirteen studies compared clonidine with a control, whilst seven compared dexmedetomidine with a control. The doses, methods, and time of administration varied between studies: three studies gave the drug orally or as an intravenous bolus preoperatively and nine intraoperatively; one study gave the drug as an infusion starting preoperatively and seven started at varying points from anaesthetic induction to the end of surgery. Whilst all the studies were described as randomized, many provided insufficient detail on methods used. We had anticipated that attempts would be made to reduce performance bias by blinding of personnel and participants, however this was detailed in only six of the papers. Similarly, in some studies detail was lacking on methods to reduce the risk of detection bias. We therefore downgraded the quality of evidence in our 'Summary of findings' table by one level for risk of bias using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. All 20 included studies presented outcome data for postoperative shivering, and in meta-analysis α-2 agonists were shown to significantly reduce the risk of shivering (Mantel-Haenszel risk ratio 0.28, 95% confidence interval 0.18 to 0.43, P value < 0.0001). We found significant evidence of heterogeneity (I2 = 80%) for this result that was not explained by sensitivity or subgroup analysis; we therefore downgraded the inconsistency of the evidence by one level. Although we did not feel that there were concerns with imprecision or indirectness of the data, we downgraded the quality of the evidence for the risk of publication bias following visual analysis of a funnel plot. Using GRADEpro, we rated the overall quality of the data for shivering as very low. Only one study reported the incidence of core hypothermia, whilst 12 studies measured core temperature. However, as the results for core temperature were reported in different styles, pooling the results was inappropriate. We found no studies with participant-reported outcomes such as experience of shivering or participant satisfaction. We found limited data for the outcomes of length of stay in the postanaesthetic care unit (three studies, 200 participants) and the following adverse effects: sedation (nine studies, 875 participants), bradycardia (eight studies, 716 participants), and hypotension (seven studies, 688 participants). Unpooled analysis suggested that sedation and bradycardia were significantly more common with dexmedetomidine than placebo, with all seven dexmedetomidine studies and none of the clonidine studies reporting statistically significantly higher levels of sedation as an adverse effect. There is evidence that clonidine and dexmedetomidine can reduce postoperative shivering, but patients given dexmedetomidine may be more sedated. However, our assessment of the quality of this evidence is very low.
Four studies met the inclusion criteria (715 pregnant women), and reported on at least one of the outcomes of interest. We performed no meta-analyses as the interventions and outcomes measured in the studies were not sufficiently similar. For most outcomes there were no significant differences between groups; and results relating to abstaining or reducing alcohol consumption were mixed. Results from individual studies suggest that interventions may encourage women to abstain from alcohol in pregnancy. There was very little information provided on the effects of interventions on the health of mothers and babies. The evidence from the limited number of studies suggests that psychological and educational interventions may result in increased abstinence from alcohol, and a reduction in alcohol consumption among pregnant women. However, results were not consistent, and the paucity of studies, the number of total participants, the high risk of bias of some of the studies, and the complexity of interventions limits our ability to determine the type of intervention which would be most effective in increasing abstinence from, or reducing the consumption of, alcohol among pregnant women.
As of 2013, the review includes 29 studies describing nine possible chemoprotective agents, as well as description of two published meta-analyses. Among these trials, there were sufficient data in some instances to combine the results from different studies, most often using data from secondary non-quantitative measures. Nine of the studies were newly included at this update. Few of the included studies were at a high risk of bias overall, although often there was too little information to make an assessment. At least two review authors performed a formal review of an additional 44 articles but we did not include them in the final review for a variety of reasons. Of seven eligible amifostine trials (743 participants in total), one used quantitative sensory testing (vibration perception threshold) and demonstrated a favourable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Furthermore the change measured was subclinical. None of the three eligible Ca/Mg trials (or four trials if a single retrospective study was included) described our primary outcome measures. The four Ca/Mg trials included a total of 886 participants. Of the seven eligible glutathione trials (387 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing but reported disparate results; meta-analyses of three of these trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. Similarly, none of the three eligible vitamin E trials (246 participants) reported quantitative sensory testing. The eligible single trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), oxcarbazepine (32 participants), and retinoic acid (92 participants) did not perform quantitative sensory testing. In all, this review includes data from 2906 participants. However, only seven trials reported data for the primary outcome measure of this review, (quantitative sensory testing) and only nine trials reported our objective secondary measure, nerve conduction test results. Additionally, methodological heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) ≥ 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766). Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity. At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results were negative and did not support the positive findings based on the qualitative measures. In summary, the present studies are limited by the small number of participants receiving any particular agent, a lack of objective measures of neuropathy, and differing results among similar trials, which make it impossible to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs.
A total of four high-quality RCTs and six low-quality RCTs met the search criteria of this review. These studies included a total of 733 participants. Investigators compared three different posterior decompression techniques versus conventional laminectomy. Three studies (173 participants) compared unilateral laminotomy for bilateral decompression versus conventional laminectomy. Four studies (382 participants) compared bilateral laminotomy versus conventional laminectomy (one study included three treatment groups and compared unilateral and bilateral laminotomy vs conventional laminectomy). Finally, four studies (218 participants) compared a split-spinous process laminotomy versus conventional laminectomy. Evidence of low or very low quality suggests that different techniques of posterior decompression and conventional laminectomy have similar effects on functional disability and leg pain. Only perceived recovery at final follow-up was better in people who underwent bilateral laminotomy compared with conventional laminectomy (two RCTs, 223 participants, odds ratio 5.69, 95% confidence interval (CI) 2.55 to 12.71). Among the secondary outcome measures, unilateral laminotomy for bilateral decompression and bilateral laminotomy resulted in numerically fewer cases of iatrogenic instability, although in both cases, the incidence of instability was low (three RCTs, 166 participants, odds ratio 0.28, 95% CI 0.07 to 1.15; three RCTs, 294 participants, odds ratio 0.10, 95% CI 0.02 to 0.55, respectively). The difference in severity of postoperative low back pain following bilateral laminotomy (two RCTs, 223 participants, mean difference -0.51, 95% CI -0.80 to -0.23) and split-spinous process laminotomy compared with conventional laminectomy (two RCTs, 97 participants, mean difference -1.07, 95% CI -2.15 to -0.00) was significantly less, but was too small to be clinically important. A quantitative comparison between unilateral laminotomy and conventional laminectomy was not possible because of different reporting of outcome measures. We found no evidence to show that the incidence of complications, length of the procedure, length of hospital stay and postoperative walking distance differed between techniques of posterior decompression. The evidence provided by this systematic review for the effects of unilateral laminotomy for bilateral decompression, bilateral laminotomy and split-spinous process laminotomy compared with conventional laminectomy on functional disability, perceived recovery and leg pain is of low or very low quality. Therefore, further research is necessary to establish whether these techniques provide a safe and effective alternative for conventional laminectomy. Proposed advantages of these techniques regarding the incidence of iatrogenic instability and postoperative back pain are plausible, but definitive conclusions are limited by poor methodology and poor reporting of outcome measures among included studies. Future research is necessary to establish the incidence of iatrogenic instability using standardised definitions of radiological and clinical instability at comparable follow-up intervals. Long-term results with these techniques are currently lacking.
We did not identify any new trials from the updated search so the results remain unchanged as follows. We have included 10 studies describing two dosages of paracetamol. Of these, five studies (526 women) assessed 500 mg to 650 mg and six studies (841 women) assessed 1000 mg of paracetamol. We chose to use random-effects meta-analyses because of the heterogeneity in dosage used. Studies were from the 1970s to the early 1990s, and there was insufficient information to assess the risk of bias adequately, hence the findings need to be interpreted within this context. More women experienced pain relief with paracetamol compared with placebo (average risk ratio (RR) 2.14, 95% confidence interval (CI) 1.59 to 2.89, 10 studies, 1279 women). In addition, there were significantly fewer women having additional pain relief with paracetamol compared with placebo (RR 0.34, 95% CI 0.21 to 0.55, eight studies, 1132 women). Both the 500 mg to 650 mg and 1000 mg doses were effective in providing more pain relief than placebo. Maternal and neonatal potential adverse drug effects were not assessed in any of the included studies. Indeed few secondary outcomes were assessed. More women experienced pain relief, and fewer had additional pain relief, with paracetamol compared with placebo, although potential adverse effects were not assessed and generally the quality of studies was unclear.
We included 10 studies with a total of 1066 infants. All studies were conducted during early childhood immunisation. As the breastfeeding intervention cannot be blinded, we rated all studies as being at high risk of bias for blinding of participants and personnel. We assessed nine studies as being at low risk of bias for incomplete outcome data. In addition, we rated nine studies as high risk for blinding of outcome assessment. We scored risk of bias related to random sequence generation, allocation concealment, and selective reporting as unclear for the majority of the studies due to lack of information. Our primary outcome was pain. Breastfeeding reduced behavioural pain responses (cry time and pain scores) during vaccination compared to no treatment, oral water, and other interventions such as cuddling, oral glucose, topical anaesthetic, massage, and vapocoolant. Breastfeeding did not consistently reduce changes in physiological indicators, such as heart rate. We pooled data for duration of cry from six studies (n = 547 infants). Breastfeeding compared to water or no treatment resulted in a 38-second reduction in cry time (MD -38, 95% CI -50 to -26; P < 0.00001). The quality of the evidence according to GRADE for this outcome was moderate, as most infants were 6 months or younger, and outcomes may be different for infants during their 12-month immunisation. We pooled data for pain scores from five studies (n = 310 infants). Breastfeeding was associated with a 1.7-point reduction in standardised pain scores (SMD -1.7, 95% CI -2.2 to -1.3); we considered this evidence to be of moderate quality as data were primarily from infants younger than 6 months of age. We could pool heart rate data following injections for only two studies (n = 186); we considered this evidence to be of low quality due to insufficient data. There were no differences between breastfeeding and control (MD -3.6, -23 to 16). Four of the 10 studies had more than two study arms. Breastfeeding was more effective in reducing crying duration or pain scores during vaccination compared to: 25% dextrose and topical anaesthetic cream (EMLA), vapocoolant, maternal cuddling, and massage. No included studies reported adverse events. We conclude, based on the 10 studies included in this review, that breastfeeding may help reduce pain during vaccination for infants beyond the neonatal period. Breastfeeding consistently reduced behavioural responses of cry duration and composite pain scores during and following vaccinations. However, there was no evidence that breastfeeding had an effect on physiological responses. No studies included in this review involved populations of hospitalised infants undergoing other skin-breaking procedures. Although it may be possible to extrapolate the review results to this population, further studies of efficacy, feasibility, and acceptability in this population are warranted.
We included 18 trials (421 participants; 3817 endoscopic procedures). We judged three trials as at low risk of bias. Ten trials compared VR training with no training, five trials with conventional endoscopy training, one trial with another form of endoscopy simulation training, and two trials compared two different methods of VR training. Due to substantial clinical and methodological heterogeneity across our four comparisons, we did not perform a meta-analysis for several outcomes. We rated the quality of evidence as moderate, low, or very low due to risk of bias, imprecision, and heterogeneity. Virtual reality endoscopy simulation training versus no training: There was insufficient evidence to determine the effect on composite score of competency (MD 3.10, 95% CI -0.16 to 6.36; 1 trial, 24 procedures; low-quality evidence). Composite score of competency was based on 5-point Likert scales assessing seven domains: atraumatic technique, colonoscope advancement, use of instrument controls, flow of procedure, use of assistants, knowledge of specific procedure, and overall performance. Scoring range was from 7 to 35, a higher score representing a higher level of competence. Virtual reality training compared to no training likely provides participants with some benefit, as measured by independent procedure completion (RR 1.62, 95% CI 1.15 to 2.26; 6 trials, 815 procedures; moderate-quality evidence). We evaluated overall rating of performance (MD 0.45, 95% CI 0.15 to 0.75; 1 trial, 18 procedures), visualisation of mucosa (MD 0.60, 95% CI 0.20 to 1.00; 1 trial, 55 procedures), performance time (MD -0.20 minutes, 95% CI -0.71 to 0.30; 2 trials, 29 procedures), and patient discomfort (SMD -0.16, 95% CI -0.68 to 0.35; 2 trials, 145 procedures), all with very low-quality evidence. No trials reported procedure-related complications or critical flaws (e.g. bleeding, luminal perforation) (3 trials, 550 procedures; moderate-quality evidence). Virtual reality endoscopy simulation training versus conventional patient-based training: One trial reported composite score of competency but did not provide sufficient data for quantitative analysis. Virtual reality training compared to conventional patient-based training resulted in fewer independent procedure completions (RR 0.45, 95% CI 0.27 to 0.74; 2 trials, 174 procedures; low-quality evidence). We evaluated performance time (SMD 0.12, 95% CI -0.55 to 0.80; 2 trials, 34 procedures), overall rating of performance (MD -0.90, 95% CI -4.40 to 2.60; 1 trial, 16 procedures), and visualisation of mucosa (MD 0.0, 95% CI -6.02 to 6.02; 1 trial, 18 procedures), all with very low-quality evidence. Virtual reality training in combination with conventional training appears to be advantageous over VR training alone. No trials reported any procedure-related complications or critical flaws (3 trials, 72 procedures; very low-quality evidence). Virtual reality endoscopy simulation training versus another form of endoscopy simulation: Based on one study, there were no differences between groups with respect to composite score of competency, performance time, and visualisation of mucosa. Virtual reality training in combination with another form of endoscopy simulation training did not appear to confer any benefit compared to VR training alone. Two methods of virtual reality training: Based on one study, a structured VR simulation-based training curriculum compared to self regulated learning on a VR simulator appears to provide benefit with respect to a composite score evaluating competency. Based on another study, a progressive-learning curriculum that sequentially increases task difficulty provides benefit with respect to a composite score of competency over the structured VR training curriculum. VR simulation-based training can be used to supplement early conventional endoscopy training for health professions trainees with limited or no prior endoscopic experience. However, we found insufficient evidence to advise for or against the use of VR simulation-based training as a replacement for early conventional endoscopy training. The quality of the current evidence was low due to inadequate randomisation, allocation concealment, and/or blinding of outcome assessment in several trials. Further trials are needed that are at low risk of bias, utilise outcome measures with strong evidence of validity and reliability, and examine the optimal nature and duration of training.
The review currently includes ten short to medium term trials with 1549 participants on three comparisons: amisulpride versus olanzapine, risperidone and ziprasidone. The overall attrition rate was considerable (34.7%) with no significant difference between groups. Amisulpride was similarly effective as olanzapine and risperidone and more effective than ziprasidone (leaving the study early due to inefficacy: n=123, 1 RCT, RR 0.21 CI 0.05 to 0.94, NNT 8 CI 5 to 50). Amisulpride induced less weight gain than risperidone (n=585, 3 RCTs, MD -0.99 CI -1.61 to -0.37) or olanzapine (n=671, 3 RCTs, MD -2.11 CI -2.94 to -1.29). Olanzapine was also associated with a higher increase of glucose (n=406, 2 RCTs, MD -7.30 CI -7.62 to -6.99). There was no difference in terms of cardiac effects and extra pyramidal symptoms (EPS) compared with olanzapine (akathisia: n= 587, 2 RCTs, RR 0.66 CI 0.36 to 1.21), compared with risperidone (akathisia: n=586, 3 RCTs, RR 0.80 CI 0.58 to 1.11) and compared with ziprasidone (akathisia: n=123, 1 RCT, RR 0.63, CI 0.11 to 3.67). There is little randomised evidence comparing amisulpride with other second generation antipsychotic drugs. We could only find trials comparing amisulpride with olanzapine, risperidone and ziprasidone. We found amisulpride may be somewhat more effective than ziprasidone, and more tolerable in terms of weight gain and other associated problems than olanzapine and risperidone. These data, however, are based on only ten short to medium term studies and therefore too limited to allow for firm conclusions. Note: the 47 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.
Three trials were identified in this review as satisfying inclusion criteria. Results of all three trials were evaluated, however, one of these trials had compromised methodological quality and, therefore the focus was placed on the other two trials. Data were not pooled due to the heterogeneity between trials. The first trial (n = 24) showed a benefit of cognitive behavioural therapy (CBT) in people with mild TBI and acute stress disorder. Fewer people receiving CBT had diagnosis of post-traumatic stress disorder (PTSD) at post-treatment compared to the control supportive counselling group, with maintenance of treatment gains found at six-month follow up. The second trial (n = 20) showed that post-treatment anxiety symptomatology of people with mild to moderate TBI was lower in the combined CBT and neurorehabilitation group compared to the no intervention control group. This review provides some evidence for the effectiveness of CBT for treatment of acute stress disorder following mild TBI and CBT combined with neurorehabilitation for targeting general anxiety symptomatology in people with mild to moderate TBI. These findings need to be viewed in light of the small number, small sample size and heterogeneous characteristics of current trials published in this area. More trials focusing on comparable psychological interventions, severity of injury of participants and diagnosis of anxiety disorder(s) are needed.
There were no data comparing best supportive care with chemotherapy. Cisplatin-based regimens are the most widely used and therefore we have concentrated on these trials. In terms of response rates some non-platinum regimens are equivalent but toxicity is higher. The most common cisplatin regimen was 50 mg/m2 day 1 q21days. Higher doses had similar survivals. There was no direct comparison between single-agent cisplatin and carboplatin. Overall survival (OS) and progression-free survival (PFS) were not adequately reported and quality of life (QoL) outcomes were incompletely documented. Combination regimens were more toxic than single agents, but in the limited reported data this did not appear to adversely affect QoL. No significant difference in response rate by site of recurrence was found, although there was a trend towards improved response when the main site of disease was beyond the previously irradiated pelvis. Combination cisplatin-based chemotherapy could be a viable option for patients of good performance status with recurrent/metastatic cervical cancer, but further trials that report adequate survival and QoL data are sought. Response rates and improvements in survival are low. Cisplatin-based combinations have significant toxicity. Outcomes are poor and novel cytotoxic/biological agents and optimal scheduling need further investigation. Future trials need to stratify for and perform planned subgroup analysis with respect to previous treatment and site of recurrence.
We did not find any studies fulfilling the inclusion criteria, therefore no outcome data are reported. We identified nine studies after initial screening and, after further evaluation, we excluded these. The excluded studies involved a total of 163 individuals aged two years to 18 years. We excluded studies for three main reasons: they were non-randomized or case series studies, they were studies of people over 18 years of age or even where the study was randomised, the study population was mixed and results pertaining to the visually impaired cohort could not be independently evaluated. No significant adverse effects of melatonin were reported in these excluded studies. There is currently no high quality data to support or refute the use of melatonin for sleep disorders in visually impaired children. Placebo-controlled trials examining important clinical outcomes such as sleep quality, sleep latency, duration of sleep and night-time awakenings are needed. As the numbers of children meeting study inclusion criteria are likely to be low at individual sites, multicentre collaboration between developmental paediatricians, sleep physicians and other health care professionals is essential to achieve sufficient sample size for controlled studies. Such collaboration would help facilitate local recruitment at multiple sites, with study oversight being provided by paediatricians with expertise in sleep disorders. Participation of collaborators with experience in evidence-based practice research is also desirable due to the lack of protocols on melatonin therapy in the target population.
We identified 28 randomised trials including 8950 participants (newly incorporated in this update: 10 trials including 4227 participants). The overall quality of the evidence was generally low to moderate. Pooled estimates showed a reduction in thromboembolic events (RR 0.58, 95% CI 0.45 to 0.75; participants = 7594; studies = 18; moderate quality of evidence). Both, trials of self-management or self-monitoring showed reductions in thromboembolic events (RR 0.47, 95% CI 0.31 to 0.70; participants = 3497; studies = 11) and (RR 0.69, 95% CI 0.49 to 0.97; participants = 4097; studies = 7), respectively; the quality of evidence for both interventions was moderate. No reduction in all-cause mortality was found (RR 0.85, 95% CI 0.71 to 1.01; participants = 6358; studies = 11; moderate quality of evidence). While self-management caused a reduction in all-cause mortality (RR 0.55, 95% CI 0.36 to 0.84; participants = 3058; studies = 8); self-monitoring did not (RR 0.94, 95% CI 0.78 to 1.15; participants = 3300; studies = 3); the quality of evidence for both interventions was moderate. In 20 trials (8018 participants) self-monitoring or self-management did not reduce major haemorrhage (RR 0.95, 95% CI, 0.80 to 1.12; moderate quality of evidence). There was no significant difference found for minor haemorrhage (RR 0.97, 95% CI 0.67 to 1.41; participants = 5365; studies = 13). The quality of evidence was graded as low because of serious risk of bias and substantial heterogeneity (I2 = 82%). Participants who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. Thromboembolic events were reduced, for both those self-monitoring or self-managing oral anticoagulation therapy. A reduction in all-cause mortality was observed in trials of self-management but not in self-monitoring, with no effects on major haemorrhage.
Our search identified a total of 8124 records, from which we included 17 studies (54 papers) with 23,200 children in the review. The included studies reported on one or more of the pre-specified primary outcomes, and five studies included multiple comparison groups. Overall, the majority of trials were at low risk of bias for random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias, but at high risk of bias for blinding of participants and personnel due to the nature of the intervention. Using the GRADE approach, we judged the quality of the evidence for most outcomes as low or moderate. LNS+complementary feeding compared with no intervention Thirteen studies compared LNS plus complementary feeding with no intervention. LNS plus complementary feeding reduced the prevalence of moderate stunting by 7% (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.88 to 0.98; nine studies, 13,372 participants; moderate-quality evidence), severe stunting by 15% (RR 0.85, 95% CI 0.74 to 0.98; five studies, 6151 participants; moderate-quality evidence), moderate wasting by 18% (RR 0.82, 95% CI 0.74 to 0.91; eight studies; 13,172 participants; moderate-quality evidence), moderate underweight by 15% (RR 0.85, 95% CI 0.80 to 0.91; eight studies, 13,073 participants; moderate-quality evidence), and anaemia by 21% (RR 0.79, 95% CI 0.69 to 0.90; five studies, 2332 participants; low-quality evidence). There was no impact of LNS plus complementary feeding on severe wasting (RR 1.27, 95% CI 0.66 to 2.46; three studies, 2329 participants) and severe underweight (RR 0.78, 95%CI 0.54 to 1.13; two studies, 1729 participants). Adverse effects did not differ between the groups (RR 0.86, 95% CI 0.74 to 1.01; three studies, 3382 participants). LNS+complementary feeding compared with FBF Five studies compared LNS plus complementary feeding with other FBF, including corn soy blend and UNIMIX. We pooled four of the five studies in meta-analyses and found that, when compared to other FBF, LNS plus complementary feeding significantly reduced the prevalence of moderate stunting (RR 0.89, 95% CI 0.82 to 0.97; three studies, 2828 participants; moderate-quality evidence), moderate wasting (RR 0.79, 95% CI 0.65 to 0.97; two studies, 2290 participants; moderate-quality evidence), and moderate underweight (RR 0.81, 95% CI 0.73 to 0.91; two studies, 2280 participants; moderate-quality evidence). We found no difference between LNS plus complementary feeding and FBF for severe stunting (RR 0.41, 95% CI 0.12 to 1.42; two studies, 729 participants; low-quality evidence), severe wasting (RR 0.64, 95% CI 0.19 to 2.81; two studies, 735 participants; moderate-quality evidence), and severe underweight (RR 1.23, 95% CI 0.67 to 2.25; one study, 173 participants; low-quality evidence). LNS+complementary feeding compared with MNP Four studies compared LNS plus complementary feeding with MNP. We pooled data from three of the four studies in meta-analyses and found that compared to MNP, LNS plus complementary feeding significantly reduced the prevalence of moderate underweight (RR 0.88, 95% CI 0.78 to 0.99; two studies, 2004 participants; moderate-quality evidence) and anaemia (RR 0.38, 95% CI 0.21 to 0.68; two studies, 557 participants; low-quality evidence). There was no difference between LNS plus complementary feeding and MNP for moderate stunting (RR 0.92, 95% CI 0.82 to 1.02; three studies, 2365 participants) and moderate wasting (RR 0.97, 95% CI 0.77 to 1.23; two studies, 2004 participants). The findings of this review suggest that LNS plus complementary feeding compared to no intervention is effective at improving growth outcomes and anaemia without adverse effects among children aged six to 23 months in low- and middle-income countries (LMIC) in Asia and Africa, and more effective if provided over a longer duration of time (over 12 months). Limited evidence also suggests that LNS plus complementary feeding is more effective than FBF and MNP at improving growth outcomes.
Twenty-six randomized clinical trials fulfilled entry criteria. No study assessed combined long-term morbidity. Routine vitamin E supplementation significantly increased hemoglobin concentration by a small amount. Vitamin E significantly reduced the risk of germinal matrix/intraventricular hemorrhage and increased the risk of sepsis; however, heterogeneity limits the strength of these latter two inferences. Vitamin E did not significantly affect other morbidity or mortality. In VLBW infants, vitamin E supplementation significantly increased the risk of sepsis, and reduced the risk of severe retinopathy and blindness among those examined.  Subgroup analyses demonstrated (1) an association between intravenous, high-dose vitamin E supplementation and increased risk of sepsis and of parenchymal cerebral hemorrhage; (2) an association between vitamin E supplementation by other than the intravenous route and reduced risk of germinal matrix-intraventricular hemorrhage and of severe intraventricular hemorrhage; and (3) an association between serum tocopherol levels greater than 3.5 mg/dl and increased risk of sepsis and reduced risk for severe retinopathy among those examined. Vitamin E supplementation in preterm infants reduced the risk of intracranial hemorrhage but increased the risk of sepsis. In very low birth weight infants, vitamin E increased the risk of sepsis, and reduced the risk of severe retinopathy and blindness among those examined. Evidence does not support the routine use of vitamin E supplementation by intravenous route at high doses or aiming at serum tocopherol levels greater than 3.5 mg/dl.
We included eight trials involving 5701 patients. Six trials tested ancrod and two trials tested defibrase (patients were treated for less than three hours to less than 48 hours). Allocation concealment was adequate in seven trials. Fibrinogen depleting agents marginally reduced the proportion of patients who were dead or disabled at the end of follow-up (risk ratio (RR) 0.95, 95% confidence Interval (CI) 0.90 to 0.99, 2P = 0.02). There was no statistically significant difference in death from all causes during the scheduled treatment or follow-up period. There were fewer stroke recurrences in the treatment group than in the control group (RR 0.67, 95% CI 0.49 to 0.92, 2P = 0.01). However, symptomatic intracranial haemorrhage was about twice as common in the treatment group compared with the control group (RR 2.42, 95% CI 1.65 to 3.56, 2P < 0.00001). The current evidence is promising but not yet sufficiently robust to support the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke. Further trials are needed to determine whether there is worthwhile benefit, and if so, which categories of patients are most likely to benefit.
We included 11 trials that enrolled a total of 2412 pregnant women who smoked at enrolment, nine trials of NRT and two trials of bupropion as adjuncts to behavioural support, with comparable behavioural support provided in the control arms. No trials investigated varenicline or ECs. We assessed four trials as at low risk of bias overall. The overall certainty of the evidence was low across outcomes and comparisons as assessed using GRADE, with reductions in confidence due to risk of bias, imprecision, and inconsistency. Compared to placebo and non-placebo (behavioural support only) controls, there was low-certainty evidence that NRT increased the likelihood of smoking abstinence in later pregnancy (RR 1.37, 95% CI 1.08 to 1.74; I² = 34%, 9 studies, 2336 women). However, in subgroup analysis by comparator type, there was a subgroup difference between placebo-controlled and non-placebo controlled RCTs (test for subgroup differences P = 0.008). There was unclear evidence of an effect in placebo-controlled RCTs (RR 1.21, 95% CI 0.95 to 1.55; I² = 0%, 6 studies, 2063 women), whereas non-placebo-controlled trials showed clearer evidence of a benefit (RR 8.55, 95% CI 2.05 to 35.71; I² = 0%, 3 studies, 273 women). An additional subgroup analysis in which studies were grouped by the type of NRT used found no difference in the effectiveness of NRT in those using patches or fast-acting NRT (test for subgroup differences P = 0.08). There was no evidence of a difference between NRT and control groups in rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care, caesarean section, congenital abnormalities, or neonatal death. In one study infants born to women who had been randomised to NRT had higher rates of 'survival without developmental impairment' at two years of age compared to the placebo group. Non-serious adverse effects observed with NRT included headache, nausea, and local reactions (e.g. skin irritation from patches or foul taste from gum), but data could not be pooled. Adherence to NRT treatment regimens was generally low. We identified low-certainty evidence that there was no difference in smoking abstinence rates observed in later pregnancy in women using bupropion when compared to placebo control (RR 0.74, 95% CI 0.21 to 2.64; I² = 0%, 2 studies, 76 women). Evidence investigating the safety outcomes of bupropion use was sparse, but the existing evidence showed no difference between the bupropion and control group. NRT used for smoking cessation in pregnancy may increase smoking cessation rates in late pregnancy. However, this evidence is of low certainty, as the effect was not evident when potentially biased, non-placebo-controlled RCTs were excluded from the analysis. Future studies may therefore change this conclusion. We found no evidence that NRT has either positive or negative impacts on birth outcomes; however, the evidence for some of these outcomes was also judged to be of low certainty due to imprecision and inconsistency. We found no evidence that bupropion may be an effective aid for smoking cessation during pregnancy, and there was little evidence evaluating its safety in this population. Further research evidence on the efficacy and safety of pharmacotherapy and EC use for smoking cessation in pregnancy is needed, ideally from placebo-controlled RCTs that achieve higher adherence rates and that monitor infants' outcomes into childhood. Future RCTs of NRT should investigate higher doses than those tested in the studies included in this review.
The search yielded 7057 references of which we identified three RCTs for inclusion, four ongoing trials and one study awaiting classification. All three included RCTs compared videolaryngoscopy with direct laryngoscopy during intubation attempts by trainees. Time to intubation was similar between videolaryngoscopy and direct laryngoscopy (mean difference (MD) -0.62, 95% confidence interval (CI) -6.50 to 5.26; 2 studies; 311 intubations) (very low quality evidence). Videolaryngoscopy did not decrease the number of intubation attempts (MD -0.05, 95% CI -0.18 to 0.07; 2 studies; 427 intubations) (very low quality evidence). Moderate quality evidence suggested that videolaryngoscopy increased the success of intubation at first attempt (typical risk ratio (RR) 1.44, 95% CI 1.20 to 1.73; typical risk difference (RD) 0.19, 95% CI 0.10 to 0.28; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 10; 3 studies; 467 intubation attempts). Desaturation episodes during intubation attempts were similar between videolaryngoscopy and direct laryngoscopy (MD -0.76, 95% CI -5.74 to 4.23; 2 studies; 359 intubations) (low quality evidence). There was no difference in the incidence of airway trauma due to intubation attempts (RR 0.10, 95% CI 0.01 to 1.80; RD -0.04, 95% CI -0.09 to -0.00; 1 study; 213 intubations) (low quality evidence). There were no data available on other adverse effects of videolaryngoscopy. Moderate to very low quality evidence suggests that videolaryngoscopy increases the success of intubation in the first attempt but does not decrease the time to intubation or the number of attempts for intubation. However, these studies were conducted with trainees performing the intubations and these results highlight the potential usefulness of the videolaryngoscopy as a teaching tool. Well-designed, adequately powered RCTs are necessary to confirm efficacy and address safety and cost-effectiveness of videolaryngoscopy for endotracheal intubation in neonates by trainees and those proficient in direct laryngoscopy.
We included four studies with a total of 115 patients randomised to undergo a vascular procedure with remote ischaemic preconditioning and 117 patients randomised to have the procedure without remote ischaemic preconditioning. None of the trials were of low risk of bias. There was no significant difference in mortality between the two groups (RR 1.70, 95% CI 0.51 to 5.72). Similarly, there was no statistically significant difference between the two groups for all other outcomes except reduced risk of myocardial infarction in the remote ischaemic preconditioning group, which was significant by the fixed-effect model (RR 0.31, 95% CI 0.10 to 0.90) but not by the random-effects model (RR 0.34, 95% CI 0.11 to 1.08). This positive effect was from the results of only one trial and was not consistently observed. Furthermore, it was noted that there was an observed trend of high incidence of unplanned critical care admission in the remote ischaemic preconditioning group, although this was not statistically significant (RR 2.15, 95% CI 0.87 to 5.33). Based on current evidence from small pilot trials, there are too few data to be able to say whether remote ischaemic preconditioning has any beneficial or harmful effects. The safety of this technique needs to be confirmed in adequately powered trials. Therefore, further randomised trials on this technique are required.
We included 13 studies involving 5810 participants from Latin America, Africa and Asia. We excluded 38 studies and identified six ongoing/unpublished trials. All trials compared the provision of MNP for point-of-use fortification with no intervention or placebo. No trials compared the effects of MNP versus iron-containing supplements (as drops, tablets or syrup). The sample sizes in the included trials ranged from 90 to 2193 participants. Six trials included participants younger than 59 months of age only, four included only children aged 60 months or older, and three trials included children both younger and older than 59 months of age. MNPs contained from two to 18 vitamins and minerals. The iron doses varied from 2.5 mg to 30 mg of elemental iron. Four trials reported giving 10 mg of elemental iron as sodium iron ethylenediaminetetraacetic acid (NaFeEDTA), chelated ferrous sulphate or microencapsulated ferrous fumarate. Three trials gave 12.5 mg of elemental iron as microencapsulated ferrous fumarate. Three trials gave 2.5 mg or 2.86 mg of elemental iron as NaFeEDTA. One trial gave 30 mg and one trial provided 14 mg of elemental iron as microencapsulated ferrous fumarate, while one trial gave 28 mg of iron as ferrous glycine phosphate. In comparison with receiving no intervention or a placebo, children receiving iron-containing MNP for point-of-use fortification of foods had lower risk of anaemia prevalence ratio (PR) 0.66, 95% confidence interval (CI) 0.49 to 0.88, 10 trials, 2448 children; moderate-quality evidence) and iron deficiency (PR 0.35, 95% CI 0.27 to 0.47, 5 trials, 1364 children; moderate-quality evidence) and had higher haemoglobin (mean difference (MD) 3.37 g/L, 95% CI 0.94 to 5.80, 11 trials, 2746 children; low-quality evidence). Only one trial with 115 children reported on all-cause mortality (zero cases; low-quality evidence). There was no effect on diarrhoea (risk ratio (RR) 0.97, 95% CI 0.53 to 1.78, 2 trials, 366 children; low-quality evidence). Point-of-use fortification of foods with MNPs containing iron reduces anaemia and iron deficiency in preschool- and school-age children. However, information on mortality, morbidity, developmental outcomes and adverse effects is still scarce.
We included six studies (involving 122 women) but only four studies (involving only 116 women) contributed data to the analyses. Infant There were very little data of relevance to the three main (primary) outcomes considered in this review: There was no significant difference between planned immediate caesarean section and planned vaginal delivery with respect to birth injury to infant (risk ratio (RR) 0.56, 95%, confidence interval (CI) 0.05 to 5.62; one trial, 38 women) or birth asphyxia (RR 1.63, 95% CI 0.84 to 3.14; one trial, 12 women). The only cases of birth trauma were a laceration of the buttock in a baby who was delivered by caesarean section and mild bruising in another allocated to the group delivered vaginally. The difference between the two groups with regard to perinatal deaths was not significant (0.29, 95% CI 0.07 to 1.14; three trials, 89 women) and there were no data specifically relating to neonatal admission to special care and/or intensive care unit. There was also no difference between the caesarean or vaginal delivery groups in terms of markers of possible birth asphyxia (RR 1.63, 95% CI 0.84 to 3.14; one trial, 12 women) or Apgar score less than seven at five minutes (RR 0.83, 95% CI 0.43 to 1.60; four trials, 115 women) and no difference in attempts at breastfeeding (RR 1.40, 95% 0.11 to 17.45; one trial, 12 women). There was also no difference in neonatal fitting/seizures (RR 0.22, 95% CI 0.01 to 4.32; three trials, 77 women), hypoxic ischaemic encephalopathy (RR 4.00, 95% CI 0.20 to 82.01;one trial, 12 women) or respiratory distress syndrome (RR 0.55, 95% CI 0.27 to 1.10; three trials, 103 women). There were no data reported in the trials specifically relating to meconium aspiration. There was also no significant difference between the two groups for abnormal follow-up in childhood (RR 0.65, 95% CI 0.19 to 2.22; one trial, 38 women) or delivery less than seven days after entry (RR 0.95, 95% CI 0.73 to 1.24; two trials, 51 women). Mother There were no data reported on maternal admissions to intensive care. However, there were seven cases of major maternal postpartum complications in the group allocated to planned immediate caesarean section and none in the group randomised to vaginal delivery (RR 7.21, 95% CI 1.37 to 38.08; four trials, 116 women). There were no data reported in the trials specifically relating to maternal satisfaction (postnatal). There was no significant difference between the two groups with regard to postpartum haemorrhage. A number of non-prespecified secondary outcomes were also considered in the analyses. There was a significant advantage for women in the vaginal delivery group with respect to maternal puerperal pyrexia (RR 2.98, 95% CI 1.18 to 7.53; three trials, 89 women) and other maternal infection (RR 2.63, 95% CI 1.02 to 6.78; three trials, 103 women), but no significant differences in wound infection (RR 1.16, 95% CI 0.18 to 7.70; three trials, 103 women), maternal stay more than 10 days (RR 1.27, 95% CI 0.35 to 4.65; three trials, 78 women) or the need for blood transfusion (results not estimable). There is not enough evidence to evaluate the use of a policy of planned immediate caesarean delivery for preterm babies. Further studies are needed in this area, but recruitment is proving difficult.
Of the 370 records that we identified as a result of the search (excluding duplicates), we regarded six abstracts and titles as potentially relevant studies. Of these six studies, three met the inclusion criteria involving 708 participants; most trials were at moderate or high risk of bias (risk mainly due to lack of blinding and high rate of incomplete data). We did not identify any ongoing trials. Although all included studies had been published in peer-reviewed journals at the time of the search and data extraction, numerical data regarding the outcome measured in one trial involving 77 participants were insufficient for inclusion in a meta-analyses. The difference in the rates of prolonged vaginal discharge or presumed cervicitis (one study; 348 participants; risk ratio (RR), 1.29; 95% confidence interval (CI) 0.72 to 2.31; low-quality evidence) and severe vaginal bleeding (two studies; 638 participants; RR 1.21; 95% CI 0.52 to 2.82; very low-quality evidence) among the two comparison groups did not reach the level for clinically important effect. In addition, there was no difference in adverse events related to antibiotics i.e. nausea/vomiting, diarrhoea, and headache among the two comparison groups (two studies; 638 participants; RR 1.69; 95% CI 0.85 to 3.34; very low-quality evidence). There were no differences in the incidence of fever (RR, 2.23; 95% CI 0.20 to 24.36), lower abdominal pain (RR, 1.03; 95% CI 0.61 to 1.72), unscheduled medical consultation (RR 2.68, 95% CI 0.97 to 7.41), and additional self-medication (RR 1.22; 95% CI 0.56 to 2.67) between the two comparison groups (one study; 290 participants; low to very low-quality evidence). As only limited data are available from three trials with overall moderate to high risk of bias, there is insufficient evidence to support use of antibiotics to reduce infectious complications following excision of the cervical transformation zone. In addition, there were minimal data about antibiotic-related adverse events and no information on the risk of developing antibiotic resistance. Antibiotics given for infection prevention after excision of the cervical transformation zone should only be used in the context of clinical research, to avoid unnecessary prescription of antibiotics and to prevent further increases in antibiotic resistance.
Fourteen trials were included, but only 12 trials involving 910 women contributed data to outcome analysis. Women who exercised did not lose significantly more weight than women in the usual care group (two trials; n = 53; MD -0.10 kg; 95% confidence interval (CI) -1.90 to 1.71). Women who took part in a diet (one trial; n = 45; MD -1.70 kg; 95% CI -2.08 to -1.32), or diet plus exercise programme (seven trials; n = 573; MD -1.93 kg; 95% CI -2.96 to -0.89; random-effects, T² = 1.09, I² = 71%), lost significantly more weight than women in the usual care group. There was no difference in the magnitude of weight loss between diet alone and diet plus exercise group (one trial; n = 43; MD 0.30 kg; 95% CI -0.06 to 0.66). The interventions seemed not to affect breastfeeding performance adversely. Evidence from this review suggests that both diet and exercise together and diet alone help women to lose weight after childbirth. Nevertheless, it may be preferable to lose weight through a combination of diet and exercise as this improves maternal cardiorespiratory fitness and preserves fat-free mass, while diet alone reduces fat-free mass. This needs confirmation in large trials of high methodological quality. For women who are breastfeeding, more evidence is required to confirm whether diet or exercise, or both, is not detrimental for either mother or baby.
We identified a total of 27 randomized controlled trials (RCTs) of migraine symptom-relieving medications, in which 9158 children and adolescents were enrolled and 7630 (range of mean age between 8.2 and 14.7 years) received medication. Twenty-four studies focused on drugs in the triptan class, including almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, sumatriptan + naproxen sodium, and zolmitriptan. Other medications studied included paracetamol (acetaminophen), ibuprofen, and dihydroergotamine (DHE). More than half of the studies evaluated sumatriptan. All but one study reported adverse event data. Most studies presented a low or unclear risk of bias, and the overall quality of evidence, according to GRADE criteria, was low to moderate, downgraded mostly due to imprecision and inconsistency. Ibuprofen was more effective than placebo for producing pain freedom at two hours in two small studies that included 162 children (RR 1.87, 95% confidence interval (CI) 1.15 to 3.04) with low quality evidence (due to imprecision). Paracetamol was not superior to placebo in one small study of 80 children. Triptans as a class of medication were superior to placebo in producing pain freedom in 3 studies involving 273 children (RR 1.67, 95% CI 1.06 to 2.62, NNTB 13) (moderate quality evidence) and 21 studies involving 7026 adolescents (RR 1.32, 95% CI 1.19 to 1.47, NNTB 6) (moderate quality evidence). There was no significant difference in the effect sizes between studies involving children versus adolescents. Triptans were associated with an increased risk of minor (non-serious) adverse events in adolescents (RD 0.13, 95% CI 0.08 to 0.18, NNTH 8), but studies did not report any serious adverse events. The risk of minor adverse events was not significant in children (RD 0.06, 95% CI − 0.04 to 0.17, NNTH 17). Sumatriptan plus naproxen sodium was superior to placebo in one study involving 490 adolescents (RR 3.25, 95% CI 1.78 to 5.94, NNTB 6) (moderate quality evidence). Oral dihydroergotamine was not superior to placebo in one small study involving 13 children. Low quality evidence from two small trials shows that ibuprofen appears to improve pain freedom for the acute treatment of children with migraine. We have only limited information on adverse events associated with ibuprofen in the trials included in this review. Triptans as a class are also effective at providing pain freedom in children and adolescents but are associated with higher rates of minor adverse events. Sumatriptan plus naproxen sodium is also effective in treating adolescents with migraine.
We included 20 trials involving 2527 patients. Concealment of allocation was poorly described. Different doses (of tissue plasminogen activator, urokinase, desmoteplase or tenecteplase) were compared in 13 trials (N = 1433 patients). Different agents (tissue plasminogen activator versus urokinase, tissue-cultured urokinase versus conventional urokinase, tenecteplase versus tissue plasminogen activator) were compared in five trials (N = 875 patients). Five trials (N = 485) compared different routes of administration. As some trials compared different agents and different doses, some patients contributed to two analyses. There was an approximately three-fold increase in fatal intracranial haemorrhages in patients allocated to higher than to lower doses of the same thrombolytic drug (odds ratio (OR) 2.71, 95% confidence interval (CI) 1.22 to 6.04). There was no difference in the number of patients who were dead or dependent at the end of follow-up between those allocated higher or lower doses of thrombolytic drug (OR 0.86, 95% CI 0.62 to 1.19). Higher versus lower doses of desmoteplase were associated with more deaths at the end of follow-up (OR 3.21, 95% CI 1.23 to 8.39). There was no evidence of any benefit for intra-arterial over intravenous treatment. These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.
Fourteen studies including 758 participants were included in this review. The types of trauma participants had been exposed to included sexual abuse, civil violence, natural disaster, domestic violence and motor vehicle accidents. Most participants were clients of a trauma-related support service. The psychological therapies used in these studies were cognitive behavioural therapy (CBT), exposure-based, psychodynamic, narrative, supportive counselling, and eye movement desensitisation and reprocessing (EMDR). Most compared a psychological therapy to a control group. No study compared psychological therapies to pharmacological therapies alone or as an adjunct to a psychological therapy. Across all psychological therapies, improvement was significantly better (three studies, n = 80, OR 4.21, 95% CI 1.12 to 15.85) and symptoms of PTSD (seven studies, n = 271, SMD -0.90, 95% CI -1.24 to -0.42), anxiety (three studies, n = 91, SMD -0.57, 95% CI -1.00 to -0.13) and depression (five studies, n = 156, SMD -0.74, 95% CI -1.11 to -0.36) were significantly lower within a month of completing psychological therapy compared to a control group. The psychological therapy for which there was the best evidence of effectiveness was CBT. Improvement was significantly better for up to a year following treatment (up to one month: two studies, n = 49, OR 8.64, 95% CI 2.01 to 37.14; up to one year: one study, n = 25, OR 8.00, 95% CI 1.21 to 52.69). PTSD symptom scores were also significantly lower for up to one year (up to one month: three studies, n = 98, SMD -1.34, 95% CI -1.79 to -0.89; up to one year: one study, n = 36, SMD -0.73, 95% CI -1.44 to -0.01), and depression scores were lower for up to a month (three studies, n = 98, SMD -0.80, 95% CI -1.47 to -0.13) in the CBT group compared to a control. No adverse effects were identified. No study was rated as a high risk for selection or detection bias but a minority were rated as a high risk for attrition, reporting and other bias. Most included studies were rated as an unclear risk for selection, detection and attrition bias. There is evidence for the effectiveness of psychological therapies, particularly CBT, for treating PTSD in children and adolescents for up to a month following treatment. At this stage, there is no clear evidence for the effectiveness of one psychological therapy compared to others. There is also not enough evidence to conclude that children and adolescents with particular types of trauma are more or less likely to respond to psychological therapies than others. The findings of this review are limited by the potential for methodological biases, and the small number and generally small size of identified studies. In addition, there was evidence of substantial heterogeneity in some analyses which could not be explained by subgroup or sensitivity analyses. More evidence is required for the effectiveness of all psychological therapies more than one month after treatment. Much more evidence is needed to demonstrate the relative effectiveness of different psychological therapies or the effectiveness of psychological therapies compared to other treatments. More details are required in future trials in regards to the types of trauma that preceded the diagnosis of PTSD and whether the traumas are single event or ongoing. Future studies should also aim to identify the most valid and reliable measures of PTSD symptoms and ensure that all scores, total and sub-scores, are consistently reported.
We identified 10 new studies (an additional 869 participants) in the updated search. The review thus included a total of 47 studies, with 2884 children and adolescents completing treatment (mean age 12.65 years, SD 2.21 years). Twenty-three studies addressed treatments for headache (including migraine); 10 for abdominal pain; two studies treated participants with either a primary diagnosis of abdominal pain or irritable bowel syndrome, two studies treated adolescents with fibromyalgia, two studies included adolescents with temporomandibular disorders, three were for the treatment of pain associated with sickle cell disease, and two studies treated adolescents with inflammatory bowel disease. Finally, three studies included adolescents with mixed pain conditions. Overall, we judged the included studies to be at unclear or high risk of bias. Children with headache pain We found that psychological therapies reduced pain frequency post-treatment for children and adolescents with headaches (risk ratio (RR) 2.35, 95% confidence interval (CI) 1.67 to 3.30, P < 0.01, number needed to treat for an additional beneficial outcome (NNTB) = 2.86), but these effects were not maintained at follow-up. We did not find a beneficial effect of psychological therapies on reducing disability in young people post-treatment (SMD -0.26, 95% CI -0.56 to 0.03), but we did find a beneficial effect in a small number of studies at follow-up (SMD -0.34, 95% CI -0.54 to -0.15). We found no beneficial effect of psychological interventions on depression or anxiety symptoms. Children with mixed pain conditions We found that psychological therapies reduced pain intensity post-treatment for children and adolescents with mixed pain conditions (SMD -0.43, 95% CI -0.67 to -0.19, P < 0.01), but these effects were not maintained at follow-up. We did find beneficial effects of psychological therapies on reducing disability for young people with mixed pain conditions post-treatment (SMD -0.34, 95% CI -0.54 to -0.15) and at follow-up (SMD -0.27, 95% CI -0.49 to -0.06). We found no beneficial effect of psychological interventions on depression symptoms. In contrast, we found a beneficial effect on anxiety at post-treatment in children with mixed pain conditions (SMD -0.16, 95% CI -0.29 to -0.03), but this was not maintained at follow-up. Across all pain conditions, we found that adverse events were reported in seven trials, of which two studies reported adverse events that were study-related. Quality of evidence We found the quality of evidence for all outcomes to be low or very low, mostly downgraded for unexplained heterogeneity, limitations in study design, imprecise and sparse data, or suspicion of publication bias. This means our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect, or we have very little confidence in the effect estimate; or the true effect is likely to be substantially different from the estimate of effect. Psychological treatments delivered predominantly face-to-face might be effective for reducing pain outcomes for children and adolescents with headache or other chronic pain conditions post-treatment. However, there were no effects at follow-up. Psychological therapies were also beneficial for reducing disability in children with mixed chronic pain conditions at post-treatment and follow-up, and for children with headache at follow-up. We found no beneficial effect of therapies for improving depression or anxiety. The conclusions of this update replicate and add to those of a previous version of the review which found that psychological therapies were effective in reducing pain frequency/intensity for children with headache and mixed chronic pain conditions post-treatment.
We identified only one randomized controlled trial that met our inclusion criteria and no further trials were identified in subsequent updates. The included study was a trial of moderate intensity, endurance type exercise versus 'usual activities' in 25 patients with amyotrophic lateral sclerosis. The risk of bias was high and no adverse events were reported. At three months patients performing the 15 minute twice daily exercises had significantly less spasticity overall (mean reduction of -0.43, 95% confidence interval (CI) -1.03 to +0.17 in the treatment group versus an increase of +0.25, 95% CI -0.46 to +0.96 in control) but the mean change between groups was not significant (-0.68, 95% CI -1.62 to +0.26), as measured by the Ashworth scale (possible scores 0 to 5, where higher is worse). The single trial performed was too small to determine whether individualized moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population. More research is needed.
Two studies were included involving a total of 529 people. One open quasi-randomised trial of 129 participants with traumatic hip fractures showed a reduction in PE but not mortality over a 34 day period in the filter group. The PREPIC (Prévention du Risque d'Embolie Pulmonaire par Interruption Cave) trial, was an open RCT of 400 participants with documented proximal deep vein thrombosis (DVT) or PE who received concurrent anticoagulation. Permanent VCFs prevented PE at eight years. No reduction in mortality was seen, but this reflected an older study population; the majority of deaths were due to cancer or cardiovascular causes. There was an increased incidence of (DVT) in the filter group. Adverse events were not reported. No recommendations can be drawn from the two studies. One study showed a reduction in PE rates but not mortality, but was subject to significant biases. The PREPIC study lacked statistical power to detect a reduction in PE over shorter and more clinically significant time periods. However, the trial demonstrated that permanent VCFs were associated with an increased risk of long term lower limb DVT. There is a paucity of VCFs outcome evidence when used within currently approved indications and a lack of trials on retrievable filters. Further trials are needed to assess vena caval filter safety and effectiveness.
The searches identified 76 studies (302 references); 35 studies (total of 1138 participants) met the inclusion criteria. Studies varied in duration from up to one week to one year; 20 of the studies were cross-over in design. The studies also varied in type of intervention and the outcomes measured, data were not published in sufficient detail in most of these studies, so meta-analysis was limited. Few studies were considered to have a low risk of bias in any domain. It is not possible to blind participants and clinicians to physiotherapy interventions, but 11 studies did blind the outcome assessors. Forced expiratory volume in one second was the most frequently measured outcome and while many of the studies reported an improvement in those people using a vibrating device compared to before the study, there were few differences when comparing the different devices to each other or to other airway clearance techniques. One study identified an increase in frequency of exacerbations requiring antibiotics whilst using high frequency chest wall oscillation when compared to positive expiratory pressure. There were some small but significant changes in secondary outcome variables such as sputum volume or weight, but not wholly in favour of oscillating devices. Participant satisfaction was reported in 15 studies but this was not specifically in favour of an oscillating device, as some participants preferred breathing techniques or techniques used prior to the study interventions. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high level evidence. There was no clear evidence that oscillation was a more or less effective intervention overall than other forms of physiotherapy; furthermore there was no evidence that one device is superior to another. The findings from one study showing an increase in frequency of exacerbations requiring antibiotics whilst using an oscillating device compared to positive expiratory pressure may have significant resource implications. More adequately-powered long-term randomised controlled trials are necessary and outcomes measured should include frequency of exacerbations, individual preference, adherence to therapy and general satisfaction with treatment. Increased adherence to therapy may then lead to improvements in other parameters, such as exercise tolerance and respiratory function. Additional evidence is needed to evaluate whether oscillating devices combined with other forms of airway clearance is efficacious in people with cystic fibrosis.There may also be a requirement to consider the cost implication of devices over other forms of equally advantageous airway clearance techniques. Using the GRADE method to assess the quality of the evidence, we judged this to be low or very low quality, which suggests that further research is very likely to have an impact on confidence in any estimate of effect generated by future interventions.
The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I2 = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy). Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.
We identified two eligible studies, both comparing nurse-led POA with POA led by non-specialist doctors, with a total of 2469 participants. One study was randomized and the other quasi-randomized. Blinding of staff and participants to allocation was not possible. In both studies, all participants were additionally assessed by a specialist doctor (anaesthetist in training), who acted as the reference standard. In neither study did participants proceed from assessment by nurse or junior doctor to surgery. Neither study reported on cancellations of surgery, gain in participant information or knowledge or perioperative complications. Reported outcomes focused on the accuracy of the assessment. One study undertook qualitative assessment of participant satisfaction with the two forms of POA in a small number of non-randomly selected participants (42 participant interviews), and both groups of participants expressed high levels of satisfaction with the care received. This study also examined economic modelling of costs of the POA as performed by the nurse and by the non-specialist doctor based on the completeness of the assessment as noted in the study and found no difference in cost. Currently, no evidence is available from RCTs to allow assessment of whether nurse-led POA leads to an increase or a decrease in cancellations or perioperative complications or in knowledge or satisfaction among surgical participants. One study, which was set in the UK, reported equivalent costs from economic models. Nurse-led POA is now widespread, and it is not clear whether future RCTs of this POA strategy are feasible. A diagnostic test accuracy review may provide useful information.
A total of 26 trials (among which six had a cross-over design) were included. Among the 6950 randomly assigned participants, 54% (range 0 to100%) were female, mean age was 35 years (range 26 to 45.1), and the mean number of recurrences per year was 11 (range 6.3 to 17.8). Duration of treatment was two to 12 months. Risk of bias was considered high for half of the studies and unclear for the other half. A total of 14 trials compared acyclovir versus placebo, four trials compared valacyclovir versus placebo and 2 trials compared valacyclovir versus no treatment. Three trials compared famciclovir versus placebo. Two trials compared valacyclovir versus famciclovir and one trial compared acyclovir versus valacyclovir versus placebo. We analyzed data from 22 trials for the outcome: risk of having at least one clinical recurrence. We could not obtain the outcome data for four trials. In placebo-controlled trials, there was a low quality evidence that the risk of having at least one clinical recurrence was reduced with acyclovir (nine parallel-group trials, n = 2049; pooled RR 0.48, 95% confidence interval (CI) 0.39 to 0.58), valacyclovir (four trials, n = 1788; pooled RR 0.41, 95% CI 0.24 to 0.69), or famciclovir (two trials, n = 732; pooled RR 0.57, 95% CI 0.50 to 0.64). The six cross-over trials showed larger treatment effects on average than the parallel-group trials. We found evidence of a small-study effect for acyclovir placebo-controlled trials (adjusted pooled RR 0.61, 95% CI 0.49 to 0.75). In analyzing parallel-group trials by daily dose, no clear evidence was found of a dose-response relationship for any drug. In head-to-head trials, the risk of having at least one recurrence was increased with valacyclovir rather than acyclovir (one trial, n = 1345; RR 1.16, 95% CI 1.01 to 1.34) and was not significantly different from that seen with famciclovir as compared with valacyclovir (one trial, n = 320; RR 1.18, 95% CI 0.86 to 1.63). We included 16 parallel-arm trials in a network meta-analysis and we were unable to determine which of the drugs was most effective in reducing the risk of at least one clinical recurrence (after adjustment for small-study effects, pooled RR 0.83, 95% CI 0.61 to 1.11 for valacyclovir vs acyclovir; pooled RR 1.04, 95% CI, 0.71 to 1.49 for famciclovir vs acyclovir; and pooled RR 1.26, 95% CI 0.89 to 1.75 for famciclovir vs valacyclovir). Safety data were sought but were reported as total numbers of adverse events. Owing to risk of bias and inconsistency, there is low quality evidence that suppressive antiviral therapy with acyclovir, valacyclovir or famciclovir in pacients experiencing at least four recurrences of genital herpes per year decreases the number of pacients with at least one recurrence as compared with placebo. Network meta-analysis of the few direct comparisons and the indirect comparisons did not show superiority of one drug over another.
Twenty six trials involving a total of 2933 participants were included in the review. One trial included three treatment groups. In 11 RCTs amongst 1389 people, there was no significant difference in need for recatheterisation, although recatheterisation after removal at night was more likely to be during working hours. Pooled results demonstrated that, following urological surgery and procedures, patients whose indwelling urethral catheters were removed at midnight passed significantly larger volumes at their first void (Difference (fixed) 96 ml; 95% CI 62 to 130). Similar findings were reported for patients following TURP (Difference (fixed) 27; 95% CI 23 to 31). Removal at midnight was also associated with longer time to first void, and shorter lengths of hospitalisation (relative risk of not going home on day of removal = 0.71, 95% CI 0.64 to 0.79). Results in 13 trials amongst 1422 participants having early rather than delayed catheter removal were consistent with a higher risk of voiding problems and a lower risk of infection, with shorter hospitalisation. In three trials involving 234 participants the data were too few to assess differential effects of catheter clamping compared with free drainage prior to withdrawal. No eligible trials compared flexible with fixed duration of catheterisation, or assessed prophylactic alpha sympathetic blocker drugs prior to catheter removal. There is suggestive but inconclusive evidence of a benefit from midnight removal of the indwelling urethral catheter. There are resource implications but the magnitude of these is not clear from the trials. The evidence also suggests shorter hospital stay after early rather than delayed catheter removal but the effects on other outcomes are unclear. There is little evidence on which to judge other aspects of management, such as catheter clamping.
Twenty-three trials involving 2861 older and mainly female patients with proximal femoral fractures are included. Cemented prostheses, when compared with uncemented prostheses (6 trials, 899 participants) were associated with a less pain at a year or later and improved mobility. No significant difference in surgical complications was found. One trial of 220 participants compared a hydroxyapatite coated hemiarthroplasty with a cemented prosthesis and reported no notable differences between the two prosthesis. Comparison of unipolar hemiarthroplasty with bipolar hemiarthroplasty (7 trials, 857 participants, 863 fractures) showed no significant differences between the two types of implant. Seven trials involving 734 participants compared hemiarthroplasty with a total hip replacement (THR). Most studies involved cemented implants. Dislocation of the prosthesis was more common with the THR but there was a general trend within these studies to better functional outcome scores for those treated with the THR. There is good evidence that cementing the prostheses in place will reduce post-operative pain and lead to better mobility. From the trials to date there is no evidence of any difference in outcome between bipolar and unipolar prosthesis. There is some evidence that a total hip replacement leads to better functional outcome than a hemiarthroplasty. Further well-conducted randomised trials are required.
Forty-six comparisons (from 42 trials) were included (as compared with 26 comparisons in the last update) including a wide range of drugs in inpatient and outpatient settings. All were randomized controlled trials except two studies. Interventions usually targeted doctors, although some studies attempted to influence prescriptions by pharmacists and nurses. Drugs evaluated were anticoagulants, insulin, aminoglycoside antibiotics, theophylline, anti-rejection drugs, anaesthetic agents, antidepressants and gonadotropins. Although all studies used reliable outcome measures, their quality was generally low. This update found similar results to the previous update and managed to identify specific therapeutic areas where the computerized advice on drug dosage was beneficial compared with routine care: 1. it increased target peak serum concentrations (standardized mean difference (SMD) 0.79, 95% CI 0.46 to 1.13) and the proportion of people with plasma drug concentrations within the therapeutic range after two days (pooled risk ratio (RR) 4.44, 95% CI 1.94 to 10.13) for aminoglycoside antibiotics; 2. it led to a physiological parameter more often within the desired range for oral anticoagulants (SMD for percentage of time spent in target international normalized ratio +0.19, 95% CI 0.06 to 0.33) and insulin (SMD for percentage of time in target glucose range: +1.27, 95% CI 0.56 to 1.98); 3. it decreased the time to achieve stabilization for oral anticoagulants (SMD -0.56, 95% CI -1.07 to -0.04); 4. it decreased the thromboembolism events (rate ratio 0.68, 95% CI 0.49 to 0.94) and tended to decrease bleeding events for anticoagulants although the difference was not significant (rate ratio 0.81, 95% CI 0.60 to 1.08). It tended to decrease unwanted effects for aminoglycoside antibiotics (nephrotoxicity: RR 0.67, 95% CI 0.42 to 1.06) and anti-rejection drugs (cytomegalovirus infections: RR 0.90, 95% CI 0.58 to 1.40); 5. it tended to reduce the length of time spent in the hospital although the difference was not significant (SMD -0.15, 95% CI -0.33 to 0.02) and to achieve comparable or better cost-effectiveness ratios than usual care; 6. there was no evidence of differences in mortality or other clinical adverse events for insulin (hypoglycaemia), anaesthetic agents, anti-rejection drugs and antidepressants. For all outcomes, statistical heterogeneity quantified by I2 statistics was moderate to high. This review update suggests that computerized advice for drug dosage has some benefits: it increases the serum concentrations for aminoglycoside antibiotics and improves the proportion of people for which the plasma drug is within the therapeutic range for aminoglycoside antibiotics. It leads to a physiological parameter more often within the desired range for oral anticoagulants and insulin. It decreases the time to achieve stabilization for oral anticoagulants. It tends to decrease unwanted effects for aminoglycoside antibiotics and anti-rejection drugs, and it significantly decreases thromboembolism events for anticoagulants. It tends to reduce the length of hospital stay compared with routine care while comparable or better cost-effectiveness ratios were achieved. However, there was no evidence that decision support had an effect on mortality or other clinical adverse events for insulin (hypoglycaemia), anaesthetic agents, anti-rejection drugs and antidepressants. In addition, there was no evidence to suggest that some decision support technical features (such as its integration into a computer physician order entry system) or aspects of organization of care (such as the setting) could optimize the effect of computerized advice. Taking into account the high risk of bias of, and high heterogeneity between, studies, these results must be interpreted with caution.
We identified five RCTs including 663 patients with one to four brain metastases. The risk of bias associated with lack of blinding was high and impacted to a greater or lesser extent on the quality of evidence for all of the outcomes. Adding upfront WBRT decreased the relative risk of any intracranial disease progression at one year by 53% (RR 0.47, 95% CI 0.34 to 0.66, P value < 0.0001, I2 =34%, Chi2 P value = 0.21, low quality evidence) but there was no clear evidence of a difference in  OS (HR 1.11, 95% CI 0.83 to 1.48, P value = 0.47, I2 = 52%, Chi2 P value = 0.08, low quality evidence) and PFS (HR 0.76, 95% CI 0.53 to 1.10, P value = 0.14, I2 = 16%, Chi2 P value = 0.28, low quality evidence). Subgroup analyses showed that the effects on overall survival were similar regardless of types of focal therapy used, number of brain metastases, dose and sequence of WBRT. The evaluation of the impact of upfront WBRT on NF, HRQL and neurological adverse events was limited by the unclear and high risk of reporting, performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies. There is low quality evidence that adding upfront WBRT to surgery or SRS decreases any intracranial disease progression at one year. There was no clear evidence of an effect on overall and progression free survival. The impact of upfront WBRT on neurocognitive function, health related quality of life and neurological adverse events was undetermined due to the high risk of performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies
Four studies (108 participants) were included. Three studies investigated cyclosporin A (CSA) with or without prednisone versus prednisone or no treatment and one compared chlorambucil plus prednisone versus no treatment. Outcome data was only available for complete or partial remission and doubling of serum creatinine. There was a significant increase in the number of participants who obtained complete or partial remission with CSA plus low dose prednisone versus prednisone alone (one study, 49 participants: RR 8.85, 95% CI 1.22 to 63.92). Pooled analyses were not performed due to the heterogeneity of the data. Adult patients treated with CSA at an initial dose of 3.5-5 mg/kg/d in two divided doses perhaps in combination with oral prednisolone 0.15 mg/kg/d are more likely to achieve a partial remission of the nephrotic syndrome compared with symptomatic treatment or prednisolone alone. However, there is a probability of deterioration of kidney function due to the nephrotoxic effect of CSA in the long term. For CSA, a larger controlled trial with longer follow-up should be performed to prove the benefit of this regimen not only on proteinuria but also on the preservation of kidney function. Present available data do not support the general use of alkylating substances for the treatment of FSGS in adults.
Two studies were included that enrolled people with CNV located at 100 microns or more from the foveal centre. One study compared photocoagulation with observation. At the final examination, 16/35 participants randomised to photocoagulation versus 31/35 randomised to observation had visual acuity of 20/100 or worse after six to 48 months. The second study randomised 27 eyes (26 participants) to photocoagulation with three laser wavelengths (nine eyes per group). The number of eyes losing two or more lines was two (577 nm), three (590 nm) and three (620 nm) after three to 17 months. In both studies comparisons were made using outcomes assessed at the final examination. As the final examination took place at different follow-up times it was difficult to interpret the findings and it was impossible to extract data for further analyses. Despite its use over several years the effectiveness of laser photocoagulation for myopic CNV has not been established. Although there was a suggestion of short-term effectiveness in one small study on non-subfoveal CNV the results were potentially biased. Observational studies suggest that the enlargement of the atrophic laser scar after laser treatment of non-subfoveal CNV could be a potentially vision-threatening long-term complication, even in eyes free of CNV recurrence.
We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes. An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.
The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%). Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01). Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.
Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse. This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.
One study reporting on 154 neonates was found eligible. No significant difference between surgical closure and indomethacin treatment was found for in-hospital mortality, chronic lung disease, necrotising enterocolitis, sepsis, creatinine level or intraventricular haemorrhage. There was a significant increase in the surgical group in the incidence of pneumothorax (risk ratio (RR) 2.68; 95% confidence interval (CI) 1.45 to 4.93; risk difference (RD) 0.25; 95% CI 0.11 to 0.38; number needed to treat to harm (NNTH) 4 (95% CI 3 to 9)) and retinopathy of prematurity stage III and IV (RR 3.80; 95% CI 1.12 to 12.93; RD 0.11; 95% CI 0.02 to 0.20; NNTH 9 (95% CI 5 to 50)) compared to the indomethacin group. There was a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group (RR 0.04; 95% CI 0.01 to 0.27; RD -0.32; 95% CI -0.43 to -0.21, number needed to treat to benefit (NNTB) 3 (95% CI 2 to 4)). No new trials were identified for inclusion in the 2012 update. There are insufficient data to conclude whether surgical ligation or medical treatment with indomethacin is preferred as the initial treatment for symptomatic PDA in preterm infants.
Three trials involving 106 infants were included in this review. In one trial (n = 20) CPT was no better than standard care in clearing secretions. No increase in the risk of intraventricular haemorrhage was noted. Two trials compared different types of active CPT. One trial (n = 56) showed that non-resolved atelectasis was reduced in more neonates receiving the lung squeezing technique (LST) when compared to postural drainage, percussion and vibration (PDPV) (RR 0.25; 95% CI 0.11 to 0.57). No difference in secretion clearance or in the rate of intraventricular haemorrhage or periventricular leucomalacia was demonstrated. The other trial (n = 30) showed that the use of percussion or 'cupping' resulted in an increased incidence of hypoxaemia (RR 0.53; 95% CI 0.28 to 0.99) and increased oxygen requirements (MD -9.68; 95% CI -14.16 to -5.20) when compared with contact heel percussion. There was insufficient information to adequately assess important short and longer-term outcomes, including adverse effects. The results of this review do not provide sufficient evidence on which to base clinical practice. There is a need for larger randomised controlled trials to address these issues.
We included 91 studies that evaluated seven tests — blood tests for human placental lactogen (hPL), oestriol, placental growth factor (PlGF) and uric acid, ultrasound EFW and placental grading and urinary oestriol — in a total of 175,426 pregnant women, in which 15,471 pregnancies ended in the birth of a small baby and 740 pregnancies which ended in stillbirth. The quality of included studies was variable with most domains at low risk of bias although 59% of studies were deemed to be of unclear risk of bias for the reference standard domain. Fifty-three per cent of studies were of high concern for applicability due to inclusion of only high- or low-risk women. Using all available data for SGA (86 studies; 159,490 pregnancies involving 15,471 SGA infants), there was evidence of a difference in accuracy (P < 0.0001) between the seven tests for detecting pregnancies that are SGA at birth. Ultrasound EFW was the most accurate test for detecting SGA at birth with a diagnostic odds ratio (DOR) of 21.3 (95% CI 13.1 to 34.6); hPL was the most accurate biochemical test with a DOR of 4.78 (95% CI 3.21 to 7.13). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.88 and median prevalence of 19%, EFW, hPL, oestriol, urinary oestriol, uric acid, PlGF and placental grading will miss 50 (95% CI 32 to 68), 116 (97 to 133), 124 (108 to 137), 127 (95 to 152), 139 (118 to 154), 144 (118 to 161), and 144 (122 to 161) SGA infants, respectively. For the detection of pregnancies ending in stillbirth (21 studies; 100,687 pregnancies involving 740 stillbirths), in an indirect comparison of the four biochemical tests, PlGF was the most accurate test with a DOR of 49.2 (95% CI 12.7 to 191). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.78 and median prevalence of 1.7%, PlGF, hPL, urinary oestriol and uric acid will miss 2 (95% CI 0 to 4), 4 (2 to 8), 6 (6 to 7) and 8 (3 to 13) stillbirths, respectively. No studies assessed the accuracy of ultrasound EFW for detection of pregnancy ending in stillbirth. Biochemical markers of placental dysfunction used alone have insufficient accuracy to identify pregnancies ending in SGA or stillbirth. Studies combining U and placental biomarkers are needed to determine whether this approach improves diagnostic accuracy over the use of ultrasound estimation of fetal size or biochemical markers of placental dysfunction used alone. Many of the studies included in this review were carried out between 1974 and 2016. Studies of placental substances were mostly carried out before 1991 and after 2013; earlier studies may not reflect developments in test technology.
We included 15 RCTs that compared eight different interventions versus no treatment for 1992 women in five countries. Most interventions were assessed by only one RCT with evidence quality ranging from very low to moderate. The main limitation was imprecision, associated with small sample sizes and low event rates. Pelvic floor muscle training (PFMT) compared with no treatment (three RCTs) - peri-operative intervention The simplest of the PFMT programmes required women to attend six perioperative consultations in the three months surrounding prolapse surgery. Trial results provided no clear evidence of a difference between groups in objective failure at any site at 12 to 24 months (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.56 to 1.54; two RCTs, 327 women; moderate-quality evidence). With respect to awareness of prolapse, findings were inconsistent. One RCT found no evidence of a difference between groups at 24 months (OR 1.07, 95% CI 0.61 to 1.87; one RCT, 305 women; low-quality evidence), and a second small RCT reported symptom reduction from the Pelvic Organ Prolapse Symptom Questionnaire completed by the intervention group at 12 months (mean difference (MD) -3.90, 95% CI -6.11 to -1.69; one RCT, 27 women; low-quality evidence). Researchers found no clear differences between groups at 24-month follow-up in rates of repeat surgery (or pessary) for prolapse (OR 1.92, 95% CI 0.74 to 5.02; one RCT, 316 women; low-quality evidence). Other interventions Single RCTs evaluated the following interventions: preoperative guided imagery (N = 44); injection of vasoconstrictor agent at commencement of vaginal prolapse surgery (N = 76); ureteral stent placement during uterosacral ligament suspension (N = 91); vaginal pack (N = 116); prophylactic antibiotics for women requiring postoperative urinary catheterisation (N = 159); and postoperative vaginal dilators (N = 60). Two RCTs evaluated bowel preparation (N = 298), and four RCTs assessed the method and timing of postoperative catheterisation (N = 514) - all in different comparisons. None of these studies reported our primary review outcomes. One study reported intraoperative blood loss and suggested that vaginal injection of vasoconstrictors at commencement of surgery may reduce blood loss by a mean of about 30 mL. Another study reported intraoperative ureteral injury and found no clear evidence that ureteral stent placement reduces ureteral injury. Three RCTs reported postoperative urinary tract infection and found no conclusive evidence that rates of urinary tract infection were influenced by use of a vaginal pack, prophylactic antibiotics, or vaginal dilators. Other studies did not report these outcomes. There was a paucity of data about perioperative interventions in pelvic organ prolapse surgery. A structured programme of pelvic floor muscle training before and after prolapse surgery did not consistently demonstrate any benefit for the intervention; however, this finding is based on the results of two small studies. With regard to other interventions (preoperative bowel preparation and injection of vasoconstrictor agent, ureteral stent placement during uterosacral ligament suspension, postoperative vaginal pack insertion, use of vaginal dilators, prophylactic antibiotics for postoperative catheter care), we found no evidence regarding rates of recurrent prolapse and no clear evidence that these interventions were associated with clinically meaningful reductions in adverse effects, such as intraoperative or postoperative blood transfusion, intraoperative ureteral injury, or postoperative urinary tract infection.
Three trials with 392 participants met the inclusion criteria. Studies were conducted in three European countries (Switzerland, Netherlands, and Germany). The median age of participants ranged from 62 to 66 years; 53% to 64% were female. Inclusion criteria differed among studies. One trial included participants with Hinchey I characteristics as well as those who underwent Hartmann’s procedure; the second trial included only participants with "a proven stage II/III disease according to the classification of Stock and Hansen"; the third trial considered for inclusion patients with "diverticular disease of sigmoid colon documented by colonoscopy and 2 episodes of uncomplicated diverticulitis, one at least being documented with CT scan, 1 episode of complicated diverticulitis, with a pericolic abscess (Hinchey stage I) or pelvic abscess (Hinchey stage II) requiring percutaneous drainage." We determined that two studies were at low risk of selection bias; two that reported considerable dropouts were at high risk of attrition bias; none reported blinding of outcome assessors (unclear detection bias); and all were exposed to performance bias owing to the nature of the intervention. Available low-quality evidence suggests that laparoscopic surgical resection may lead to little or no difference in mean hospital stay compared with open surgical resection (3 studies, 360 participants; MD -0.62 (days), 95% CI -2.49 to 1.25; I² = 0%). Low-quality evidence suggests that operating time was longer in the laparoscopic surgery group than in the open surgery group (3 studies, 360 participants; MD 49.28 (minutes), 95% CI 40.64 to 57.93; I² = 0%). We are uncertain whether laparoscopic surgery improves postoperative pain between day 1 and day 3 more effectively than open surgery. Low-quality evidence suggests that laparoscopic surgery may improve postoperative pain at the fourth postoperative day more effectively than open surgery (2 studies, 250 participants; MD = -0.65, 95% CI -1.04 to -0.25). Researchers reported quality of life differently across trials, hindering the possibility of meta-analysis. Low-quality evidence from one trial using the Short Form (SF)-36 questionnaire six weeks after surgery suggests that laparoscopic intervention may improve quality of life, whereas evidence from two other trials using the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) v3 and the Gastrointestinal Quality of Life Index score, respectively, suggests that laparoscopic surgery may make little or no difference in improving quality of life compared with open surgery. We are uncertain whether laparoscopic surgery improves the following outcomes: 30-day postoperative mortality, early overall morbidity, major and minor complications, surgical complications, postoperative times to liquid and solid diets, and reoperations due to anastomotic leak. Results from the present comprehensive review indicate that evidence to support or refute the safety and effectiveness of laparoscopic surgery versus open surgical resection for treatment of patients with acute diverticular disease is insufficient. Well-designed trials with adequate sample size are needed to investigate the efficacy of laparoscopic surgery towards important patient-oriented (e.g. postoperative pain) and health system-oriented outcomes (e.g. mean hospital stay).
We included 15 studies in the review, comprising a total of 1822 adult participants. There are 12 studies awaiting classification, and eight ongoing studies. None of the 15 included studies considered the paediatric population. Four studies were conducted in the abdominal and orthopaedic surgery setting (lumbar spine, or knee and hip replacement), one study in the carotid endarterectomy setting, and the remaining 10 studies in the aortic or cardiac surgery setting. The main sources of bias in the included studies related to potential conflict of interest from industry sponsorship, unclear blinding status or missing participant data. Two studies with 312 participants considered postoperative neurological injury, however no pooled effect estimate could be calculated due to discordant direction of effect between studies (low-quality evidence). One study (N = 126) in participants undergoing major abdominal surgery reported that 4/66 participants experienced neurological injury with blinded monitoring versus 0/56 in the active monitoring group. A second study (N = 195) in participants having coronary artery bypass surgery reported that 1/96 participants experienced neurological injury in the blinded monitoring group compared with 4/94 participants in the active monitoring group. We are uncertain whether active cerebral NIRS monitoring has an important effect on the risk of postoperative stroke because of the low number of events and wide confidence interval (RR 0.25, 95% CI 0.03 to 2.20; 2 studies, 240 participants; low-quality evidence). We are uncertain whether active cerebral NIRS monitoring has an important effect on postoperative delirium because of the wide confidence interval (RR 0.63, 95% CI 0.27 to 1.45; 1 study, 190 participants; low-quality evidence). Two studies with 126 participants showed that active cerebral NIRS monitoring may reduce the incidence of mild postoperative cognitive dysfunction (POCD) as defined by the original studies at one week after surgery (RR 0.53, 95% CI 0.30 to 0.95, I2 = 49%, low-quality evidence). Based on six studies with 962 participants, there was moderate-quality evidence that active cerebral oxygenation monitoring probably does not decrease the occurrence of POCD (decline in cognitive function) at one week after surgery (RR 0.62, 95% CI 0.37 to 1.04, I2 = 80%). The different type of monitoring equipment in one study could potentially be the cause of the heterogeneity. We are uncertain whether active cerebral NIRS monitoring has an important effect on intraoperative mortality or postoperative mortality because of the low number of events and wide confidence interval (RR 0.63, 95% CI 0.08 to 5.03, I2= 0%; 3 studies, 390 participants; low-quality evidence). There was no evidence to determine whether routine use of NIRS-based cerebral oxygenation monitoring causes adverse effects. The effects of perioperative active cerebral NIRS monitoring of brain oxygenation in adults for reducing the occurrence of short-term, mild POCD are uncertain due to the low quality of the evidence. There is uncertainty as to whether active cerebral NIRS monitoring has an important effect on postoperative stroke, delirium or death because of the low number of events and wide confidence intervals. The conclusions of this review may change when the eight ongoing studies are published and the 12 studies awaiting assessment are classified. More RCTs performed in the paediatric population and high-risk patients undergoing non-cardiac surgery (e.g. neurosurgery, carotid endarterectomy and other surgery) are needed.
We included a total of 96 studies (10,401 participants) in this review. More than half of the studies (50/96) were carried out in China. Generally the studies were heterogeneous, and many were poorly reported. Physical rehabilitation was found to have a beneficial effect, as compared with no treatment, on functional recovery after stroke (27 studies, 3423 participants; standardised mean difference (SMD) 0.78, 95% confidence interval (CI) 0.58 to 0.97, for Independence in ADL scales), and this effect was noted to persist beyond the length of the intervention period (nine studies, 540 participants; SMD 0.58, 95% CI 0.11 to 1.04). Subgroup analysis revealed a significant difference based on dose of intervention (P value < 0.0001, for independence in ADL), indicating that a dose of 30 to 60 minutes per day delivered five to seven days per week is effective. This evidence principally arises from studies carried out in China. Subgroup analyses also suggest significant benefit associated with a shorter time since stroke (P value 0.003, for independence in ADL). We found physical rehabilitation to be more effective than usual care or attention control in improving motor function (12 studies, 887 participants; SMD 0.37, 95% CI 0.20 to 0.55), balance (five studies, 246 participants; SMD 0.31, 95% CI 0.05 to 0.56) and gait velocity (14 studies, 1126 participants; SMD 0.46, 95% CI 0.32 to 0.60). Subgroup analysis demonstrated a significant difference based on dose of intervention (P value 0.02 for motor function), indicating that a dose of 30 to 60 minutes delivered five to seven days a week provides significant benefit. Subgroup analyses also suggest significant benefit associated with a shorter time since stroke (P value 0.05, for independence in ADL). No one physical rehabilitation approach was more (or less) effective than any other approach in improving independence in ADL (eight studies, 491 participants; test for subgroup differences: P value 0.71) or motor function (nine studies, 546 participants; test for subgroup differences: P value 0.41). These findings are supported by subgroup analyses carried out for comparisons of intervention versus no treatment or usual care, which identified no significant effects of different treatment components or categories of interventions. Physical rehabilitation, comprising a selection of components from different approaches, is effective for recovery of function and mobility after stroke. Evidence related to dose of physical therapy is limited by substantial heterogeneity and does not support robust conclusions. No one approach to physical rehabilitation is any more (or less) effective in promoting recovery of function and mobility after stroke. Therefore, evidence indicates that physical rehabilitation should not be limited to compartmentalised, named approaches, but rather should comprise clearly defined, well-described, evidenced-based physical treatments, regardless of historical or philosophical origin.
We included seven trials (six randomised controlled trials and one quasi-randomised controlled trial) with 704 participants; three of these trials (234 participants) are new to this update. The mean age across the trials was 29 years (range 12 to 90 years), and 82% of the participants were male. All trials compared immobilisation in external rotation (with or without an additional abduction component) versus internal rotation (the traditional method) following closed reduction. No trial evaluated any other interventions or comparisons, such as rehabilitation. All trials provided data for a follow-up of one year or longer; the commonest length was two years or longer. All trials were at some risk of bias, commonly performance and detection biases given the lack of blinding. Two trials were at high risk of selection bias and some trials were affected by attrition bias for some outcomes. We rated the certainty of the evidence as very low for all outcomes. We are uncertain whether immobilisation in external rotation makes a difference to the risk of re-dislocation after 12 months' or longer follow-up compared with immobilisation in internal rotation (55/245 versus 73/243; risk ratio (RR) 0.67, 95% confidence interval (CI) 0.38 to 1.19; 488 participants; 6 studies; I² = 61%; very low certainty evidence). In a moderate-risk population with an illustrative risk of 312 per 1000 people experiencing a dislocation in the internal rotation group, this equates to 103 fewer (95% CI 194 fewer to 60 more) re-dislocations after immobilisation in external rotation. Thus this result covers the possibility of a benefit for each intervention. Individually, the four studies (380 participants) reporting on validated patient-reported outcome measures for shoulder instability at a minimum of 12 months' follow-up found no evidence of a clinically important difference between the two interventions. We are uncertain of the relative effects of the two methods of immobilisation on resumption of pre-injury activities or sports. One study (169 participants) found no evidence of a difference between interventions in the return to pre-injury activity of the affected arm. Two studies (135 participants) found greater return to sports in the external rotation group in a subgroup of participants who had sustained their injury during sports activities. None of the trials reported on participant satisfaction or health-related quality of life. We are uncertain whether there is a difference between the two interventions in the number of participants experiencing instability, defined as either re-dislocation or subluxation (RR 0.84, 95% CI 0.62 to 1.14; 395 participants, 3 studies; very low certainty evidence). Data on adverse events were collected only in an ad hoc way in the seven studies. Reported "transient and resolved adverse events" were nine cases of shoulder stiffness or rigidity in the external rotation group and two cases of axillary rash in the internal rotation group. There were three "important" adverse events: hyperaesthesia and moderate hand pain; eighth cervical dermatome paraesthesia; and major movement restriction between 6 and 12 months. It was unclear to what extent these three events could be attributed to the treatment. The available evidence from randomised trials is limited to that comparing immobilisation in external versus internal rotation. Overall, the evidence is insufficient to draw firm conclusions about whether immobilisation in external rotation confers any benefit over immobilisation in internal rotation. Considering that there are several unpublished and ongoing trials evaluating immobilisation in external versus internal rotation, the main priority for research on this question consists of the publication of completed trials and the completion and publication of ongoing trials. Meanwhile, evaluation of other interventions, including rehabilitation, is warranted. There is a need for sufficiently large, good-quality, well-reported randomised controlled trials with long-term follow-up. Future research should aim to determine the optimal immobilisation duration, precise indications for immobilisation, optimal rehabilitation interventions, and the acceptability of these different interventions.
We identified 95 studies enrolling over 15,000 women. Compared with placebo or no treatment, the use of prophylactic antibiotics in women undergoing cesarean section reduced the incidence of wound infection (RR 0.40, 95% CI 0.35 to 0.46, 82 studies, 14,407 women), endometritis (RR 0.38, 95% CI 0.34 to 0.42, 83 studies, 13,548 women) and maternal serious infectious complications (RR 0.31, 95% CI 0.20 to 0.49, 32 studies, 6159 women). When only studies that included women undergoing an elective cesarean section were analyzed, there was also a reduction in the incidence of wound infections (RR 0.62, 95% CI 0.47 to 0.82, 17 studies, 3537 women) and endometritis (RR 0.38, 95% CI 0.24 to 0.61, 15 studies, 2502 women) with prophylactic antibiotics. Similar estimates of effect were seen whether the antibiotics were administered before the cord was clamped or after. The effect of different antibiotic regimens was studied and similar reductions in the incidence of infections were seen for most of the antibiotics and combinations. There were no data on which to estimate the effect of maternal administration of antibiotics on infant outcomes. No studies systematically collected and reported on adverse infant outcomes nor the effect of antibiotics on the developing infant immune system. No studies reported on the incidence of oral candidiasis (thrush) in babies. Maternal adverse effects were also rarely described. We judged the evidence for antibiotic treatment compared with no treatment to be of moderate quality; most studies lacked an adequate description of methods and were assessed as being at unclear risk of bias. The conclusions of this review support the recommendation that prophylactic antibiotics should be routinely administered to all women undergoing cesarean section to prevent infection. Compared with placebo or no treatment, the use of prophylactic antibiotics in women undergoing cesarean section reduced the incidence of wound infection, endometritis and serious infectious complications by 60% to 70%. There were few data on adverse effects and no information on the effect of antibiotics on the baby, making the assessment of overall benefits and harms difficult. Prophylactic antibiotics given to all women undergoing elective or non-elective cesarean section is beneficial for women but there is uncertainty about the consequences for the baby.
We included 14 studies with 923 participants in this review. Studies took place in Australia, Canada, the UK, and the USA. Six of the 14 included studies were funded by government agencies and one was funded by a university grant. The rest were funded by charitable foundations or trusts. Each study compared phonics training alone, or in conjunction with one other reading-related skill, to either no training (i.e. treatment as usual) or alterative training (e.g. maths). Participants were English-speaking children or adolescents, of low and middle socioeconomic status, whose reading was one year, one grade, or one standard deviation below the level expected for their age or grade for no known reason. Phonics training varied between studies in intensity (up to four hours per week), duration (up to seven months), training group size (individual and small groups), and delivery (human and computer). We measured the effect of phonics training on seven primary outcomes (mixed/regular word reading accuracy, non-word reading accuracy, irregular word reading accuracy, mixed/regular word reading fluency, non-word reading fluency, reading comprehension, and spelling). We judged all studies to be at low risk of bias for most risk criteria, and used the GRADE approach to assess the quality of the evidence. There was low-quality evidence that phonics training may have improved poor readers' accuracy for reading real and novel words that follow the letter-sound rules (standardised mean difference (SMD) 0.51, 95% confidence interval (CI) 0.13 to 0.90; 11 studies, 701 participants), and their accuracy for reading words that did not follow these rules (SMD 0.67, 95% CI 0.26 to 1.07; 10 studies, 682 participants). There was moderate-quality evidence that phonics training probably improved English-speaking poor readers' fluency for reading words that followed the letter-sounds rules (SMD 0.45, 95% CI 0.19 to 0.72; 4 studies, 224 participants), and non-word reading fluency (SMD 0.39, 95% CI 0.10 to 0.68; 3 studies, 188 participants), as well as their accuracy for reading words that did not follow these rules (SMD 0.84, 95% CI 0.30 to 1.39; 4 studies, 294 participants). In addition, there was low-quality evidence that phonics training may have improved poor readers' spelling (SMD 0.47, 95% CI –0.07 to 1.01; 3 studies, 158 participants), but only slightly improve their reading comprehension (SMD 0.28, 95% CI –0.07 to 0.62; 5 studies, 343 participants). Phonics training appears to be effective for improving literacy-related skills, particularly reading fluency of words and non-words, and accuracy of reading irregular words. More studies are needed to improve the precision of outcomes, including word and non-word reading accuracy, reading comprehension, spelling, letter-sound knowledge, and phonological output. More data are also needed to determine if phonics training in English-speaking poor readers is moderated by factors such as training type, intensity, duration, group size, or administrator.
Four trials (involving a total of 269 participants) were included. The participants were children with cystic fibrosis and their parents or caregivers in three trials and adults with cystic fibrosis in one trial. The trials compared four different self-management education interventions versus standard treatment: (1) a training programme for managing cystic fibrosis in general; (2) education specific to aerosol and airway clearance treatments; (3) disease-specific nutrition education; and (4) general and disease-specific nutrition education. Training children to manage cystic fibrosis in general had no statistically significant effects on weight after six to eight weeks, mean difference -7.74 lb (i.e. 3.51 kg) (95% confidence interval -35.18 to 19.70). General and disease-specific nutrition education for adults had no statistically significant effects on: pulmonary function (forced expiratory volume at one second), mean difference -5.00 % (95% confidence interval -18.10 to 8.10) at six months and mean difference -5.50 % (95% confidence interval -18.46 to 7.46) at 12 months; or weight, mean difference - 0.70 kg (95% confidence interval -6.58 to 5.18) at six months and mean difference -0.70 kg (95% confidence interval -6.62 to 5.22) at 12 months; or dietary fat intake scores, mean difference 1.60 (85% confidence interval -2.90 to 6.10) at six months and mean difference 0.20 (95% confidence interval -4.08 to 4.48) at 12 months. There is some limited evidence to suggest that self-management education may improve knowledge in patients with cystic fibrosis but not in parents or caregivers. There is also some limited evidence to suggest that self-management education may result in positively changing a small number of behaviours in both patients and caregivers. The available evidence from this review is of insufficient quantity and quality to draw any firm conclusions about the effects of self-management education for cystic fibrosis. Further trials are needed to investigate the effects of self-management education on a range of clinical and behavioural outcomes in children, adolescents and adults with cystic fibrosis and their caregivers.
This updated review includes a total of 24 studies (six cross-over studies, 11 parallel group studies with two arms; five with three arms, and two studies with a factorial design) with a total of 4473 participants. Ten studies were included in the 2008 update, and 14 studies have been added to this update. Thirteen studies (2380 participants) evaluated cranberry juice/concentrate; nine studies (1032 participants) evaluated cranberry tablets or capsules; one study compared cranberry juice and tablets; and one study compared cranberry capsules and tablets. The comparison/control arms were placebo, no treatment, water, methenamine hippurate, antibiotics, or lactobacillus. Eleven studies were not included in the meta-analyses because either the design was a cross-over study and data were not reported separately for the first phase, or there was a lack of relevant data. Data included in the meta-analyses showed that, compared with placebo, water or not treatment, cranberry products did not significantly reduce the occurrence of symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04) or for any the subgroups: women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31); older people (RR 0.75, 95% CI 0.39 to 1.44); pregnant women (RR 1.04, 95% CI 0.97 to 1.17); children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22); cancer patients (RR 1.15 95% CI 0.75 to 1.77); or people with neuropathic bladder or spinal injury (RR 0.95, 95% CI: 0.75 to 1.20). Overall heterogeneity was moderate (I² = 55%). The effectiveness of cranberry was not significantly different to antibiotics for women (RR 1.31, 95% CI 0.85, 2.02) and children (RR 0.69 95% CI 0.32 to 1.51). There was no significant difference between gastrointestinal adverse effects from cranberry product compared to those of placebo/no treatment (RR 0.83, 95% CI 0.31 to 2.27). Many studies reported low compliance and high withdrawal/dropout problems which they attributed to palatability/acceptability of the products, primarily the cranberry juice. Most studies of other cranberry products (tablets and capsules) did not report how much of the 'active' ingredient the product contained, and therefore the products may not have had enough potency to be effective. Prior to the current update it appeared there was some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. The addition of 14 further studies suggests that cranberry juice is less effective than previously indicated. Although some of small studies demonstrated a small benefit for women with recurrent UTIs, there were no statistically significant differences when the results of a much larger study were included. Cranberry products were not significantly different to antibiotics for preventing UTIs in three small studies. Given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and the evidence that the benefit for preventing UTI is small, cranberry juice cannot currently be recommended for the prevention of UTIs. Other preparations (such as powders) need to be quantified using standardised methods to ensure the potency, and contain enough of the 'active' ingredient, before being evaluated in clinical studies or recommended for use.
Ten efficacy trials of SPf66 involving 9698 participants were included. Results with SPf66 in reducing new episodes of P. falciparum malaria were heterogeneous: it was not effective in four African trials (RR 0.98, 95% CI 0.90 to 1.07; 2371 participants) or in one Asian trial (RR 1.06, 95% CI 0.90 to 1.25; 1221 participants). In four trials in South America the number of first attacks with P. falciparum was reduced by 28% (RR 0.72, 95% CI 0.63 to 0.82; 3807 participants). It did not reduce episodes of P. vivax malaria or admission to hospital with severe malaria. Trials have not indicated any serious adverse events with SPf66 vaccine. There is no evidence for protection by SPf66 vaccines against P. falciparum in Africa. There is a modest reduction in attacks of P. falciparum malaria following vaccination with SPf66 in South America. There is no justification for further trials of SPf66 in its current formulation. Further research with SPf66 vaccines in South America or with new formulations of SPf66 may be justified.
We found three trials which met our inclusion criteria, covering 1567 smokers (cessation: STRATUS-EU and STRATUS-US), and 1661 quitters (relapse prevention: STRATUS-WW). At one year, the pooled risk ratio (RR) for quitting with rimonabant 20 mg was 1.50 (95% confidence interval (CI) 1.10 to 2.05). No significant benefit was demonstrated for rimonabant at 5 mg dosage. Adverse events included nausea and upper respiratory tract infections.  In the relapse prevention trial, smokers who had quit on the 20 mg regimen were more likely to remain abstinent on either active regimen than on placebo; the RR for the 20 mg maintenance group was 1.29 (95% CI 1.06 to 1.57), and for the 5 mg maintenance group 1.30 (95% CI 1.06 to 1.59). There appeared to be no significant benefit of maintenance treatment for the 5 mg quitters.  One trial of taranabant was not included in our meta-analyses, as it followed participants only until end of treatment; at eight weeks it found no benefit for treatment over placebo, with an OR of 1.2 (90% CI 0.6 to 2.5).  For rimonabant, weight gain was reported to be significantly lower among the 20 mg quitters than in the 5 mg or placebo quitters. During treatment, overweight or obese smokers tended to lose weight, while normal weight smokers did not. For taranabant, weight gain was significantly lower for 2-8 mg versus placebo at the end of eight weeks of treatment.  In 2008, post-marketing surveillance led the European Medicines Agency (EMEA) to require Sanofi Aventis to withdraw rimonabant, because of links to mental disorders. The development of taranabant was also suspended by Merck & Co because of unacceptable adverse events. From the trial reports available, rimonabant 20 mg may increase the chances of quitting approximately 1½-fold. The evidence for rimonabant in maintaining abstinence is inconclusive.  Rimonabant 20 mg may moderate weight gain in the long term. Taranabant 2-8 mg may moderate weight gain, at least in the short term.  In 2008, development of both rimonabant and taranabant was discontinued by the manufacturers.
This is an update of a 2001 review that identified no eligible trials. One trial including 40 infants met the inclusion criteria for this review. Using GRADE criteria, we judged the quality of the evidence as low owing to risk of bias (inadequate reporting of methods of randomisation, allocation concealment and/or blinding) and imprecision (wide confidence intervals and data from a single small trial). We found no evidence of a difference between calcium and phosphorus supplementation versus no supplementation for neonatal growth outcomes (weight, length, head circumference) at any time point reported (two, four or six weeks postnatal age). At six weeks postnatal age, supplementation with calcium/phosphorus was associated with a decrease in serum alkaline phosphatase concentration (MD -56.85 IU/L, 95% CI -101.27 to -12.43; one randomised controlled trial (RCT); n = 40 infants). Investigators provided no data on growth at 12 to 18 months, neonatal fractures, feed intolerance, breastfeeding or any of the prespecified childhood outcomes for this review (fractures, growth, neurodevelopmental outcomes). We identified one small trial including only 40 infants that compared supplementation of human milk with calcium and phosphorus versus no supplementation in hospitalised preterm infants. We judged the evidence to be of low quality and found no evidence of differences between groups for clinically important outcomes including growth and fractures. Although serum alkaline phosphatase concentration was reduced in the group receiving supplementation at six weeks postnatal age, this difference is unlikely to be of clinical significance. We conclude that evidence is insufficient to determine whether benefit or harm ensues when human milk is supplemented with calcium and/or phosphorus for the hospitalised preterm infant. We see no advantage of conducting further trials of this intervention because with the advent of multi-component human milk fortifier, supplementation of human milk with calcium and/or phosphorus alone is no longer common practice. Future trials should consider assessing effects of multi-component fortifiers with different mineral compositions on clinically important outcomes during the neonatal period and in later childhood.
There were a total of 19 trials that met inclusion criteria and that had data sufficient for analysis. Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures. It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses. For the 12 trials that used global ratings, there was a significant effect favouring hydergine (OR 3.78, 95% CI, 2.72 to 5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favouring hydergine (WMD 0.96, 95%CI, 0.54 to 1.37). Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses. Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant. As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant moderating effects. Unfortunately, most of the randomized, double-blind, and placebo-controlled trials of hydergine were conducted and published before the advent of consensus-based diagnostic standards of dementia in 1984; therefore diagnostic criteria were less specific. As a result, uncertainty remains regarding hydergine's efficacy in dementia.
We included three RCTs in the review, randomising a total of 161 overweight and obese women with endometrial cancer. All studies compared combined behavioural and lifestyle interventions to facilitate weight loss through dietary modification and increased physical activity. The included RCTs were of low or very low quality, due to high risk of bias by failing to blind participants, personnel and outcome assessors, and significant loss to follow-up (attrition rate up to 29%). Combined behaviour and lifestyle interventions were not associated with improved overall survival (risk ratio (RR mortality), 0.23 95% confidence interval (CI) 0.01 to 4.55, P = 0.34, one RCT, 37 participants; very low-certainty evidence) compared with usual care at 24 months. There was no evidence that such interventions were associated with improvements in cancer-specific survival or cardiovascular event frequency as no cancer-related deaths, myocardial infarctions or strokes were reported in the included studies. None of the included RCTs reported data for the outcome of recurrence-free survival. Combined behaviour and lifestyle interventions were not associated with significant weight loss at either six months (mean difference (MD) -1.88 kg, 95% CI -5.98 to 2.21 kg, P = 0.37, three RCTs, 131 participants, I2= 0%; low-certainty evidenc e)or 12 months (MD -8.98 kg, 95% CI -19.88 to 1.92 kg, P = 0.11, two RCTs, 91 participants, I2= 0%; very low-certainty evidence) when compared with usual care. Combined behaviour and lifestyle interventions were not associated with increased quality of life, when measured using either the SF-12 Physical Health questionnaire or FACT-G at six months (FACT-G MD 2.51, 95% CI -5.61 to 10.64, P = 0.54, two RCTs, 95 participants, I2= 83%; very low-certainty evidence), or by FACT-G alone at 12 months (MD 2.77, 95% CI -0.65 to 6.20, P = 0.11, two RCTs, 89 participants, I2= 0%; very low-certainty evidence) when compared with usual care. No serious adverse events, for example hospitalisation or deaths, were reported in included trials. Lifestyle and behavioural interventions were associated with a higher risk of musculoskeletal symptoms (RR 19.03, 95% CI 1.17, 310.52, P = 0.04, two RCTs, 91 participants; low-certainty evidence). There is currently insufficient high-quality evidence to determine the effect of combined lifestyle and behavioural interventions on survival, quality of life, or significant weight loss in women with a history of endometrial cancer compared to those receiving usual care. The limited evidence suggests that there is little or no serious or life-threatening adverse effects due to these interventions, although musculoskeletal problems were increased, presumably due to increased activity levels. Our conclusion is based on low- and very low-quality evidence from a small number of trials and very few patients. We therefore have very little confidence in the evidence: the true effect of weight-loss interventions in obese women with endometrial cancer is currently not known. Further methodologically-rigorous, adequately-powered RCTs are required with follow-up of 5 to 10 years duration. These should focus on the effects of varying dietary modification regimens, pharmacological treatments associated with weight loss and bariatric surgery on survival, quality of life, weight loss and adverse events.
We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97). Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.
We included three trials with a total of 420 children; there were no trials in adult populations. The largest of the three trials was conducted in settings with high mortality rates and was judged to have low risk of bias for all domains, except performance bias which was high risk. The other two smaller trials were not of high quality.The meta-analysis found no significant difference between the maintenance-fluid and restricted-fluid groups in number of deaths (RR 0.82, 95% confidence interval (CI) 0.53 to 1.27; 407 participants; low quality of evidence) or acute severe neurological sequelae (RR 0.67, 95% CI 0.41 to 1.08; 407 participants; low quality of evidence). However, when neurological sequelae were defined further, there was a statistically significant difference in favour of the maintenance-fluid group for spasticity (RR 0.50, 95% CI 0.27 to 0.93; 357 participants); and seizures at both 72 hours (RR 0.59, 95% CI 0.42 to 0.83; 357 participants) and 14 days (RR 0.19, 95% CI 0.04 to 0.88; 357 participants). There was very low quality of evidence favouring maintenance fluid over restrictive fluid for chronic severe neurological sequelae at three months follow-up (RR 0.42, 95% CI 0.20 to 0.89; 351 participants). The quality of evidence regarding fluid therapy in children with acute bacterial meningitis is low to very low and more RCTs need to be conducted. There is insufficient evidence to guide practice as to whether maintenance fluids should be chosen over restricted fluids in the treatment of acute bacterial meningitis.
A total of 4092 titles were screened and 14 full text reports reviewed; a single small study met the inclusion criteria. In the included RCT, 40 women (35 with ovarian cancer) had extensive elective surgery including bowel resection for treatment of gynaecological malignancy. Randomisation was made to either early oral feeding (oral fluids in the first 24 hours, solid foods on the following day) or to a 'traditional' feeding regimen where oral fluids and foods were delayed until there was evidence of bowel function. Most women in the early feeding group (14/18) were able to resume eating solid food one day after surgery. This resulted in a significantly shorter hospital stay with no increase in postoperative complications or change in quality of life measures in comparison with the women on the 'traditional' feeding regimen. The incidence of nausea and vomiting during the postoperative stay was similar in both groups and was noted in slightly more than half of the women. Overall survival was evaluated until 30 days following discharge from hospital; in this period, there was one death of a woman who had been in the 'traditional oral feeding' group, cause of death was not noted. We assessed risk of bias and found no high risk of bias was identified in the methodology and reporting of the included study, although there was an increased risk of bias due to the small size of the study in which not all of the women had ovarian cancer. Although women with ovarian cancer have been shown to be at risk of malnutrition, there is a lack of evidence derived from RCTs evaluating the identification, assessment and treatment of malnutrition during the perioperative phase of treatment. There is evidence from one small study that some women with ovarian cancer undergoing surgery with associated bowel resection may safely commence oral fluids within 24 hours of surgery and solid foods on the following day. Further research is required, including a RCT, to generate guidance concerning the treatment of malnutrition in this patient group.
One study from Australia including 46 children aged 8 to 18 years was eligible for inclusion. There were multiple reports identified, including one unpublished report, that focused on different outcomes of the same study. The study had unclear risk of selection bias, high risks of performance, detection and attrition biases, and low risks of reporting biases. We are very uncertain about the effects of TES on bowel movements, colonic transit, soiling symptoms and quality of life due to high risk of bias, indirectness and imprecision. For our outcomes of interest the 95% CI of most analysis results include potential benefit and no effect. There is insufficient evidence to determine the effect of TES on bowel movements and colonic transit. The study reported that 16/21 children in the TES group and 15/21 in the sham group had > 3 complete spontaneous bowel movements (CSBM) per week (RR 1.07, 95% CI 0.74 to 1.53; very low-quality evidence). Ten out of 14 children in the TES group had improved colonic transit compared to 1/7 in the sham group (RR 5.00, 95% CI 0.79 to 31.63; very low-quality evidence). Mean colonic transit rate, measured as the position of the geometric centre of the radioactive substance ingested along the intestinal tract, was higher in children who received TES compared to sham (MD 1.05, 95% CI 0.36 to 1.74; one study, 30 participants; very low-quality evidence). The radiological assessment of colonic transit outcomes means that these results might not translate to important improvement in clinical symptoms or increased bowel movements. There is insufficient evidence to determine the effect of TES on symptoms and quality of life (QoL) outcomes. Nine out of 13 children in the TES group had improved soiling-related symptoms compared to 4/12 sham participants (RR 2.08, 95% CI 0.86 to 5.00; very low-quality evidence). Four out of 8 TES participants reported an improvement in QoL compared to 1/8 sham participants (RR 4.00, 95% CI 0.56 to 28.40; very low-quality evidence). The effects of TES on self-perceived (MD 5.00, 95% CI -1.21 to 11.21; one study, 33 participants; very low-quality evidence) or parent-perceived QoL (MD -0.20, 95% CI -7.57 to 7.17, one study, 33 participants; very low-quality evidence) are uncertain. No adverse effects were reported in the included study. The results for the outcomes assessed in this review are uncertain. Thus no firm conclusions regarding the efficacy and safety of TES in children with chronic constipation can be drawn. Further randomized controlled trials assessing TES for the management of childhood constipation should be conducted. Future trials should include clear documentation of methodologies, especially measures to evaluate the effectiveness of blinding, and incorporate patient-important outcomes such as the number of patients with improved CSBM, improved clinical symptoms and quality of life.
Sixty-five (65) studies were identified for possible inclusion in this review. Fourteen published RCTs with a total of 1551 participants met the inclusion criteria. Duration of cry was significantly reduced in infants who were administered a sweet-tasting solution [MD -13.47 (95% CI -16.80 to -10.15)], P < 0.00001 compared with water. However, there was considerable heterogeneity between the studies (I2 = 94%) that we were unable to explain. Meta-analysis was not able to be undertaken for any of the other outcome measures, except for cry duration, because of differences in study design. However, most of the individual studies that measured pain found sucrose to significantly reduce pain compared with the control group. One study compared sucrose and Lidocaine-prilocaine cream and no significant difference was found between the two treatments for the outcomes pain and cry duration. Due to the differences between the studies, we were unable to identify the optimal concentration, volume or method of administration of sweet-tasting solutions in infants aged one to 12 months. Further large RCTs are needed. There is insufficient evidence to confidently judge the effectiveness of sweet-tasting solutions in reducing needle-related pain in infants (one month to 12 months of age). The treatments do, however, appear promising. Data from a series of individual trials are promising, as are the results from a subset meta-analysis of studies measuring duration of crying. Further well controlled RCTs are warranted in this population to determine the optimal concentration, volume, method of administration, and possible adverse effects.
The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis. We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic. However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003). Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria. Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone.
One trial involving 1639 women was included. It compared SFH measurement with clinical abdominal palpation. There was no difference in the two reported primary outcomes of incidence of small-for-gestational age (risk ratio (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.90, low quality evidence) or perinatal death.(RR 1.25, 95% CI 0.38 to 4.07; participants = 1639, low quality evidence). There were no data on the neonatal detection of large-for-gestational age (variously defined by authors). There was no difference in the reported secondary outcomes of neonatal hypoglycaemia, admission to neonatal nursery, admission to the neonatal nursery for IUGR (low quality evidence), induction of labour and caesarean section (very low quality evidence). The trial did not address the other outcomes specified in the 'Summary of findings' table (intrauterine death; neurodevelopmental outcome in childhood). GRADEpro software was used to assess the quality of evidence, downgrading of evidence was based on including a small single study with unclear risk of bias and a wide confidence interval crossing the line of no effect. There is insufficient evidence to determine whether SFH measurement is effective in detecting IUGR. We cannot therefore recommended any change of current practice. Further trials are needed.
We included two RCTs examining a total of 191 young children, 180 of whom were included in the analyses. The two trials tested different comparisons. Both trials were at high risk of bias, particularly from lack of blinding of participants and personnel, and of outcome assessment. The trials did not record fingertip function, nail growth or nail deformity. The quality of the evidence for the reported outcomes was judged to be 'low' using the GRADE approach (i.e. further research is very likely to have an important impact on our confidence in the estimate of the effect and is likely to change the estimate). One trial compared a seven-day course of antibiotics with no antibiotics after formal surgical repair of fingertip entrapment injuries. One child in each group had an infection at day seven (1/66 antibiotic group versus 1/69 no antibiotic group; RR 1.05, 95% CI 0.07 to 16.37). Both participants with infections had a more severe injury (partial fingertip amputation). The other trial compared two different dressings (silicone net and paraffin gauze) for use after either surgical or initial conservative management of fingertip entrapment injuries. It reported that two of 20 children in the silicone group versus one of 25 in the paraffin group had complications of wound infection (RR 2.50, 95% CI 0.24 to 25.63) and that one of 20 children in the silicone group versus two of 25 in the paraffin group had skin necrosis (RR 0.63, 95% CI 0.06 to 6.41). All complications healed with conservative treatment. The results for mean healing times and mean number of dressing changes were similar between groups but benefits of either silicone or paraffin dressings could not be excluded (silicone mean 4.1 weeks versus paraffin mean 4.0 weeks; MD 0.10 weeks, 95% CI -0.61 to 0.81); (silicone mean 4.3 dressing changes versus paraffin mean 4.2 dressing changes; MD 0.10, 95% CI -0.57 to 0.77). The trial found that a silicone dressing was less likely to adhere to the wound or cause distress for the child at the one-week dressing change. There is a lack of evidence from RCTs to inform all key treatment decisions for the management of fingertip entrapment injuries in children. Given that the quality of evidence is low from one trial, we do not have conclusive evidence that prophylactic use of antibiotics after surgical repair fails to reduce risk of infection. The two children who experienced infection had more severe wounds. Similarly, the low quality evidence from one trial has not enabled us to draw firm conclusions regarding the effect on healing time or complications (infection, skin necrosis) at four-week follow-up between a silicone net dressing and a paraffin gauze dressing when applied post-surgery or after simple wound irrigation; however, the silicone net dressing may be easier to remove in the first week. Further RCTs are required in this area, preferably comparing surgical with conservative methods of managing fingertip entrapment injuries. Outcome assessment should include fingertip function, nail growth and nail deformity for a minimum of three months post treatment.
Seven studies were included in the review, including a total of 298 children in the out-patient/home group. The one high quality trial identified suggested that home-based management of children with newly diagnosed type 1 diabetes may lead to slightly improved long term metabolic control (at two and three years follow-up). No differences between comparison groups were found in any of the psychosocial and behavioural variables assessed or in rates of acute diabetic complications within two years. Parental costs were found to be decreased, while health system costs were increased, leaving total social costs virtually unchanged. None of the other studies assessing metabolic control found a difference between the comparison groups. There seemed to be no differences in hospitalisations or acute diabetic complications between the out-patient/home groups and the hospital groups. Due to the generally low quality or limited applicability of the studies identified, the results of this review are inconclusive. On the whole, the data seem to suggest that where adequate out-patient/home management of type 1 diabetes in children at diagnosis can be provided, this does not lead to any disadvantages in terms of metabolic control, acute diabetic complications and hospitalisations, psychosocial variables and behaviour, or total costs.
Six trials including a total of 454 patients met our inclusion criteria. The methodological quality of most included trials was not high. It was shown that compared to placebo, Huperzine A had beneficial effects on the improvement of general cognitive function measured by MMSE (WMD 2.81; 95% CI 1.87 to 3.76; P < 0.00001) and ADAS-Cog at six weeks (WMD 1.91; 95% CI 1.27 to 2.55) and at 12 weeks (WMD 2.51; 95% CI 1.74 to 3.28), global clinical assessment measured by CDR (WMD -0.80; 95% CI -0.95 to -0.65) and CIBIC-plus (OR 4.32, 95% CI 2.37 to 7.90), behavioral disturbance measured by ADAS-non-Cog at six weeks (WMD -1.33, 95%CI -2.12 to -0.54) and at 12 weeks (WMD -1.52, 95% CI-2.39 to -0.65), and functional performance measured by ADL (WMD = -7.17; 95% CI -9.13 to -5.22; P < 0.00001). However, Huperzine A was not superior to placebo in the improvement of general cognitive function measured by Hasegawa Dementia Scale (HDS) (WMD: 2.78; 95% CI -0.17 to 5.73, P = 0.06) and specific cognitive function measured by Weshler Memory Scale (WMS) (WMD = 6.64; 95% CI -3.22 to 16.50; P = 0.19). No data were available on quality of life and caregiver burden. The adverse events of Huperzine A were mild and there were no significant differences of adverse events between Huperzine A groups and control groups. From the available evidence, Huperzine A seems to have some beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance, with no obvious serious adverse events for patients with AD. However, only one study was of adequate quality and size. There is therefore inadequate evidence to make any recommendation about its use. Rigorous design, randomized, multi-centre, large-sample trials of Huperzine A for AD are needed to further assess the effects.
We included only one study in this review, which compared two surgical interventions: pedicled buccal fat pad flap and buccal flap for the treatment of oro-antral communications. The study involved 20 participants. The risk of bias was unclear. The relevant outcome reported in this trial was successful (complete) closure of oro-antral communication. The quality of the evidence for the primary outcome was very low. The study did not find evidence of a difference between interventions for the successful (complete) closure of an oro-antral communication (RR 1.00, 95% Cl 0.83 to 1.20) one month after the surgery. All oro-antral communications in both groups were successfully closed so there were no adverse effects due to treatment failure. We did not find trials evaluating any other intervention for treating oro-antral communications or fistulae due to dental procedures. We found very low quality evidence from a single small study that compared pedicled buccal fat pad and buccal flap. The evidence was insufficient to judge whether there is a difference in the effectiveness of these interventions as all oro-antral communications in the study were successfully closed by one month after surgery. Large, well-conducted RCTs investigating different interventions for the treatment of oro-antral communications and fistulae caused by dental procedures are needed to inform clinical practice.
We identified 15 trials, with a total of 3129 ICU participants from university-associated hospitals in the USA, Colombia, Saudi Arabia, Canada, Greece, Germany and Iran. There are two ongoing studies. Participants suffered from medical and surgical conditions, with a variety of inclusion criteria. Four studies used parenteral nutrition and nine studies used only enteral nutrition; it was unclear whether the remaining two used parenteral nutrition. Most of them could not achieve the proposed caloric targets, resulting in small differences in the administered calories between intervention and control groups. Most studies were funded by the US government or non-governmental associations, but three studies received funding from industry. Five studies did not specify their funding sources. The included studies suffered from important clinical and statistical heterogeneity. This heterogeneity did not allow us to report pooled estimates of the primary and secondary outcomes, so we have described them narratively. When comparing hypocaloric nutrition support with a control nutrition support, for hospital mortality (9 studies, 1775 participants), the risk ratios ranged from 0.23 to 5.54; for ICU mortality (4 studies, 1291 participants) the risk ratios ranged from 0.81 to 5.54, and for mortality at 30 days (7 studies, 2611 participants) the risk ratios ranged from 0.79 to 3.00. Most of these estimates included the null value. The quality of the evidence was very low due to unclear or high risk of bias, inconsistency and imprecision. Participants who received hypocaloric nutrition support compared to control nutrition support had a range of mean hospital lengths of stay of 15.70 days lower to 10.70 days higher (10 studies, 1677 participants), a range of mean ICU lengths of stay 11.00 days lower to 5.40 days higher (11 studies, 2942 participants) and a range of mean lengths of mechanical ventilation of 13.20 days lower to 8.36 days higher (12 studies, 3000 participants). The quality of the evidence for this outcome was very low due to unclear or high risk of bias in most studies, inconsistency and imprecision. The risk ratios for infectious complications (10 studies, 2804 participants) of each individual study ranged from 0.54 to 2.54. The quality of the evidence for this outcome was very low due to unclear or high risk of bias, inconsistency and imprecision We were not able to explain the causes of the observed heterogeneity using subgroup and sensitivity analyses or meta-regression. The included studies had substantial clinical heterogeneity. We found very low-quality evidence about the effects of prescribed hypocaloric nutrition support on mortality in hospital, in the ICU and at 30 days, as well as in length of hospital and ICU stay, infectious complications and the length of mechanical ventilation. For these outcomes there is uncertainty about the effects of prescribed hypocaloric nutrition, since the range of estimates includes both appreciable benefits and harms. Given these limitations, results must be interpreted with caution in the clinical field, considering the unclear balance of the risks and harms of this intervention. Future research addressing the clinical heterogeneity of participants and interventions, study limitations and sample size could clarify the effects of this intervention.
We included 121 trials. The risk of bias must be kept in mind as only 13 trials were double blind. Compared to placebo, misoprostol was associated with reduced failure to achieve vaginal delivery within 24 hours (average relative risk (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.71). Uterine hyperstimulation, without fetal heart rate (FHR) changes, was increased (RR 3.52 95% CI 1.78 to 6.99). Compared with vaginal prostaglandin E2, intracervical prostaglandin E2 and oxytocin, vaginal misoprostol was associated with less epidural analgesia use, fewer failures to achieve vaginal delivery within 24 hours and more uterine hyperstimulation. Compared with vaginal or intracervical prostaglandin E2, oxytocin augmentation was less common with misoprostol and meconium-stained liquor more common. Lower doses of misoprostol compared to higher doses were associated with more need for oxytocin augmentation and less uterine hyperstimulation, with and without FHR changes. We found no information on women's views. Vaginal misoprostol in doses above 25 mcg four-hourly was more effective than conventional methods of labour induction, but with more uterine hyperstimulation. Lower doses (25 mcg four-hourly or less) were similar to conventional methods in effectiveness and risks. The authors request information on cases of uterine rupture known to readers. The vaginal route should not be researched further as another Cochrane review has shown that the oral route of administration is preferable to the vaginal route. Professional and governmental bodies should agree guidelines for the use of misoprostol, based on the best available evidence and local circumstances. [Note: The 27 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
We included seven studies of 324 adults and children with eczema. Overall, the included studies had a high risk of bias. Four of the seven trials tested interventions with multiple components, and three tested a single intervention. Two of the seven trials included only children, four included children and adults, and one included only adults. Interventions to reduce or avoid exposure to house dust mite included covers for mattresses and bedding, increased or high-quality vacuuming of carpets and mattresses, and sprays that kill house dust mites. Four studies assessed our first primary outcome of 'Clinician-assessed eczema severity using a named scale'. Of these, one study (n = 20) did not show any significant short-term benefit from allergen impermeable polyurethane mattress encasings and acaricide spray versus allergen permeable cotton mattress encasings and placebo acaricide spray. One study (n = 60) found a modest statistically significant benefit in the Six Area, Six Sign Atopic Dermatitis (SASSAD) scale over six months (mean difference of 4.2 (95% confidence interval 1.7 to 6.7), P = 0.008) in favour of a mite impermeable bedding system combined with benzyltannate spray and high-filtration vacuuming versus mite permeable cotton encasings, water with a trace of alcohol spray, and a low-filtration vacuum cleaner. The third study (n = 41) did not compare the change in severity of eczema between the two treatment groups. The fourth study (n = 86) reported no evidence of a difference between the treatment groups. With regard to the secondary outcomes 'Participant- or caregiver-assessed global eczema severity score' and the 'Amount and frequency of topical treatment required', one study (n = 20) assessed these outcomes with similar results being reported for these outcomes in both groups. Four studies (n = 159) assessed 'Sensitivity to house dust mite allergen using a marker'; there was no clear evidence of a difference in sensitivity levels reported between treatments in any of the four trials. None of the seven included studies assessed our second primary outcome 'Participant- or caregiver-assessed eczema-related quality of life using a named instrument' or the secondary outcome of 'Adverse effects'. We were unable to combine any of our results because of variability in the interventions and paucity of data. We were unable to determine clear implications to inform clinical practice from the very low-quality evidence currently available. The modest treatment responses reported were in people with atopic eczema, specifically with sensitivity to one or more aeroallergens. Thus, their use in the eczema population as a whole is unknown. High-quality long-term trials of single, easy-to-administer house dust mite reduction or avoidance measures are worth pursuing.
We included 19 RCTs (1099 participants). The mean age of participants ranged from 47 to 66 years. Most studies (12/19) had fewer than 25 patients in each treatment group. Most studies (16/19) used immunonutrition formulas containing arginine, but there was variation in the actual products and amounts used, and in the length of intervention postoperatively. Follow-up time for outcome measurement varied considerably across studies, ranging from five days to greater than or equal to 16 months. Primary outcomes We found no evidence of a difference in the length of hospital stay (mean difference -2.5 days, 95% confidence interval (CI) -5.11 to 0.12; 10 studies, 757 participants; low-quality evidence). Similarly, we found no evidence of an effect of immunonutrition on wound infection (risk ratio (RR) 0.94, 95% CI 0.70 to 1.26; 12 studies, 812 participants; very low-quality evidence). Fistula formation may be reduced with immunonutrition; the absolute risks were 11.3% and 5.4% in the standard care and immunonutrition groups, with a RR of 0.48 (95% CI 0.27 to 0.85; 10 studies, 747 participants; low-quality evidence). We found no evidence of a difference in terms of tolerance of feeds ('adverse events') between treatments (RR 1.33, 95% CI 0.86 to 2.06; 9 studies, 719 participants; very low-quality evidence). Secondary outcomes We found no evidence of a difference between treatments in all-cause mortality (RR 1.33, 95% CI 0.48 to 3.66; 14 studies, 776 participants; low-quality evidence). Other postoperative complications such as pneumonia and urinary tract infections were not commonly reported. The risk of postoperative fistula formation may be reduced with immunonutrition, but we found no evidence of an effect of immunonutrition on any of the other outcomes that we assessed. The studies included in this review were generally small or at high risk of bias (or both). We judged the overall quality of the evidence to be low for the outcomes length of hospital stay and all-cause mortality, and very low for wound infection and adverse events. Further research should include larger, better quality studies.
We included two trials (105 participants) comparing ergonomic versus placebo keyboards. Neither trial assessed the primary outcome (short-term overall improvement) or adverse effects of interventions. In one small trial (25 participants) an ergonomic keyboard significantly reduced pain after 12 weeks (MD -2.40; 95% CI -4.45 to -0.35) but not six weeks (MD -0.20; 95% CI -1.51 to 1.11). In this same study, there was no difference between ergonomic and standard keyboards in hand function at six or 12 weeks or palm-wrist sensory latency at 12 weeks. The second trial (80 participants) reported no significant difference in pain severity after six months when using either of the three ergonomic keyboards versus a standard keyboard. No trials comparing (i) ergonomic positioning or equipment with no treatment, (ii) ergonomic positioning or equipment with another non-surgical treatment, or (iii) different ergonomic positioning or equipment regimes, were found. There is insufficient evidence from randomised controlled trials to determine whether ergonomic positioning or equipment is beneficial or harmful for treating carpal tunnel syndrome.
We included 14 RCTs analysing 1280 participants. The vast majority of participants did not receive radiotherapy to the head and neck, so this review primarily assesses prevention of chemotherapy-induced oral mucositis. All studies were at high risk of bias. The following results are for the main comparison: oral cryotherapy versus control (standard care or no treatment). Adults receiving fluorouracil-based (5FU) chemotherapy for solid cancers Oral cryotherapy probably reduces oral mucositis of any severity (RR 0.61, 95% CI 0.52 to 0.72, 5 studies, 444 analysed, moderate quality evidence). In a population where 728 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 444 (95% CI 379 to 524). The number needed to treat to benefit one additional person (NNTB), i.e. to prevent them from developing oral mucositis, is 4 people (95% CI 3 to 5). The results were similar for moderate to severe oral mucositis (RR 0.52, 95% CI 0.41 to 0.65, 5 studies, 444 analysed, moderate quality evidence). NNTB 4 (95% CI 4 to 6). Severe oral mucositis is probably reduced (RR 0.40, 95% CI 0.27 to 0.61, 5 studies, 444 analysed, moderate quality evidence). Where 300 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 120 (95% CI 81 to 183), NNTB 6 (95% CI 5 to 9). Adults receiving high-dose melphalan-based chemotherapy before haematopoietic stem cell transplantation (HSCT) Oral cryotherapy may reduce oral mucositis of any severity (RR 0.59, 95% CI 0.35 to 1.01, 5 studies, 270 analysed, low quality evidence). Where 824 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 486 (95% CI reduced to 289 to increased to 833). The NNTB is 3, although the uncertainty surrounding the effect estimate means that the 95% CI ranges from 2 NNTB, to 111 NNTH (number needed to treat in order to harm one additional person, i.e. for one additional person to develop oral mucositis). The results were similar for moderate to severe oral mucositis (RR 0.43, 95% CI 0.17 to 1.09, 5 studies, 270 analysed, low quality evidence). NNTB 3 (95% CI 2 NNTB to 17 NNTH). Severe oral mucositis is probably reduced (RR 0.38, 95% CI 0.20 to 0.72, 5 studies, 270 analysed, moderate quality evidence). Where 427 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 162 (95% CI 85 to 308), NNTB 4 (95% CI 3 to 9). Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, numbness/taste disturbance, and tooth pain. This appears to contribute to the high rates of compliance seen in the included studies. There was limited or no evidence on the secondary outcomes of this review, or on patients undergoing other chemotherapies, radiotherapy, targeted therapy, or on comparisons of oral cryotherapy with other interventions or different oral cryotherapy regimens. Therefore no further robust conclusions can be made. There was also no evidence on the effects of oral cryotherapy in children undergoing cancer treatment. We are confident that oral cryotherapy leads to large reductions in oral mucositis of all severities in adults receiving 5FU for solid cancers. We are less confident in the ability of oral cryotherapy to reduce oral mucositis in adults receiving high-dose melphalan before HSCT. Evidence suggests that it does reduce oral mucositis in these adults, but we are less certain about the size of the reduction, which could be large or small. However, we are confident that there is an appreciable reduction in severe oral mucositis in these adults. This Cochrane review includes some very recent and currently unpublished data, and strengthens international guideline statements for adults receiving the above cancer treatments.
We included nine RCTs (N = 2955 infertile couples). The quality of the evidence ranged from very low to low. The main limitations were high risk of bias in the included studies, imprecision, indirectness, and inconsistency. There were no data on cumulative live birth or ongoing pregnancy rate or cumulative clinical pregnancy rate. TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessment It is unclear whether there is any difference between interventions in rates of live birth or ongoing pregnancy (odds ratio (OR) 0.91, 95% confidence interval (CI) 0.67 to 1.23, 3 RCTs, N = 826, I2 = 33%, low-quality evidence) or in miscarriage rates (OR 1.90, 95% CI 0.99 to 3.61, 3 RCTs, N = 826, I2 = 0%, low-quality evidence). The evidence suggests that if the rate of live birth or ongoing pregnancy associated with conventional incubation and assessment is 35%, the rate with the use of TLS with conventional morphological assessment of still TLS images would be between 27% and 40%, and if the miscarriage rate with conventional incubation is 4%, the rate associated with conventional morphological assessment of still TLS images would be between 4% and 14%. It is unclear whether there is a difference between the interventions in rates of stillbirth (OR 1.00, 95% CI 0.13 to 7.49, 1 RCT, N = 76, low-quality evidence) or clinical pregnancy (OR 1.06, 95% CI 0.79 to 1.41, 4 RCTs, N = 875, I2 = 0%, low-quality evidence). TLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS images All findings for this comparison were very uncertain due to the very low-quality of the evidence. No data were available on live birth, but one RCT reported ongoing pregnancy. It is unclear whether there is any difference between the interventions in rates of ongoing pregnancy (OR 0.61, 95% CI 0.32 to 1.20, 1 RCT, N = 163); miscarriage (OR 1.39, 95% CI 0.64 to 3.01, 2 RCTs, N = 463, I2 = 0%); or clinical pregnancy (OR 0.97, 95% CI 0.67 to 1.42, 2 RCTs, N = 463, I2 = 0%). The evidence suggests that if the rate of ongoing pregnancy associated with TLS with conventional morphological assessment of still TLS images is 47%, the rate associated with TLS utilising embryo selection software would be between 22% and 52%, and if the miscarriage rate associated with conventional morphological assessment of still TLS images is 5%, the rate associated with TLS utilising embryo selection software would be between 4% and 15%. No studies reported stillbirth. TLS utilising embryo selection software versus conventional incubation and assessment The findings for this comparison were also very uncertain due to the very low quality of the evidence. It is unclear whether there is any difference between the interventions in rates of live birth (OR 1.12, 95% CI 0.92 to 1.36, 3 RCTs, N = 1617, I2 = 84%). There was very low-quality evidence that TLS might reduce miscarriage rates (OR 0.63, 95% CI 0.45 to 0.89, 3 RCTs, N = 1617, I2 = 0%). It is unclear whether there is any difference between the interventions in rates of clinical pregnancy (OR 0.95, 95% CI 0.78 to 1.16, 3 RCTs, N = 1617, I2 = 89%). The evidence suggests that if the rate of live birth associated with conventional incubation and assessment is 48%, the rate with TLS utilising embryo selection software would be between 46% and 55%, and if the miscarriage rate with conventional incubation and assessment is 11%, the rate associated with TLS would be between 5% and 10%. No stillbirths occurred in the only study reporting this outcome. There is insufficient good-quality evidence of differences in live birth or ongoing pregnancy, miscarriage and stillbirth, or clinical pregnancy to choose between TLS, with or without embryo selection software, and conventional incubation. As the evidence is of low or very low-quality, our findings should be interpreted with caution.
Data from 8447 participants in 23 studies were included in the analyses. In people undergoing surgery for closed fracture fixation, single dose antibiotic prophylaxis significantly reduced deep surgical site infection (risk ratio 0.40, 95% CI 0.24 to 0.67), superficial surgical site infections, urinary infections, and respiratory tract infections. Multiple dose prophylaxis had an effect of similar size on deep surgical site infection (risk ratio 0.35, 95% CI 0.19 to 0.62), but significant effects on urinary and respiratory infections were not confirmed. Although the risk of bias in many studies as reported was unclear, sensitivity analysis showed that removal from the meta-analyses of studies at high risk of bias did not alter the conclusions. Economic modelling using data from one large trial indicated that single dose prophylaxis with ceftriaxone is a cost-effective intervention. Data for the incidence of adverse effects were very limited, but as expected they appeared to be more common in those receiving antibiotics, compared with placebo or no prophylaxis. Antibiotic prophylaxis should be offered to those undergoing surgery for closed fracture fixation.
From 6394 references, we included four studies evaluating 77 participants, including two RCTs, studying children and adults with hypoglycaemia, respectively, and two non-RCTs with healthy volunteers. The studies included three different routes of glucose administration (sublingual, buccal and a combination of oral and buccal administration). All studies had a high risk of bias in one or more 'Risk of bias' domain. Glucose administration by the sublingual route, in the form of table sugar under the tongue, resulted in a higher blood glucose concentration after 20 minutes compared with the oral route in the very specific setting of children with hypoglycaemia and symptoms of concomitant malaria or respiratory tract infection (MD 17 mg/dL, 95% CI 4.4 to 29.6; P = 0.008; 1 study; 42 participants; very low-quality evidence). Resolution of hypoglycaemia at 80 minutes may favour sublingual administration (RR 2.10, 95% CI 1.24 to 3.54; P = 0.006; 1 study; 42 participants; very low-certainty evidence), but no substantial difference could be demonstrated at 20 minutes (RR 1.26, 95% CI 0.91 to 1.74; P = 0.16; 1 study; 42 participants; very low-certainty evidence). A decrease in the time to resolution of hypoglycaemia was found in favour of sublingual administration (MD -51.5 min, 95% CI -58 to -45; P < 0.001; 1 study; 42 participants; very low-certainty evidence). No adverse events were reported in either group. No data were available for resolution of symptoms and time to resolution of symptoms, and treatment delay. Glucose administered by the buccal route in one study resulted in a lower plasma glucose concentration after 20 minutes compared with oral administration (MD -14.4 mg/dL, 95% CI -17.5 to -11.4 for an imputed within-participants correlation coefficient of 0.9; P < 0.001; 1 trial; 16 participants; very low-quality evidence). In another study there were fewer participants with increased blood glucose at 20 minutes favouring oral glucose (RR 0.07, 95% CI 0.00 to 0.98; P = 0.05; 1 study; 7 participants; very low-certainty evidence). No data were available for resolution of symptoms and time to resolution of symptoms, resolution of hypoglycaemia and time to resolution of hypoglycaemia, adverse events, and treatment delay. For the combined oral and buccal mucosal route (in the form of a dextrose gel) the MD was -15.3 mg/dL, 95%CI -33.6 to 3; P = 0.09; 1 study; 18 participants; very low-quality evidence . No improvement was identified for either route in the resolution of symptoms at 20 minutes or less following glucose administration (RR 0.36, 95% CI 0.12 to 1.14; P = 0.08; 1 study; 18 participants; very low-certainty evidence). No data were available for time to resolution of symptoms, resolution of hypoglycaemia and time to resolution of hypoglycaemia, adverse events, and treatment delay. When providing first aid to individuals with hypoglycaemia, oral glucose administration results in a higher blood glucose concentrations after 20 minutes when compared with buccal administration of glucose. A difference in plasma glucose concentration could not be demonstrated, when administering a dextrose gel, defined as “a combined oral and buccal mucosal route” compared to oral administration of a glucose tablet or solution. In the specific population of children with concomitant malaria and respiratory illness, sublingual sugar results in a higher blood glucose concentration after 20 minutes when compared with oral administration.These results need to be interpreted cautiously because our confidence in the body of evidence is very low due to the low number of participants and studies as well as methodological deficiencies in the included studies.
A total of three studies met the inclusion criteria, allocating 2971 participants to the intervention and control groups. The total number of participants randomised to the intervention groups was 1467, whilst 1504 were randomised to the control groups. The length of intervention was 9, 12 and 24 months in the different trials. The use of TTM SOC in combination with diet or physical activity, or both, and other interventions in the included studies produced inconclusive evidence that TTM SOC interventions led to sustained weight loss (the mean difference between intervention and control groups varied from 2.1 kg to 0.2 kg at 24 months; 2971 participants; 3 trials; low quality evidence). Following application of TTM SOC there were improvements in physical activity and dietary habits, such as increased exercise duration and frequency, reduced dietary fat intake and increased fruit and vegetable consumption (very low quality evidence). Weight gain was reported as an adverse event in one of the included trials. None of the trials reported health-related quality of life, morbidity, or economic costs as outcomes. The small number of studies and their variable methodological quality limit the applicability of the findings to clinical practice. The main limitations include inadequate reporting of outcomes and the methods for allocation, randomisation and blinding; extensive use of self-reported measures to estimate the effects of interventions on a number of outcomes, including weight loss, dietary consumption and physical activity levels; and insufficient assessment of sustainability due to lack of post-intervention assessments. The evidence to support the use of TTM SOC in weight loss interventions is limited by risk of bias and imprecision, not allowing firm conclusions to be drawn. When combined with diet or physical activity, or both, and other interventions we found very low quality evidence that it might lead to better dietary and physical activity habits. This systematic review highlights the need for well-designed RCTs that apply the principles of the TTM SOC appropriately to produce conclusive evidence about the effect of TTM SOC lifestyle interventions on weight loss and other health outcomes.
No study examined the effect of screening (clinical and/or ultrasound) and early treatment versus not screening and later treatment. One study reported universal ultrasound compared to clinical examination alone did not result in a significant reduction in late diagnosed DDH or surgery but was associated with a significant increase in treatment. One study reported targeted ultrasound compared to clinical examination alone did not result in a significant reduction in late diagnosed DDH or surgery, with no significant difference in rate of treatment. Meta-analysis of two studies found universal ultrasound compared to targeted ultrasound did not result in a significant reduction in late diagnosed DDH or surgery. There was heterogeneity between studies reporting the effect on treatment rate. Meta-analysis of two studies found delayed ultrasound and targeted splinting compared to immediate splinting of infants with unstable (but not dislocated) hips resulted in no significant difference in the rate of late diagnosed DDH. Both studies reported a significant reduction in treatment with use of delayed ultrasound and targeted splinting. One study reported delayed ultrasound and targeted splinting compared to immediate splinting of infants with mild hip dysplasia on ultrasound resulted in no significant difference in late diagnosed DDH but a significant reduction in treatment. No infants in either group received surgery. There is insufficient evidence to give clear recommendations for practice. There is inconsistent evidence that universal ultrasound results in a significant increase in treatment compared to the use of targeted ultrasound or clinical examination alone. Neither of the ultrasound strategies have been demonstrated to improve clinical outcomes including late diagnosed DDH and surgery. The studies are substantially underpowered to detect significant differences in the uncommon event of late detected DDH or surgery. For infants with unstable hips or mildly dysplastic hips, use of delayed ultrasound and targeted splinting reduces treatment without significantly increasing the rate of late diagnosed DDH or surgery.
Seven studies were included in the analysis (368 participants in total). All were on mania, hypomania, mixed episodes or rapid-cycling disorder. Overall, their methodological quality was relatively low. There was no difference in the primary outcome analysis – a fall of  50% or more on the Young Mania Rating Scale (YMRS) - between oxcarbazepine and placebo (N=1, n=110, OR =2.10, 95% CI 0.94 to 4.73) in one study, conducted in children; no studies were available in adult participants. In comparison with other mood stabilisers, there was no difference between oxcarbazepine and valproate as an antimanic agent using the primary outcome (50% or more fall in YMRS, OR=0.44, 95% CI 0.10 to 1.97, 1 study, n=60, P=0.273) or the secondary outcome measure (differences in YMRS between the two groups, SMD=0.18, 95% CI -0.24 to 0.59, 2 studies, n=90, P=0.40). No primary or secondary efficacy outcome measures were found comparing oxcarbazepine with lithium monotherapy. As an adjunctive treatment to lithium, oxcarbazepine reduced depression rating scale scores more than carbamazepine in a group of manic participants on the Montgomery-Åsberg Depression Rating Scale (MADRS) (SMD=- 1.12, 95% CI -1.71 to -0.53, 1 study, n=52, P=0.0002) and on the Hamilton Depression Rating Scale (HDRS) (SMD=- 0.77, 95% CI -1.35 to -0.20, 1 study, n=52, P=0.008). There was a higher incidence of adverse effects, particularly neuropsychiatric, in participants randomised to oxcarbazepine compared to those on placebo (1 study, n=115, 17% to 39% of participants on oxcarbazepine had at least one such event compared to 7% to 10% on placebo).There was no difference in adverse events rates between oxcarbazepine and other mood stabilisers or haloperidol. Currently, there are insufficient trials of adequate methodological quality on oxcarbazepine in the acute treatment of bipolar disorder to inform us on its efficacy and acceptability. Studies predominantly examine the treatment of mania: there are data from subgroup analysis on mixed affective, hypomania and rapid-cycling states. From the few studies included in this review, oxcarbazepine did not differ in efficacy compared to placebo in children and adolescents. It did not differ from other active agents in adults. It may have a poorer tolerability profile compared to placebo. No data were found on outcomes relevant to patients and clinicians, such as length of hospital admission. There is a need for adequately powered randomised controlled trials of good methodological quality to inform us of the therapeutic potential of oxcarbazepine across the spectrum of acute episodes in bipolar disorder.
We identified 2190 unique records, evaluated the full text of seven studies and included one study with 1236 participants. This study reported tumour recurrence in 2.3% of women in the oestrogen arm versus 1.9% of women receiving placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.54 to 2.50; very low-certainty evidence). The study reported one woman in the HRT arm (0.16%) and three women in the placebo arm (0.49%) who developed breast cancer (new malignancy) during follow-up (RR 0.80, 95% CI 0.32 to 2.01; 1236 participants, 1 study; very low-certainty evidence). The study did not report on symptom relief, overall survival or progression-free survival for HRT versus placebo. However, they did report the percentage of women alive with no evidence of disease (94.3% in the HRT group and 95.6% in the placebo group) and the percentage of women alive irrespective of disease progression (95.8% in the HRT group and 96.9% in the placebo group) at the end of the 36 months' follow-up. The study did not report time to recurrence and it was underpowered due to closing early. The authors closed it as a result of the publication of the Women's Health Initiative (WHI) study, which, at that time, suggested that risks of exogenous hormone therapy outweighed benefits and had an impact on study recruitment. No assessment of efficacy was reported. Currently, there is insufficient high-quality evidence to inform women considering HRT after treatment for endometrial cancer. The available evidence (both the single RCT and non-randomised evidence) does not suggest significant harm, if HRT is used after surgical treatment for early-stage endometrial cancer. There is no information available regarding use of HRT in higher-stage endometrial cancer (FIGO stage II and above). The use of HRT after endometrial cancer treatment should be individualised, taking account of the woman's symptoms and preferences, and the uncertainty of evidence for and against HRT use.
For this update, we added five studies (606 participants), meaning that the review now includes a total of 12 RCTs involving 2171 participants with COPD. Average age of participants was 66 years, male participants accounted for 67% and mean forced expiratory volume in one second (FEV1) was 1.2 L (five studies), 54% predicted (four studies). We assessed risks of selection, attrition and reporting bias as low, and risks of performance and detection bias as moderate. Compared with control, the vaccine group had a lower likelihood of developing community-acquired pneumonia (CAP) (odds ratio (OR) 0.59 , 95% confidence interval (CI) 0.41 to 0.85; six studies, n = 1372; GRADE: moderate), but findings did not differ specifically for pneumococcal pneumonia (Peto OR 0.26, 95% CI 0.05 to 1.31; three studies, n = 1158; GRADE: low). The number needed to treat for an additional beneficial outcome (NNTB) (preventing one episode of CAP) was 19 (95% CI 13 to 52). Mortality from cardiorespiratory causes did not differ between vaccine and control groups (OR 1.07, 95% CI 0.69 to 1.66; three studies, n = 888; GRADE: moderate), nor did all-cause mortality differ (OR 1.00, 95% CI 0.72 to 1.40; five studies, n = 1053; GRADE: moderate). The likelihood of hospital admission for any cause, or for cardiorespiratory causes, did not differ between vaccine and control groups. Vaccination significantly reduced the likelihood of a COPD exacerbation (OR 0.60, 95% CI 0.39 to 0.93; four studies, n = 446; GRADE: moderate). The NNTB to prevent a patient from experiencing an acute exacerbation was 8 (95% CI 5 to 58). Only one study (n = 181) compared the efficacy of different vaccine types - 23-valent PPV versus 7-valent PCV - and reported no differences for CAP, all-cause mortality, hospital admission or likelihood of a COPD exacerbation, but investigators described a greater likelihood of some mild adverse effects of vaccination with PPV-23. Injectable polyvalent pneumococcal vaccination provides significant protection against community-acquired pneumonia, although no evidence indicates that vaccination reduced the risk of confirmed pneumococcal pneumonia, which was a relatively rare event. Vaccination reduced the likelihood of a COPD exacerbation, and moderate-quality evidence suggests the benefits of pneumococcal vaccination in people with COPD. Evidence was insufficient for comparison of different pneumococcal vaccine types.
While there were no eligible trials in people with VWD identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of EACA published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference (RD) of -0.64 (95% confidence interval (CI) -0.93 to - 0.36) and the EACA trial a RD of -0.50 (95% CI 0.77 to -0.22). The combined RD of both trials was -0.57 (95% CI -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping EACA (combined RD of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the EACA trial, but overall the risk of bias appeared to be low for both trials. Despite the discovery of a beneficial effect of systemically administered tranexamic acid and EACA in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with VWD.
We included five single-centre trials (undertaken in Italy) with 153 women and 154 pregnancies in this review. There were no clear differences in the primary outcomes reported between CSII and MDI in the included trials: caesarean section (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.66 to 1.77; three trials, 71 women, evidence graded very low), large-for-gestational age (RR 4.15, 95% CI 0.49 to 34.95; three trials, 73 infants; evidence graded very low), and perinatal mortality (RR 2.33, 95% CI 0.38 to 14.32; four trials, 83 infants, evidence graded very low). Other primary outcomes were not reported in these trials (hypertensive disorders of pregnancy, development of type 2 diabetes, composite outcome of serious neonatal outcomes, and neurosensory disability). There was no clear evidence of differences in the maternal secondary outcomes: maternal weight gain during pregnancy, 24 hour mean blood glucose in each trimester, mean maternal HbA1c in each trimester, maternal hypoglycaemia, and maternal hyperglycaemia. The included studies did not report several GRADE outcomes: perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour. Many maternal secondary outcomes were also not reported. In two trials, including a total of 61 infants, CSII was associated with an increase in mean birthweight compared with MDI (mean difference (MD) 220.56 g, 95% CI -2.09 g to 443.20 g; P = 0.05). However, the large CI including anything from a small reduction to an increase in mean birthweight and the lack of a difference in macrosomia rate (RR 3.20, CI 0.14 to 72.62; two trials, 61 infants) suggests uncertainty. Large-for-gestational age (see above), andsmall-for-gestational age also suggests uncertainty of effect. No significant differences were found in: gestation at delivery, preterm birth < 37 weeks' gestation, preterm birth < 32 weeks' gestation, neonatal hypoglycaemia (evidence graded very low),respiratory distress syndrome, neonatal hyperbilirubinaemia, and fetal anomaly. There were no data reported on many important infant outcomes, including the GRADE outcomes adiposity and diabetes. There was no follow-up of infants in childhood or adulthood, so longer-term outcomes were not reported. The only outcome reported for use of health service resources wasmaternal days hospitalised, which did not show a difference between groups in the small number of women included (MD 9.40, CI -6.04 to 24.84; one trial, 10 women). The methods used by the trials were poorly reported, for example although blinding of participants and clinicians regarding intervention allocation is impossible, it is possible to blind assessors and this along with other aspects of trial methods was not reported, which means that the trials are at an unclear or high risk of bias. We do not know if the women who participated were representative, and therefore if the results can be generalised. Most GRADE outcomes were not reported. For the GRADE outcomes that were reported, our assessment was that the evidence is very low quality (caesarean section, large-for-gestational age, perinatal mortality, andneonatal hypoglycaemia). This was due to design limitations in the included trials, small sample sizes in the trials contributing data, wide CIs crossing both the line of no effect and the line of appreciable benefit and/or harm, and often few events. We are therefore uncertain whether CSII or MDI improves outcomes for pregnant women with diabetes and their infants, and the results of further studies may differ substantially from those presented in this review. There is no evidence to support the use of one particular form of insulin administration over another for pregnant women with diabetes. There are only a small number of trials appropriate for meta-analysis, a small number of women included and questionable generalisability of the trial population. Pump technology has progressed since these trials were undertaken. Well-designed randomised trials are required to evaluate comparisons such as patch pumps against MDI and more conventional CSII against MDI. These trials should be adequately powered to assess the effect of interventions, and report the core set of outcomes used in Cochrane reviews of diabetes in pregnancy. Trials to assess the effects of pumps on birthweight and macrosomia rates are needed. It would be beneficial for future trials to undertake longer-term follow-up of participants and their infants, assess women's preferences, and conduct an economic evaluation.
The current review included the eight trials from the initial review and six new trials which randomised 595 participants (< 21 years of age) with leukaemias or solid tumours undergoing chemotherapy. The trials were all of low quality with the exception of two of the trials looking at glutamine supplementation. One small trial found that compared to EN, PN significantly increased weight (mean difference (MD) 4.12, 95% CI 1.91 to 6.33), serum albumin levels (MD 0.70, 95% CI 0.14 to 1.26), calorie intake (MD 22.00, 95% CI 5.12 to 38.88) and protein intake (MD 0.80, 95% CI 0.45 to 1.15). One trial comparing peripheral PN and EN with central PN found that mean daily weight gain (MD -27.00, 95% CI -43.32 to -10.68) and energy intake (MD -15.00, 95% CI -26.81 to -3.19) were significantly less for the peripheral PN and EN group, whereas mean change in serum albumin was significantly greater for that group (MD 0.47, 95% CI 0.13 to 0.81, P = 0.008). Another trial with few participants found an increase in mean energy intake (% recommended daily amount) in children fed an energy dense feed compared to a standard calorie feed (MD +28%, 95% CI 17% to 39%). Three studies looked at glutamine supplementation. The evidence suggesting that glutamine reduces severity of mucositis was not statistically significant in two studies (RR 0.64, 95% CI 0.19 to 2.2 and RR 0.85, 95% CI 0.66 to 1.1) and differences in reduction of infection rates were also not significant in two studies (RR 1.0, 95% CI 0.72 to 1.4 and RR 0.98, 95% CI 0.63 to 1.51). Only one study compared olive oil based PN to standard lipid containing PN. Despite similar calorie contents in both feeds, the standard lipid formula lead to greater weight gain (MD -0.34 z-scores, 95% CI -0.68 to 0.00). A single study compared standard EN with fructooligosaccharide containing EN. There was no difference in weight gain between groups (mean difference -0.12, 95% CI -0.57 to 0.33), with adverse effects (nausea) occurring equally between the groups (RR 0.92, 95% CI 0.48 to 1.74). There is limited evidence from individual trials to suggest that PN is more effective than EN in well-nourished children and young people with cancer undergoing chemotherapy. The evidence for other methods of nutritional support remains unclear. Limited evidence suggests an energy dense feed increases mean daily energy intake and has a positive effect on weight gain. Evidence suggesting glutamine supplementation reduces incidence and severity of mucositis, infection rates and length of hospital stay is not statistically significant. Further research, incorporating larger sample sizes and rigorous methodology utilising valid and reliable outcome measures, is essential.
We identified 2292 unique records.We included 129 records reporting on 121 studies, including 12 ongoing studies and two studies awaiting classification. We judged the overall risk of bias of two studies as low. Selection bias was the most relevant risk of bias domain across the included studies, with 78 studies not clearly reporting the method used for random sequence generation. Reporting bias was the domain with least risk of bias, with 12 studies not reporting all outcomes that researchers intended to investigate. Any intervention versus placebo or no prophylaxis In comparison with placebo, any intervention seems to have a beneficial effect on the occurrence of upper GI bleeding (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.57; moderate certainty of evidence). The use of any intervention reduced the risk of upper GI bleeding by 10% (95% CI -12.0% to -7%). The effect estimate of any intervention versus placebo or no prophylaxis with respect to the occurrence of nosocomial pneumonia, all-cause mortality in the ICU, duration of ICU stay, duration of intubation (all with low certainty of evidence), the number of participants requiring blood transfusions (moderate certainty of evidence), and the units of blood transfused was consistent with benefits and harms. None of the included studies explicitly reported on serious adverse events. Individual interventions versus placebo or no prophylaxis In comparison with placebo or no prophylaxis, antacids, H2 receptor antagonists, and sucralfate were effective in preventing upper GI bleeding in ICU patients. Researchers found that with H2 receptor antagonists compared with placebo or no prophylaxis, 11% less developed upper GI bleeding (95% CI -0.16 to -0.06; RR 0.50, 95% CI 0.36 to 0.70; 24 studies; 2149 participants; moderate certainty of evidence). Of ICU patients taking antacids versus placebo or no prophylaxis, 9% less developed upper GI bleeding (95% CI -0.17 to -0.00; RR 0.49, 95% CI 0.25 to 0.99; eight studies; 774 participants; low certainty of evidence). Among ICU patients taking sucralfate versus placebo or no prophylaxis, 5% less had upper GI bleeding (95% CI -0.10 to -0.01; RR 0.53, 95% CI 0.32 to 0.88; seven studies; 598 participants; moderate certainty of evidence). The remaining interventions including proton pump inhibitors did not show a significant effect in preventing upper GI bleeding in ICU patients when compared with placebo or no prophylaxis. Regarding the occurrence of nosocomial pneumonia, the effects of H2 receptor antagonists (RR 1.12, 95% CI 0.85 to 1.48; eight studies; 945 participants; low certainty of evidence) and of sucralfate (RR 1.33, 95% CI 0.86 to 2.04; four studies; 450 participants; low certainty of evidence) were consistent with benefits and harms when compared with placebo or no prophylaxis. None of the studies comparing antacids versus placebo or no prophylaxis provided data regarding nosocomial pneumonia. H2 receptor antagonists versus proton pump inhibitors H2 receptor antagonists and proton pump inhibitors are most commonly used in practice to prevent upper GI bleeding in ICU patients. Proton pump inhibitors significantly more often prevented upper GI bleeding in ICU patients compared with H2 receptor antagonists (RR 2.90, 95% CI 1.83 to 4.58; 18 studies; 1636 participants; low certainty of evidence). When taking H2 receptor antagonists, 4.8% more patients might experience upper GI bleeding (95% CI 2.1% to 9%). Nosocomial pneumonia occurred in similar proportions of participants taking H2 receptor antagonists and participants taking proton pump inhibitors (RR 1.02, 95% CI 0.77 to 1.35; 10 studies; 1256 participants; low certainty of evidence). This review shows that antacids, sucralfate, and H2 receptor antagonists might be more effective in preventing upper GI bleeding in ICU patients compared with placebo or no prophylaxis. The effect estimates of any treatment versus no prophylaxis on nosocomial pneumonia were consistent with benefits and harms. Evidence of low certainty suggests that proton pump inhibitors might be more effective than H2 receptor antagonists. Therefore, patient-relevant benefits and especially harms of H2 receptor antagonists compared with proton pump inhibitors need to be assessed by larger, high-quality RCTs to confirm the results of previously conducted, smaller, and older studies.
This review includes 11 published studies (172 participants); only one examined long-term oxygen therapy (28 participants). There was no statistically significant improvement in survival, lung, or cardiac health. There was an improvement in regular attendance at school or work in those receiving oxygen therapy at 6 and 12 months. Four studies examined the effect of oxygen supplementation during sleep by polysomnography. Although oxygenation improved, mild hypercapnia was noted. Participants fell asleep quicker and spent a reduced percentage of total sleep time in rapid eye movement sleep, but there were no demonstrable improvements in qualitative sleep parameters. Six studies evaluated oxygen supplementation during exercise. Again, oxygenation improved, but mild hypercapnia resulted. Participants receiving oxygen therapy were able to exercise for a significantly longer duration during exercise. Other exercise parameters were not altered by the use of oxygen. There are no published data to guide the prescription of chronic oxygen supplementation to people with advanced lung disease due to CF. Short-term oxygen therapy during sleep and exercise improves oxygenation but is associated with modest and probably clinically inconsequential hypercapnia. There are improvements in exercise duration, time to fall asleep and regular attendance at school or work. There is a need for larger, well-designed clinical trials to assess the benefits of long-term oxygen therapy in people with CF administered continuously or during exercise or sleep or both. However, we do not expect any new research to be undertaken in this area any time soon and do not plan to update this review again until any new evidence does become available.
We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results. None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence). The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence). No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects. Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.
A total of four trials including 4265 participants were included in this review. Two of the included trials were of high quality, while two were of relatively low quality with limitations and biases in design and conduct. Analysis showed that administration of a single dose of antihelminthic in the second trimester of pregnancy is not associated with any impact on maternal anaemia in the third trimester (risk ratio (RR) 0.94; 95% confidence interval (CI) 0.81 to 1.10; 3266 participants; four trials; low quality evidence). Subgroup analysis on the basis of co-interventions other than antihelminthic, which included iron supplementation given to both groups was also not associated with any impact on maternal anaemia (RR 0.76; 95% CI 0.47 to 1.23; 1290 participants; three trials; moderate quality evidence). No impact was found for the outcomes of low birthweight (RR 1.00; 95% CI 0.79 to 1.27; 3255 participants; three trials; moderate quality evidence), preterm birth (RR 0.88; 95% CI 0.43 to 1.78; 1318 participants; two trials, moderate quality evidence) and perinatal mortality (RR 1.09; 95% CI 0.71 to 1.67; 3385 participants; two trials; moderate quality evidence). None of the included studies reported impact on infant survival at six months of age. The evidence to date is insufficient to recommend use of antihelminthic for pregnant women after the first trimester of pregnancy. More well-designed, large scale randomised controlled trials are needed to establish the benefit of antihelminthic treatment during pregnancy.
We identified seven RCTs that enrolled 372 women. We could not pool results of trials as the treatment comparisons differed. Six RCTs (n = 340) conducted over 15 years ago, evaluated adjuvant therapy (chemotherapy, pelvic external irradiation or intra-peritoneal radioactive isotope therapy) after radical surgery; over 87% of participants had Stage I tumours. Most participants were followed up for over 10 years. Overall and recurrence-free survival were similar between both arms of these trials, except that one trial (n = 66) showed a significantly lower survival (P = 0.03) in women who received chemotherapy (thio-TEPA). Adverse effects of treatment were incompletely reported and all six trials were at high risk of bias. One further trial (n = 32) that recruited participants with bilateral serous tumours who were wishing fertility preservation, revealed a significantly increased chance of pregnancy (hazard ratio (HR) = 3.3, 95% CI 1.4 to 8.0) but non-significantly earlier disease recurrence (HR = 1.5, 95% CI 0.6 to 3.8) in the women who had ultra-conservative surgery (bilateral cystectomy) than in those who had conservative surgery (cystectomy and contralateral oophorectomy). This trial was at low risk of bias. Quality of life (QoL) was not documented in any included trial. We did not find any trials that compared radical with conservative surgery or laparoscopy with laparotomy. We did not find evidence to support the use of any specific type of adjuvant therapy for borderline ovarian tumours. RCTs evaluating the benefit of adjuvant therapy with optimally dosed chemotherapy and newer targeted drugs are necessary, particularly for advanced borderline ovarian tumours. The low mortality from borderline ovarian tumours should make recurrence-free survival, time to recurrence and morbidity important end points in such trials. Bilateral cystectomy may be offered to women with bilateral borderline ovarian tumours diagnosed intra-operatively who are wishing to preserve their fertility. Similarly, women who had RCTs comparing radical with conservative surgery and comparing laparoscopy with laparotomy are needed.
The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow-up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision. We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion.
Three small studies have been included in this review. Prophylactic antibiotics in neonates with central venous catheters had no effect on overall mortality (typical RR 0.68, 95% confidence interval 0.31, 1.51). Prophylactic antibiotics in neonates with central venous catheters decreased the rate of proven bacterial sepsis (typical RR 0.38, 95% confidence interval 0.18, 0.82). Prophylactic antibiotics in neonates with central venous catheters decreased the rate of suspected or proven bacterial septicaemia (typical RR 0.40, 95% confidence interval 0.20, 0.78). No resistant organisms colonising infants were identified in any of the studies. No pooled data were available for other important outcome measures such as chronic lung disease or neurodevelopmental outcome. Prophylactic systemic antibiotics in neonates with a central venous catheter reduces the rate of proven or suspected septicaemia. However, this may not be clinically important in the face of no significant difference in overall mortality and the lack of data on long-term neurodevelopmental outcome. Furthermore, there is a lack of data pertaining to the potentially significant disadvantages of this approach such as the selection of resistant organisms. The routine use of prophylactic antibiotics in infants with central venous catheters in neonatal units cannot currently be recommended.
We identified one new trial for inclusion in this update. In total, the evidence for this review rests on three studies with a total of 207 participants. We found no evidence for an effect of dance/movement therapy on depression (standardized mean difference (SMD) = 0.02, 95% confidence interval (CI) -0.28 to 0.32, P = 0.89, I2 = 0%) (two studies, N = 170), stress (SMD = -0.18, 95% CI -0.48 to 0.12, P = 0.24, I2 = 0%) (two studies, N = 170), anxiety (SMD = 0.21, 95% CI -0.09 to 0.51 P = 0.18, I2 = 0%) (two studies, N = 170), fatigue (SMD = -0.36, 95% -1.26 to 0.55, P = 0.44, I² = 80%) (two studies, N = 170) and body image (SMD = -0.13, 95% CI -0.61 to 0.34, P = 0.58, I2 = 0%) (two studies, N = 68) in women with breast cancer. The data of one study with moderate risk of bias suggested that dance/movement therapy had a large beneficial effect on 37 participants' quality of life (QoL) (SMD = 0.89, 95% CI 0.21 to 1.57). One study with a high risk of bias reported greater improvements in vigor and greater reduction in somatization in the dance/movement therapy group compared to a standard care control group (N = 31). The individual studies did not find support for an effect of dance/movement therapy on mood, mental health, and pain. It is unclear whether this was due to ineffectiveness of the treatment, inappropriate outcome measures or limited power of the trials. Finally, the results of one study did not find evidence for an effect of dance/movement therapy on shoulder range of motion (ROM) or arm circumference in 37 women who underwent a lumpectomy or breast surgery. However, this was likely due to large within-group variability for shoulder ROM and a limited number of participants with lymphedema. Two studies presented moderate risk of bias and one study high risk of bias. Therefore, overall, the quality of the evidence is very low. We did not find support for an effect of dance/movement therapy on depression, stress, anxiety, fatigue and body image . The findings of individual studies suggest that dance/movement therapy may have a beneficial effect on QoL, somatization, and vigor. However, the limited number of studies prevents us from drawing conclusions concerning the effects of dance/movement therapy on psychological and physical outcomes in cancer patients.
We identified nine randomised controlled trials in which 1106 infants participated. Few participants were extremely preterm (less 28 weeks' gestation) or extremely low birth weight (less than 1000 g). The trials defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or less after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical RR 0.93, 95% CI 0.64 to 1.34; 8 trials; 1092 infants) or all-cause mortality (typical RR 1.18, 95% CI 0.75 to 1.88; 7 trials; 967 infants). Four of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials found no statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median differences two to four days). The evidence available from randomised controlled trials suggested that delaying the introduction of progressive enteral feeds beyond four days after birth did not reduce the risk of developing NEC in very preterm or VLBW infants, including growth-restricted infants. Delaying the introduction of progressive enteral feeds resulted in a few days' delay in establishing full enteral feeds but the clinical importance of this effect was unclear. The applicability of these findings to extremely preterm or extremely low birth weight was uncertain. Further randomised controlled trials in this population may be warranted.
Seven randomised trials were included.  Four trials with 403 patients compared an antibiotic with placebo or no intervention. Three trials compared at least one antibiotic regimen with another antibiotic regimen. The trials all had high risk of bias. The trials varied in the severity of leptospirosis among trial patients. The ability to group data for meta-analysis was limited. While all four trials that compared antibiotics with placebo reported mortality and used parenteral penicillin, there were no deaths in two of them. Since odds ratio calculations cannot employ zero-event trials, only two trials contributed to this estimate. The number of deaths were 16/200 (8.0%) in the antibiotic arm versus 11/203 (5.4%) in the placebo arm giving a fixed-effect OR 1.56 (95% CI 0.70 to 3.46). The random-effects OR is 1.16 (95% CI 0.23 to 5.95). The heterogeneity among these four trials for the mortality outcome was moderate (I2= 50%). Only one trial (253 patients) reported days of hospitalisation. It compared parenteral penicillin to placebo without significant effect of therapy (8.9 versus 8.8 days; mean difference (MD) 0.10 days, 95% CI -0.83 to 1.03). The difference in days of clinical illness was reported in two of these trials (71 patients). While parenteral penicillin therapy conferred 4.7 to 5.6 days of clinical illness in contrast to 7.7 to 11.6 days in the placebo arm, the size of the estimate of effect increased but statistical significance was lost under the random-effect model (fixed-effect: MD -2.13 days, 95% CI -2.46 to -1.80; random-effects: MD -4.04, 95% CI -8.66 to 0.58). I2 for this outcome was high (81%). When duration of fever alone was assessed between antibiotics and placebo in a single trial (79 patients), no significant difference existed (6.9 versus 6.6 days; MD 0.30, 95% CI -1.26 to 1.86). Two trials with 332 patients in relatively severe and possibly late leptospirosis, resulted in trends towards increased dialysis when penicillin was used rather than placebo, but the estimate of effect was small and did not reach statistical significance (42/163 (25.8%) versus 31/169 (18.4%); OR 1.54, 95% CI 0.91 to 2.60). When one antibiotic was assessed against another antibiotic, there were no statistically significant results. For mortality in particular, these comparisons included cephalosporin versus penicillin (2 trials, 6/176 (3.4%) versus 9/175 (5.2%); fixed-effect: OR 0.65, 95% CI 0.23 to 1.87, I2= 16%), doxycycline versus penicillin (1 trial, 2/81 (2.5%) versus 4/89 (4.5); OR 0.54, 95% CI 0.10 to 3.02), cephalosporin versus doxycycline (1 trial, 1/88 (1.1%) versus 2/81 (2.5%); OR 0.45, 95% CI 0.04 to 5.10). There were no adverse events of therapy which reached statistical significance. Insufficient evidence is available to advocate for or against the use of antibiotics in the therapy for leptospirosis. Among survivors who were hospitalised for leptospirosis, use of antibiotics for leptospirosis may have decreased the duration of clinical illness by two to four days, though this result was not statistically significant. When electing to treat with an antibiotic, selection of penicillin, doxycycline, or cephalosporin does not seem to impact mortality nor duration of fever. The benefit of antibiotic therapy in the treatment of leptospirosis remains unclear, particularly for severe disease. Further clinical research is needed to include broader panels of therapy tested against placebo.
All identified studies were performed before and in the early 1990s and used various terms and criteria for cognitive decline and dementia. The three studies included in the review involved a total of 583 people with dementia treated with vinpocetine or placebo. The reports of these studies did not make possible any differentiation of effects for degenerative or vascular dementia. The results show benefit associated with treatment with vinpocetine 30 mg/day and 60 mg/day compared with placebo, but the number of patients treated for six months or more was small. Only one study extended treatment to one year. Adverse effects were inconsistently reported and without regard for relationship to dose. The available data do not demonstrate many problems of adverse effects but intention-to-treat data were not available for any of the trials. Although the basic science is interesting, the evidence for beneficial effect of vinpocetine on patients with dementia is inconclusive and does not support clinical use. The drug seems to have few adverse effects at the doses used in the studies. Large studies evaluating the use of vinpocetine for people suffering from well defined types of cognitive impairment are needed to explore possible efficacy of this treatment.
We identified 11 eligible RCTs which randomised a total of 3673 participants. One further trial, which was published in abstract form in 1990 but has yet to be reported fully, is currently 'awaiting assessment'. Six of the 11 included studies have been included for the first time in this latest (2012) update. The trials were heterogeneous in terms of their inclusion and exclusion criteria, the nature of the intervention, and the outcome measures assessed. We judged two of the trials to be of high quality and graded the remainder as poor quality. Meta-analyses of data on clinical and microbiological remission rates revealed that topical antibiotics were of benefit in improving 'early' (days two to five) clinical (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.15 to 1.61) and microbiological (RR 1.55, 95% CI 1.37 to 1.76) remission rates. At the 'late' time point (days six to 10), antibiotics were found to still confer modest benefits in clinical remission (RR 1.21, 95% CI 1.10 to 1.33) and microbiological cure rates (RR 1.37, 95% CI 1.24 to 1.52). By days six to 10, 41% (95% CI 38 to 43) of cases had resolved in those receiving placebo. We found no data on the cost-effectiveness of antibiotics. No serious outcomes were reported in either the active or placebo arms of these trials, suggesting that important sight-threatening complications are an infrequent occurrence. Although acute bacterial conjunctivitis is frequently self limiting, the findings from this updated systematic review suggest that the use of antibiotic eye drops is associated with modestly improved rates of clinical and microbiological remission in comparison to the use of placebo. Use of antibiotic eye drops should therefore be considered in order to speed the resolution of symptoms and infection.
We included 83 randomised trials with 12,707 patients. Most trials had unclear or high risk of bias. We did not find any significant influence of bias on our results but cannot exclude outcome measure reporting bias as many trials did not report on the primary outcomes of this review. Compared with interferon, ribavirin plus interferon had a significant beneficial effect on sustained virological response in subgroups of naive patients (RR 0.72, 95% confidence interval (CI) 0.68 to 0.75), relapsers (RR 0.62, 95% CI 0.54 to 0.70), non-responders (RR 0.89, 95% CI 0.84 to 0.93), and in all patients (RR 0.75, 95% CI 0.71 to 0.79). Combination therapy significantly reduced morbidity plus mortality in all patients (Peto OR, 0.43, 95% CI 0.23 to 0.79), but not in naive, relapsers, or non-responders individually. Combination therapy significantly increased the risk of haematological, dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnoea, fatigue) adverse reactions. Accordingly, combination therapy significantly increased the risk of treatment discontinuation and dose reductions. Trial sequential analyses confirmed our findings regarding virological effects, but not regarding liver-related morbidity and all-cause mortality. Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus from the blood. Combination therapy may reduce liver-related morbidity and all-cause mortality, but we need more evidence. The number needed to treat to obtain a beneficial effect is considerable considering the increased risk of several severe adverse reactions and costs.
We included 13 case-control and 24 cohort studies (an additional nine new cohort and two case-control studies), which included a total of 4,684,724 women. Two cohort studies reported an increased incidence of invasive ovarian cancer in exposed subfertile women compared with unexposed women. One reported a standardised incidence ratio (SIR) of 1.19 (95% confidence interval (CI) 0.54 to 2.25) based on 17 cancer cases. The other cohort study reported a hazard ratio (HR) of 1.93 (95% CI 1.18 to 3.18), and this risk was increased in women remaining nulligravid after using clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) versus multiparous women (HR 1.52, 95% CI 0.67 to 3.42) (very low-certainty evidence). The slight increase in ovarian cancer risk among women having between one and three cycles of in vitro fertilisation (IVF) was reported, but this was not clinically significant (P = 0.18). There was no increase in risk of invasive ovarian cancer after use of infertility drugs in women with the BRCA mutation according to one cohort and one case-control study. The certainty of evidence as assessed using GRADE was very low. For borderline ovarian tumours, one cohort study reported increased risk in exposed women with an SIR of 3.61 (95% CI 1.45 to 7.44), and this risk was greater after treatment with clomiphene citrate (SIR 7.47, 95% CI 1.54 to 21.83) based on 12 cases. In another cohort study, the risk of a borderline ovarian tumour was increased, with an HR of 4.23 (95% CI 1.25 to 14.33), for subfertile women treated with IVF compared with a non-IVF-treated group with more than one year of follow-up. A large cohort reported increased risk of borderline ovarian tumours, with HR of 2.46 (95% CI 1.20 to 5.04), and this was based on 17 cases. A significant increase in serous borderline ovarian tumours was reported in one cohort study after the use of progesterone for more than four cycles (risk ratio (RR) 2.63, 95% CI 1.04 to 6.64). A case-control study reported increased risk after clomiphene citrate was taken, with an SIR of 2.5 (95% CI 1.3 to 4.5) based on 11 cases, and another reported an increase especially after human menopausal gonadotrophin was taken (odds ratio (OR) 9.38, 95% CI 1.66 to 52.08). Another study estimated an increased risk of borderline ovarian tumour, but this estimation was based on four cases with no control reporting use of fertility drugs. The certainty of evidence as assessed using GRADE was very low. However, although some studies suggested a slight increase in risks of ovarian cancer and borderline ovarian tumour, none provided moderate- or high-certainty evidence, as summarised in the GRADE tables. Since the last version of this review, only a few new relevant studies have provided additional findings with supporting evidence to suggest that infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated with infertility drugs when compared to the general population or to subfertile women not treated. The risk is slightly higher in nulliparous than in multiparous women treated with infertility drugs, and for borderline ovarian tumours. However, few studies have been conducted, the number of cancers is very small, and information on the dose or type of fertility drugs used is insufficient.
This review included 19 randomised trials with a total of 823 participants. Almost all included trials had several methodological weaknesses. Meta-analysis showed that oral stimulation reduced the time to transition to oral feeding compared with standard care (mean difference (MD) -4.81, 95% confidence interval (CI) -5.56 to -4.06 days) and compared with another non-oral intervention (MD -9.01, 95% CI -10.30 to -7.71 days), as well as the duration of initial hospitalisation compared with standard care (MD -5.26, 95% CI -7.34 to -3.19 days) and compared with another non-oral intervention (MD -9.01, 95% CI -10.30 to -7.71 days). Investigators reported shorter duration of parenteral nutrition for infants compared with standard care (MD -5.30, 95% CI -9.73 to -0.87 days) and compared with another non-oral intervention (MD -8.70, 95% CI -15.46 to -1.94 days). They could identify no effect on breast-feeding outcomes nor on weight gain. Although the included studies suggest that oral stimulation shortens hospital stay, days to exclusive oral feeding and duration of parenteral nutrition, one must interpret results of these studies with caution, as risk of bias and poor methodological quality are high overall. Well-designed trials of oral stimulation interventions for preterm infants are warranted. Such trials should use reliable methods of randomisation while concealing treatment allocation, blinding caregivers to treatment when possible and paying particular attention to blinding of outcome assessors.
In this update in 2017, we did not identify any new randomised controlled trials (RCT) for inclusion. We identified one ongoing trial that we are likely to include in a future update. Accordingly, our results are unchanged. The only included trial is a multicentre RCT conducted at 24 locations in North America and India that compared bone marrow injection with steroid (methylprednisolone acetate) injection for treating simple bone cysts. Up to three injections were planned for participants in each group. The trial involved 90 children (mean age 9.5 years) and presented results for 77 children at two-year follow-up. Although the trial had secure allocation concealment, it was at high risk of performance bias and from major imbalances in baseline characteristics. Reflecting these study limitations, we downgraded the quality of evidence by two levels to 'low' for most outcomes, meaning that we are unsure about the estimates of effect. For outcomes where there was serious imprecision, we downgraded the quality of evidence by a further level to 'very low'. The trial provided very low quality evidence that fewer children in the bone marrow injection group had radiographically assessed healing of bone cysts at two years than in the steroid injection group (9/39 versus 16/38; RR 0.55 favouring steroid injection, 95% CI 0.28 to 1.09). However, the result was uncertain and may be compatible with no difference or small benefit favouring bone marrow injection. Based on an illustrative success rate of 421 children with healed bone cysts per 1000 children treated with steroid injections, this equates to 189 fewer (95% CI 303 fewer to 38 more) children with healed bone cysts per 1000 children treated with bone marrow injections. There was low quality evidence of a lack of difference between the two interventions at two years in functional outcome, based on the Activity Scale for Kids function score (0 to 100; higher scores equate to better outcome: MD -0.90; 95% CI -4.26 to 2.46) or in pain assessed using the Oucher pain score. There was very low quality evidence of a lack of differences between the two interventions for adverse events: subsequent pathological fracture (9/39 versus 11/38; RR 0.80, 95% CI 0.37 to 1.70) or superficial infection (two cases in the bone marrow group). Recurrence of bone cyst, unacceptable malunion, return to normal activities, and participant satisfaction were not reported. The available evidence is insufficient to determine the relative effects of bone marrow versus steroid injections, although the bone marrow injections are more invasive. Noteably, the rate of radiographically assessed healing of the bone cyst at two years was well under 50% for both interventions. Overall, there is a lack of evidence to determine the best method for treating simple bone cysts in the long bones of children. Further RCTs of sufficient size and quality are needed to guide clinical practice.
This review includes 13 trials (10 RCTs and three quasi-randomised trials), as well as two economic evaluations based on two of the trials. Overall, there were 1078 participants (646 in the intervention group; 432 in the control group). The results indicate that parent training produced a statistically significant reduction in child conduct problems, whether assessed by parents (standardised mean difference (SMD) -0.53; 95% confidence interval (CI) -0.72 to -0.34) or independently assessed (SMD -0.44; 95% CI -0.77 to -0.11). The intervention led to statistically significant improvements in parental mental health (SMD -0.36; 95% CI -0.52 to -0.20) and positive parenting skills, based on both parent reports (SMD -0.53; 95% CI -0.90 to -0.16) and independent reports (SMD -0.47; 95% CI -0.65 to -0.29). Parent training also produced a statistically significant reduction in negative or harsh parenting practices according to both parent reports (SMD -0.77; 95% CI -0.96 to -0.59) and independent assessments (SMD -0.42; 95% CI -0.67 to -0.16). Moreover, the intervention demonstrated evidence of cost-effectiveness. When compared to a waiting list control group, there was a cost of approximately $2500 (GBP 1712; EUR 2217) per family to bring the average child with clinical levels of conduct problems into the non-clinical range. These costs of programme delivery are modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Behavioural and cognitive-behavioural group-based parenting interventions are effective and cost-effective for improving child conduct problems, parental mental health and parenting skills in the short term. The cost of programme delivery was modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Further research is needed on the long-term assessment of outcomes.
Two RCTs and one controlled before-and-after study were included (735 participants). All were conducted in the USA and had several potential sources of bias. Few outcomes for residents were assessed. One study reported higher satisfaction with care and the other found lower observed discomfort in residents with end-stage dementia. Two studies reported group differences on some process measures. Both reported higher referral to hospice services in their intervention group, one found fewer hospital admissions and days in hospital in the intervention group, the other found an increase in do-not-resuscitate orders and documented advance care plan discussions. We found few studies, and all were in the USA. Although the results are potentially promising, high quality trials of palliative care service delivery interventions which assess outcomes for residents are needed, particularly outside the USA. These should focus on measuring standard outcomes, assessing cost-effectiveness, and reducing bias.
We included ten trials in which 652 patients were randomised. The risk of bias was considered high in most trials. There was no significant effect of prostaglandins on all-cause mortality (37/298[12.4%] in prostaglandin group versus 47/312[15.1%] in control group; OR 0.84, 95% CI 0.53 to 1.37; I2 = 0%), on primary non-function of the allograft (8/238 [3.4%] versus. 16/250[6.4%] ;OR 0.55, 95% CI 0.23 to 1.33; I2 = 0%), and on liver re-transplantation (12/161[7.5%] versus 14/171[8.2%]; OR 0.99, 95% CI 0.44 to 2.25; I2 = 0%). Prostaglandins seemed to significantly decrease the risk of acute kidney failure requiring dialysis (13/158[8.2%] versus 34/171[9.9%]; OR 0.37, 95% CI 0.18 to 0.75; I2 = 0%). There was no significant increase in the risk of adverse events with prostaglandins. We found no evidence that the administration of prostaglandins to liver transplanted patients reduces the risk of death, primary non-function of the allograft, or liver re-transplantation. Prostaglandins might reduce the risk of acute kidney failure requiring dialysis, but the quality of the evidence is considered only moderate due to high risk of bias in most of the included trials. Moreover, there are risks of outcome measure reporting bias and random errors. Therefore, further randomised, placebo-controlled trials are deemed necessary.
We included eight studies with a total of 2227 women undergoing elective caesarean section. Of these, 1097 underwent intraoperative cervical dilatation with a double-gloved index finger or Hegar dilator inserted into the cervical canal to dilate, and 1130 did not undergo intraoperative cervical dilatation. Six of the eight included trials had high risk of bias for some of the risk of bias domains. Very low-quality evidence suggested it was unclear whether cervical dilatation had any impact on postpartum haemorrhage (estimated blood loss greater than 1000 mL; risk ratio (RR) 1.97, 95% confidence interval (CI) 0.48 to 8.13; 5/205 versus 3/242; one study, 447 women). Low- or very low-quality evidence showed no clear difference for the need for blood transfusion (RR 3.54, 95% CI 0.37 to 33.79; two studies, 847 women); postoperative haemoglobin (mean difference (MD -0.05, 95% CI -0.15 to 0.06; three studies, 749 women), or haematocrit (MD 0.01%, 95% CI -0.18 to 0.20; one study, 400 women); the incidence of drop from baseline haemoglobin above 0.5 g/dL (RR 0.92, 95% CI 0.64 to 1.31; two studies, 722 women), or amount of haemoglobin drop (MD -0.01 g/dL, 95% -0.14 to 0.13; three studies, 796 women); the incidence of secondary postpartum haemorrhage within six weeks (RR 1.18, 95% CI 0.07 to 18.76; one study, 447 women); febrile morbidity (RR 1.18, 95% CI 0.76 to 1.85; seven studies, 2126 women); endometritis (RR 0.94, 95% CI 0.35 to 2.52; four studies, 1536 women); or uterine subinvolution (RR 0.34, 95% CI 0.08 to 1.36; two studies, 654 women); the results crossed the line of no effect for all of the outcomes. There were no data for cervical trauma. We found a slight improvement with mechanical dilatation for these secondary outcomes, not prespecified in the protocol: mean blood loss, endometrial cavity thickness, retained products of conception, distortion of uterine incision, and healing ratio. The evidence for these outcomes was based on one or two studies. Cervical dilatation did not have a clear effect on these secondary outcomes, not prespecified in the protocol: wound infection, urinary tract infection, operative time, infectious morbidity, and integrity of uterine scar. At this time, the evidence does not support or refute the use of mechanical dilatation of the cervix during elective caesarean section for reducing postoperative morbidity. Further large, well-designed studies are required to compare the effect of intraoperative mechanical dilatation of the cervix with no intraoperative mechanical cervical dilatation for reducing postoperative morbidity.
We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate. Primary outcomes Cannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence). Secondary outcomes Cannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence). We found no information about long-term risks in the studies analysed. Subgroup analyses We are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.
Three studies (one cluster-RCT and two CBAs) comprising a total of 13,885 participants (9640 children and 4245 adults) as well as 1200 households in two LMICs (Nicaragua and Niger) met the inclusion criteria. They examined five UCTs between USD 145 and USD 250 (or more, depending on household characteristics) that were provided by governmental, non-governmental or research organisations during experiments or pilot programmes in response to droughts. Two studies examined the effectiveness of UCTs, and one study examined the relative effectiveness of in-hand UCTs compared with in-kind transfers and UCTs paid via mobile phone. Due to the methodologic limitations of the retrieved records, which carried a high risk of bias and very serious indirectness, we considered the body of evidence to be of very low overall quality and thus very uncertain across all outcomes. Depending on the specific health services use and health outcomes examined, the included studies either reported no evidence that UCTs had impacted the outcome, or they reported that UCTs improved the outcome. No single outcome was reported by more than one study. There was a very small increase in the proportion of children who received vitamin or iron supplements (mean difference (MD) 0.10 standard deviations (SDs), 95% confidence interval (CI) 0.06 to 0.14) and on the child's home environment, as well as clinically meaningful, very large reductions in the chance of child death (hazard ratio (HR) 0.26, 95% CI 0.10 to 0.66) and the incidence of severe acute malnutrition (HR 0.44, 95% CI 0.24 to 0.80). There was also a moderate reduction in the number of days children spent sick in bed (MD − 0.36 SDs, 95% CI − 0.62 to − 0.10). There was no evidence for any effect on the proportion of children receiving deworming drugs, height for age among children, adults' level of depression, or the quality of parenting behaviour. No adverse effects were identified. The included comparisons did not examine several important outcomes, including food security and equity impacts. With regard to the relative effectiveness of UCTs compared with a food transfer providing a relatively high total caloric value, there was no evidence that a UCT had any effect on the chance of child death (HR 2.27, 95% CI 0.69 to 7.44) or severe acute malnutrition (HR 1.15, 95% CI 0.67 to 1.99). A UCT paid in-hand led to a clinically meaningful, moderate increase in the household dietary diversity score, compared with the same UCT paid via mobile phone (difference-in-differences estimator 0.43 scores, 95% CI 0.06 to 0.80), but there was no evidence for an effect on social determinants of health, health service expenditure, or local markets and infrastructure. Additional high-quality evidence (especially RCTs of humanitarian disaster contexts other than droughts) is required to reach clear conclusions regarding the effectiveness and relative effectiveness of UCTs for improving health services use and health outcomes in humanitarian disasters in LMICs.
We included 14 articles describing 13 studies, comprising 11 single-centre studies and two multi-centre studies. These studies involved 944 hands of 940 participants; of these, 93 participants were reported twice in separate articles describing early and late outcomes of one trial. Three papers reported the outcomes of two trials comparing different procedures. One trial compared needle fasciotomy versus fasciectomy (125 hands, 121 participants), and the other compared interposition firebreak skin grafting versus z-plasty closure of fasciectomy (79 participants). The other 11 studies reported trials of technical refinements of procedures or rehabilitation adjuncts. Of these, three investigated effects of postoperative splinting on surgical outcomes. Ten studies (11 articles) were randomised controlled trials (RCTs) of varying methodological quality; one was a controlled clinical trial. Trial design was unclear in two studies awaiting classification. All trials had high or unclear risk of at least one type of bias. High risks of performance and detection bias were particularly common. We downgraded the quality of evidence (Grades of Recommendation, Assessment, Development and Evaluation - GRADE) of outcomes to low because of concerns about risk of bias and imprecision. Outcomes measured varied between studies. Five articles assessed recurrence; two defined this as reappearance of palpable disease and two as deterioration in angular deformity; one did not explicitly define recurrence. Hand function on the Disabilities of the Arm, Shoulder and Hand (DASH) Scale (scores between 0 and 100, with higher scores indicating greater impairment) was 5 points lower after needle fasciotomy than after fasciectomy at five weeks. Patient satisfaction was better after fasciotomy at six weeks, but the magnitude of effect was not specified. Fasciectomy improved contractures more effectively in severe disease: Mean percentage reduction in total passive extension deficit at six weeks for Tubiana grades I and II was 11% lower after needle fasciotomy than after fasciectomy, whereas for grades III and IV disease, it was 29% and 32% lower. Paraesthesia (defined as subjective tingling sensation without objective evidence of altered sensation) was more common than needle fasciotomy at one week after fasciectomy (228/1000 vs 67/1000), but reporting of complications was variable. By five years, satisfaction (on a scale from 0 to 10, with higher scores showing greater satisfaction) was 2.1/10 points higher in the fasciectomy group than in the fasciotomy group, and recurrence was greater after fasciotomy (849/1000 vs 209/1000). Firebreak skin grafting did not improve outcomes more than fasciectomy alone, although this procedure took longer to perform. One trial investigated four weeks of day and night splinting followed by two months of night splinting after surgery. The other two trials investigated three months of night splinting after surgery, but participants in 'no splint' groups with early deterioration at one week were issued a splint for use. All three studies demonstrated no benefit from splinting. The two trials investigating postoperative night splinting were suitable for meta-analysis, which demonstrated no benefit from splinting: Mean DASH score in the splint groups was 1.15 points lower (95% confidence interval (CI) -2.32 to 4.62) than in the no splint groups. Mean total active extension in the splint groups was 2.21 degrees greater (95% CI -3.59 to 8.01 degrees) than in the no splint groups. Mean total active flexion in the splint groups was 8.42 degrees less (95% CI 1.78 to 15.07 degrees) than in the no splint groups. Currently, insufficient evidence is available to show the relative superiority of different surgical procedures (needle fasciotomy vs fasciectomy, or interposition firebreak skin grafting vs z-plasty closure of fasciectomy). Low-quality evidence suggests that postoperative splinting may not improve outcomes and may impair outcomes by reducing active flexion. Further trials on this topic are urgently required.
Overall, we included 15 reviews published in the Cochrane Library, comprising 164 randomised controlled trials (RCTs) and four controlled clinical trials, with a total of 10,396 participants. The included reviews evaluated a wide range of rehabilitation interventions, including: physical activity and exercise therapy, hyperbaric oxygen therapy (HBOT), whole-body vibration, occupational therapy, cognitive and psychological interventions, nutritional and dietary supplements, vocational rehabilitation, information provision, telerehabilitation, and interventions for the management of spasticity. We assessed all reviews to be of high to moderate methodological quality, based on R-AMSTAR criteria. Moderate-quality evidence suggested that physical therapeutic modalities (exercise and physical activities) improved functional outcomes (mobility, muscular strength), reduced impairment (fatigue), and improved participation (quality of life). Moderate-quality evidence suggested that inpatient or outpatient multidisciplinary rehabilitation programmes led to longer-term gains at the levels of activity and participation, and interventions that provided information improved patient knowledge. Low-qualitty evidence suggested that neuropsychological interventions, symptom-management programmes (spasticity), whole body vibration, and telerehabilitation improved some patient outcomes. Evidence for other rehabilitation modalities was inconclusive, due to lack of robust studies. The evidence suggests that regular specialist evaluation and follow-up to assess the needs of patients with all types of MS for appropriate rehabilitation interventions may be of benefit, although the certainty of evidence varies across the different types of interventions evaluated by the reviews. Structured, multidisciplinary rehabilitation programmes and physical therapy (exercise or physical activities) can improve functional outcomes (mobility, muscle strength, aerobic capacity), and quality of life. Overall, the evidence for many rehabilitation interventions should be interpreted cautiously, as the majority of included reviews did not include data from current studies. More studies, with appropriate design, which report the type and intensity of modalities and their cost-effectiveness are needed to address the current gaps in knowledge.
Due to the small numbers of trials in each category, the limited quantitative data available and the marked differences between trials in terms of participants, interventions and outcome measurement, we felt that pooling of the results was inappropriate. We included 29 trials (19 in adults, 10 in children) involving 4835 people (3799 adults and 1036 children). All studies were placebo-controlled RCTs. However, assessment of the risk of bias of the included studies was limited by poor reporting, particularly for the earlier studies. In the adult studies, six trials compared antitussives with placebo and had variable results. Three trials compared the expectorant guaifenesin with placebo; one indicated significant benefit, whereas the other two did not. One trial found that a mucolytic reduced cough frequency and symptom scores. Two studies examined antihistamine-decongestant combinations and found conflicting results. Four studies compared other combinations of drugs with placebo and indicated some benefit in reducing cough symptoms. Three trials found that antihistamines were no more effective than placebo in relieving cough symptoms. In the child studies, antitussives (data from three studies), antihistamines (data from three studies), antihistamine-decongestants (two studies) and antitussive/bronchodilator combinations (one study) were no more effective than placebo. No studies using expectorants met our inclusion criteria. The results of one trial favoured active treatment with mucolytics over placebo. One trial tested two paediatric cough syrups and both preparations showed a 'satisfactory response' in 46% and 56% of children compared to 21% of children in the placebo group. One new trial indicated that three types of honey were more effective than placebo over a three-day period. Twenty-one studies reported adverse effects. There was a wide range across studies, with higher numbers of adverse effects in participants taking preparations containing antihistamines and dextromethorphan. The results of this review have to be interpreted with caution because the number of studies in each category of cough preparations was small. Availability, dosing and duration of use of over-the-counter cough medicines vary significantly in different countries. Many studies were poorly reported making assessment of risk of bias difficult and studies were also very different from each other, making evaluation of overall efficacy difficult. There is no good evidence for or against the effectiveness of OTC medicines in acute cough. This should be taken into account when considering prescribing antihistamines and centrally active antitussive agents in children; drugs that are known to have the potential to cause serious harm.
Only one study (DiSessa 1981) was eligible. This study compared low dose dopamine at 2.5 mcg/kg/min with placebo (dextrose in water). This study enrolled 14 term infants with a 5 minute Apgar <6 and a systolic BP >=50 mmHg at a mean of 10 hours age. Seven infants only were randomised to treatment with dopamine and seven to receive placebo. No significant differences between these two groups were found for mortality or long term neurodevelopmental outcome. Length of hospitalisation was not significantly different between the two groups. No study was found that examined the effect of dopamine in infants with evidence of cardiovascular compromise, nor were any studies identified in which dopamine was compared to other inotropic agents for term infants with suspected asphyxia. There is currently insufficient evidence from randomised controlled trials that the use of dopamine in term infants with suspected perinatal asphyxia improves mortality or long-term neurodevelopmental outcome. The question of whether dopamine improves outcome for term infants with suspected perinatal asphyxia has not been answered. Further research is required to determine whether or not the use of dopamine improves mortality and long-term morbidity for these infants and if so, issues such as which infants, at what dose and with what co-interventions should be addressed.
No new trials were identified. This review includes two RCTs with low risk of bias that compared urinary human chorionic gonadotrophin (hCG) versus no treatment in anovulatory women receiving clomiphene citrate. Urinary hCG did not result in an increase in live birth rate over no hCG (OR 0.97, 95% CI 0.52 to 1.83; two trials, 305 participants, I2 = 16%; low-quality evidence), but very serious imprecision around the effect estimate reduces our confidence in the apparent lack of effect of hCG as an ovulation trigger in clomiphene-induced cycles in anovulatory women. Among this review's secondary outcomes, urinary hCG may not increase ovulation rate (OR 0.99, 95% CI 0.36 to 2.77; two trials, 305 participants, I2 = 55%; low-quality evidence), clinical pregnancy rate (OR 1.02, 95% CI 0.56 to 1.89; two trials, 305 participants, I2 = 35%; low-quality evidence) or miscarriage rate in pregnant women (OR 1.19, 95% CI 0.17 to 8.23; two trials, 54 participants, I2 = 0%; low-quality evidence). Multiple pregnancies and preterm deliveries were uncommon, and ovarian hyperstimulation syndrome, adverse events and deaths were not reported as outcomes in either trial.  We found no trials evaluating other ovulation triggers. Evidence is inadequate to recommend or refute the use of urinary hCG as an ovulation trigger in anovulatory women treated with clomiphene citrate. We found no trials evaluating the use of ovulation triggers in anovulatory women treated with other ovulation-inducing agents.
Twelve studies conducted in China, including 762 children with nephrotic syndrome were identified. No studies were identified in adults. All studies compared one kind of prophylactic pharmacotherapy (intravenous immunoglobulin (IVIG), thymosin, oral transfer factor, mannan peptide tablet, Bacillus Calmette-Guerin (BCG) vaccine injection, polyvalent bacterial vaccine (Lantigen B) and two kinds of Chinese medicinal herbs: a compound of Chinese medicinal herbs (TIAOJINING) and Huangqi (astragalus) granules) plus baseline treatment with baseline treatment alone. No RCTs were identified comparing antibiotics, non-pharmacological prophylaxis, or pneumococcal vaccination. Four studies showed a significantly beneficial effect of IVIG on preventing nosocomial or unspecified infection in children with nephrotic syndrome (RR 0.47, 95% CI 0.31 to 0.73). Thymosin (RR 0.50, 95% CI 0.26 to 0.97), oral transfer factor (RR 0.51, 95% CI 0.35 to 0.73), BCG vaccine injection (RR 0.68, 95% CI 0.48 to 0.95), Huangqi granules (RR 0.62, 95% CI 0.47 to 0.83) and TIAOJINING (RR 0.59, 95% CI 0.43 to 0.81) were also effective in reducing the risk of infection in children with nephrotic syndrome. However mannan peptide tablet (RR 0.46, 95% CI 0.21 to 1.01) and polyvalent bacterial vaccine (RR 0.24, 95% CI 0.06 to1.00) were not superior to baseline treatment in reducing the risk of infection for nephrotic children. No serious adverse events were reported. IVIG, thymosin, oral transfer factor, BCG vaccine, Huangqi granules and TIAOJINING may have positive effects on the prevention of nosocomial or unspecified infection with no obvious serious adverse events in children with nephrotic syndrome. However the methodological quality of all studies was poor, the sample sizes small, and all studies were from China, and thus there is no strong evidence on the effectiveness of these interventions.
We included 7 RCTs, with a total of 249 participants, covering 6 treatments. Six of these RCTs tested the efficacy of one active intervention against placebo or another active intervention, while the other trial tested three active interventions against placebo. When compared to placebo in one trial, clobetasol propionate 0.05% was effective in treating genital lichen sclerosus in relation to the following outcomes: 'participant-rated improvement or remission of symptoms' (risk ratio (RR) 2.85, 95% confidence interval (CI) 1.45 to 5.61) and 'investigator-rated global degree of improvement' (standardised mean difference (SMD) 5.74, 95% CI 4.26 to 7.23). When mometasone furoate 0.05% was compared to placebo in another trial, there was a significant improvement in the 'investigator-rated change in clinical grade of phimosis' (SMD -1.04, 95% CI -1.77 to -0.31). Both trials found no significant differences in reported adverse drug reactions between the corticosteroid and placebo groups.  The data from four trials found no significant benefit for topical testosterone, dihydrotestosterone, and progesterone. When used as maintenance therapy after an initial treatment with topical clobetasol propionate in another trial, topical testosterone worsened the symptoms (P < 0.05), but the placebo did not. One trial found no differences between pimecrolimus and clobetasol propionate in relieving symptoms through change in pruritus (itching) (SMD -0.33, 95% CI -0.99 to 0.33) and burning/pain (SMD 0.03, 95% CI -0.62 to 0.69). However, pimecrolimus was less effective than clobetasol propionate with regard to the 'investigator-rated global degree of improvement' (SMD -1.64, 95% CI -2.40 to -0.87). This trial found no significant differences in reported adverse drug reactions between the pimecrolimus and placebo groups. The current limited evidence demonstrates the efficacy of clobetasol propionate, mometasone furoate, and pimecrolimus in treating genital lichen sclerosus. Further RCTs are needed to determine the optimal potency and regimen of topical corticosteroids, examine other topical interventions, assess the duration of remission or prevention of flares, evaluate the reduction in the risk of genital squamous cell carcinoma or genital intraepithelial neoplasia, and examine the efficacy in improving the quality of the sex lives of people with this condition.
We identified 28 RCTs (3497 participants) with 1773 mortality outcomes. Six different vasopressors, given alone or in combination, were studied in 12 different comparisons. All 28 studies reported mortality outcomes; 12 studies reported length of stay. Investigators reported other morbidity outcomes in a variable and heterogeneous way. No data were available on quality of life nor on anxiety and depression outcomes. We classified 11 studies as having low risk of bias for the primary outcome of mortality; only four studies fulfilled all trial quality criteria. In summary, researchers reported no differences in total mortality in any comparisons of different vasopressors or combinations in any of the pre-defined analyses (evidence quality ranging from high to very low). More arrhythmias were observed in participants treated with dopamine than in those treated with norepinephrine (high-quality evidence). These findings were consistent among the few large studies and among studies with different levels of within-study bias risk. We found no evidence of substantial differences in total mortality between several vasopressors. Dopamine increases the risk of arrhythmia compared with norepinephrine and might increase mortality. Otherwise, evidence of any other differences between any of the six vasopressors examined is insufficient. We identified low risk of bias and high-quality evidence for the comparison of norepinephrine versus dopamine and moderate to very low-quality evidence for all other comparisons, mainly because single comparisons occasionally were based on only a few participants. Increasing evidence indicates that the treatment goals most often employed are of limited clinical value. Our findings suggest that major changes in clinical practice are not needed, but that selection of vasopressors could be better individualised and could be based on clinical variables reflecting hypoperfusion.
Nine trials were included in the review but only 3 trials could be included in the meta-analysis. Sufficient data to include the other trials in the meta-analysis could not be obtained. From this limited analysis it appears that TENS produced a statistically significant improvement directly after treatment in: delayed recall of 8 words in one trial, face recognition in two trials and motivation in one trial. However, no effect of TENS was found on any of the many other neuropsychological and behavioural measures evaluated either directly after TENS treatment or 6 weeks after treatment was completed. Although a number of studies suggest that TENS may produce short lived improvements in some neuropsychological or behavioural aspects of dementia, the limited presentation and availability of data from these studies does not allow definite conclusions on the possible benefits of this intervention. Since most of the currently published studies are well designed, although the numbers of subjects in each study is small, analysis of the complete original data from these and/or future studies may allow more definitive conclusions to be drawn.
Forty-one trials involving over 5000 patients were included. Variation in study design and quality made synthesis of the data problematic. Allocation concealment was adequate in only two trials. Most data were from areas of multidrug resistant falciparum malaria in South-East Asia. Compared with standard antimalarial treatments, artemisinin drugs showed fast parasite clearance and high cure rates at follow-up, provided the duration of treatment with artemisinin drugs was adequate. Combination with mefloquine improved sustained parasite clearance and was effective in multidrug resistant areas. When doses were adequate, the combination shortened the duration of treatment. We found no evidence that artemisinin drugs are more harmful than standard treatment drugs over a typical trial period of 28 days. The evidence suggests that artemisinin drugs are effective and safe for treating uncomplicated malaria. There is no evidence from randomised trials that one artemisinin derivative is better than the others. In areas where there is mefloquine resistance, combination therapy with an artemisinin derivative appears to improve sustained parasite clearance compared with either drug alone. This review summarizes trials up to 1999. For the reasons in the 'What's new' section, this review will no longer be updated.
We included 23 RCTs (1513 participants randomised) examining the effect of dietary fibre. The risk of bias was unclear for most studies and studies had small sample sizes. Few studies had an intervention duration of longer than 12 weeks. There was a wide variety of fibre sources used, with little similarity between groups in the choice of intervention. None of the studies reported on mortality (total or cardiovascular) or cardiovascular events. Results on lipids suggest there is a significant beneficial effect of increased fibre on total cholesterol levels (17 trials (20 comparisons), 1067 participants randomised, mean difference -0.20 mmol/L, 95% CI -0.34 to -0.06), and LDL cholesterol levels (mean difference -0.14 mmol/L, 95% CI -0.22 to -0.06) but not on triglyceride levels (mean difference 0.00 mmol/L, 95% CI -0.04 to 0.05), and there was a very small but statistically significant decrease rather than increase in HDL levels with increased fibre intake (mean difference -0.03 mmol/L, 95% CI -0.06 to -0.01). Fewer studies (10 trials, 661 participants randomised) reported blood pressure outcomes where there is a significant effect of increased fibre consumption on diastolic blood pressure (mean difference -1.77 mmHg, 95% CI -2.61 to -0.92) whilst there is a reduction in systolic blood pressure with fibre but this does not reach statistical significance (mean difference -1.92 mmHg, 95% CI -4.02 to 0.19). There did not appear to be any subgroup effects by the nature of the type of intervention (fibre supplements or provision of foods/advice to increase fibre consumption) or the type of fibre (soluble/insoluble) although the number of studies contributing to each subgroup were small. All analyses need to be viewed with caution given the risks of bias observed for total cholesterol and the statistical heterogeneity observed for systolic blood pressure. Adverse events, where reported, appeared to mostly reflect mild to moderate gastrointestinal side-effects and these were generally reported more in the fibre intervention groups than the control groups. Studies were short term and therefore did not report on our primary outcomes, CVD clinical events. The pooled analyses for CVD risk factors suggest reductions in total cholesterol and LDL cholesterol with increased fibre intake, and reductions in diastolic blood pressure. There were no obvious effects of subgroup analyses by type of intervention or fibre type but the number of studies included in each of these analyses were small. Risk of bias was unclear in the majority of studies and high for some quality domains so results need to be interpreted cautiously. There is a need for longer term, well-conducted RCTs to determine the effects of fibre type (soluble versus insoluble) and administration (supplements versus foods) on CVD events and risk factors for the primary prevention of CVD.
Of 56 trials identified, none reported data on violent injuries. Aggressive behaviour was significantly reduced in intervention groups compared to no intervention groups immediately post intervention in 34 trials with data, (Standardised Mean Difference (SMD) = -0.41; 95% confidence interval (CI) -0.56 to -0.26). This effect was maintained in the seven studies reporting 12 month follow-up (SMD = -0.40, (95% CI -0.73 to -0.06)). School or agency disciplinary actions in response to aggressive behaviour were reduced in intervention groups for nine trials with data, SMD = -0.48; 95% CI -1.16 to 0.19, although this difference may have been due to chance and was not maintained, based on two studies reporting follow-up to two to four months (SMD = 0.03; 95% CI -0.42 to 0.47). Subgroup analyses suggested that interventions designed to improve relationship or social skills may be more effective than interventions designed to teach skills of non-response to provocative situations, but that benefits were similar when delivered to children in primary versus secondary school, and to groups of mixed sex versus boys alone. School-based secondary prevention programmes to reduce aggressive behaviour appear to produce improvements in behaviour greater than would have been expected by chance. Benefits can be achieved in both primary and secondary school age groups and in both mixed sex groups and boys-only groups. Further research is required to establish whether such programmes reduce the incidence of violent injuries or if the benefits identified can be maintained beyond 12 months.
We included one Canadian trial of 180 women, recruited between 20 to 32 weeks' gestation, who had been diagnosed with GDM. Data from 171 of the 180 women were published as a conference abstract and no full report has been identified. The overall risk of bias of the single included study was judged to be unclear. The included trial did not report on any of this review's primary outcomes. For the mother, these were hypertension disorders of pregnancy or subsequent development of type 2 diabetes. For the infant, our primary outcomes were (perinatal (fetal and neonatal) mortality; large-for-gestational age; composite of death or severe morbidity or later childhood neurosensory disability). The trial did report data relating to some of this review's secondary outcomes. There was no clear difference in caesarean section rates for women assigned to using strict glycaemic targets (pre-prandial 5.0 mmol/L (90 mg/L) and at one-hour postprandial 6.7 mmol/L (120 mg/dL)) (28/85, 33%) when compared with women assigned to using liberal glycaemic targets (pre-prandial 5.8 mmol/L (103 mg/dL) and at one-hour postprandial 7.8 mmol/L (140 mg/dL)) (21/86, 24%) (risk ratio (RR) 1.35, 95% confidence interval (CI) 0.83 to 2.18, one trial, 171 women; very low quality). Using the GRADE approach, we found the quality of the evidence to bevery low for caesarean section due to poor reporting of risk of bias, imprecision and publication bias. Strict glycaemic targets were associated with an increase in the use of pharmacological therapy (identified as the use of insulin in this study) (33/85; 39%) compared with liberal glycaemic targets (18/86; 21%) (RR 1.85, 95% CI 1.14 to 3.03; one trial, 171 women). CIs are wide suggesting imprecision and caution is required when interpreting the data. No other secondary maternal outcome data relevant to this review were reported. For the infant, there were no clear differences between the groups of women receiving strict and liberal glycaemic targets for macrosomia (birthweight greater than 4000 g) (RR 1.35, 95% CI 0.31 to 5.85, one trial, 171 babies); small-for-gestational age (RR 1.12, 95% CI 0.48 to 2.63, one trial, 171 babies); birthweight (mean difference (MD) -92.00 g, 95% CI -241.97 to 57.97, one trial, 171 babies) or gestational age (MD -0.30 weeks, 95% CI -0.73 to 0.13, one trial, 171 babies). Adverse effects data were not reported. No other secondary neonatal outcomes relevant to this review were reported. This review is based on a single study (involving 180 women) with an unclear risk of bias. The trial (which was only reported in a conference abstract) did not provide data for any of this review's primary outcomes but did provide data for a limited number of our secondary outcomes. There is insufficient evidence to guide clinical practice for targets for glycaemic control for women with GDM to minimise adverse effects on maternal and fetal health. Glycaemic target recommendations from international professional organisations for maternal glycaemic control vary widely and are reliant on consensus given the lack of high-quality evidence. Further high-quality trials are needed, and these should compare different glycaemic targets for guiding treatment of women with GDM, assess both short-term and long-term health outcomes for women and their babies, include women's experiences and assess health services costs. Four studies are ongoing.
The 32 eligible studies included one randomized controlled trial, eight controlled before-after studies, 14 controlled ITS studies, six ITS studies, and three studies with both ITS and controlled before-after analyses. Most interventions targeted only alcohol-impaired driving (69%) and included additional interventions such as media campaigns or special training for police officers (91%). Only two studies reported sufficient information to assess study quality completely. Two-thirds of studies were scored 'not adequate' on at least one feature. Five of six studies evaluating traffic fatalities reported reductions with the intervention, but differences were statistically significant in only one study. Effects of intervention on traffic injuries were inconsistent in the six studies evaluating this outcome, and no results were statistically significant. All four controlled studies evaluating fatal crashes reported reductions with the intervention, which were statistically significant in one study. All 12 controlled studies assessing injury crashes reported greater reductions with the intervention, though effects were minimal or not significant in several studies. ITS studies showed less consistent effects on fatal crashes (three studies) and injury crashes (four studies), and effect estimates were typically imprecise. Thirteen of 20 studies showed reductions in total crashes and about two-thirds of these were statistically significant. Studies examining increased police patrol programs were generally consistent in reporting beneficial effects on traffic crashes and fatalities, but study quality and reporting were often poor. Methodological limitations included inadequate sample size, dissimilar baseline measures, contamination, and inadequate data analysis. Thus existing evidence, although supportive, does not firmly establish whether increased police patrols, implemented with or without other intervention elements, reduce the adverse consequences of alcohol-impaired driving.
Six trials involving 610 patients were included. Trial quality was generally low. Four of the trials looked at the effect of tricyclic antidepressants on tinnitus, investigating 405 patients. One trial investigated the effect of a selective serotonin reuptake inhibitor (SSRI) in a group of 120 patients. One study investigated trazodone, an atypical antidepressant, versus placebo. Only the trial using the SSRI drug reached the highest quality standard. None of the other included trials met the highest quality standard, due to use of inadequate outcome measures, large drop-out rates or failure to separate the effects on tinnitus from the effects on symptoms of anxiety and depression. All the trials assessing tricyclic antidepressants suggested that there was a slight improvement in tinnitus but these effects may have been attributable to methodological bias. The trial that investigated the SSRI drug found no overall improvement in any of the validated outcome measures that were used in the study although there was possible benefit for a subgroup that received higher doses of the drug. This observation merits further investigation. In the trial investigating trazodone, the results showed an improvement in tinnitus intensity and in quality of life after treatment, but in neither case reached statistical significance. Reports of side effects including sedation, sexual dysfunction and dry mouth were common. There is as yet insufficient evidence to say that antidepressant drug therapy improves tinnitus.
We included five studies (535 participants) in the review: these compared hydrocolloids with basic wound contact dressings, foam dressings, alginate dressings and a topical treatment. Meta-analysis of two studies indicated no statistically significant difference in ulcer healing between fibrous-hydrocolloids and basic wound contact dressings: risk ratio 1.01 (95% CI 0.74 to 1.38). One of these studies found that a basic wound contact dressing was more cost-effective than a fibrous-hydrocolloid dressing. One study compared a hydrocolloid-matrix dressing with a foam dressing and found no statistically significant difference in the number of ulcers healed. There was no statistically significant difference in healing between an antimicrobial (silver) fibrous-hydrocolloid dressing and standard alginate dressing; an antimicrobial dressing (iodine-impregnated) and a standard fibrous hydrocolloid dressing or a standard fibrous hydrocolloid dressing and a topical cream containing plant extracts. Currently there is no research evidence to suggest that any type of hydrocolloid wound dressing is more effective in healing diabetic foot ulcers than other types of dressing or a topical cream containing plant extracts. Decision makers may wish to consider aspects such as dressing cost and the wound management properties offered by each dressing type e.g. exudate management.
We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease. In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or laser therapy; and arterial hypotension or bradycardia requiring inotropic support. Evidence was of moderate quality for the following outcomes: progression to stage 2 with plus disease; progression to stage 3 ROP; and progression to stage 4 or 5 ROP. Meta-analysis of three trials (N = 366) suggested beneficial effects of oral beta-blockers on the risk of requiring anti-VEGF agents (typical risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.86; I² = 0%; typical risk difference (RD) −0.06, 95% CI −0.10 to −0.01; I² = 75%; number needed to treat for an additional beneficial outcome (NNTB) 18, 95% CI 14 to 84) and laser therapy (typical RR 0.54, 95% CI 0.32 to 0.89; typical RD −0.09, 95% CI −0.16 to −0.02; I² = 31%; NNTB 12, 95% CI 8 to 47). Meta-analysis of two trials (N = 161) demonstrated a beneficial effect of oral beta-blockers on progression to stage 3 ROP (typical RR 0.60, 95% CI 0.37 to 0.96; I² = 0%; typical RD −0.15, 95% CI −0.28 to −0.02; I² = 73%; NNTB 7, 95% CI 5 to 67). There was no significant effect of oral beta-blockers on progression to stage 2 ROP with plus disease or to stage 4 or 5 ROP. Although meta-analysis did not indicate a significant effect of beta-blockers on arterial hypotension or bradycardia, propranolol dosage in one study was reduced by 50% in infants of less than 26 weeks' gestational age due to severe hypotension, bradycardia, and apnoea in several participants. Analyses did not indicate significant effects of beta-blockers on complications of prematurity or mortality. None of the trials reported on long-term visual impairment. Limited evidence of low-to-moderate quality suggests that prophylactic administration of oral beta-blockers might reduce progression towards stage 3 ROP and decrease the need for anti-VEGF agents or laser therapy. The clinical relevance of those findings is unclear as no data on long-term visual impairment were reported. Adverse events attributed to oral propranolol at a dose of 2 mg/kg/d raise concerns regarding systemic administration of this drug for prevention of ROP at the given dose. There is insufficient evidence to determine the efficacy and safety of beta-blockers for prevention of ROP due to high risk of bias in two included trials and the lack of long-term functional outcomes. We would encourage researchers to conduct large, well-designed trials to confirm or refute the role of beta-blockers for prevention and treatment of ROP in preterm infants. Trials should report on long-term visual impairment. Researchers should consider dose-finding studies of systemic beta-blockers and topical administration of beta-blockers, in order to optimise drug delivery and minimise adverse events.
We studied 8228 women in nine studies. Eight out of nine studies were at low or unclear risk of bias. Altered fraction size (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not have a clinically meaningful effect on: local recurrence-free survival (Hazard Ratio (HR) 0.94, 95% CI 0.77 to 1.15, 7095 women, four studies, high-quality evidence), cosmetic outcome (Risk ratio (RR) 0.90, 95% CI 0.81 to 1.01, 2103 women, four studies, high-quality evidence) or overall survival (HR 0.91, 95% CI 0.80 to 1.03, 5685 women, three studies, high-quality evidence). Acute radiation skin toxicity (RR 0.32, 95% CI 0.22 to 0.45, 357 women, two studies) was reduced with altered fraction size. Late radiation subcutaneous toxicity did not differ with altered fraction size (RR 0.93, 95% CI 0.83 to 1.05, 5130 women, four studies, high-quality evidence). Breast cancer-specific survival (HR 0.91, 95% CI 0.78 to 1.06, 5685 women, three studies, high quality evidence) and relapse-free survival (HR 0.93, 95% CI 0.82 to 1.05, 5685 women, three studies, moderate-quality evidence) did not differ with altered fraction size. We found no data for mastectomy rate. Altered fraction size was associated with less patient-reported (P < 0.001) and physician-reported (P = 0.009) fatigue at six months (287 women, one study). We found no difference in the issue of altered fractionation for patient-reported outcomes of: physical well-being (P = 0.46), functional well-being (P = 0.38), emotional well-being (P = 0.58), social well-being (P = 0.32), breast cancer concerns (P = 0.94; 287 women, one study). We found no data with respect to costs. We found that using altered fraction size regimens (greater than 2 Gy per fraction) does not have a clinically meaningful effect on local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance, late toxicity or patient-reported quality-of-life measures for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins.
We included nine trials about CME, of which six trials with 333 patient-caregiver couples were included in the meta-analysis. The small number of studies, participants, and a variety of outcome measures rendered summarising and combining of data in meta-analysis difficult. In addition, in some studies, CME was the only intervention (CME-core), whereas in other studies, caregivers provided another, existing intervention, such as constraint-induced movement therapy. For trials in the latter category, it was difficult to separate the effects of CME from the effects of the other intervention. We found no significant effect of CME on basic ADL when pooling all trial data post intervention (4 studies; standardised mean difference (SMD) 0.21, 95% confidence interval (CI) -0.02 to 0.44; P = 0.07; moderate-quality evidence) or at follow-up (2 studies; mean difference (MD) 2.69, 95% CI -8.18 to 13.55; P = 0.63; low-quality evidence). In addition, we found no significant effects of CME on extended ADL at post intervention (two studies; SMD 0.07, 95% CI -0.21 to 0.35; P = 0.64; low-quality evidence) or at follow-up (2 studies; SMD 0.11, 95% CI -0.17 to 0.39; P = 0.45; low-quality evidence). Caregiver burden did not increase at the end of the intervention (2 studies; SMD -0.04, 95% CI -0.45 to 0.37; P = 0.86; moderate-quality evidence) or at follow-up (1 study; MD 0.60, 95% CI -0.71 to 1.91; P = 0.37; very low-quality evidence). At the end of intervention, CME significantly improved the secondary outcomes of standing balance (3 studies; SMD 0.53, 95% CI 0.19 to 0.87; P = 0.002; low-quality evidence) and quality of life (1 study; physical functioning: MD 12.40, 95% CI 1.67 to 23.13; P = 0.02; mobility: MD 18.20, 95% CI 7.54 to 28.86; P = 0.0008; general recovery: MD 15.10, 95% CI 8.44 to 21.76; P < 0.00001; very low-quality evidence). At follow-up, we found a significant effect in favour of CME for Six-Minute Walking Test distance (1 study; MD 109.50 m, 95% CI 17.12 to 201.88; P = 0.02; very low-quality evidence). We also found a significant effect in favour of the control group at the end of intervention, regarding performance time on the Wolf Motor Function test (2 studies; MD -1.72, 95% CI -2.23 to -1.21; P < 0.00001; low-quality evidence). We found no significant effects for the other secondary outcomes (i.e. patient: motor impairment, upper limb function, mood, fatigue, length of stay and adverse events; caregiver: mood and quality of life). In contrast to the primary analysis, sensitivity analysis of CME-core showed a significant effect of CME on basic ADL post intervention (2 studies; MD 9.45, 95% CI 2.11 to 16.78; P = 0.01; moderate-quality evidence). The methodological quality of the included trials and variability in interventions (e.g. content, timing, and duration), affected the validity and generalisability of these observed results. There is very low- to moderate-quality evidence that CME may be a valuable intervention to augment the pallet of therapeutic options for stroke rehabilitation. Included studies were small, heterogeneous, and some trials had an unclear or high risk of bias. Future high-quality research should determine whether CME interventions are (cost-)effective.
We identified three randomized controlled trials (855 children enrolled) in this review. These trials were all conducted in the UK with follow-up periods ranging from one to 3.5 years. We judged the included studies to be at high risk of bias, due to use of quasi-random methods for assigning children to treatment, no masking of outcomes assessors, and high proportions of drop-outs. None of the three trials accounted for missing data and analyses were limited to the available-case data (674 (79%) of 855 children enrolled for the primary outcome). These factors impair our ability to assess the effectiveness of treatment. Analyses incorporating the three trials we identified in this review (674 children) suggested the effect of spectacle correction initiated prior to the age of one year in hyperopic children between three and four years of age is uncertain with respect to preventing strabismus (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.44 to 1.15; very low quality evidence). Based on a meta-analysis of three trials (664 children), the risk of having visual acuity worse than 20/30 at three years of age was also uncertain for children with spectacles compared with those without spectacle correction irrespective of compliance (RR 0.87; 95% CI 0.60 to 1.26; very low quality evidence). Emmetropization was reported in two trials: one trial suggested that spectacles impede emmetropization, and the second trial reported no difference in the rate of refractive error change. Although children who were allocated to the spectacle group were less likely to develop strabismus and less likely to have visual acuity worse than 20/30 children allocated to no spectacles, these effects may have been chance findings, or due to bias. Due to the high risk of bias and poor reporting of included trials, the true effect of spectacle correction for hyperopia on strabismus is still uncertain.
Three double-blind, parallel group, randomised, controlled trials have been conducted on 263 patients. The two phase II studies were relatively small, were conducted over the short term (12 weeks), and used relatively low doses of ropinirole (mean administered doses 3.3 and 3.5 mg/d) in a twice daily regime. In view of this clinical heterogeneity and some statistical heterogeneity, the results of these trials have not been included in a meta-analysis. The conclusions of this review are based on the evidence from a single phase III study which was medium term (26 weeks) and used ropinirole doses in line with the current UK licensed maximum in a thrice daily regime. In view of difficulties in assessing changes in off time in Leiberman 98, caused by the initial imbalance between the arms of the trial, it is unsafe to draw any firm conclusion about the effect of ropinirole on off time. However, as an adverse event, dyskinesia was significantly increased in those who received ropinirole (Leiberman 98; odds ratio 2.90; 1.36, 6.19 95% CI; Table 8). Measurements of motor impairments and disability were poor in this study with incomplete information available. Levodopa dose could be reduced in Leiberman 98 with a significantly larger reduction on ropinirole than on placebo (weighted mean difference 180 mg/d; 106, 253 95% CI; Table 2). No significant differences in the frequency of adverse event reports were noted between ropinirole and placebo apart from the increase in dyskinesia with ropinirole. There was a trend towards fewer withdrawals from ropinirole in Leiberman 98 but this did not reach statistical significance. Ropinirole therapy can reduce levodopa dose but at the expense of increased dyskinetic adverse events. No clear effect on off time reduction was found but this may have been due to the under-powering of the single evaluable trial. Inadequate data on motor impairments and disability was collected to assess these outcomes. These conclusions apply to short and medium term treatment, up to 26 weeks. Further longer term trials are required, with measurements of effectiveness, and also studies to compare the newer with the older dopamine agonists.
Six randomised controlled trials including 446 participants. Two trials compared three types of instruments (MES vs UCS vs EBVS). One trial compared MES and UCS. One trial compared UCS and EBVS. One trial compared 5 mm versus 10 mm EBVS. One trial compared the technique of laparoscopic staplers and clips versus EBVS in pedicle ligation during laparoscopic colectomy. The limitation of this review is the heterogeneity of the trials included. The measured outcomes were covered by one to three studies with small number of participants. With this in mind, there was significant less blood loss in UCS compared to MES. The operating time was significantly shorter with the use of EBVS than MES. No difference between UCS and EBVS apart from EBVS appeared to be handling better than UCS in one study. Haemostatic control was better in UCS and EBVS over MES. No definite conclusion on the cost difference between these three instrument but this would lie in the balance between the instrument cost and the operating time. The handling of 5 mm EBVS was better than 10 mm and its main advantage was trocar flexibility. Laparoscopic staplers/clips used for pedicle ligation in colectomy associated with more failure in vessel ligation and cost more when compared to EBVS. The limitations of this review is the small number of trials and heterogeneity of the studies included. With the current evidence it is not possible to demonstrate which is the best instrument in laparoscopic colectomy. Hopefully more data would follow and subsequent updates of this review could become more informative.
Seven trials involving a total of 266 participants were included. Four trials studied the effects of NSAIDs in chronic CMO while the other three examined the effect of NSAIDs in acute CMO. Of the studies examining chronic CMO, one study enrolled 120 participants, but the remainder had 34 or fewer participants. Four different NSAIDs were used and administered in different ways. Indomethacin was used orally and was found to be ineffective for chronic CMO in one trial. Topical fenoprofen appeared effective but not statistically significantly so for chronic CMO in another small trial. Treatment with topical 0.5% ketorolac for chronic CMO was found to be effective in two trials. Three trials examined the effect of topical NSAIDs on acute CMO. The comparisons among these studies were of an NSAID to placebo, prednisolone or another NSAID. The study design differed between the studies in other important aspects thus they could not be combined in a meta-analysis. This review found two trials which showed that topical NSAID (0.5% ketorolac tromethamine ophthalmic solution) has a positive effect on chronic CMO and two trials which revealed no significant difference between comparative groups. As such, the effects of NSAIDs in acute and chronic CMO remain unclear and needs further investigation.
We include 41 studies of either structured telephone support or non-invasive home telemonitoring for people with heart failure, of which 17 were new and 24 had been included in the previous Cochrane review. In the current review, 25 studies evaluated structured telephone support (eight new studies, plus one study previously included but classified as telemonitoring; total of 9332 participants), 18 evaluated telemonitoring (nine new studies; total of 3860 participants). Two of the included studies trialled both structured telephone support and telemonitoring compared to usual care, therefore 43 comparisons are evident. Non-invasive telemonitoring reduced all-cause mortality (RR 0.80, 95% CI 0.68 to 0.94; participants = 3740; studies = 17; I² = 24%, GRADE: moderate-quality evidence) and heart failure-related hospitalisations (RR 0.71, 95% CI 0.60 to 0.83; participants = 2148; studies = 8; I² = 20%, GRADE: moderate-quality evidence). Structured telephone support reduced all-cause mortality (RR 0.87, 95% CI 0.77 to 0.98; participants = 9222; studies = 22; I² = 0%, GRADE: moderate-quality evidence) and heart failure-related hospitalisations (RR 0.85, 95% CI 0.77 to 0.93; participants = 7030; studies = 16; I² = 27%, GRADE: moderate-quality evidence). Neither structured telephone support nor telemonitoring demonstrated effectiveness in reducing the risk of all-cause hospitalisations (structured telephone support: RR 0.95, 95% CI 0.90 to 1.00; participants = 7216; studies = 16; I² = 47%, GRADE: very low-quality evidence; non-invasive telemonitoring: RR 0.95, 95% CI 0.89 to 1.01; participants = 3332; studies = 13; I² = 71%, GRADE: very low-quality evidence). Seven structured telephone support studies reported length of stay, with one reporting a significant reduction in length of stay in hospital. Nine telemonitoring studies reported length of stay outcome, with one study reporting a significant reduction in the length of stay with the intervention. One telemonitoring study reported a large difference in the total number of hospitalisations for more than three days, but this was not an analysis of length of stay per hospitalisation. Nine of 11 structured telephone support studies and five of 11 telemonitoring studies reported significant improvements in health-related quality of life. Nine structured telephone support studies and six telemonitoring studies reported costs of the intervention or cost effectiveness. Three structured telephone support studies and one telemonitoring study reported a decrease in costs and two telemonitoring studies reported increases in cost, due both to the cost of the intervention and to increased medical management. Adherence was rated between 55.1% and 98.5% for those structured telephone support and telemonitoring studies which reported this outcome. Participant acceptance of the intervention was reported in the range of 76% to 97% for studies which evaluated this outcome. Seven of nine studies that measured these outcomes reported significant improvements in heart failure knowledge and self-care behaviours. For people with heart failure, structured telephone support and non-invasive home telemonitoring reduce the risk of all-cause mortality and heart failure-related hospitalisations; these interventions also demonstrated improvements in health-related quality of life and heart failure knowledge and self-care behaviours. Studies also demonstrated participant satisfaction with the majority of the interventions which assessed this outcome.
Six studies were selected for inclusion (106 participants). No results were combined as the studies were all of a crossover design. EFFECTS OF NEGATIVE ION GENERATORS (five studies) No study reported a significant difference in lung function between ionised and control air (morning Peak expiratory flow (PEF) - three studies; forced expiratory flow in one second (FEV1) - one study). There were no significant differences in symptoms or beta-2 agonist usage between ionised and control air in three studies. EFFECTS OF POSITIVE ION GENERATORS (one study) This study demonstrated that although positively ionised air was associated with a larger fall in FEV1 with exercise, this did not reach statistical significance. Baseline FEV1 was not demonstrated to be significantly different between treatment groups. Based on the evidence currently available from randomised controlled trials, a recommendation cannot be given for the use of room air ionisers to reduce symptoms in patients with chronic asthma.
We included in the review data from one quasi-randomised trial with 88 infants from 75 families. Infants in the early discharge programme with home gavage feeding had a mean hospital stay that was 9.3 days shorter (mean difference (MD) -9.3, 95% confidence interval (CI) -18.49 to -0.11) than that of infants in the control group. Infants in the early discharge programme also had lower risk of clinical infection during the home gavage period compared with those in the control group spending corresponding time in hospital (risk ratio 0.35, 95% CI 0.17 to 0.69). No significant differences were noted between groups in duration and extent of breast feeding, weight gain, re-admission within the first 12 months post discharge from the home gavage programme or from hospital, scores reflecting parental satisfaction or overall health service use. Experimental evidence on the benefits and risks for preterm infants of early discharge from hospital with home gavage feeding compared with later discharge upon attainment of full sucking feeds is limited to the results of one small quasi-randomised controlled trial. High-quality trials with concealed allocation, complete follow-up of all randomly assigned infants and adequate sample size are needed before practice recommendations can be made.
Of 11 RCTs identified 4 were included in this review, with 8,912 participants. Treatment for 4 to 5 years with antihypertensive drugs as compared to placebo did not reduce total mortality (RR 0.85, 95% CI 0.63, 1.15). In 7,080 participants treatment with antihypertensive drugs as compared to placebo did not reduce coronary heart disease (RR 1.12, 95% CI 0.80, 1.57), stroke (RR 0.51, 95% CI 0.24, 1.08), or total cardiovascular events (RR 0.97, 95% CI 0.72, 1.32). Withdrawals due to adverse effects were increased by drug therapy (RR 4.80, 95%CI 4.14, 5.57), Absolute risk increase (ARI) 9%. Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs. Treatment caused 9% of patients to discontinue treatment due to adverse effects. More RCTs are needed in this prevalent population to know whether the benefits of treatment exceed the harms.
Of 23 trials included, 19 examined contraceptive effectiveness. The triphasic and monophasic preparations did not differ significantly. About half of the included trials reported favorable bleeding patterns, that is less spotting, breakthrough bleeding or amenorrhea, in triphasic versus monophasic OC users. However, meta-analysis was generally not possible due to differences in measuring and reporting the cycle disturbance data as well as differences in progestogen type and hormone dosages. No significant differences were found in the numbers of women who discontinued due to medical reasons, cycle disturbances, intermenstrual bleeding or adverse events. The available evidence is insufficient to determine whether triphasic OCs differ from monophasic OCs in effectiveness, bleeding patterns or discontinuation rates. Therefore, we recommend monophasic pills as a first choice for women starting OC use. Large, high-quality RCTs that compare triphasic and monophasic OCs with identical progestogens are needed to determine whether triphasic pills differ from monophasic OCs. Future studies should follow the recommendations of Belsey or Mishell on recording menstrual bleeding patterns and the CONSORT reporting guidelines.
We included 28 studies, with a total of 2306 participants. We assessed most of the studies at high 'risk of bias', particularly in blinding of participants and personnel, and there was substantial inconsistency between studies, so any positive effect of CHM must be treated with caution. We did not include the four studies from the previous version in this review, because they investigated a CHM product that has been withdrawn from the market since 2004. Four studies (three oral and one topical) compared CHM to placebo. Pooled data from 2 studies showed the total effectiveness rate in the CHM group was higher (by risk ratio (RR) 2.09, 95% confidence interval (CI) 1.32 to 3.32; 2 studies; n = 85), and the itching visual analogue score (VAS) in the CHM group was 1.53 lower (by standardised mean difference (SMD), 95% CI 2.64 to 0.41; 2 Studies; n = 94) than the placebo group, where a lower VAS score indicates reduced itch. One study of 85 participants with moderate to severe eczema who received an oral CHM formula for 12 weeks reported a quality of life (QoL) score 2.5 lower in the CHM group (by difference in means (MD), 95% CI 4.77 to 0.23; 1 study; n = 85) than the placebo group, where a lower score indicates better QoL. Twenty-two studies and 1 arm from a study with a 4-arm parallel controlled design compared CHM (5 oral, 6 topical, and 12 mixed oral and topical) to conventional medicines. The total effectiveness rate in the CHM groups was superior (RR 1.43, 95% CI 1.27 to 1.61; 21 studies; n = 1868; very low quality evidence), and the itching VAS in the CHM groups was 0.83 lower (SMD, 95% CI 1.43 to 0.22; 7 studies; n = 465) than the comparators. Two studies compared combined oral and topical CHM to the same oral CHM formula alone. The total effectiveness rate in 1 study was not statistically significant (RR 1.13, 95% CI 0.78 to 1.63; 1 study; n = 20). In the other study, the itching VAS in the CHM group was 1.05 lower (MD, 95% CI 1.75 to 0.35; 1 study; n = 23) than the control group. With regard to side-effects, four studies did not give any report of adverse events. The other 24 studies reported minor adverse events, which were reversed soon after stopping CHM. One participant withdrew from one trial because of exacerbation of their condition after using the CHM intervention. Eight studies received government funding. We could not find conclusive evidence that CHM taken by mouth or applied topically to the skin could reduce the severity of eczema in children or adults. Well-designed, adequately powered RCTs are needed to evaluate the efficacy and safety of CHM for managing eczema.
We included one randomised and one quasi-randomised controlled trial involving a total of 94 participants and reporting results for a maximum of 84 participants. One trial included patients with spinal cord injuries and the other included patients without spinal cord injuries. Both trials compared anterior versus posterior surgical approaches. Both trials were at high risk of bias, including selection bias (one trial), performance bias (both trials) and attrition bias (one trial). Data were pooled for one outcome only: non-union. Reflecting also the imprecision of the results, the evidence was deemed to be of very low quality for all outcomes; which means that our level of uncertainty about the estimates is high. Neither trial found differences between the two approaches in neurological recovery or status, as shown in one study by small clinically insignificant differences in NASS (Northern American Spine Society) neurological scores (0 to 100: optimal score) at one year of follow-up: anterior mean score: 85.23 versus posterior mean score: 83.86; mean difference (MD) 1.37 favouring anterior approach, 95% confidence interval (CI) -9.76 to 12.50; 33 participants; 1 study). The same trial found no relevant between-approach differences at one year in patient-reported quality of life measured using the 36-item Short Form Survey physical (MD -0.08, 95% CI -7.26 to 7.10) and mental component scores (MD 2.88, 95% CI -3.32 to 9.08). Neither trial found evidence of significant differences in long-term pain, or non-union (2/38 versus 2/46; risk ratio (RR) 1.18, 95% CI 0.04 to 34.91). One trial found better sagittal and more 'normal' alignment after the anterior approach (MD -10.31 degrees favouring anterior approach, 95% CI -14.95 degrees to -5.67 degrees), while the other trial reported no significant differences in cervical alignment. There was insufficient evidence to indicate between-group differences in medical adverse events, rates of instrumentation failure and infection. One trial found that the several participants had voice and swallowing disorders after anterior approach surgery (11/20) versus none (0/22) in the posterior approach group: RR 25.19, 95% CI 1.58 to 401.58); all had recovered by three months. Very low quality evidence from two trials indicated little difference in long-term neurological status, pain or patient-reported quality of life between anterior and posterior surgical approaches to the management of individuals with subaxial cervical spine facet dislocations. Sagittal alignment may be better achieved with the anterior approach. There was insufficient evidence available to indicate between-group differences in medical adverse events, rates of instrumentation failure and infection. The disorders of the voice and swallowing that occurred exclusively in the anterior approach group all resolved by three months. We are very uncertain about this evidence and thus we cannot say whether one approach is better than the other. There was no evidence available for other approaches. Further higher quality multicentre randomised trials are warranted.
No new studies met the inclusion criteria for this update. We included one randomised controlled trial in the review. A subgroup of 227 participants with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. We considered the study to be at a generally low risk of bias. We downgraded the quality of the evidence for all outcomes to low. We downgraded the quality of evidence for imprecision as only one study with a small number of participants was available, the number of events was small and the result was consistent with benefit and harm. Due to the limited number of included trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials that examine many types of prophylaxis with long-term follow-up are required before firm conclusions can be made.
Four studies, comprising 104 participants, met the inclusion criteria. One study did not report data within the appropriate follow-up timeframe and data from two studies were insufficient for analysis. The single study from which we extracted data had 47 participants and was a randomised, controlled, parallel-group trial conducted in Sweden. It tested the hypothesis that combined treatment with serial casting and botulinum toxin type A (BTX) was more effective than serial casting alone in reducing ITW gait. This study found that more participants treated with BTX improved (defined as toe walking less than 50% of the time, as reported by parents) (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.57 to 2.55; 1 trial, 46 participants; very low-certainty evidence). However, there was little or no difference between groups in passive ankle joint dorsiflexion range of movement on the right with the knee extended (mean difference (MD) -1.48º, 95% CI -4.13 to 1.16; 1 trial, 47 participants), on the right with the knee flexed (MD -0.04º, 95% CI -1.80 to 1.73; 1 trial, 46 participants), on the left with the knee flexed (MD 1.07, 95% CI -1.22 to 3.37), or on the left with the knee extended (MD 0.05, 95% CI -0.91 to 1.91). Nor was there a clear difference between the groups in recurrence of toe-walking gait (assessed via severity of toe walking (graded 1 (mild), 2 (moderate), or 3 (severe)) on gait analysis, analysed as continuous data: MD 0.34 points, 95% CI -0.09 to 0.78; 46 participants). In principle, MDs greater than zero (i.e.) positive values) would favour BTX and casting and negative values would favour casting alone. We have not reported effects as better or worse because all results were from evidence of very low certainty. We downgraded the certainty of evidence because of study limitations (outcome assessment was not blinded) and imprecision. Outcomes of pain and active range of motion were not reported in the included study. In terms of adverse events, calf pain was reported twice in the casting-only group and three times in the BTX group. There were three minor skin problems in each group and one reported case of pain directly after BTX injection. The report did not state if calf pain and skin irritation were from the same or different participants. The study authors reported that adverse events did not alter treatment adherence. The certainty of evidence from one study, which compared serial casting with serial casting with BTX for ITW in children, was too low for conclusions to be drawn. A further three studies reported outcomes relating to BTX, footwear, exercises, and different types of orthoses as interventions, however the outcome data were too limited to assess their effects.
We included 15 RCTs, conducted primarily in North America and Europe, that had enrolled 4157 type 1 and 9512 type 2 diabetic participants, ranging from 16 to 2130 participants in individual trials. In 10 of the 15 RCTs, one group of participants was assigned to one or more anti-hypertensive agents and the control group received placebo. In three trials, intense blood pressure control was compared to less intense blood pressure control. In the remaining two trials, blood pressure control was compared with usual care. Five of the 15 trials enrolled type 1 diabetics, and 10 trials enrolled type 2 diabetics. Six trials were sponsored entirely by pharmaceutical companies, seven trials received partial support from pharmaceutical companies, and two studies received support from government-sponsored grants and institutional support. Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate. For the primary outcomes, incidence and progression of retinopathy, the quality of evidence was downgraded due to inconsistency and imprecision of estimates from individual studies and differing characteristics of participants. For primary outcomes among type 1 diabetics, one of the five trials reported incidence of retinopathy and one trial reported progression of retinopathy after 4 to 5 years of treatment and follow-up; four of the five trials reported a combined outcome of incidence and progression over the same time interval. Among type 2 diabetics, 5 of the 10 trials reported incidence of diabetic retinopathy and 3 trials reported progression of retinopathy; one of the 10 trials reported a combined outcome of incidence and progression during a 4- to 5-year follow-up period. One trial in which type 2 diabetics participated had reported no primary (or secondary) outcome targeted for this review. The evidence from these trials supported a benefit of more intensive blood pressure control intervention with respect to 4- to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). The available evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). The available evidence regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (type 1 and type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings. The adverse event reported most often (7 of 15 trials) was death, yielding an estimated RR 0.86 (95% CI 0.64 to 1.14). Hypotension was reported from three trials; the estimated RR was 2.08 (95% CI 1.68 to 2.57). Other adverse ocular events were reported from single trials. Hypertension is a well-known risk factor for several chronic conditions in which lowering blood pressure has proven to be beneficial. The available evidence supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.
No studies of vitamin A or other retinoid supplementation were eligible for inclusion. However, one randomised study of beta (β)-carotene supplementation involving 24 people with CF who were receiving pancreatic enzyme substitution was included. The study compared successive β-carotene supplementation periods (high dose followed by low dose) compared to placebo. The results for the low-dose supplementation period should be interpreted with caution, due to the lack of a wash-out period after the high-dose supplementation. The included study did not report on two of the review's primary outcomes (vitamin A deficiency disorders and mortality); results for our third primary outcome of growth and nutritional status (reported as z score for height) showed no difference between supplementation and placebo, mean difference (MD) -0.23 (95% confidence interval (CI) -0.89 to 0.43) (low-quality evidence). With regards to secondary outcomes, supplementation with high-dose β-carotene for three months led to significantly fewer days of systemic antibiotics required to treat pulmonary exacerbations, compared to controls, MD -15 days (95% CI -27.60 to -2.40); however, this was not maintained in the second three-month section of the study when the level of β-carotene supplementation was reduced, MD -8 days (95% CI -18.80 to 2.80) (low-quality evidence). There were no statistically significant effects between groups in lung function (low-quality evidence) and no adverse events were observed (low-quality evidence). Supplementation affected levels of β-carotene in plasma, but not vitamin A levels. The study did not report on quality of life or toxicity. Since no randomised or quasi-randomised controlled studies on retinoid supplementation were identified, no conclusion on the supplementation of vitamin A in people with CF can be drawn. Additionally, due to methodological limitations in the included study, also reflected in the low-quality evidence judged following the specific evidence grading system (GRADE), no clear conclusions on β-carotene supplementation can be drawn. Until further data are available, country- or region-specific guidelines regarding these practices should be followed.
Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria. At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and liver dysfunction. One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12; one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95% CI 0.49 to 1.69; one trial, 545 participants, low quality evidence). One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08 to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial. Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term. Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is unlikely to be quantitatively important when compared to the reduction in mortality. The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are preserved in this group of patients.
Eight RCTs met the inclusion criteria. Six of the trials provided data for this review and all of these were at high risk of bias. Six trials randomised a total of 815 participants to subcutaneous closure (410 participants) or no subcutaneous closure (405 participants). Overall, 7.7% of participants (63/815 of participants) developed superficial surgical site infections and there was no clear evidence of a difference between the two intervention groups (RR 0.84; 95% CI 0.53 to 1.33; very low quality evidence). Only two trials reported superficial wound dehiscence, with 7.9% (17/215) of participants developing the problem. It is not clear whether the lack of reporting of this outcome in other trials was because it did not occur, or was not measured. There was no clear evidence of a between-group difference in the proportion of participants who developed superficial wound dehiscence in the trials that reported this outcome (RR 0.56; 95% CI 0.22 to 1.41; very low quality evidence). Only one trial reported deep wound dehiscence, which occurred in 8.3% (5/60) of participants. There was no clear evidence of a difference in the proportion of participants who developed deep wound dehiscence between the two groups (RR 0.25; 95% CI 0.03 to 2.11; very low quality evidence). Three trials reported the length of hospital stay and found no significant difference between groups (MD 0.10 days; 95% CI -0.45 to 0.64; very low quality evidence). We do not know whether this review reveals a lack of effect or lack of evidence of effect. The confidence intervals for these outcomes were wide, and significant benefits or harms from subcutaneous closure cannot be ruled out. In addition, none of the trials assessed the impact of subcutaneous closure on quality of life, long-term patient outcomes (the follow-up period in the trials varied between one week and two months after surgery) or financial implications to the healthcare provider. There is currently evidence of very low quality which is insufficient to support or refute subcutaneous closure after non-caesarean operations. The use of subcutaneous closure has the potential to affect patient outcomes and utilisation of healthcare resources. Further well-designed trials at low risk of bias are necessary.
Four studies were identified that met pre-determined eligibility criteria, evaluating a total of 342 adults. From the four studies, all assessed as at high risk of bias, three broad interventions were identified that may potentially reduce the risk of ORN development: one study showed no reduction in ORN when using platelet-rich plasma placed in the extraction sockets of prophylactically removed healthy mandibular molar teeth prior to radiotherapy (odds ratio (OR) 3.32, 95% confidence interval (CI) 0.58 to 19.09; one trial, 44 participants; very low-certainty evidence). Another study involved comparing fluoride gel and high-content fluoride toothpaste (1350 parts per million (ppm)) in prevention of post-radiation caries, and found no difference between their use as no cases of ORN were reported (one trial, 220 participants; very low-certainty evidence). The other two studies involved the use of perioperative hyperbaric oxygen (HBO) therapy and antibiotics. One study showed that treatment with HBO caused a reduction in the development of ORN in comparison to patients treated with antibiotics following dental extractions (risk ratio (RR) 0.18, 95% CI 0.43 to 0.76; one trial, 74 participants; very low-certainty evidence). Another study found no difference between combined HBO and antibiotics compared to antibiotics alone prior to dental implant placement (RR 3.00, 95% CI 0.14 to 65.16; one trial, 26 participants; very low-certainty evidence). Adverse effects of the different interventions were not reported clearly or were not important. Given the suboptimal reporting and inadequate sample sizes of the included studies, evidence regarding the interventions evaluated by the trials included in this review is uncertain. More well-designed RCTs with larger samples are required to make conclusive statements regarding the efficacy of these interventions.
From the three small (total n=250) short included studies, we were unable to extract any data on many broad clinically important outcomes such as global state, use of services, and satisfaction with treatment. When Ayurvedic herbs were compared with placebo, about 20% of people left the studies early (n=120, 2 RCTs, RR 0.77 CI 0.37 to 1.62). Mental state ratings were mostly equivocal with the exception of the brahmyadiyoga group using Ayurvedic assessment (n=68, 1 RCT, RR not improved 0.56 CI 0.36 to 0.88, NNT 4 CI 3 to 12). Behaviour seemed unchanged (n=43, 1 RCT, WMD Fergus Falls Behaviour Rating 1.14 CI -1.63 to 3.91). Nausea and vomiting were common in the brahmyadiyoga group (n=43, RR 13.13 CI 0.80 to 216.30). When the Ayurvedic herbs were compared with antipsychotic drugs (chlorpromazine), again, equal numbers left the study early (n=120, 2 RCTs, RR for brahmyadiyoga 0.91 CI 0.42 to 1.97) but people allocated herbs were at greater risk of no improvement in mental state compared to those allocated chlorpromazine (n=45, RR 1.82 CI 1.11 to 2.98). Again, nausea and vomiting were found with use of brahmyadiyoga (n=45, 1 RCT, RR 20.45 CI 1.09 to 383.97, NNH 2 CI 2 to 38). Finally, when Ayurvedic treatment, in this case a complex mixture of many herbs, is compared with chlorpromazine in acutely ill people with schizophrenia, it is equally (˜10% attrition, n=36, RR 0.67 CI 0.13 to 3.53), but skewed data does seem to favour the chlorpromazine group. Ayurvedic medication may have some effects for treatment of schizophrenia, but has been evaluated only in a few small pioneering trials.
We identified six RCTs (1501 participants) that met the inclusion criteria. We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians. None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset). All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence). Serious adverse events (SAEs): there was no significant difference in the total number of SAEs with cerebrolysin (RR 1.16, 95% CI 0.81 to 1.67). This comprised no difference in fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38) and an increase in the number of people with non-fatal SAEs (20/667 with cerebrolysin and 8/668 with placebo: RR 2.47, 95% CI 1.09 to 5.58, P = 0.03) (3 trials, 1335 participants, moderate-quality evidence). Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence). The findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence of an increase in non-fatal SAEs with cerebrolysin use but not in total SAEs.
We included 19 studies involving 1940 participants in this updated review. Of those 1940 participants, 952 received topical or systemic lidocaine therapy and 795 were allocated to the control groups. Topical and systemic lidocaine therapy appeared to reduce the risk of postoperative sore throat (16 studies, 1774 participants, risk ratio (RR) was 0.64 (95% confidence interval (CI) 0.48 to 0.85), the quality of the evidence was low), although when only high-quality trials were included (eight studies, 814 participants) the effect was no longer significant (RR 0.71, 95% CI 0.47 to 1.09). Lidocaine given systemically in two studies (320 participants) did not reveal evidence of an effect (RR 0.44, 95% CI 0.19 to 1.05 ). The severity of sore throat as measured on a visual-analogue scale (VAS) was reduced by lidocaine therapy (six trials, 611 participants, (mean difference (MD) -10.80, 95% CI -14.63 to -6.98). The adverse effects of lidocaine were not reported in these studies, though toxicity is generally rare. In our revised systematic review, although the results of included studies show generally positive results, they should be interpreted carefully. The effect size of lidocaine appeared to be affected by study quality; drug concentration; route of administration; management of cuff pressure during anaesthesia; the included population; and the type of outcome measured.
No new studies were found for this update. Thirteen studies (4222 participants) compared aspirin 900 mg or 1000 mg, alone or in combination with metoclopramide 10 mg, with placebo or other active comparators, mainly sumatriptan 50 mg or 100 mg. For all efficacy outcomes, all active treatments were superior to placebo, with NNTs of 8.1, 4.9 and 6.6 for 2-hour pain-free, 2-hour headache relief, and 24-hour headache relief with aspirin alone versus placebo, and 8.8, 3.3 and 6.2 with aspirin plus metoclopramide versus placebo. Sumatriptan 50 mg did not differ from aspirin alone for 2-hour pain-free and headache relief, while sumatriptan 100 mg was better than the combination of aspirin plus metoclopramide for 2-hour pain-free, but not headache relief; there were no data for 24-hour headache relief. Adverse events were mostly mild and transient, occurring slightly more often with aspirin than placebo. Additional metoclopramide significantly reduced nausea (P < 0.00006) and vomiting (P = 0.002) compared with aspirin alone. We found no new studies since the last version of this review. Aspirin 1000 mg is an effective treatment for acute migraine headaches, similar to sumatriptan 50 mg or 100 mg. Addition of metoclopramide 10 mg improves relief of nausea and vomiting. Adverse events were mainly mild and transient, and were slightly more common with aspirin than placebo, but less common than with sumatriptan 100 mg.
Seven studies met the inclusion criteria of the review (2652 participants). Monotherapy comparison (six studies): There was a significantly greater change in favour of salmeterol in morning PEF and FEV1. There were no significant differences in quality of life, exacerbations, or symptoms. Formoterol appeared to confer some benefits over ipratropium treatment in terms of morning peak flow. Combination comparison (three studies): There was a significant improvement in post-bronchodilator lung function, supplemental short-acting beta-agonist use and HRQL in favour of combination therapy compared with salmeterol alone. The available data from the trials suggest that there is little difference between regular long term use of IpB alone and salmeterol if the aim is to improve COPD symptoms and exercise tolerance. However, salmeterol was more effective in improving lung function variables. In terms of post-bronchodilator lung function, combination therapy conferred modest benefits, a significant improvement in HRQL, and reduced supplemental short-acting beta-agonist requirement, although this effect was not consistent. Additional studies are needed to assess the relative effects of combining therapies, using validated subjective measurements, and should consider concordance and the convenience of people having to use different inhaler devices.
Ten heterogenous trials involving 874 adults with generally unstable fractures were grouped into six comparisons. No trial had proven allocation concealment. Four trials (239 participants) found implantation of bone scaffolding (autogenous bone graft (one trial); Norian SRS - a bone substitute (two trials); methylmethacrylate cement (one trial)) improved anatomical outcomes compared with plaster cast alone; and two found it improved function. Reported complications of bone scaffolding were transient discomfort resulting from extraosseous deposits of Norian SRS; with surgical removal of one intra-articular deposit. One trial (323 participants) comparing bone substitute (Norian SRS) versus plaster cast or external fixation found no difference in functional or anatomical outcomes at one year. Statistically significant complications in the respective groups were extraosseous Norian SRS deposits and pin track infection.   One trial (48 participants with external fixation) found that autogenous bone graft did not significantly change outcome. There was one serious donor-site complication. One trial (21 participants) found some indication of worse outcomes for hydroxyapatite bone cement compared with Kapandji's intrafocal pinning. Three trials (180 participants) found bone scaffolding (autogenous bone graft (one trial); Norian SRS (one trial); methylmethacrylate cement (one trial)) gave no significant difference in functional outcomes but some indication of better anatomical outcomes compared with external fixation. Most reported complications were associated with external fixation; extraosseous deposits of Norian SRS occurred in one trial. One trial (93 participants with dorsal plate fixation) found autografts slightly improved wrist function compared with allogenic bone material but with an excess of donor site complications. Bone scaffolding may improve anatomical outcome compared with plaster cast alone but there is insufficient evidence to conclude on functional outcome and safety; or for other comparisons.
We included 14 studies in this review. Thirteen were before-and-after studies and one was a cost-effectiveness analysis. Three studies each took place in Switzerland and the USA, while two studies each were from the UK, Canada, New Zealand, and Australia respectively. The majority of studies (10/14) assessed jumping means restriction interventions delivered in isolation, half of which were at bridges. Due to the observational nature of included studies, none compared comparator interventions or control conditions. During the pre- and postintervention period among the 13 before-and-after studies, a total of 742.3 suicides (5.5 suicides per year) occurred during the pre-intervention period (134.5 study years), while 70.6 suicides (0.8 suicides per year) occurred during the postintervention period (92.4 study years) - a 91% reduction in suicides. A meta-analysis of all studies assessing jumping means restriction interventions (delivered in isolation or in combination with other interventions) showed a directionality of effect in favour of the interventions, as evidenced by a reduction in the number of suicides at intervention sites (12 studies; incidence rate ratio (IRR) = 0.09, 95% confidence interval (CI) 0.03 to 0.27; P < 0.001; I2 = 88.40%). Similar findings were demonstrated for studies assessing jumping means restriction interventions delivered in isolation (9 studies; IRR = 0.05, 95% CI 0.01 to 0.16; P < 0.001; I2 = 73.67%), studies assessing jumping means restriction interventions delivered in combination with other interventions (3 studies; IRR = 0.54, 95% CI 0.31 to 0.93; P = 0.03; I2 = 40.8%), studies assessing the effectiveness of physical barriers (7 studies; IRR = 0.07, 95% CI 0.02 to 0.24; P < 0.001; I2 = 84.07%), and studies assessing the effectiveness of safety nets (2 studies; IRR = 0.09, 95% CI 0.01 to 1.30; P = 0.07; I2 = 29.3%). Data on suicide attempts were limited and none of the studies used self-harm as an outcome. There was considerable heterogeneity between studies for the primary outcome (suicide) in the majority of the analyses except those relating to jumping means restriction delivered in combination with other interventions, and safety nets. Nevertheless, every study included in the forest plots showed the same directional effects in favour of jumping means restriction. Due to methodological limitations of the included studies, we rated the quality of the evidence from these studies as low. A cost-effectiveness analysis suggested that the construction of a physical barrier on a bridge would be a highly cost-effective project in the long term as a result of overall reduced suicide mortality. The findings from this review suggest that jumping means restriction interventions are capable of reducing the frequency of suicides by jumping. However, due to methodological limitations of included studies, this finding is based on low-quality evidence. Therefore, further well-designed high-quality studies are required to further evaluate the effectiveness of these interventions, as well as other measures at jumping sites. In addition, further research is required to investigate the potential for suicide method substitution and displacement effects in populations exposed to interventions to prevent suicide by jumping.
We included a total of 20 studies with 2068 participants. We studied the anticonvulsant drugs carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate and vigabatrin. All studies compared anticonvulsants versus placebo. Only one study had one arm by which the anticonvulsant was compared with the antidepressant desipramine. Upon comparison of anticonvulsant versus placebo, we found no significant differences for any of the efficacy and safety measures. Dropouts: risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.05, 17 studies, 20 arms, 1695 participants, moderate quality of evidence. Use of cocaine: RR 0.92, 95% CI 0.84 to 1.02, nine studies, 11 arms, 867 participants, moderate quality of evidence; side effects: RR 1.39, 95% CI 1.01 to 1.90, eight studies, 775 participants; craving: standardised mean difference (SMD) -0.25, 95% CI -0.59 to 0.09, seven studies, eight arms, 428 participants, low quality of evidence. Although caution is needed when results from a limited number of small clinical trials are assessed, no current evidence supports the clinical use of anticonvulsant medications in the treatment of patients with cocaine dependence. Although the findings of new trials will improve the quality of study results, especially in relation to specific medications, anticonvulsants as a category cannot be considered first-, second- or third-line treatment for cocaine dependence.
We identified nine trials for inclusion with all nine contributing outcome data. Two trials reported on people with thalassaemia (n = 152) and seven on sickle cell anaemia (n = 307). In people with thalassaemia, in one trial, the serum zinc level value showed no difference between the zinc supplemented group and the control group, mean difference 47.40 (95% confidence interval -12.95 to 107.99). Regarding anthropometry, in one trial, height velocity was significantly increased in patients who received zinc supplementation for one to seven years duration, mean difference 3.37 (95% confidence interval 2.36 to 4.38) (total number of participants = 26). In one trial, however, there was no difference in body mass index between treatment groups. Zinc acetate supplementation for three months (in one trial) and one year (in two trials) (total number of participants = 71) was noted to increase the serum zinc level significantly in patients with sickle cell anaemia, mean difference 14.90 (95% confidence interval 6.94 to 22.86) and 20.25 (95% confidence interval 11.73 to 28.77) respectively. There was no significant difference in haemoglobin level between intervention and control groups, at either three months (one trial) or one year (one trial), mean difference 0.06 (95% confidence interval -0.84 to 0.96) and mean difference -0.07 (95% confidence interval -1.40 to 1.26) respectively. Regarding anthropometry, one trial showed no significant changes in body mass index or weight after one year of zinc acetate supplementation. In patients with sickle cell disease, the total number of sickle cell crises at one year were significantly decreased in the zinc sulphate supplemented group as compared to controls, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (total participants 130), but not in zinc acetate group, mean difference 1.54 (95% confidence interval -2.01 to 5.09) (total participants 22). In one trial at three months and another at one year, the total number of clinical infections were significantly decreased in the zinc supplemented group as compared to controls, mean difference 0.05 (95% confidence interval 0.01 - 0.43) (total number of participants = 36), and mean difference -7.64 (95% confidence interval -10.89 to -4.39) (total number of participants = 21) respectively. According to the results, there is no evidence from randomised controlled trials to indicate any benefit of zinc supplementation with regards to serum zinc level in patients with thalassaemia. However, height velocity was noted to increase among those who received this intervention. There is mixed evidence on the benefit of using zinc supplementation in people with sickle cell disease. For instance, there is evidence that zinc supplementation for one year increased the serum zinc levels in patients with sickle cell disease. However, though serum zinc level was raised in patients receiving zinc supplementation, haemoglobin level and anthropometry measurements were not significantly different between groups. Evidence of benefit is seen with the reduction in the number of sickle cell crises among sickle cell patients who received one year of zinc sulphate supplementation and with the reduction in the total number of clinical infections among sickle cell patients who received zinc supplementation for both three months and for one year. The conclusion is based on the data from a small group of trials,which were generally of good quality, with a low risk of bias. The authors recommend that more trials on zinc supplementation in thalassaemia and sickle cell disease be conducted given that the literature has shown the benefits of zinc in these types of diseases.
There were six eligible studies but only four had sufficient data at the time of this review. The four RCTs included in this review reported on a total of 262 participants. One study, a placebo-controlled trial with a low risk of bias, found that individuals on sulthiame were significantly more likely to remain in seizure remission during the three and six months from commencement of treatment than those on placebo (3 months: RR 2.26, 95% CI 1.48 to 3.44; 6 months: RR 2.63, 95% CI 1.43 to 4.86, 66 participants, moderate quality evidence). The other three trials, all open-labelled studies, had a high risk of bias and did not show any significant differences in terms of seizure remission between AEDs. One compared levetiracetam with oxcarbazepine (3 months: RR 1.13, 95% CI of 0.93 - 1.36; 12 months: RR of 1.29 with 95% CI of 0.89 - 1.86, 39 participants, low to very low quality evidence), one clobazam with carbamazepine (4-40 weeks: RR of 1.04, 95% CI of 0.67 - 1.62; last 9 months: RR of 1.06 with 95% CI of 0.84, 1.34, 45 participants, low quality evidence), and one carbamazepine with topiramate (28 weeks: RR 1.02 with 95% CI of 0.8 - 1.3, 112 participants, low quality evidence). Other outcome measures assessed included time to first seizure after randomisation which was only obtained in the sulthiame versus placebo study as a hazard ratio of 7.8 (95% CI 2.66 - 22.87). There were no significant differences between the proportion of participants who had adverse events, apart from a higher incidence of rash in the carbamazepine group (14.8%) when compared with topiramate (1.7%), or the proportion who withdrew from treatment due to adverse events, when this was reported. Two trials (carbamazepine versus topiramate, and clobazam versus carbamazepine) evaluated the effects on cognition. The studies were of low to very low quality evidence showing no clear difference in cognition at the end of the study periods between the AEDs compared. A meta-analysis was not performed as the RCTs evaluated different therapies. There is evidence from one trial reviewed that sulthiame is effective for seizure remission in the short term in children with BECTS although the precision of the effect estimate is uncertain due to its small sample size. There were no significant differences in the proportion of adverse events between treatment groups studied, including those resulting in withdrawal of treatment. There is insufficient evidence about the medium to longer term effects on seizure control, the optimum antiepileptic drug treatment and the effects of AED treatment on cognition. There is a need for more good quality randomised controlled trials to address these questions to aid the management of children with BECTS.
We included one study involving 883 women. Comparison of sonographic assessment of amniotic fluid index (AFI) on admission versus no sonographic assessment of AFI on admission. The incidence of cesarean section for fetal distress in the intervention group (29 of 447) was significantly higher than those of controls (14 of 436) (risk ratio (RR) 2.02; 95% confidence interval (CI) 1.08 to 3.77). The incidence of Apgar score less than seven at five minutes in the intervention group (10 of 447) was not significantly different from controls (seven of 436) (RR 1.39, 95% CI 0.54 to 3.63). The incidence of artificial oxytocin for augmentation of labour in the intervention group (213 of 447) was significantly higher than controls (132 of 436) (RR 1.57; 95% CI 1.32 to 1.87). The incidence of neonatal NICU admission in the intervention group (35 of 447) was not significantly different from the controls (33 of 436) (RR 1.03; 95% CI 0.66 to 1.63) There is not enough evidence to support the use of admission tests other than cardiotocography for fetal assessment during labour. Appropriate randomised controlled trials with adequate sample size of admission tests other than cardiotocography for fetal assessment during labour are required.
We included 10 RCTs (1611 participants) in this review with a majority of women (72%), mostly parturients (women in labour) (913), after a lumbar puncture for regional anaesthesia. Drugs assessed were epidural and spinal morphine, spinal fentanyl, oral caffeine, rectal indomethacin, intravenous cosyntropin, intravenous aminophylline and intravenous dexamethasone. All the included RCTs reported data on the primary outcome, i.e. the number of participants affected by PDPH of any severity after a lumbar puncture. Epidural morphine and intravenous cosyntropin reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to placebo. Also, intravenous aminophylline reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to no intervention, while intravenous dexamethasone increased it. Spinal morphine increased the number of participants affected by pruritus when compared to placebo, and epidural morphine increased the number of participants affected by nausea and vomiting when compared to placebo. Oral caffeine increased the number of participants affected by insomnia when compared to placebo. The remainder of the interventions analysed did not show any relevant effect for any of the outcomes. None of the included RCTs reported the number of days that patients stayed in hospital. Morphine and cosyntropin have shown effectiveness for reducing the number of participants affected by PDPH of any severity after a lumbar puncture, when compared to placebo, especially in patients with high risk of PDPH, such as obstetric patients who have had an inadvertent dural puncture. Aminophylline also reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to no intervention in patients undergoing elective caesarean section. Dexamethasone increased the risk of PDPH, after spinal anaesthesia for caesarean section, when compared to placebo. Morphine also increased the number of participants affected by adverse events (pruritus and nausea and vomiting) There is a lack of conclusive evidence for the other drugs assessed (fentanyl, caffeine, indomethacin and dexamethasone). These conclusions should be interpreted with caution, owing to the lack of information, to allow correct appraisal of risk of bias and the small sample sizes of studies.
Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.
Only one study with 45 participants met the inclusion criteria. Men were divided in two sub-groups (minimal or total incontinence) and each group was randomised to artificial urethral sphincter (AUS) implantation or Macroplastique injection. Follow-up ranged from six to 120 months. In the trial as a whole, the men treated with AUS were more likely to be dry (18/20, 82%) than those who had the injectable treatment (11/23, 46%) (odds ratio (OR) 5.67, 95% confidence interval (CI) 1.28 to 25.10). However, this effect was only statistically significant for the men with more severe ('total') incontinence (OR 8.89, 95% CI 1.40 to 56.57) and the CIs were wide. There were more severe complications in the group undergoing AUS, and the costs were higher. AUS implantation was complicated in 5/22 (23%) men: the implant had to be removed from one man because of infection and in one man due to the erosion of the cuff, in one man the pump was changed due to mechanical failure, in one man there was migration to the intraperitoneal region, and one man experienced scrotal erosion. In the injectable group, 3/23 (13%) men had a complication: one man treated with Macroplastique injection had to be catheterised because of urinary retention and two men developed urinary tract infections. The evidence available at present was of very low quality because we identified only one small randomised clinical trial. Although the result was favourable for the implantation of AUS in the group with severe incontinence, this result should be considered with caution due to the small sample size and uncertain methodological quality of the study found.
In the original version of this review, we identified three RCTs that assessed different intervention and control diets in 192 participants (97 randomised to intervention diet; 95 to control diet) with different types of malignancies. For the update, we identified no eligible new studies. Co-interventions (e.g. protective environment, antimicrobial prophylaxis, central venous catheter care, oral care, hygiene practices, colony-stimulating factors) and outcome definitions also differed between studies. In all included studies, it was standard policy to give empirical antibiotics (and sometimes also antimycotics) to (some of) the participants diagnosed with an infection. Two studies included adults and one study included children. In all studies, only a scant description of treatment regimens was provided. All studies had methodological limitations. Pooling of results of included studies was not possible. In two individual studies, no statistically significant differences in infection rate were identified between intervention and control diets; another study showed no significant differences between treatment groups in the number of chemotherapy cycles with an infection. None of the studies mentioned infection-related mortality, but in one study, no significant difference in overall survival was observed between treatment groups. Time from onset of neutropenia to fever, duration of empirical antibiotics and antimycotics, diet acceptability (i.e. following the diet easily and following the diet throughout all chemotherapy cycles) and quality of life were all evaluated by only one study; for all outcomes, no statistically significant differences between treatment arms were identified. At the moment, no evidence from individual RCTs in children and adults with different malignancies underscores use of an LBD for prevention of infection and related outcomes. All studies differed with regard to co-interventions, outcome definitions and intervention and control diets. As pooling of results was not possible, and as all studies had serious methodological limitations, we could reach no definitive conclusions. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. On the basis of currently available evidence, we are not able to provide recommendations for clinical practice. Additional high-quality research is needed.
We identified eight randomized trials with a total of 300 adult participants for our analysis. We did not identify any trials in children. Four trials assessed thermal biofeedback. One trial assessed rectosigmoidal biofeedback. Two trials assessed heart rate variability biofeedback. Two trials assessed electrocutaneous biofeedback. Comparators were: no treatment (symptom monitoring group; three studies), attention control (pseudomeditation; two studies), relaxation control (one study), counseling (two studies), hypnotherapy (one study), standard therapy (one study), and sham biofeedback (one study). We judged all trials to have a high or unclear risk of bias. Global/Clinical improvement The clinical benefit of biofeedback plus standard therapy compared to standard therapy alone was uncertain (RR 4.20, 95% CI 1.40 to 12.58; 1 study, 20 participants; very low-certainty evidence). The same study also compared biofeedback plus standard therapy to sham biofeedback plus standard therapy. The clinical benefit in the biofeedback group was uncertain (RR 2.33, 95% CI 1.13 to 4.80; 1 study, 20 participants; very low-certainty evidence). The clinical benefit of heart rate biofeedback compared to hypnotherapy was uncertain when measured with the IBS severity scoring system (IBS-SSS) (MD -58.80, 95% CI -109.11 to -8.49; 1 study, 61 participants; low-certainty evidence). Compared to counseling, the effect of heart rate biofeedback was unclear when measured with a composite symptom reduction score (MD 7.03, 95% CI -51.07 to 65.13; 1 study, 29 participants; low-certainty evidence) and when evaluated for clinical response (50% improvement) (RR 1.09, 95% CI 0.48 to 2.45; 1 study, 29 participants; low-certainty evidence). The clinical benefit of thermal biofeedback used in a multi-component psychological intervention (MCPI) compared to no treatment was uncertain when measured with a composite clinical symptom reduction score (MD 30.34, 95% CI 8.47 to 52.21; 3 studies, 101 participants; very low-certainty evidence), and when evaluated as clinical response (50% improvement) (RR 2.12, 95% CI 1.24 to 3.62; 3 studies, 101 participants; very low-certainty evidence). Compared to attention control, the effects of thermal biofeedback within an MCPI were unclear when measured with a composite clinical symptom reduction score (MD 4.02, 95% CI -21.41 to 29.45; 2 studies, 80 participants; very low-certainty evidence) and when evaluated as clinical response (50% improvement) (RR 1.10, 95% CI 0.72 to 1.69, 2 studies, 80 participants; very low-certainty evidence). Quality of life A single trial used overall quality of life as an outcome measure, and reported that both the biofeedback and cognitive therapy groups improved after treatment. The trial did not note any between-group differences, and did not report any outcome data. Adverse events Only one of the eight trials explicitly reported adverse events. This study reported no adverse events in either the biofeedback or cognitive therapy groups (RD 0.00, 95% CI -0.12 to 0.12; 29 participants; low-certainty evidence). There is currently not enough evidence to assess whether biofeedback interventions are effective for controlling symptoms of IBS. Given the positive results reported in small trials to date, biofeedback deserves further study in people with IBS. Future research should include active control groups that use high provider-participant interaction, in an attempt to balance non-specific effects of interventions between groups, and report both commonly used outcome measures (e.g. IBS-SSS) and historical outcome measures (e.g. the composite primary symptom reduction (CPSR) score) to allow for meta-analysis with previous studies. Future studies should be explicit in their reporting of adverse events.
Seventeen trials with 1466 women contribute data to the review. Thirteen examined TENS applied to the back, two to acupuncture points, and two to the cranium. Overall, there was little difference in pain ratings between TENS and control groups, although women receiving TENS to acupuncture points were less likely to report severe pain (average risk ratio 0.41, 95% confidence interval 0.31 to 0.54; measured in two studies). The majority of women using TENS said they would be willing to use it again in a future labour. Where TENS was used as an adjunct to epidural analgesia there was no evidence that it reduced pain. There was no consistent evidence that TENS had any impact on interventions and outcomes in labour. There was little information on outcomes for mothers and babies. No adverse events were reported. There is only limited evidence that TENS reduces pain in labour and it does not seem to have any impact (either positive or negative) on other outcomes for mothers or babies. The use of TENS at home in early labour has not been evaluated. TENS is widely available in hospital settings and women should have the choice of using it in labour.
Five studies were eligible for inclusion (329 patients). Three studies (270 patients) compared low molecular weight heparin to placebo, one study (34 patients) compared LMWH in addition to standard therapy, and one study (25 patients) compared UFH to corticosteroids. The study comparing UFH to corticosteroids was rated at high risk of bias due to a single-blind design. The study that compared the addition of LMWH to standard therapy to standard therapy alone was rated at high risk of bias due to open-label design. The other three studies were rated as low risk of bias. LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission (very low quality of evidence), and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (RR 1.39; 95% CI 1.09 to 1.77 ; P = 0.008; very low quality of evidence), clinical improvement (RR 1.28; 95% CI 1.06 to 1.55; P = 0.01; very low quality of evidence), and endoscopic improvement (RR 1.21; 95% CI 1.00 to 1.47 ; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.
We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity. Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence). Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively. Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%. There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.
Six randomised trials involving 206 patients with acute hepatitis C met the inclusion criteria. Four trials assessing interferon alfa-2b in 141 patients, all with transfusion-acquired acute hepatitis C, were included. They demonstrated no significant heterogeneity in the outcomes assessed. When compared with no treatment, interferon alfa-2b was associated with an increase in the rates of virologic ETR and SR by 45% (95% CI 31-59%, P < 0.00001) and 29% (95% CI 14-44%, P = 0.0002), respectively. The virologic ETR was 42% (95% CI: 30-56%) in the interferon alfa-2b group versus 4% (95% CI 0-13%, P < 0.00001) in the control group. At the end of follow-up, a virologic SR was seen in 32% (95% CI 21-46%) of interferon-treated patients versus only 4% (95% CI 0-13%, P = 0.00007) of controls. Interferon also improved liver biochemistry to a similar extent. The tolerability of therapy, or the impact of interferon alfa-2b on hepatic histology, was not reported. Two trials assessed interferon beta in a total 65 patients. The efficacy of interferon beta could not be assessed, however, due to heterogeneity of these trials. Interferon alfa is effective in improving biochemical outcomes and achieving sustained virologic clearance in patients with transfusion-acquired acute hepatitis C. The effect on long-term clinical outcomes could not be assessed due to limitations in the current data.
We included 23 studies (from 35 reports) with a total of 11,170 caregiver-infant pairs who were randomly assigned to receive an educational intervention delivered to the caregiver or usual care. Nineteen of the included studies were community-based studies while four were facility-based studies. In addition, 13 of the included studies were cluster-randomised while the others were individually randomised. Generally, the interventions were focused on the introduction of complementary feeding at the appropriate time, the types and amount of complementary foods to be fed to infants, and hygiene. Using the GRADE criteria, we assessed the quality of the evidence as moderate, mostly due to inadequate allocation concealment and insufficient blinding. Educational interventions led to improvements in complementary feeding practices for age at introduction of complementary foods (average RR 0.88, 95% CI 0.83 to 0.94; 4 studies, 1738 children; moderate-quality evidence) and hygiene practices (average RR 1.38, 95% CI 1.23 to 1.55; 4 studies, 2029 participants; moderate-quality evidence). For duration of exclusive breastfeeding, pooled results were compatible with both a reduction and an increase in the outcome (average RR 1.58, 95% CI 0.77 to 3.22; 3 studies, 1544 children; very low-quality evidence). There was limited (low to very low-quality) evidence of an effect for all growth outcomes. Quality of evidence There is moderate to very low-quality evidence that educational interventions can improve complementary feeding practices but insufficient evidence to conclude that it impacts growth outcomes. Overall, we found evidence that education improves complementary feeding practices.
Our search led to 5518 potentially relevant references. From these, we included seven RCTs in the analyses involving 2564 patients. In contrast to the first version of this review including five trials, we excluded trials randomising children. As a result, we excluded one trial from the former analyses and we identified three new trials. Five trials with 1388 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with the same number of chemotherapy cycles in both arms. The addition of radiotherapy to chemotherapy has probably little or no difference on OS (HR 0.48; 95% confidence interval (CI) 0.22 to 1.06; P = 0.07, moderate- quality evidence), however two included trials had potential other high risk of bias due to a high number of patients not receiving planned radiotherapy. After excluding these trials in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved OS compared to chemotherapy alone (HR 0.31; 95% CI 0.19 to 0.52; P <0.00001, moderate- quality evidence). In contrast to chemotherapy alone the use of chemotherapy and radiotherapy improved PFS (HR 0.42; 95% CI 0.25 to 0.72; P = 0.001; moderate- quality evidence). Regarding infection- related mortality (RR 0.33; 95% CI 0.01 to 8.06; P = 0.5; low- quality evidence), second cancer- related mortality (RR 0.53; 95% CI 0.07 to 4.29; P = 0.55; low- quality evidence) and cardiac disease- related mortality (RR 2.94; 95% CI 0.31 to 27.55; P = 0.35;low- quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. For complete response rate (CRR) (RR 1.08; 95% CI 0.93 to 1.25; P = 0.33; low- quality evidence), there is also no evidence for a difference between treatment groups. Two trials with 1176 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with different numbers of chemotherapy cycles in both arms. OS is reported in one trial only, the use of chemotherapy alone (more chemotherapy cycles) may improve OS compared to chemotherapy plus radiotherapy (HR 2.12; 95% CI 1.03 to 4.37; P = 0.04; low- quality evidence). This trial also had a potential other high risk of bias due to a high number of patients not receiving planned therapy. There is no evidence for a difference between chemotherapy alone and chemotherapy plus radiotherapy regarding PFS (HR 0.42; 95% CI 0.14 to 1.24; P = 0.12; low- quality evidence). After excluding the trial with patients not receiving the planned therapy in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved PFS compared to chemotherapy alone (HR 0.24; 95% CI 0.070 to 0.88; P = 0.03, based on one trial). For infection- related mortality (RR 6.90; 95% CI 0.36 to 132.34; P = 0.2; low- quality evidence), second cancer- related mortality (RR 2.22; 95% CI 0.7 to 7.03; P = 0.18; low- quality evidence) and cardiac disease-related mortality (RR 0.99; 95% CI 0.14 to 6.90; P = 0.99; low-quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. CRR rate was not reported. This systematic review compared the effects of chemotherapy alone and chemotherapy plus radiotherapy in adults with early stage HL . For the comparison with same numbers of chemotherapy cycles in both arms, we found moderate- quality evidence that PFS is superior in patients receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. The addition of radiotherapy to chemotherapy has probably little or no difference on OS . The sensitivity analysis without the trials with potential other high risk of bias showed that chemotherapy plus radiotherapy improves OS compared to chemotherapy alone. For the comparison with different numbers of chemotherapy cycles between the arms there are no implications for OS and PFS possible, because of the low quality of evidence of the results.
We added 10 RCTs to this updated review. The review now includes 54 published trials (45 fully published reports, four abstracts, and five subsets of data from previously published RCTs) involving 11,898 participants. Lower biological WBRT doses versus control  The hazard ratio (HR) for overall survival (OS) with lower biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 1.21 (95% confidence interval (CI) 1.04 to 1.40; P = 0.01; moderate-certainty evidence) in favour of control. The HR for neurological function improvement (NFI) was 1.74 (95% CI 1.06 to 2.84; P = 0.03; moderate-certainty evidence) in favour of control fractionation. Higher biological WBRT doses versus control The HR for OS with higher biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 0.97 (95% CI 0.83 to 1.12; P = 0.65; moderate-certainty evidence). The HR for NFI was 1.14 (95% CI 0.92 to 1.42; P = 0.23; moderate-certainty evidence). WBRT and radiosensitisers  The addition of radiosensitisers to WBRT did not confer additional benefit for OS (HR 1.05, 95% CI 0.99 to 1.12; P = 0.12; moderate-certainty evidence) or for brain tumour response rates (odds ratio (OR) 0.84, 95% CI 0.63 to 1.11; P = 0.22; high-certainty evidence). Radiosurgery and WBRT versus WBRT alone  The HR for OS with use of WBRT and radiosurgery boost as compared with WBRT alone for selected participants was 0.61 (95% CI 0.27 to 1.39; P = 0.24; moderate-certainty evidence). For overall brain control at one year, the HR was 0.39 (95% CI 0.25 to 0.60; P < 0.0001; high-certainty evidence) favouring the WBRT and radiosurgery boost group. Radiosurgery alone versus radiosurgery and WBRT The HR for local brain control was 2.73 (95% CI 1.87 to 3.99; P < 0.00001; high-certainty evidence)favouring the addition of WBRT to radiosurgery. The HR for distant brain control was 2.34 (95% CI 1.73 to 3.18; P < 0.00001; high-certainty evidence) favouring WBRT and radiosurgery. The HR for OS was 1.00 (95% CI 0.80 to 1.25; P = 0.99; moderate-certainty evidence). Two trials reported worse neurocognitive outcomes and one trial reported worse quality of life outcomes when WBRT was added to radiosurgery. We could not pool data from trials related to chemotherapy, optimal supportive care (OSC), molecular targeted agents, neurocognitive protective agents, and hippocampal sparing WBRT. However, one trial reported no differences in quality-adjusted life-years for selected participants with brain metastases from non-small-cell lung cancer randomised to OSC and WBRT versus OSC alone. None of the trials with altered higher biological WBRT dose-fractionation schemes reported benefit for OS, NFI, or symptom control compared with standard care. However, OS and NFI were worse for lower biological WBRT dose-fractionation schemes than for standard dose schedules. The addition of WBRT to radiosurgery improved local and distant brain control in selected people with brain metastases, but data show worse neurocognitive outcomes and no differences in OS. Selected people with multiple brain metastases from non-small-cell lung cancer may show no difference in OS when OSC is given and WBRT is omitted. Use of radiosensitisers, chemotherapy, or molecular targeted agents in conjunction with WBRT remains experimental. Further trials are needed to evaluate the use of neurocognitive protective agents and hippocampal sparing with WBRT. As well, future trials should examine homogeneous participants with brain metastases with focus on prognostic features and molecular markers.
We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate. We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low. Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.
The risk of bias was high in many of the included studies. Random sequence generation and allocation concealment was reported in three (12%) and four studies (16%), respectively. Participants and personnel were blinded in 13 studies (52%), and outcome assessors were blinded in five studies (20%). Complete outcome reporting occurred in nine studies (36%). Adverse events were only reported in nine studies (36%); 11 studies (44%) reported industry funding. We included 25 studies (8289 participants) in this latest update; 23 studies (24 comparisons, 8166 participants) compared statins with placebo or no treatment, and two studies (123 participants) compared statins directly with one or more other statins. Statins had little or no effect on major cardiovascular events (4 studies, 7084 participants: RR 0.95, 95% CI 0.88 to 1.03), all-cause mortality (13 studies, 4705 participants: RR 0.96, 95% CI 0.90 to 1.02), cardiovascular mortality (13 studies, 4627 participants: RR 0.94, 95% CI 0.84 to 1.06) and myocardial infarction (3 studies, 4047 participants: RR 0.87, 95% CI 0.71 to 1.07); and uncertain effects on stroke (2 studies, 4018 participants: RR 1.29, 95% CI 0.96 to 1.72). Risks of adverse events from statin therapy were uncertain; these included effects on elevated creatine kinase (5 studies, 3067 participants: RR 1.25, 95% CI 0.55 to 2.83) or liver function enzymes (4 studies, 3044 participants; RR 1.09, 95% CI 0.41 to 1.25), withdrawal due to adverse events (9 studies, 1832 participants: RR 1.04, 95% CI 0.87 to 1.25) or cancer (2 studies, 4012 participants: RR 0.90, 95% CI 0.72 to 1.11). Statins reduced total serum cholesterol (14 studies, 1803 participants; MD -44.86 mg/dL, 95% CI -55.19 to -34.53) and low-density lipoprotein cholesterol (12 studies, 1747 participants: MD -39.99 mg/dL, 95% CI -52.46 to -27.52) levels. Data comparing statin therapy directly with another statin were sparse. Statins have little or no beneficial effects on mortality or cardiovascular events and uncertain adverse effects in adults treated with dialysis despite clinically relevant reductions in serum cholesterol levels.
We included six RCTs with a total of 421 patients with various types of atrial fibrillation. All trials were conducted between 2006 and 2016, and had short follow-up (eight weeks to six months). Risks of bias ranged from high risk to low risk.The exercise-based programmes in four trials consisted of both aerobic exercise and resistance training, in one trial consisted of Qi-gong (slow and graceful movements), and in another trial, consisted of inspiratory muscle training. For mortality, very low-quality evidence from six trials suggested no clear difference in deaths between the exercise and no-exercise groups (relative risk (RR) 1.00, 95% confidence interval (CI) 0.06 to 15.78; participants = 421; I² = 0%; deaths = 2). Very low-quality evidence from five trials suggested no clear difference between groups for serious adverse events (RR 1.01, 95% CI 0.98 to 1.05; participants = 381; I² = 0%; events = 8). Low-quality evidence from two trials suggested no clear difference in health-related quality of life for the Short Form-36 (SF-36) physical component summary measure (mean difference (MD) 1.96, 95% CI -2.50 to 6.42; participants = 224; I² = 69%), or the SF-36 mental component summary measure (MD 1.99, 95% CI -0.48 to 4.46; participants = 224; I² = 0%). Exercise capacity was assessed by cumulated work, or maximal power (Watt), obtained by cycle ergometer, or by six minute walking test, or ergospirometry testing measuring VO2 peak. We found moderate-quality evidence from two studies that exercise-based rehabilitation increased exercise capacity, measured by VO2 peak, more than no exercise (MD 3.76, 95% CI 1.37 to 6.15; participants = 208; I² = 0%); and very low-quality evidence from four studies that exercise-based rehabilitation increased exercise capacity more than no exercise, measured by the six-minute walking test (MD 75.76, 95% CI 14.00 to 137.53; participants = 272; I² = 85%). When we combined the different assessment tools for exercise capacity, we found very low-quality evidence from six trials that exercise-based rehabilitation increased exercise capacity more than no exercise (standardised mean difference (SMD) 0.86, 95% CI 0.46 to 1.26; participants = 359; I² = 65%). Overall, the quality of the evidence for the outcomes ranged from moderate to very-low. Due to few randomised patients and outcomes, we could not evaluate the real impact of exercise-based cardiac rehabilitation on mortality or serious adverse events. The evidence showed no clinically relevant effect on health-related quality of life. Pooled data showed a positive effect on the surrogate outcome of physical exercise capacity, but due to the low number of patients and the moderate to very low-quality of the underpinning evidence, we could not be certain of the magnitude of the effect. Future high-quality randomised trials are needed to assess the benefits and harms of exercise-based cardiac rehabilitation for adults with atrial fibrillation on patient-relevant outcomes.
This review included two studies of good methodological quality that enrolled 1073 participants with COPD. The studies used a similar design and inclusion criteria and were of at least 12 weeks duration; the participants had a mean forced expiratory volume in one second (FEV1) of 40% predicted value at baseline. One study used tiotropium via the HandiHaler (18 µg) for 12 months and the other via the Respimat device (5 µg and 10 µg) for 12 weeks. In general, the treatment groups were well matched at baseline but not all outcomes were reported for both studies. Overall the risk of bias across the included RCTs was low. For primary outcomes this review found that at the three months trough (the lowest level measured before treatment) FEV1 significantly increased with tiotropium compared to ipratropium bromide (mean difference (MD) 109 mL; 95% confidence interval (CI) 81 to 137, moderate quality evidence, I2 = 62%). There were fewer people experiencing one or more non-fatal serious adverse events on tiotropium compared to ipratropium (odds ratio (OR) 0.5; 95% CI 0.34 to 0.73, high quality evidence). This represents an absolute reduction in risk from 176 to 97 per 1000 people over three to 12 months. Concerning disease specific adverse events, the tiotropium group were also less likely to experience a COPD-related serious adverse event when compared to ipratropium bromide (OR 0.59; 95% CI 0.41 to 0.85, moderate quality evidence). For secondary outcomes, both studies reported fewer hospital admissions in the tiotropium group (OR 0.34; 95% CI 0.15 to 0.70, moderate quality evidence); as well as fewer patients experiencing one or more exacerbations leading to hospitalisation in the people on tiotropium in both studies (OR 0.56; 95% CI 0.31 to 0.99, moderate quality evidence). There was no significant difference in mortality between the treatments (OR 1.39; 95% CI 0.44 to 4.39, moderate quality evidence). One study measured quality of life using the St George's Respiratory Questionnaire (SGRQ); the mean SGRQ score at 52 weeks was lower in the tiotropium group than the ipratropium group (lower on the scale is favourable) (MD -3.30; 95% CI -5.63 to -0.97, moderate quality evidence). There were fewer participants suffering one of more exacerbations in the tiotropium arm (OR 0.71; 95% CI 0.52 to 0.95, high quality evidence) and there was also a reported difference in the mean number of exacerbations per person per year which reached statistical significance (MD -0.23; 95% CI -0.39 to -0.07, P = 0.006, moderate quality evidence). From the 1073 participants there were significantly fewer withdrawals from the tiotropium group (OR 0.58; 95% CI 0.41 to 0.83, high quality evidence). This review shows that tiotropium treatment, when compared with ipratropium bromide, was associated with improved lung function, fewer hospital admissions (including those for exacerbations of COPD), fewer exacerbations of COPD and improved quality of life. There were both fewer serious adverse events and disease specific events in the tiotropium group, but no significant difference in deaths with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a reasonable choice (instead of ipratropium bromide) for patients with stable COPD, as proposed in guidelines. A recent large double-blind trial of the two delivery devices found no substantial difference in mortality using 2.5 µg or 5 µg of tiotropium via Respimat in comparison to 18 µg via Handihaler.
This review includes eight studies conducted in 22,604 participants (mostly adults). Six studies compared formoterol as-needed to terbutaline whilst two studies compared formoterol with salbutamol as-needed. Background maintenance therapy varied across the trials. Asthma exacerbations and serious adverse events showed a direction of treatment effect favouring formoterol, of which one outcome reached statistical significance (exacerbations requiring a course of oral corticosteroids). In patients on short-acting beta2-agonists, 117 people out of 1000 had exacerbations requiring oral corticosteroids over 30 weeks, compared to 101 (95% CI 93 to 108) out of 1000 for patients on formoterol as-needed. In patients on maintenance inhaled corticosteroids there were also significantly fewer exacerbations requiring a course of oral corticosteroids on formoterol as-needed (Peto OR 0.75; 95% CI 0.62 to 0.91). There was one death per 1000 people on formoterol or on short-acting beta2-agonists. In adults, formoterol was similar to short-acting beta2-agonists when used as a reliever, and showed a reduction in the number of exacerbations requiring a course of oral corticosteroids. Clinicians should weigh the relatively modest benefits of formoterol as-needed against the benefits of single inhaler therapy and the potential danger of long-term use of long-acting beta2-agonists in some patients. We did not find evidence to recommend changes to guidelines that suggest that long-acting beta2-agonists should be given only to patients already taking inhaled corticosteroids. There was insufficient information reported from children in the included trials to come to any conclusion on the safety or efficacy of formoterol as relief medication for children with asthma.
These results include data from one extra trial and so update those in the original publication ABC 2003. Platinum based combination chemotherapy showed a significant benefit on overall survival with a combined hazard ratio (HR) 0.86 (95% CI 0.77 to 0.95, P = 0.003); 14% reduction in the risk of death; 5% absolute benefit at 5 years (95% CI 1% to 7%); overall survival increased from 45% to 50%. This effect was observed irrespective of the type of local treatment and did not vary between subgroups of patients. The HR for all trials, including those that used single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR= 0.89, 95% CI 0.81 to 0.98, P = 0.022). Although platinum based combination chemotherapy was beneficial, there was no clear evidence to support the use of single-agent platinum, indeed there was significant difference in the effect between these groups of trials (P = 0.029). This improvement in survival encourages the use of platinum based combination chemotherapy for patients with invasive bladder cancer.
We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full-text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias. We report results for the following four main comparisons. Sumatriptan versus placebo (1 parallel study; 102 participants) Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan. Magnesium citrate versus placebo (1 parallel study; 70 participants) The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE. Spironolactone versus placebo (2 parallel studies; 205 participants) Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I² = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. Acetazolamide versus spironolactone (1 parallel study; 232 participants) Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review.
We included 21 trials in this review. The 21 included studies investigated a range of technologies aiming to support the provision of care from a distance. These included: telephone (n = 9); video-conferencing (n = 2); Internet (n = 2); other networked communications (n = 6); text Short Messaging Service (n = 1); or a combination of text and Internet (n = 1). Meta-analysis showed that these interventions did not result in clinically important improvements in asthma quality of life (minimum clinically important difference = 0.5): mean difference in Juniper's Asthma Quality of Life Questionnaire (AQLQ) 0.08 (95% CI 0.01 to 0.16). Telehealthcare for asthma resulted in a non-significant increase in the odds of emergency department visits over a 12-month period: OR 1.16 (95% CI 0.52 to 2.58). There was, however, a significant reduction in hospitalisations over a 12-month period: OR 0.21 (95% CI 0.07 to 0.61), the effect being most marked in people with more severe asthma managed predominantly in secondary care settings. Telehealthcare interventions are unlikely to result in clinically relevant improvements in health outcomes in those with relatively mild asthma, but they may have a role in those with more severe disease who are at high risk of hospital admission. Further trials evaluating the effectiveness and cost-effectiveness of a range of telehealthcare interventions are needed.
Twenty-five studies met the inclusion criteria (3615 randomly assigned participants). Only 12 of these studies were randomised controlled trials with appropriate allocation concealment. Variability was evident with regard to focus and intensity of the intervention, participant characteristics and length of follow-up. Meta-analysis led to the conclusion that intervention improved cognitive outcomes at infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.32 standard deviations (SDs), 95% confidence interval (CI) 0.16 to 0.47; P value < 0.001; 16 studies; 2372 participants) and at preschool age (intelligence quotient (IQ); SMD 0.43 SDs, 95% CI 0.32 to 0.54; P value < 0.001; eight studies; 1436 participants). However, this effect was not sustained at school age (IQ: SMD 0.18 SDs, 95% CI -0.08 to 0.43; P value = 0.17; five studies; 1372 participants). Heterogeneity between studies for cognitive outcomes at infancy and at school age was significant. With regards to motor outcomes, meta-analysis of 12 studies showed a significant effect in favour of early developmental interventions at infancy only; however, this effect was small (motor scale DQ: SMD 0.10 SDs, 95% CI 0.01 to 0.19; P value = 0.03; 12 studies; 1895 participants). No effect was noted on the rate of cerebral palsy among survivors (risk ratio (RR) 0.82, 95% CI 0.52 to 1.27; seven studies; 985 participants). Little evidence showed a positive effect on motor outcomes in the long term, but only five included studies reported outcomes at preschool age (n = 3) or at school age (n = 2). Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with cognitive benefits persisting into preschool age. A great deal of heterogeneity between studies was due to the variety of early developmental intervention programmes tested and to gestational ages of included preterm infants; thus, comparisons of intervention programmes were limited. Further research is needed to determine which early developmental interventions are most effective in improving cognitive and motor outcomes, and to discern the longer-term effects of these programmes.
We included five randomised clinical trials with 517 participants (257 underwent a laparoscopic-endoscopic rendezvous technique versus 260 underwent a sequential approach), which fulfilled our inclusion criteria and provided data for analysis. Trial participants were scheduled for laparoscopic cholecystectomy because of suspected cholecysto-choledocholithiasis. Male/female ratio was 0.7; age of men and women ranged from 21 years to 87 years. The run-in and follow-up periods of the trials ranged from 32 months to 84 months. Overall, the five trials were judged at high risk of bias. Athough all trials measured mortality, there was just one death reported in one trial, in the laparoscopic-endoscopic rendezvous group (low-quality evidence). The overall morbidity (surgical morbidity plus general morbidity) may be lower with laparoscopic rendezvous (RR 0.59, 95% CI 0.29 to 1.20; participants = 434, trials = 4; I² = 28%; low-quality evidence); the effect was a little more certain when a fixed-effect model was used (RR 0.56, 95% CI 0.32 to 0.99). There was insufficient evidence to determine the effects of the two approaches on the failure of primary clearance of the bile duct (RR 0.55, 95% CI 0.22 to 1.38; participants = 517; trials = 5; I² = 58%; very low-quality evidence). The effects of either approach on clinical post-operative pancreatitis were unclear (RR 0.29, 95% CI 0.07 to 1.12; participants = 517, trials = 5; I² = 24%; low-quality evidence). Hospital stay appeared to be lower in the laparoscopic-endoscopic rendezvous group by about three days (95% CI 3.51 to 2.50 days shorter; 515 participants in five trials; low-quality evidence). There was very low-quality evidence that suggested longer operative time with laparoscopic-endoscopic rendezvous (MD 34.07 minutes, 95% CI 11.41 to 56.74; participants = 313; trials = 3; I² = 93%). The Trial Sequential Analyses of operating time and the length of hospital stay indicated that all the trials crossed the conventional boundaries, suggesting that the sample sizes were adequate, with a low risk of random error. There was insufficient evidence to determine the effects of the laparoscopic-endoscopic rendezvous versus preoperative endoscopic sphincterotomy techniques in people undergoing laparoscopic cholecystectomy on mortality and morbidity. The laparoscopic-endoscopic rendezvous procedure may lead to longer operating times, but it may reduce the length of the hospital stay when compared with preoperative endoscopic sphincterotomy followed by laparoscopic cholecystectomy. However, no firm conclusions could be drawn because the quality of evidence was low or very low. If confirmed by future trials, these data might re-design the scenario of treatment of this condition, albeit requiring greater organisational effort. Future trials should also address issues such as quality of life and cost analysis.
We included nine RCTs with 1208 patients; 622 patients were randomized to a PS spontaneous breathing trial (SBT) and 586 to a T-tube SBT. The studies were classified into three categories of weaning: simple, difficult, and prolonged. Four studies placed patients in two categories of weaning. Pressure support ventilation (PSV) and a T-tube were used directly as SBTs in four studies (844 patients, 69.9% of the sample). In 186 patients (15.4%) both interventions were used along with gradual weaning from mechanical ventilation; the PS was gradually decreased, twice a day, until it was minimal and periods with a T-tube were gradually increased to two and eight hours for patients with difficult and prolonged weaning. In two studies (14.7% of patients) the PS was lowered to 2 to 4 cm H2O and 3 to 5 cm H2O based on ventilatory parameters until the minimal PS levels were reached. PS was then compared to the trial with the T-tube (TT). We identified 33 different reported outcomes in the included studies; we took 14 of them into consideration and performed meta-analyses on nine. With regard to the sequence of allocation generation, allocation concealment, selective reporting and attrition bias, no study presented a high risk of bias. We found no clear evidence of a difference between PS and TT for weaning success (RR 1.07, 95% CI 0.97 to 1.17, 9 studies, low quality of evidence), intensive care unit (ICU) mortality (RR 0.81, 95% CI 0.53 to 1.23, 5 studies, low quality of evidence), reintubation (RR 0.92, 95% CI 0.66 to 1.26, 7 studies, low quality evidence), ICU and long-term weaning unit (LWU) length of stay (MD -7.08 days, 95% CI -16.26 to 2.1, 2 studies, low quality of evidence) and pneumonia (RR 0.67, 95% CI 0.08 to 5.85, 2 studies, low quality of evidence). PS was significantly superior to the TT for successful SBTs (RR 1.09, 95% CI 1.02 to 1.17, 4 studies, moderate quality of evidence). Four studies reported on weaning duration, however we were unable to combined the study data because of differences in how the studies presented their data. One study was at high risk of other bias and four studies were at high risk for detection bias. Three studies reported that the weaning duration was shorter with PS, and in one study the duration was shorter in patients with a TT. To date, we have found evidence of generally low quality from studies comparing pressure support ventilation (PSV) and with a T-tube. The effects on weaning success, ICU mortality, reintubation, ICU and LWU length of stay, and pneumonia were imprecise. However, PSV was more effective than a T-tube for successful spontaneous breathing trials (SBTs) among patients with simple weaning. Based on the findings of single trials, three studies presented a shorter weaning duration in the group undergoing PS SBT, however a fourth study found a shorter weaning duration with a T-tube.
Although eight trials involving 1301 participants were included in this review, only 919 (71%) contributed to the results concerning exacerbations and progression of the disease at two years. Specifically interferon significantly reduced the occurrence of exacerbations (Relative risk [RR] 0.80, 95% confidence interval [CI] 0.73 to 0.88, p < 0.001) and progression of the disease (RR 0.69, 95% CI 0.55 to 0.87, p = 0.002) two years after randomisation. However, the correct assignment of dropouts was essential to the demonstration of efficacy, most conspicuously concerning the effect of the drug on disease progression. If interferon-treated participants who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost (RR 1.31, 95% CI 0.60 to 2.89, p = 0.5). The evolution in magnetic resonance imaging (MRI) technology in the decade in which these trials were performed and different reporting of data among trials made it impossible to perform a quantitative analysis of the MRI results. Both clinical and laboratory side effects reported in the trials were more frequent in treated participants than in controls; there was no information after two years of follow-up. The impact of interferon treatment (and its side effects) on the quality of life of patients was not reported in any trial included in this review. The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment. Interferon administered by the oral route was not effective for prevention of relapses. Longer follow-up and more uniform reporting of clinical and MRI outcomes among these trials might have allowed for a more convincing conclusion.
Twenty-three studies met the inclusion criteria. Overall methodological quality was poor. Five studies used an injury outcome measure; one of these studies was randomised, the remaining four where CBA studies. The RCT targeting the alcohol server setting environment with an injury outcome compared the introduction of toughened glassware (experimental) to annealed glassware (control) on the number of bar staff injuries; a greater number of injuries were detected in the experimental group (relative risk 1.72, 95% CI 1.15 to 2.59). One CBA study investigated server training and estimated a reduction of 23% in single-vehicle, night-time crashes in the experimental area (controlled for crashes in the control area). Another CBA study examined the impact of a drink driving service, and reported a reduction in injury road crashes of 15% in the experimental area, with no change in the control; no difference was found for fatal crashes. In a CBA study investigating the impact of an intervention aiming to reduce crime in drinking premises, the study authors found a lower rate of all crime in the experimental premises (rate ratio 4.6, 95% CI 1.7 to 12, P = 0.01); no difference was found for injury (rate ratio 1.1 95% CI 0.1 to 10, P = 0.093). A CBA study investigating the impact of a policy intervention reported that pre-intervention the serious assault rate in the experimental area was 52% higher than the rate in the control area. After intervention, the serious assault rate in the experimental area was 37% lower than in the control area. The effects of such interventions on patron alcohol consumption is inconclusive. One randomised trial found a statistically significant reduction in observed severe aggression exhibited by patrons. There is some indication of improved server behaviour but it is difficult to predict what effect this might have on injury risk. There is insufficient evidence from randomised controlled trials and well conducted controlled before and after studies to determine the effect of interventions administered in the alcohol server setting on injuries. Compliance with interventions appears to be a problem; hence mandated interventions may be more likely to show an effect. Randomised controlled trials, with adequate allocation concealment and blinding are required to improve the evidence base. Further well-conducted, non-randomised trials are also needed when random allocation is not feasible.
We retrieved 11 studies. We included one trial that evaluated screening hysteroscopy versus no hysteroscopy, in women with unexplained subfertility, who were trying to conceive spontaneously. We are uncertain whether ongoing pregnancy rate improves following a screening hysteroscopy in women with at least two years of unexplained subfertility (RR 4.30, 95% CI 2.29 to 8.07; 1 RCT; participants = 200; very low-quality evidence). For a typical clinic with a 10% ongoing pregnancy rate without hysteroscopy, performing a screening hysteroscopy would be expected to result in ongoing pregnancy rates between 23% and 81%. The included study reported no adverse events in either treatment arm. We are uncertain whether clinical pregnancy rate is improved (RR 3.80, 95% CI 2.31 to 6.24; 1 RCT; participants = 200; very low-quality evidence), or miscarriage rate increases (RR 2.80, 95% CI 1.05 to 7.48; 1 RCT; participants = 200; very low-quality evidence), following screening hysteroscopy in women with at least two years of unexplained subfertility. We included ten trials that included 1836 women who had a screening hysteroscopy and 1914 women who had no hysteroscopy prior to IVF. Main limitations in the quality of evidence were inadequate reporting of study methods and higher statistical heterogeneity. Eight of the ten trials had unclear risk of bias for allocation concealment. Performing a screening hysteroscopy before IVF may increase live birth rate (RR 1.26, 95% CI 1.11 to 1.43; 6 RCTs; participants = 2745; I² = 69 %; low-quality evidence). For a typical clinic with a 22% live birth rate, performing a screening hysteroscopy would be expected to result in live birth rates between 25% and 32%. However, sensitivity analysis done by pooling results from trials at low risk of bias showed no increase in live birth rate following a screening hysteroscopy (RR 0.99, 95% CI 0.82 to 1.18; 2 RCTs; participants = 1452; I² = 0%). Only four trials reported complications following hysteroscopy; of these, three trials recorded no events in either group. We are uncertain whether a screening hysteroscopy is associated with higher adverse events (Peto odds ratio 7.47, 95% CI 0.15 to 376.42; 4 RCTs; participants = 1872; I² = not applicable; very low-quality evidence). Performing a screening hysteroscopy before IVF may increase clinical pregnancy rate (RR 1.32, 95% CI 1.20 to 1.45; 10 RCTs; participants = 3750; I² = 49%; low-quality evidence). For a typical clinic with a 28% clinical pregnancy rate, performing a screening hysteroscopy would be expected to result in clinical pregnancy rates between 33% and 40%. There may be little or no difference in miscarriage rate following screening hysteroscopy (RR 1.01, 95% CI 0.67 to 1.50; 3 RCTs; participants = 1669; I² = 0%; low-quality evidence). We found no trials that compared a screening hysteroscopy versus no hysteroscopy before IUI. At present, there is no high-quality evidence to support the routine use of hysteroscopy as a screening tool in the general population of subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work-up for improving reproductive success rates. In women undergoing IVF, low-quality evidence, including all of the studies reporting these outcomes, suggests that performing a screening hysteroscopy before IVF may increase live birth and clinical pregnancy rates. However, pooled results from the only two trials with a low risk of bias did not show a benefit of screening hysteroscopy before IVF. Since the studies showing an effect are those with unclear allocation concealment, we are uncertain whether a routine screening hysteroscopy increases live birth and clinical pregnancy, be it for all women, or those with two or more failed IVF attempts. There is insufficient data to draw conclusions about the safety of screening hysteroscopy.
We included one study that analysed 185 participants. The study compared the effects of a clinical examination every 12 months with a clinical examination every 24 months on the outcomes of caries (decayed, missing, filled surfaces (dmfs/DMFS) increment) and economic cost outcomes (total time used per person). As the study was at high risk of bias, had a small sample size and only included low-risk participants, we rated the quality of the body of evidence for these outcomes as very low. For three to five-year olds with primary teeth, the mean difference (MD) in dmfs increment was -0.90 (95% CI -1.96 to 0.16) in favour of 12-month recall. For 16 to 20-year olds with permanent teeth, the MD in DMFS increment was -0.86 (95% CI -1.75 to 0.03) also in favour of 12-month recall. There is insufficient evidence to determine whether 12 or 24-month recall with clinical examination results in better caries outcomes. For three to five-year olds with primary teeth, the MD in time used by each participant was 10 minutes (95% CI -6.7 to 26.7) in favour of 24-month recall. For 16 to 20-year olds with permanent teeth, the MD was 23.7 minutes (95% CI 4.12 to 43.28) also in favour of 24-month recall. This single study at high risk of bias represents insufficient evidence to determine whether 12 or 24-month recall with clinical examination results in better time/cost outcomes. There is a very low quality body of evidence from one RCT which is insufficient to draw any conclusions regarding the potential beneficial and harmful effects of altering the recall interval between dental check-ups. There is no evidence to support or refute the practice of encouraging patients to attend for dental check-ups at six-monthly intervals. It is important that high quality RCTs are conducted for the outcomes listed in this review in order to address the objectives of this review.
The search identified 77 trials. We included 34 trials in the review involving 69,338 babies, five studies are awaiting classification and there are two ongoing community trials. Included studies were conducted in both developed and developing countries. Among the 34 included trials, three were large, cluster-randomized trials conducted in community settings in developing countries and 31 studies were conducted in hospital settings mostly in developed countries. Data for community and hospital studies were analyzed separately. The three trials conducted in community settings contributed 78% of the total number of children included in this review. Of the trials conducted in hospital settings, the majority had small sample sizes. There were 22 different interventions studied across the included trials and the most commonly studied antiseptics were 70% alcohol, triple dye and chlorhexidine. Only one antiseptic, chlorhexidine was studied in community settings for umbilical cord care. Three community trials reported data on all-cause mortality that comprised 1325 deaths in 54,624 participants and combined results showed a reduction of 23% (average risk ratio (RR) 0.77, 95% confidence interval (CI) 0.63 to 0.94, random-effects, T² = 0.02, I² = 50%) in the chlorhexidine group compared with control. The reduction in omphalitis ranged from 27% to 56% depending on the severity of infection. Cord separation time was increased by 1.7 days in the chlorhexidine group compared with dry cord care (mean difference (MD) 1.75 days, 95% CI 0.44 to 3.05, random-effects, T² = 0.88, I² = 100%). Washing of umbilical cord with soap and water was not advantageous compared with dry cord care in community settings. Among studies conducted in hospital settings, no study reported data for mortality or tetanus. No antiseptic was advantageous to reduce the incidence of omphalitis compared with dry cord care in hospital settings. Topical triple dye application reduced bacterial colonization with Staphylococcus aureus compared with dry cord care (average RR 0.15, 95% CI 0.10 to 0.22, four studies, n = 1319, random-effects, T² = 0.04, I² = 24%) or alcohol application (average RR 0.45, 95% CI 0.25 to 0.80, two studies, n = 487, random-effects, T² = 0.00, I² = 0%). There was no advantage of application of alcohol and triple dye for reduction of colonization with streptococcus. Topical alcohol application was advantageous in reduction of colonization with Enterococcus coli compared with dry cord care (average RR 0.73, 95% CI 0.58 to 0.92, two studies, n = 432, random-effects, T² = 0.00, I² = 0%) and in a separate analysis, triple dye increased the risk of colonization compared with alcohol (RR 3.44, 95% CI 2.10 to 5.64, one study, n = 373). Cord separation time was significantly increased with topical application of alcohol (MD 1.76 days, 95% CI 0.03 to 3.48, nine studies, n = 2921, random-effects, T² = 6.54, I² = 97%) and triple dye (MD 4.10 days, 95% CI 3.07 to 5.13, one study, n = 372) compared with dry cord care in hospital settings. The number of studies was insufficient to make any inference about the efficacy of other antiseptics. There is significant evidence to suggest that topical application of chlorhexidine to umbilical cord reduces neonatal mortality and omphalitis in community and primary care settings in developing countries. It may increase cord separation time however, there is no evidence that it increases risk of subsequent morbidity or infection. There is insufficient evidence to support the application of an antiseptic to umbilical cord in hospital settings compared with dry cord care in developed countries.
Twenty trials comparing open mesh with open non-mesh repair were identified. Open mesh methods, on average, took 7-10 minutes less to perform than Shouldice procedures, but took 1-4 minutes longer than other non-mesh methods. There were no clear differences between mesh and non-mesh groups for haematomas, seromas or wound/superficial infections. Three serious operative compications were reported after open mesh repair and three following non-mesh repair. Overall, those in the mesh groups had a shorter length of hospital stay and quicker return to usual activities, but this pattern was not observed for all trials. There was a suggestion that persisting pain was less frequent after mesh repair than after non-mesh repair but this result was dependent on one trial and data were not available for 11 trials. There was no evidence of a difference between the groups with respect to persisting numbness. Fewer hernia recurrences were reported after mesh repair (Peto OR: 0.37, 95% CI: 0.26 to 0.51). There were too few data to reliably address differential effects for patients with recurrent, bilateral or femoral hernias. Two trials comparing flat mesh with plug and mesh were identified. There was no clear evidence of differences between the groups. There is evidence that the use of open mesh repair is associated with a reduction in the risk of recurrence of between 50% and 75%. Although the trials were heterogenous there is also some evidence of quicker return to work and of lower rates of persisting pain following mesh repair.
We included 29 studies in the review, 21 of which were included in at least one meta-analysis. Non-legislative interventions increased observed helmet wearing (11 studies: OR 2.08, 95% CI 1.29 to 3.34). The effect was most marked amongst community-based interventions (four studies: OR 4.30, 95% 2.24 to 8.25) and those providing free helmets (two studies: OR 4.35, 95% CI 2.13 to 8.89). Significant effects were also found amongst school-based interventions (eight studies: OR 1.73, CI 95% 1.03 to 2.91), with a smaller effect found for interventions providing education only (three studies: OR 1.43, 95% CI 1.09 to 1.88). No significant effect was found for providing subsidised helmets (seven studies: OR 2.02, 95% CI 0.98 to 4.17). Interventions provided to younger children (aged under 12) may be more effective (five studies: OR 2.50, 95% CI 1.17 to 5.37) than those provided to children of all ages (five studies: OR 1.83, 95% CI 0.98 to 3.42). Interventions were only effective in increasing self reported helmet ownership where they provided free helmets (three studies: OR 11.63, 95% CI 2.14 to 63.16). Interventions were effective in increasing self reported helmet wearing (nine studies: OR 3.27, 95% CI 1.56 to 6.87), including those undertaken in schools (six studies: OR 4.21, 95% CI 1.06 to 16.74), providing free helmets (three studies: OR 7.27, 95% CI 1.28 to 41.44), providing education only (seven studies: OR 1.93, 95% CI 1.03 to 3.63) and in healthcare settings (two studies: OR 2.78, 95% CI 1.38 to 5.61). Non-legislative interventions appear to be effective in increasing observed helmet use, particularly community-based interventions and those providing free helmets. Those set in schools appear to be effective but possibly less so than community-based interventions. Interventions providing education only are less effective than those providing free helmets. There is insufficient evidence to recommend providing subsidised helmets at present. Interventions may be more effective if provided to younger rather than older children. There is evidence that interventions offered in healthcare settings can increase self reported helmet wearing. Further high-quality studies are needed to explore whether non-legislative interventions increase helmet wearing, and particularly the effect of providing subsided as opposed to free helmets, and of providing interventions in healthcare settings as opposed to in schools or communities. Alternative interventions (e.g. those including peer educators, those aimed at developing safety skills including skills in decision making and resisting peer pressure or those aimed at improving self esteem or self efficacy) need developing and testing, particularly for 11 to 18 year olds. The effect of interventions in countries with existing cycle helmet legislation and in low and middle-income countries also requires investigation.
No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher-estrogen pills, several COCs containing 20 μg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). While COCs containing 20 μg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low-dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow-up rates are essential for meaningful interpretation of results.
We included 12 studies reporting data on 1642 participants (intervention = 833, control = 809). Eight studies targeted adults with epilepsy, one study included participants of all ages, one study included participants older than two years, one study targeted caregivers of children with epilepsy, and one study targeted families of children with epilepsy. We identified six ongoing trials. Follow-up time was generally short in most trials, ranging from one to 12 months. The trials examined three main types of interventions: educational interventions, behavioural interventions and mixed interventions. All studies compared treatment versus usual care or 'no intervention', except for two studies. Due to heterogeneity between studies in terms of interventions, methods used to measure adherence and the way the studies were reported, we did not pool the results and these findings were inappropriate to be included in a meta-analysis. Education and counselling of participants with epilepsy resulted in mixed success (moderate-quality evidence). Behavioural interventions such as use of intensive reminders provided more favourable effects on adherence (moderate-quality evidence). The effect on adherence to antiepileptic drugs described by studies of mixed interventions showed improved adherence in the intervention groups compared to the control groups (high-quality evidence). Behavioural interventions such as intensive reminders and the use of mixed interventions demonstrate some positive results; however, we need more reliable evidence on their efficacy, derived from carefully-designed randomised controlled trials before we can draw a firm conclusion. Since the last version of this review, none of the new relevant studies have provided additional information that would lead to significant changes in our conclusions. This current update includes 12 studies, of which six came from the latest searches.
We included 98 studies (147 articles). There were 88 core studies: 37 focused on advocates (4 survey-based, 3 instrument development, 30 qualitative focus) and seven on abused women (6 qualitative studies, 1 survey); 44 were experimental intervention studies (some including qualitative evaluations). Ten further studies (3 randomised controlled trials (RCTs), 1 intervention process evaluation, 1 qualitative study, 2 mixed methods studies, 2 surveys of women, and 1 mixed methods study of women and staff) did not fit the original criteria but added useful information, as befitting a realist approach. Two studies are awaiting classification and three are ongoing. Advocacy interventions varied considerably in contact hours, profession delivering and setting. We constructed a conceptual model from six essential principles based on context-mechanism-outcome (CMO) patterns. We have moderate and high confidence in evidence for the importance of considering both women's vulnerabilities and intersectionalities and the trade-offs of abuse-related decisions in the contexts of individual women's lives. Decisions should consider the risks to the woman's safety from the abuse. Whether actions resulting from advocacy increase or decrease abuse depends on contextual factors (e.g. severity and type of abuse), and the outcomes the particular advocacy intervention is designed to address (e.g. increasing successful court orders versus decreasing depression). We have low confidence in evidence regarding the significance of physical dependencies, being pregnant or having children. There were links between setting (high confidence), and potentially also theoretical underpinnings of interventions, type, duration and intensity of advocacy, advocate discipline and outcomes (moderate and low confidence). A good therapeutic alliance was important (high confidence); this alliance might be improved when advocates are matched with abused women on ethnicity or abuse experience, exercise cultural humility, and remove structural barriers to resource access by marginalised women. We identified significant challenges for advocates in inter-organisational working, vicarious traumatisation, and lack of clarity on how much support to give a woman (moderate and high confidence). To work effectively, advocates need ongoing training, role clarity, access to resources, and peer and institutional support. Our provisional model highlights the complex way that factors combine and interact for effective advocacy. We confirmed the core ingredients of advocacy according to both women and advocates, supported by studies and theoretical considerations: education and information on abuse; rights and resources; active referral and liaising with other services; risk assessment and safety planning. We were unable to confirm the impact of complexity of the intervention (low confidence). Our low confidence in the evidence was driven mostly by a lack of relevant studies, rather than poor-quality studies, despite the size of the review. Results confirm the core ingredients of advocacy and suggest its use rests on sound theoretical underpinnings. We determined the elements of a good therapeutic alliance and how it might be improved, with a need for particular considerations of the factors affecting marginalised women. Women's goals from advocacy should be considered in the contexts of their personal lives. Women's safety was not necessarily at greatest risk from staying with the abuser. Potentially, if undertaken for long enough, advocacy should benefit an abused woman in terms of at least one outcome providing the goals are matched to each woman's needs. Some outcomes may take months to be determined. Where abuse is severe, some interventions may increase abuse. Advocates have a challenging role and must be supported emotionally, through provision of resources and through professional training, by organisations and peers. Future research should consider the different principles identified in this review, and study outcomes should be considered in relation to the mechanisms and contexts elucidated. More longitudinal evidence is needed. Single-subject research designs may help determine exactly when effect no longer increases, to determine the duration of longitudinal work, which will likely differ for vulnerable and marginalised women. Further work is needed to ascertain how to tailor advocacy interventions to cultural variations and rural and resource-poor settings. The methods used in the included studies may, in some cases, limit the applicability and completeness of the data reported. Economic analyses are required to ascertain if resources devoted to advocacy interventions are cost-effective in healthcare and community settings.
We included 34 studies evaluating 1614 women and approximately 2396 groins. The overall methodological quality of included studies was moderate. The studies included in this review used the following traceable techniques to identify sentinel nodes in their participants: blue dye only (three studies), technetium only (eight studies), blue dye plus technetium combined (combined tests; 13 studies) and various inconsistent combinations of these three techniques (mixed tests; 10 studies). For studies of mixed tests, we obtained separate test data where possible. Most studies used haematoxylin and eosin (H&E) stains for the histological examination. Additionally an immunohistochemical (IHC) stain with and without ultrastaging was employed by 14 and eight studies, respectively. One study used reverse transcriptase polymerase chain reaction analysis (CA9 RT-PCR), whilst three studies did not describe the histological methods used. The pooled sensitivity estimate for studies using blue dye only was 0.94 (68 women; 95% confidence interval (CI) 0.69 to 0.99), for mixed tests was 0.91 (679 women; 95% CI 0.71 to 0.98), for technetium only was 0.93 (149 women; 95% CI 0.89 to 0.96) and for combined tests was 0.95 (390 women; 95% CI 0.89 to 0.97). Negative predictive values (NPVs) for all index tests were > 95%. Most studies also reported sentinel node detection rates (the ability of the test to identify a sentinel node) of the index test. The mean detection rate for blue dye alone was 82%, compared with 95%, 96% and 98% for mixed tests, technetium only and combined tests, respectively. We estimated the clinical consequences of the various tests for 100 women undergoing the sentinel node procedure, assuming the prevalence of groin metastases to be 30%. For the combined or technetium only tests, one and two women with groin metastases might be 'missed', respectively (95% CI 1 to 3); and for mixed tests, three women with groin metastases might be 'missed' (95% CI 1 to 9). The wide CIs associated with the pooled sensitivity estimates for blue dye and mixed tests increased the potential for these tests to 'miss' women with groin metastases. There is little difference in diagnostic test accuracy between the technetium and combined tests. The combined test may reduce the number of women with 'missed' groin node metastases compared with technetium only. Blue dye alone may be associated with more 'missed' cases compared with tests using technetium. Sentinel node assessment with technetium-based tests will reduce the need for IFL by 70% in women with early vulval cancer. It is not yet clear how the survival of women with negative sentinel nodes compares to those undergoing standard surgery (IFL). A randomised controlled trial of sentinel node dissection and IFL has methodological and ethical issues, therefore more observational data on the survival of women with early vulval cancer are needed.
One randomised trial was identified and included in the review. It was of low methodological quality. The trial compared D-penicillamine versus placebo in 70 patients with primary sclerosing cholangitis. Compared with placebo, D-penicillamine therapy had no significant effect on mortality (RR 1.14, 95% CI 0.49 to 2.64), liver transplantation (RR 1.11, 95% CI 0.39 to 3.17), hepatic histologic progression (RR 1.17, 95% CI 0.79 to 1.74), or cholangiographic deterioration (RR 0.87, 95% CI 0.43 to 1.79). D-penicillamine led to a significant improvement in the serum aspartate aminotransferase (WMD -23.00 U/L; 95% CI -30.66 to -15.34), but not in serum bilirubin level (WMD 0.40 mg/L; 95% CI -0.19 to 0.99) and serum alkaline phosphatases activity (WMD 44.00 U/L; 95% CI -37.89 to 125.89). There were significantly more adverse events in patients receiving D-penicillamine (P = 0.013). There is not sufficient evidence to support or refute the use of D-penicillamine for patients with primary sclerosing cholangitis. We do not recommend the use of D-penicillamine for patients with primary sclerosing cholangitis outside randomised trials.
Of 15440 identified citations, 7387 unique citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH enrolling 1025 participants, one compared fondaparinux with UFH and LMWH enrolling 477 participants, and one compared dalteparin with tinzaparin enrolling 113 participants. The meta-analysis of mortality at three months included 418 participants from five studies and that of recurrent VTE included 422 participants from 3 studies. The findings showed that LMWH likely decreases mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; moderate certainty evidence), but did not rule out a clinically significant increase or decrease in VTE recurrence (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; moderate certainty evidence). The study comparing fondaparinux with heparin (UFH or LMWH) did not exclude a beneficial or detrimental effect of fondaparinux on mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; moderate certainty evidence), recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; moderate certainty evidence), major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; moderate certainty evidence), or minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence) The study comparing dalteparin with tinzaparin did not exclude a beneficial or detrimental effect of dalteparin on mortality (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), major bleeding (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), or minor bleeding (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). LMWH is possibly superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.
Searches identified 5116 unique papers; we retrieved 827 for full screening. In this review, we included 105 studies from 115 papers, in which 10,302 participants were randomized. Mainly as a result of updating the search in July 2015, 38 papers are awaiting classification. Sixty-one of the 105 studies measured the outcome pain, 14 behavioural recovery, 58 length of stay and 49 negative affect. Participants underwent a wide range of surgical procedures, and a range of psychological components were used in interventions, frequently in combination. In the 105 studies, appropriate data were provided for the meta-analysis of 38 studies measuring the outcome postoperative pain (2713 participants), 36 for length of stay (3313 participants) and 31 for negative affect (2496 participants). We narratively reviewed the remaining studies (including the 14 studies with 1441 participants addressing behavioural recovery). When pooling the results for all types of intervention there was low quality evidence that psychological preparation techniques were associated with lower postoperative pain (SMD -0.20, 95% confidence interval (CI) -0.35 to -0.06), length of stay (mean difference -0.52 days, 95% CI -0.82 to -0.22) and negative affect (SMD -0.35, 95% CI -0.54 to -0.16) compared with controls. Results tended to be similar for all categories of intervention, although there was no evidence that behavioural instruction reduced the outcome pain. However, caution must be exercised when interpreting the results because of heterogeneity in the types of surgery, interventions and outcomes. Narratively reviewed evidence for the outcome behavioural recovery provided very low quality evidence that psychological preparation, in particular behavioural instruction, may have potential to improve behavioural recovery outcomes, but no clear conclusions could be reached. Generally, the evidence suffered from poor reporting, meaning that few studies could be classified as having low risk of bias. Overall,we rated the quality of evidence for each outcome as ‘low’ because of the high level of heterogeneity in meta-analysed studies and the unclear risk of bias. In addition, for the outcome behavioural recovery, too few studies used robust measures and reported suitable data for meta-analysis, so we rated the quality of evidence as `very low'. The evidence suggested that psychological preparation may be beneficial for the outcomes postoperative pain, behavioural recovery, negative affect and length of stay, and is unlikely to be harmful. However, at present, the strength of evidence is insufficient to reach firm conclusions on the role of psychological preparation for surgery. Further analyses are needed to explore the heterogeneity in the data, to identify more specifically when intervention techniques are of benefit. As the current evidence quality is low or very low, there is a need for well-conducted and clearly reported research.
Forty-one RCTs with a total of 2732 participants (1564 cell therapy, 1168 controls) were eligible for inclusion. Cell treatment was not associated with any changes in the risk of all-cause mortality (34/538 versus 32/458; RR 0.93, 95% CI 0.58 to 1.50; 996 participants; 14 studies; moderate quality evidence), cardiovascular mortality (23/277 versus 18/250; RR 1.04, 95% CI 0.54 to 1.99; 527 participants; nine studies; moderate quality evidence) or a composite measure of mortality, reinfarction and re-hospitalisation for heart failure (24/262 versus 33/235; RR 0.63, 95% CI 0.36 to 1.10; 497 participants; six studies; moderate quality evidence) at long-term follow-up. Statistical heterogeneity was low (I2  = 0% to 12%). Serious periprocedural adverse events were rare and were generally unlikely to be related to cell therapy. Additionally, cell therapy had no effect on morbidity, quality of life/performance or LVEF measured by magnetic resonance imaging. Meta-analyses of LVEF measured by echocardiography, single photon emission computed tomography and left ventricular angiography showed evidence of differences in mean LVEF between treatment groups although the mean differences ranged between 2% and 5%, which are accepted not to be clinically relevant. Results were robust to the risk of selection, performance and attrition bias from individual studies. The results of this review suggest that there is insufficient evidence for a beneficial effect of cell therapy for AMI patients. However, most of the evidence comes from small trials that showed no difference in clinically relevant outcomes. Further adequately powered trials are needed and until then the efficacy of this intervention remains unproven.
We identified two new studies, giving a total of 10 studies, involving 3655 participants. The medication adherence interventions studied were all provided in addition to standard behavioural support.They typically provided further information on the rationale for, and emphasised the importance of, adherence to medication or supported the development of strategies to overcome problems with maintaining adherence (or both). Seven studies targeted adherence to NRT, two to bupropion and one to varenicline. Most studies were judged to be at high or unclear risk of bias, with four of these studies judged at high risk of attrition or detection bias. Only one study was judged to be at low risk of bias. Meta-analysis of all 10 included studies (12 comparisons) provided moderate-certainty evidence that adherence interventions led to small improvements in adherence (i.e. the mean amount of medication consumed; SMD 0.10, 95% CI 0.03 to 0.18; I² = 6%; n = 3655), limited by risk of bias. Subgroup analyses for the primary outcome identified no significant subgroup effects, with effect sizes for subgroups imprecisely estimated. However, there was a very weak indication that interventions focused on the 'practicalities' of adhering to treatment (i.e. capabilities, resources, levels of support or skills) may be effective (SMD 0.21, 95% CI 0.03 to 0.38; I² = 39%; n = 1752), whereas interventions focused on treatment 'perceptions' (i.e. beliefs, cognitions, concerns and preferences; SMD 0.10, 95% CI –0.03 to 0.24; I² = 0%; n = 839) or on both (SMD 0.04, 95% CI –0.08 to 0.16; I² = 0%; n = 1064), may not be effective. Participant-centred interventions may be effective (SMD 0.12, 95% CI 0.02 to 0.23; I² = 20%; n = 2791), whereas those that are clinician-centred may not (SMD 0.09, 95% CI –0.05 to 0.23; I² = 0%; n = 864). Five studies assessed short-term smoking abstinence (five comparisons), while an overlapping set of five studies (seven comparisons) assessed long-term smoking abstinence of six months or more. Meta-analyses resulted in low-certainty evidence that adherence interventions may slightly increase short-term smoking cessation rates (RR 1.08, 95% CI 0.96 to 1.21; I² = 0%; n = 1795) and long-term smoking cessation rates (RR 1.16, 95% CI 0.96 to 1.40; I² = 48%; n = 3593). In both cases, the evidence was limited by risk of bias and imprecision, with CIs encompassing minimal harm as well as moderate benefit, and a high likelihood that further evidence will change the estimate of the effect. There was no evidence that interventions to increase adherence to medication led to any adverse events. Studies did not report on factors plausibly associated with increases in adherence, such as self-efficacy, understanding of and attitudes toward treatment, and motivation and intentions to quit. In people who are stopping smoking and receiving behavioural support, there is moderate-certainty evidence that enhanced behavioural support focusing on adherence to smoking cessation medications can modestly improve adherence. There is only low-certainty evidence that this may slightly improve the likelihood of cessation in the shorter or longer-term. Interventions to increase adherence can aim to address the practicalities of taking medication, change perceptions about medication, such as reasons to take it or concerns about doing so, or both. However, there is currently insufficient evidence to confirm which approach is more effective. There is no evidence on whether such interventions are effective for people who are stopping smoking without standard behavioural support.
Only one trial, involving 256 children, met the inclusion criteria for this review. This study was assessed as having high risk of bias because of non-random allocation, incomplete outcome data and insufficient control of confounding factors. Results from this study suggest that centre-based day care may have a positive effect on child cognitive ability compared with no treatment (care at home) (assessed using a modified version of the British Ability Scale-II (BAS-II) (standardised mean difference (SMD) 0.74, 95% confidence interval (CI) 0.48 to 1.00, 256 participants, 1 study, very low-quality evidence). This study did not measure other variables relevant to this review. The single study included in this review provides limited evidence on the effects of centre-based day care for children younger than five years of age in low- and middle-income countries. This study was at high risk of bias and may have limited generalisability to other low- and middle-income countries. Many of the studies excluded from this review paired day care attendance with co-interventions that are unlikely to be provided in normal day care centres. Effectiveness studies on centre-based day care without these co-interventions are few, and the need for such studies is significant. In future studies, comparisons might include home visits or alternative day care arrangements.
We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision. At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%). For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%). For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants). Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review. Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%). The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab. This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.
Thirty-four separate RCTs studying roflumilast (20 trials with 17,627 participants) or cilomilast (14 trials with 6457 participants) met the inclusion criteria, with a duration of between six weeks and one year. These included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II-IV), with a mean age of 64 years. We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall. Treatment with a PDE4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV1) over the trial period compared with placebo (MD 51.53 mL, 95% confidence interval (CI) 43.17 to 59.90, 27 trials with 20,585 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias). There were small improvements in quality of life (St George's Respiratory Questionnaire (SGRQ), MD -1.06 units, 95% CI -1.68 to -0.43, 11 trials with 7645 participants, moderate-quality evidence due to moderate levels of heterogeneity and risk of reporting bias) and COPD-related symptoms, but no significant change in exercise tolerance. Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.78, 95% CI 0.73 to 0.83; 23 trials with 19,948 participants, high-quality evidence). For every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 26). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting or dyspepsia. For every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). Roflumilast in particular was associated with weight loss during the trial period and an increase in insomnia and depressive mood symptoms. There was no significant effect of treatment on non-fatal serious adverse events (OR 0.99, 95% CI 0.91 to 1.07) or mortality (OR 0.97, 95% CI 0.76 to 1.23), although mortality was a rare event during the trials. Participants treated with PDE4 inhibitors were more likely to withdraw from the trials because of adverse effects; on average 14% in the treatment groups withdrew compared with 8% in the control groups. In people with COPD, PDE4 inhibitors offered benefit over placebo in improving lung function and reducing the likelihood of exacerbations; however, they had little impact on quality of life or symptoms. Gastrointestinal adverse effects and weight loss were common, and safety data submitted to the US Food and Drug Administration (FDA) have raised concerns over psychiatric adverse events with roflumilast. The findings of this review give cautious support to the use of PDE4 inhibitors in COPD. They may be best used as add-on therapy in a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management. This is in accordance with the GOLD 2017 guidelines. Longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation or mortality in COPD.
We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear. For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence). For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.
We included five RCTs (with 264 women) comparing gonadotrophins plus metformin versus gonadotrophins. The gonadotrophin used was recombinant FSH in four studies and highly purified FSH in one study. Evidence was of low quality: The main limitations were serious risk of bias due to poor reporting of study methods and blinding of participants and outcome assessors. Live birth Metformin plus FSH was associated with a higher cumulative live birth rate when compared with FSH (odds ratio (OR) 2.31, 95% confidence interval (CI) 1.23 to 4.34; two RCTs, n = 180; I2 = 0%; low-quality evidence). This suggests that if the chance of live birth after FSH is assumed to be 27%, then the chance after addition of metformin would be between 32% and 60%. Other pregnancy outcomes Metformin use was associated with a higher ongoing pregnancy rate (OR 2.46, 95% CI 1.36 to 4.46; four RCTs, n = 232; I2 = 0%; low-quality evidence) and a higher clinical pregnancy rate (OR 2.51, 95% CI 1.46 to 4.31; five RCTs, n = 264; I2 = 0%; low-quality evidence). Multiple pregnancy Results showed no evidence of a difference in multiple pregnancy rates between metformin plus FSH and FSH (OR 0.55, 95% CI 0.15 to 1.95; four RCTs, n = 232; I2 = 0%; low-quality evidence) and no evidence of a difference in rates of miscarriage or OHSS. Other adverse effects Evidence was inadequate as the result of limited available data on adverse events after metformin compared with after no metformin (OR 1.78, 95% CI 0.39 to 8.09; two RCTs, n = 91; I2 = 0%; very low-quality evidence). Preliminary evidence suggests that metformin may increase the live birth rate among women undergoing ovulation induction with gonadotrophins. At this moment, evidence is insufficient to show an effect of metformin on multiple pregnancy rates and adverse events. Additional trials are necessary before we can provide further conclusions that may affect clinical practice.
We included four studies in this review (251 participants), and found few significant differences between treatment and comparison groups for the outcomes of interest. Blood phenylalanine levels were significantly lower in participants with phenylketonuria following a low-phenylalanine diet compared to those on a less restricted diet, mean difference (MD) at three months -698.67 (95% confidence interval (CI) -869.44 to -527.89). Intelligence quotient was significantly higher in participants who continued the diet than in those who stopped the diet, MD after 12 months 5.00 (95% CI 0.40 to 9.60). However, these results came from a single study. The results of non-randomised studies have concluded that a low-phenylalanine diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcomes. We were unable to find any randomised controlled studies that have assessed the effect of a low-phenylalanine diet versus no diet from diagnosis. In view of evidence from non-randomised studies, such a study would be unethical and it is recommended that low-phenylalanine diet should be commenced at the time of diagnosis. There is uncertainty about the precise level of phenylalanine restriction and when, if ever, the diet should be relaxed. This should be addressed by randomised controlled studies.
Thirty-one studies involving 9571 participants, described in 33 articles, met the inclusion criteria. All were published in English. Fifteen studies were randomized controlled trials, nine were controlled before-and-after studies, four were non-equivalent controlled studies with a historical control, one was a non-equivalent controlled study with a post-test only and two were non-equivalent controlled studies with pre- and post-test findings for the intervention group and post-test for the control group. Twenty-one studies assessed the effects of interventions related to plagiarism and 10 studies assessed interventions in research integrity/ethics. Participants included undergraduates, postgraduates and academics from a range of research disciplines and countries, and the studies assessed different types of outcomes. We judged most of the included randomized controlled trials to have a high risk of bias in at least one of the assessed domains, and in the case of non-randomized trials there were no attempts to alleviate the potential biases inherent in the non-randomized designs. We identified a range of interventions aimed at reducing research misconduct. Most interventions involved some kind of training, but methods and content varied greatly and included face-to-face and online lectures, interactive online modules, discussion groups, homework and practical exercises. Most studies did not use standardized or validated outcome measures and it was impossible to synthesize findings from studies with such diverse interventions, outcomes and participants. Overall, there is very low quality evidence that various methods of training in research integrity had some effects on participants' attitudes to ethical issues but minimal (or short-lived) effects on their knowledge. Training about plagiarism and paraphrasing had varying effects on participants' attitudes towards plagiarism and their confidence in avoiding it, but training that included practical exercises appeared to be more effective. Training on plagiarism had inconsistent effects on participants' knowledge about and ability to recognize plagiarism. Active training, particularly if it involved practical exercises or use of text-matching software, generally decreased the occurrence of plagiarism although results were not consistent. The design of a journal's author contribution form affected the truthfulness of information supplied about individuals' contributions and the proportion of listed contributors who met authorship criteria. We identified no studies testing interventions for outcomes at the organizational level. The numbers of events and the magnitude of intervention effects were generally small, so the evidence is likely to be imprecise. No adverse effects were reported. The evidence base relating to interventions to improve research integrity is incomplete and the studies that have been done are heterogeneous, inappropriate for meta-analyses and their applicability to other settings and population is uncertain. Many studies had a high risk of bias because of the choice of study design and interventions were often inadequately reported. Even when randomized designs were used, findings were difficult to generalize. Due to the very low quality of evidence, the effects of training in responsible conduct of research on reducing research misconduct are uncertain. Low quality evidence indicates that training about plagiarism, especially if it involves practical exercises and use of text-matching software, may reduce the occurrence of plagiarism.
Four trials, enrolling a total of 614 infants, compared low (restrictive) to high (liberal) haemoglobin thresholds. Restrictive thresholds tended to be similar, but one trial used liberal thresholds much higher than the other three. There were no statistically significant differences in the combined outcomes of death or serious morbidity at first hospital discharge (typical risk ratio (RR) 1.19; 95% confidence interval (CI) 0.95 to 1.49) or in component outcomes. Only the largest trial reported follow-up at 18 to 21 months corrected gestational age; in this study there was no statistically significant difference in a composite of death or adverse neurodevelopmental outcome (RR 1.06; 95% CI 0.95 to 1.19). One additional trial comparing transfusion for clinical signs of anaemia versus transfusion at a set level of haemoglobin or haematocrit, reported no deaths and did not address disability. The use of restrictive as compared to liberal haemoglobin thresholds in infants of very low birth weight results in modest reductions in exposure to transfusion and in haemoglobin levels. Restrictive practice does not appear to have a significant impact on death or major morbidities at first hospital discharge or at follow-up. However, given the uncertainties of these conclusions, it would be prudent to avoid haemoglobin levels below the lower limits tested here. Further trials are required to clarify the impact of transfusion practice on long term outcome.
Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms. There is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect; as first line therapy; to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases.
A total of 16,558 patients from four trials contributed to the analyses. The methodological quality was high in all four trials. The anticoagulants tested were unfractionated heparin (UFH) and low molecular-weight heparin. Aspirin was used as control in all trials. Overall, there was no evidence that anticoagulants were superior to aspirin in reducing 'death or dependency' at long-term follow-up (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.98 to 1.15). Compared with aspirin, anticoagulants were associated with a small but significant increase in the number of deaths at the end of follow-up (OR 1.10, 95% CI 1.01 to 1.29), equivalent to 20 more deaths (95% CI 0 to 30) per 1000 patients treated; a significant increased risk of symptomatic intracranial haemorrhage (OR 2.35, 95% CI 1.49 to 3.46); and a non-significant increased risk of 'any recurrent stroke' during treatment (OR 1.20, 95% CI 0.99 to 1.46). These neutral or adverse effects outweighed a small, but significant effect on symptomatic deep vein thrombosis (OR 1.20, 95% CI 0.07 to 0.58), equivalent to 10 fewer (95% CI 0 to 30) DVTs by 14 days per 1000 patients treated with anticoagulants instead of aspirin. Subgroup analysis could not identify any type, dose, or route of administration of anticoagulants associated with net benefit, or any benefit in patients with atrial fibrillation. Overall, the combination of UFH and aspirin did not appear to be associated with a net advantage over aspirin alone. A subgroup analysis showed that, compared with aspirin, the combination of low-dose UFH and aspirin was associated with a marginally significant reduced risk of 'any recurrent stroke' (OR 0.75, 95% CI 0.56 to 1.03) and a marginally significant reduced risk of death at 14 days (OR 0.84, 95% CI 0.69 to 1.01), and with no clear adverse effect on death at end of follow-up (OR 0.98, 95% CI 0.85 to 1.12). Anticoagulants offered no net advantages over antiplatelet agents in acute ischaemic stroke. The combination of low-dose UFH and aspirin appeared in a subgroup analysis to be associated with net benefits compared with aspirin alone, and this merits further research.
The electronic search located 62 studies. We included two RCTs of oral aspirin (300 mg/daily) given in addition to compression compared with compression and placebo, or compression alone. To date, the impact of aspirin on VLUs has been examined by only two randomised clinical trials, both with a small number of participants. The first RCT was conducted in the United Kingdom (n=20) and reported that daily administration of aspirin (300mg) in addition to compression bandages increased both the rate of healing, and the number of participants healed when compared to placebo in addition to compression bandaging over a four month period. Thirty-eight per cent of the participants given aspirin reported complete healing compared with 0% in the placebo group . Improvement (assessed by reduction in wound size) occurred in 52% of the participants taking aspirin compared with 26% in those taking placebo). The study identified potential benefits of taking aspirin as an adjunct to compression but the sample size was small, and neither the mechanism by which aspirin improved healing nor its effects on recurrence were investigated. In 2012 an RCT in Spain (n=51) compared daily administration of aspirin (300mg) in addition to compression bandages with compression alone over a five month period. There was little difference in complete healing rates between groups (21/28 aspirin and 17/23 compression bandages alone) but the average time to healing was shorter (12 weeks in the treated group vs 22 weeks in the compression only group) and the average time for recurrence was longer in the aspirin group (39 days: [SD 6.0] compared with 16.3 days [SD 7.5] in the compression only group). Although this trial provides some limited data about the potential use of aspirin therapy, the sample size (only 20 patients) was too small for us to draw meaningful conclusions. In addition, patients were only followed up for 4 months and no information on placebo was reported. Low quality evidence from two trials indicate that there is currently insufficient evidence for us to draw definitive conclusions about the benefits and harms of oral aspirin on the healing and recurrence of venous leg ulcers. We downgraded the evidence to low quality due to potential selection bias and imprecision due to the small sample size. The small number of participants may have a hidden real benefit, or an increase in harm. Due to the lack of reliable evidence, we are unable to draw conclusions about the benefits and harms of oral daily aspirin as an adjunct to compression in VLU healing or recurrence. Further high quality studies are needed in this area.
Individual participant data were obtained for five studies, which recruited a total of 635 participants, representing 80% of 798 individuals from all seven identified eligible trials. For remission outcomes, an HR of less than 1 indicates an advantage for phenytoin and for first seizure and treatment failure outcomes an HR of less than 1 indicates an advantage for phenobarbitone. Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 499 participants: 1.61, 95% CI 1.22 to 2.12, low-certainty evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 499 participants: 1.99, 95% CI 1.37 to 2.87, low-certainty evidence), time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 499 participants: 1.87, 95% CI 1.32 to 2.66, moderate-certainty evidence), showing a statistically significant advantage for phenytoin compared to phenobarbitone. For our secondary outcomes, we did not find any statistically significant differences between phenytoin and phenobarbitone: time to first seizure post-randomisation (pooled HR adjusted for seizure type for 624 participants: 0.85, 95% CI 0.69 to 1.06, moderate-certainty evidence), time to 12-month remission (pooled HR adjusted for seizure type for 588 participants: 0.90, 95% CI 0.69 to 1.19, moderate-certainty evidence), and time to six-month remission pooled HR adjusted for seizure type for 588 participants: 0.91, 95% CI 0.71 to 1.15, moderate-certainty evidence). For individuals with focal onset seizures (73% of individuals contributing to analysis), numerical results were similar and conclusions the same as for analyses of all individuals and for individuals with generalised onset seizures (27% of individuals contributing to analysis), results were imprecise and no clear differences between the drugs were observed. Several confounding factors, most notably the differences in design of the trials with respect to blinding, were likely to have impacted on the results of the primary outcome 'time to treatment failure', and in turn, the treatment failure rates may have impacted on the secondary efficacy outcomes of time to first seizure and time to 12-month and six-month remission. Low-certainty evidence from this review suggests that phenytoin may be a more effective drug than phenobarbitone in terms of treatment retention (treatment failures due to lack of efficacy or adverse events or both). Moderate-certainty evidence from this review also indicates no differences between the drugs in terms of time to seizure recurrence and seizure remission. However, the trials contributing to the analyses had methodological inadequacies and methodological design differences that may have impacted upon the results of this review. Therefore, we do not suggest that results of this review alone should form the basis of a treatment choice for a patient with newly onset seizures. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.
We identified five studies that met the inclusion criteria for this review: four RCTs and one cluster-RCT. The study characteristics differed in terms of healthcare settings, the nature of the interventions studied and outcome measures reported. The cluster-RCT, and two of the RCTs, explored the effectiveness of education delivered to healthcare staff within residential or nursing home settings, or nursing home and hospital wards, compared to no intervention, or usual practices. Educational intervention in one of these studies was embedded within a broader, quality improvement bundle. The other two individually randomised controlled trials explored the effectiveness of educational intervention, delivered in two formats, to nursing staff cohorts. Due to the heterogeneity of the studies identified, pooling was not appropriate and we have presented a narrative overview. We explored a number of comparisons (1) education versus no education (2) components of educational intervention in a number of combinations and (3) education delivered in different formats. There were three primary outcomes: change in healthcare professionals' knowledge, change in healthcare professionals' clinical behaviour and incidence of new pressure ulcers. We are uncertain whether there is a difference in health professionals' knowledge depending on whether they receive education or no education on pressure ulcer prevention (hospital group: mean difference (MD) 0.30, 95% confidence interval (CI) -1.00 to 1.60; 10 participants; nursing home group: MD 0.30, 95% CI -0.77 to 1.37; 10 participants). This was based on very low-certainty evidence from one study, which we downgraded for serious study limitations, indirectness and imprecision. We are uncertain whether there is a difference in pressure ulcer incidence with the following comparisons: training, monitoring and observation, versus monitoring and observation (risk ratio (RR) 0.63, 95% CI 0.37 to 1.05; 345 participants); training, monitoring and observation, versus observation alone (RR 1.21, 95% CI 0.60 to 2.43; 325 participants) or, monitoring and observation versus observation alone (RR 1.93, 95% CI 0.96 to 3.88; 232 participants). This was based on very low-certainty evidence from one study, which we downgraded for very serious study limitations and imprecision. We are uncertain whether multilevel intervention versus attention control makes any difference to pressure ulcer incidence. The report presented insufficient data to enable further interrogation of this outcome. We are uncertain whether education delivered in different formats such as didactic education versus video-based education (MD 4.60, 95% CI 3.08 to 6.12; 102 participants) or e-learning versus classroom education (RR 0.92, 95% CI 0.80 to 1.07; 18 participants), makes any difference to health professionals' knowledge of pressure ulcer prevention. This was based on very low-certainty evidence from two studies, which we downgraded for serious study limitations and study imprecision. None of the included studies explored our other primary outcome: change in health professionals' clinical behaviour. Only one study explored the secondary outcomes of interest, namely, pressure ulcer severity and patient and carer reported outcomes (self-assessed quality of life and functional dependency level respectively). However, this study provided insufficient information to enable our independent assessment of these outcomes within the review. We are uncertain whether educating healthcare professionals about pressure ulcer prevention makes any difference to pressure ulcer incidence, or to nurses' knowledge of pressure ulcer prevention. This is because the included studies provided very low-certainty evidence. Therefore, further information is required to clarify the impact of education of healthcare professionals on the prevention of pressure ulcers.
Twelve trials on artificial or bioartificial support systems versus standard medical therapy (483 patients) and two trials comparing different artificial support systems (105 patients) were included. Most trials had unclear methodological quality. Compared to standard medical therapy, support systems had no significant effect on mortality (RR 0.86; 95% CI 0.65 to 1.12) or bridging to liver transplantation (RR 0.87; 95% CI 0.73 to 1.05), but a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95% CI 0.52 to 0.86). Meta-regression indicated that the effect of support systems depended on the type of liver failure (P = 0.03). In subgroup analyses, artificial support systems appeared to reduce mortality by 33% in acute-on-chronic liver failure (RR 0.67; 95% CI 0.51 to 0.90), but not in acute liver failure (RR 0.95; 95% CI 0.71 to 1.29). Two trials comparing artificial support systems showed significant mortality reductions with intermittent versus continuous haemofiltration (RR 0.58; 95% CI 0.36 to 0.94) and no significant difference between five versus ten hours of charcoal haemoperfusion (RR 1.03; 95% CI 0.65 to 1.62). The incidence of adverse events was inconsistently reported. This Review indicates that artificial support systems may reduce mortality in acute-on-chronic liver failure. Artificial and bioartificial support systems did not appear to affect mortality in acute liver failure. However, considering the strength of the evidence additional randomised clinical trials are needed before any support system can be recommended for routine use.
Seven RCTs (1205 patients) were included in the review. Stone-free rates were lower in patients who underwent ESWL (7 studies, 1205 participants: RR 0.84, 95% CI 0.73 to 0.96) but re-treatment rates were lower in ureteroscopy patients (6 studies, 1049 participants: RR 6.18, 95% CI 3.68 to 10.38. ESWL-treated patients had less need for auxiliary treatment (5 studies, 751 participants: RR 0.43, 95% CI 0.25 to 0.74; fewer complications (7 studies, 1205 participants: RR 0.54, 95% CI 0.33 to 0.88); and shorter length of hospital stay (2 studies, 198 participants: MD -2.55 days, 95% CI -3.24 to -1.86). Three studies adequately described the randomisation sequence, three studies were unclear on how they randomised, while one study had a high risk of selection bias. All the studies had an unclear risk of performance bias and detection bias, while all had a low risk of attrition bias, reporting bias, or other sources of bias identified. Compared with ESWL, ureteroscopic removal of ureteral stones achieves a greater stone-free state, but with a higher complication rate and longer hospital stay.
We included 53 studies primarily describing the experiences of LHWs, programme recipients, and other health workers. LHWs in high income countries mainly offered promotion, counselling and support. In low and middle income countries, LHWs offered similar services but sometimes also distributed supplements, contraceptives and other products, and diagnosed and treated children with common childhood diseases. Some LHWs were trained to manage uncomplicated labour and to refer women with pregnancy or labour complications. Many of the findings were based on studies from multiple settings, but with some methodological limitations. These findings were assessed as being of moderate certainty. Some findings were based on one or two studies and had some methodological limitations. These were assessed have low certainty. Barriers and facilitators were mainly tied to programme acceptability, appropriateness and credibility; and health system constraints. Programme recipients were generally positive to the programmes, appreciating the LHWs’ skills and the similarities they saw between themselves and the LHWs. However, some recipients were concerned about confidentiality when receiving home visits. Others saw LHW services as not relevant or not sufficient, particularly when LHWs only offered promotional services. LHWs and recipients emphasised the importance of trust, respect, kindness and empathy. However, LHWs sometimes found it difficult to manage emotional relationships and boundaries with recipients. Some LHWs feared blame if care was not successful. Others felt demotivated when their services were not appreciated. Support from health systems and community leaders could give LHWs credibility, at least if the health systems and community leaders had authority and respect. Active support from family members was also important. Health professionals often appreciated the LHWs’ contributions in reducing their workload and for their communication skills and commitment. However, some health professionals thought that LHWs added to their workload and feared a loss of authority. LHWs were motivated by factors including altruism, social recognition, knowledge gain and career development. Some unsalaried LHWs wanted regular payment, while others were concerned that payment might threaten their social status or lead recipients to question their motives. Some salaried LHWs were dissatisfied with their pay levels. Others were frustrated when payment differed across regions or institutions. Some LHWs stated that they had few opportunities to voice complaints. LHWs described insufficient, poor quality, irrelevant and inflexible training programmes, calling for more training in counselling and communication and in topics outside their current role, including common health problems and domestic problems. LHWs and supervisors complained about supervisors’ lack of skills, time and transportation. Some LHWs appreciated the opportunity to share experiences with fellow LHWs. In some studies, LHWs were traditional birth attendants who had received additional training. Some health professionals were concerned that these LHWs were over-confident about their ability to manage danger signs. LHWs and recipients pointed to other problems, including women’s reluctance to be referred after bad experiences with health professionals, fear of caesarean sections, lack of transport, and cost. Some LHWs were reluctant to refer women on because of poor co-operation with health professionals. We organised these findings and the outcome measures included in the review of LHW programme effectiveness in a logic model. Here we proposed six chains of events where specific programme components lead to specific intermediate or long-term outcomes, and where specific moderators positively or negatively affect this process. We suggest how future updates of the LHW effectiveness review could explore whether the presence of these components influences programme success. Rather than being seen as a lesser trained health worker, LHWs may represent a different and sometimes preferred type of health worker. The close relationship between LHWs and recipients is a programme strength. However, programme planners must consider how to achieve the benefits of closeness while minimizing the potential drawbacks. Other important facilitators may include the development of services that recipients perceive as relevant; regular and visible support from the health system and the community; and appropriate training, supervision and incentives.
No additional studies were identified in this 2015 review update, in total leading to no studies meeting the criteria for inclusion in this review. The efficacy of ECP in the treatment of chronic GvHD in paediatric patients after haematopoietic stem cell transplantation based on RCTs cannot be evaluated since the original version of this review and the first review update found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this patient population will be challenging due to the limited number of patients, the variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, patients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for paediatric patients that are treated with ECP.
We included three RCTs that enrolled a total of 139 eyes of 136 participants and analysed 123 (88%) eyes. Two RCTs randomised eyes into either the endothelial keratoplasty (EK) group or penetrating keratoplasty (PKP) group and one RCT randomised eyes into either the femtosecond laser-assisted endothelial keratoplasty (FLEK) group or PKP group. The RCTs comparing EK with PKP did not show any significant differences between procedures with respect to best corrected visual acuity (BCVA) at two years (mean difference (MD) 0.14 logMAR; 95% confidence interval (CI) -0.08 to 0.36; P = 0.23) or at one year (MD 0.09 logMAR; 95% CI -0.05 to 0.23; P = 0.22), whereas the trial comparing FLEK with PKP showed significantly better BCVA after PKP (MD 0.20 logMAR; 95% CI 0.10 to 0.30; P = 0.0001). Only one RCT reported on irregular astigmatism (higher-order aberration), which was less with EK than PKP (MD -1.20 µm; 95% CI -1.53 to -0.87; P < 0.001). Only one RCT reported on endothelial cell counts (lower after FLEK than PKP: MD -969 cells/mm²; 95% CI -1161 to -777; P < 0.001), primary graft failure (higher after FLEK than PKP: RR 7.76; 95% CI 0.41 to 145.22; P = 0.10), and graft rejection (more after FLEK than PKP: RR 1.11; 95% CI 0.07 to 17.12; P = 0.94). Only one RCT reported that 27.8% of participants had graft dislocation, 2.8% had epithelial ingrowth and postoperative pupillary block, and 13.9% had intraocular pressure (IOP)-related problems in the FLEK group compared with the PKP group, in whom 10% had suture-related problems, 5% had wound dehiscence and 10% had suture revision to correct astigmatism. Overall, the adverse events in the FLEK group appeared to be more frequent than in the PKP group. No trials reported information about quality of life or economic data. The overall methodological quality of the three trials was not satisfactory as most did not perform allocation concealment or masking of participants and outcome assessors, and all trials had a small sample size. The rapid growth of endothelial keratoplasty as the treatment of choice for FED is based upon the belief that visual recovery is more rapid, surgically induced astigmatism (regular and irregular) is less and rates of transplant rejection are lower with EK. This change in practice also assumes that the rates of long term transplant survival are equal for the two procedures. The practical differences between the surgical procedures mean that visual recovery is inherently more rapid following EK, but this review found no strong evidence from RCTs of any difference in the final visual outcome between EK and PKP for people with FED. This review also found that higher order aberrations are fewer following EK but endothelial cell loss is greater following EK. The RCTs that we included employed different EK techniques, which may have a bearing on these findings. EK procedures have evolved over the years and can be performed using different techniques, for example deep lamellar endothelial keratoplasty, Descemets stripping endothelial keratoplasty (DSEK), Descemets stripping automated endothelial keratoplasty (DSAEK), femtosecond laser-assisted endothelial keratoplasty and Descemet membrane endothelial keratoplasty (DMEK). More RCTs are needed to compare PKP with commonly performed EK procedures such as DSEK, DSAEK and DMEK in order to determine the answers to two key questions, whether there is any difference in the final visual outcome between these techniques and whether there are differences in the rates of graft survival in the long term?
Eight RCTs were included with a total of 3610 PAD patients. Four studies compared a recognised class of anti-hypertensive treatment with placebo and four studies compared two anti-hypertensive treatments with each other. Studies were not pooled due to the variation of the comparisons and the outcomes presented. Overall the quality of the available evidence was unclear, primarily as a result of a lack of detail in the study reports on the randomisation and blinding procedures and incomplete outcome data. Two studies compared angiotensin converting enzyme (ACE) inhibitors against placebo. In one study there was a significant reduction in the number of cardiovascular events in patients receiving ramipril (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.91; n = 1725). In the second trial using perindopril (n = 52) there was a marginal increase in claudication distance but no change in ABI and a reduction in maximum walking distance. A trial comparing the calcium antagonist verapamil versus placebo in patients undergoing angioplasty (n = 96) suggested that verapamil reduced restenosis (per cent diameter stenosis (± SD) 48.0% ± 11.5 versus 69.6% ± 12.2; P < 0.01), although this was not reflected in the maintenance of a high ABI (0.76 ± 0.10 versus 0.72 ± 0.08 for verapamil versus placebo). Another study (n = 80) demonstrated no significant difference in arterial intima-media thickness (IMT) in men receiving the thiazide diuretic hydrochlorothiazide (HCTZ) compared to those receiving the alpha-adrenoreceptor blocker doxazosin (-0.12 ± 0.14 mm and -0.08 ± 0.13 mm, respectively; P = 0.66). A study (n = 36) comparing telmisartan to placebo found a significant improvement in maximum walking distance at 12 months with telmisartan (median (interquartile range (IQR)) 191 m (157 to 226) versus 103 m (76 to 164); P < 0.001) but no differences in ABI (median (IQR) 0.60 (0.60 to 0.77) versus 0.52 (0.48 to 0.67)) or arterial IMT (median (IQR) 0.08 cm (0.07 to 0.09) versus 0.09 cm (0.08 to 0.10)). Two studies compared the beta-adrenoreceptor blocker nebivolol with either the thiazide diuretic HCTZ or with metoprolol. Both studies found no significant differences in intermittent or absolute claudication distance, ABI, or all-cause mortality between the anti-hypertensives. A subgroup analysis of PAD patients (n = 2699) in a study which compared a calcium antagonist-based strategy (verapamil slow release (SR) ± trandolapril) to a beta-adrenoreceptor blocker-based strategy (atenolol ± hydrochlorothiazide) found no significant differences in the composite endpoints of death, non-fatal myocardial infarction or non-fatal stroke with or without revascularisation (OR 0.90, 95% CI 0.76 to 1.07 and OR 0.96, 95% CI 0.82 to 1.13, respectively). Evidence on the use of various anti-hypertensive drugs in people with PAD is poor so that it is unknown whether significant benefits or risks accrue. However, lack of data specifically examining outcomes in PAD patients should not detract from the overwhelming evidence on the benefit of treating hypertension and lowering blood pressure.
We included eight randomised studies encompassing 850 participants. Five studies compared titanium clips versus ligature, two studies compared an endoscopic stapler device versus ligature, and one study compared an endoscopic stapler device, titanium clips, and ligature. In our analyses of primary outcomes, we found no differences in total complications (OR 0.97, 95% CI 0.27 to 3.50, 8 RCTs, very low-quality evidence), intraoperative complications (OR 0.93, 95% CI 0.34 to 2.55, 8 RCTs, very low-quality evidence), or postoperative complications (OR 0.80, 95% CI 0.21 to 3.13, 8 RCTs, very low-quality evidence) between ligature and all types of mechanical devices. However, our analyses of secondary outcomes revealed that use of mechanical devices saved approximately nine minutes of total operating time when compared with use of a ligature (mean difference (MD) -9.04 minutes, 95% CI -12.97 to -5.11 minutes, 8 RCTs, very low-quality evidence). However, this finding did not translate into a clinically or statistically significant reduction in inpatient hospital stay (MD 0.02 days, 95% CI -0.12 to 0.17 days, 8 RCTs, very low-quality evidence). Available information was insufficient for reliable comparison of total hospital costs and postoperative pain/quality of life between the two approaches. Overall, evidence across all analyses was of very low quality, with substantial potential for confounding factors. Given the limitations of all studies in terms of bias and the low quality of available evidence, a clear conclusion regarding superiority of any one particular type of mechanical device over another is not possible. Evidence is insufficient at present to advocate omission of conventional ligature-based appendix stump closure in favour of any single type of mechanical device over another in uncomplicated appendicitis.
We included 13 trials in this Cochrane review. Ten studies were at 'low' risk of bias. Six studies compared NSAIDs with placebo, and included 1354 participants in total. There is low quality evidence that NSAIDs are more effective than placebo, with a mean difference in pain intensity score from baseline of -6.97 (95% CI −10.74 to −3.19) on a 0 to 100 visual analogue scale (VAS) with a median follow-up of 56 days (interquartile range (IQR) 13 to 91 days). Four studies measured disability using the Roland Morris Disability Questionnaire. There is low quality evidence that NSAIDs are more effective than placebo on disability, with a mean difference from baseline of −0.85 (95% CI −1.30 to −0.40) on a scale from 0 to 24 with a median follow-up of 84 days (IQR 42 to 105 days). All six placebo controlled studies also reported adverse events, and suggested that adverse events are not statistically significant more frequent in participants using NSAIDs compared to placebo (RR 1.04, 95% CI 0.92 to 1.17). Due to the relatively small sample size and relatively short follow-up in most included trials, it is likely that the proportion of patients experiencing an adverse event is underestimated. Two studies compared different types of non-selective NSAIDs, namely ibuprofen versus diclofenac and piroxicam versus indomethacin. The trials did not find any differences between these NSAID types, but both trials had small sample sizes. One trial reported no differences in pain intensity between treatment groups that used selective or non-selective NSAIDs. One other trial compared diflunisal with paracetamol and showed no difference in improvement from baseline on pain intensity score. One trial showed a better global improvement in favour of celecoxib versus tramadol. One included trial compared NSAIDs with 'home-based exercise'. Disability improved more in participants who did exercises versus participants receiving NSAIDs, but pain scores were similar. Six of the 13 included RCTs showed that NSAIDs are more effective than placebo regarding pain intensity. NSAIDs are slightly more effective than placebo regarding disability. However, the magnitude of the effects is small, and the level of evidence was low. When we only included RCTs at low risk of bias, differences in effect between NSAIDs and placebo were reduced. We identified no difference in efficacy between different NSAID types, including selective versus non-selective NSAIDs. Due to inclusion of RCTs only, the relatively small sample sizes and relatively short follow-up in most included trials, we cannot make firm statements about the occurrence of adverse events or whether NSAIDs are safe for long-term use.
We included 36 trials involving 1472 participants in this review update. Electromechanical-assisted gait training in combination with physiotherapy increased the odds of participants becoming independent in walking (odds ratio (random effects) 1.94, 95% confidence interval (CI) 1.39 to 2.71; P < 0.001; I² = 8%; moderate-quality evidence) but did not significantly increase walking velocity (mean difference (MD) 0.04 m/s, 95% CI 0.00 to 0.09; P = 0.08; I² = 65%; low-quality evidence) or walking capacity (MD 5.84 metres walked in 6 minutes, 95% CI -16.73 to 28.40; P = 0.61; I² = 53%; very low-quality evidence). The results must be interpreted with caution because 1) some trials investigated people who were independent in walking at the start of the study, 2) we found variations between the trials with respect to devices used and duration and frequency of treatment, and 3) some trials included devices with functional electrical stimulation. Our planned subgroup analysis suggested that people in the acute phase may benefit, but people in the chronic phase may not benefit from electromechanical-assisted gait training. Post hoc analysis showed that people who are non-ambulatory at intervention onset may benefit, but ambulatory people may not benefit from this type of training. Post hoc analysis showed no differences between the types of devices used in studies regarding ability to walk, but significant differences were found between devices in terms of walking velocity. People who receive electromechanical-assisted gait training in combination with physiotherapy after stroke are more likely to achieve independent walking than people who receive gait training without these devices. We concluded that seven patients need to be treated to prevent one dependency in walking. Specifically, people in the first three months after stroke and those who are not able to walk seem to benefit most from this type of intervention. The role of the type of device is still not clear. Further research should consist of large definitive pragmatic phase III trials undertaken to address specific questions about the most effective frequency and duration of electromechanical-assisted gait training as well as how long any benefit may last.
Six RCTs ranging from 8 to 26 weeks investigating 1450 participants met the inclusion criteria. Overall, the risk of bias of these trials was unclear or high. All RCTs compared the effects of colesevelam with or without other antidiabetic drug treatments with placebo only (one study) or combined with antidiabetic drug treatments. Colesevelam with add-on antidiabetic agents demonstrated a statistically significant reduction in fasting blood glucose with a mean difference (MD) of -15 mg/dL (95% confidence interval (CI) -22 to - 8), P < 0.0001; 1075 participants, 4 trials, no trial with low risk of bias in all domains. There was also a reduction in glycosylated haemoglobin A1c (HbA1c) in favour of colesevelam (MD -0.5% (95% CI -0.6 to -0.4), P < 0.00001; 1315 participants, 5 trials, no trial with low risk of bias in all domains. However, the single trial comparing colesevelam to placebo only (33 participants) did not reveal a statistically significant difference between the two arms - in fact, in both arms HbA1c increased. Colesevelam with add-on antidiabetic agents demonstrated a statistical significant reduction in low-density lipoprotein (LDL)-cholesterol with a MD of -13 mg/dL (95% CI -17 to - 9), P < 0.00001; 886 participants, 4 trials, no trial with low risk of bias in all domains. Non-severe hypoglycaemic episodes were infrequently observed. No other serious adverse effects were reported. There was no documentation of complications of the disease, morbidity, mortality, health-related quality of life and costs. Colesevelam added on to antidiabetic agents showed significant effects on glycaemic control. However, there is a limited number of studies with the different colesevelam/antidiabetic agent combinations. More information on the benefit-risk ratio of colesevelam treatment is necessary to assess the long-term effects, particularly in the management of cardiovascular risks as well as the reduction in micro- and macrovascular complications of type 2 diabetes mellitus. Furthermore, long-term data on health-related quality of life and all-cause mortality also need to be investigated.
Six trials involving a total of 2128 people were included in this review. We did not combine the results quantitatively because the interventions and patient populations were so diverse. Early versus delayed fluid administration  Three trials reported mortality and two reported coagulation data. In the first trial (n = 598) the relative risk (RR) for death with early fluid administration was 1.26 (95% confidence interval (CI) 1.00 to 1.58). The weighted mean differences (WMD) for prothrombin time and partial thromboplastin time were 2.7 (95% CI 0.9 to 4.5) and 4.3 (95% CI 1.74 to 6.9) seconds, respectively. In the second trial (n = 50) the RR for death with early blood transfusion was 5.4 (95% CI 0.3 to 107.1). The WMD for partial thromboplastin time was 7.0 (95% CI 6.0 to 8.0) seconds. In the third trial (n = 1309) the RR for death with early fluid administration was 1.06 (95% CI 0.77 to 1.47). Larger versus smaller volume of fluid administration Three trials reported mortality and one reported coagulation data. In the first trial (n = 36) the RR for death with a larger volume of fluid resuscitation was 0.80 (95% CI 0.28 to 22.29). Prothrombin time and partial thromboplastin time were 14.8 and 47.3 seconds in those who received a larger volume of fluid, as compared to 13.9 and 35.1 seconds in the comparison group. In the second trial (n = 110) the RR for death with a high systolic blood pressure resuscitation target (100 mm Hg) maintained with a larger volume of fluid as compared to a low systolic blood pressure resuscitation target (70 mm Hg) maintained with a smaller volume of fluid was 1.00 (95% CI 0.26 to 3.81). In the third trial (n = 25) there were no deaths. We found no evidence from randomised controlled trials for or against early or larger volume of intravenous fluid administration in uncontrolled haemorrhage. There is continuing uncertainty about the best fluid administration strategy in bleeding trauma patients. Further randomised controlled trials are needed to establish the most effective fluid resuscitation strategy.
Three trials involving a total of 79 participants were included. All three trials, which compared topical nasal steroids against placebo for perennial rhinitis, provided some, albeit limited data, relevant to our primary outcomes; but in two of the trials the data analysis was flawed and in the third trial it was incomprehensible. None of the trials provided data relevant to our secondary outcomes. There were no adverse events reported from any of the interventions. The three included trials provided some weak and unreliable evidence for the effectiveness of Beconase® and flunisolide used topically intranasally for the treatment of intermittent and persistent allergic rhinitis in children. The reduction of severity in symptoms as assessed by the trialists could not be confirmed with the data provided and decisions on the use of these medications should, until such time as more robust evidence is available, be guided by the physician's clinical experience and patients' individual circumstances and preferences.
We did not find any fully-published, completed RCTs of angiogenesis inhibitors that met our inclusion criteria. We identified five abstracts of completed RCTs of four different angiogenesis-inhibiting agents, with a total of 3701 participants. Meta-analysis of two trials found no statistically significant difference in overall survival (OS) between women with newly-diagnosed advanced ovarian cancer who received concurrent and maintenance bevacizumab compared to those who received chemotherapy (carboplatin and paclitaxel) alone. However, women who received concurrent and maintenance bevacizumab had their risk of disease progression reduced by a quarter (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68 to 0.83; P < 0.001); they also had a significantly increased risk of severe gastrointestinal adverse events, moderate or severe hypertension and severe bleeding. One trial also compared chemotherapy to concurrent (but not maintenance bevacizumab), and found no statistically significant difference in OS or progression-free survival (PFS).  However, the women who received bevacizumab had a significantly higher risk of moderate or severe hypertension. A three-armed RCT, of paclitaxel alone or with low- or high-dose AMG 386, in women with recurrent ovarian cancer, found no statistically significant difference in OS. However, women who received low-dose AMG 386 had a third less risk of disease progression than those who received placebo (HR 0.57, 95% CI 0.36 to 0.91; P = 0.02). The trial found no evidence of increased adverse events in the intervention arms. Two relatively small RCTs (one of VEGF-Trap, the other of BIBF 1120) found no evidence of either significant survival benefit or increased severe adverse events, compared to placebo, but they both lacked statistical power. All five trials had unclear risk of bias, largely because they have only been published in abstract form, and thus many methodological details are unclear. We identified twelve suitable ongoing trials. There is, as yet, no fully-published RCT evidence for the efficacy or safety of angiogenesis inhibitors for the treatment of ovarian cancer, but some preliminary results are available from five trials. There is some evidence from a meta-analysis of two trials that the addition of concurrent and maintenance bevacizumab to standard chemotherapy may reduce the risk of disease progression, in women with newly-diagnosed advanced ovarian cancer. There is also some evidence from a single trial that low-dose AMG 386 may reduce the risk of disease progression in women with recurrent ovarian cancer. However, there is currently no evidence that angiogenesis inhibitors improve OS, nor is there enough evidence to justify the routine use of angiogenesis inhibitors in treating women with ovarian cancer. We eagerly await both the more detailed results of these five completed trials, and the preliminary results of the several ongoing trials.
Eighteen randomised trials with 50,623 participants provided data for the analyses. All trials came from high-income countries. Most of the trials had a high risk of bias, mainly for-profit bias. Most trials included elderly community-dwelling women (aged 47 to 97 years). Vitamin D was administered for a weighted mean of six years. Fourteen trials tested vitamin D₃, one trial tested vitamin D₂, and three trials tested calcitriol supplementation. Cancer occurrence was observed in 1927/25,275 (7.6%) recipients of vitamin D versus 1943/25,348 (7.7%) recipients of control interventions (RR 1.00 (95% confidence interval (CI) 0.94 to 1.06); P = 0.88; I² = 0%; 18 trials; 50,623 participants; moderate quality evidence according to the GRADE instrument). Trial sequential analysis (TSA) of the 18 vitamin D trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. We did not observe substantial differences in the effect of vitamin D on cancer in subgroup analyses of trials at low risk of bias compared to trials at high risk of bias; of trials with no risk of for-profit bias compared to trials with risk of for-profit bias; of trials assessing primary prevention compared to trials assessing secondary prevention; of trials including participants with vitamin D levels below 20 ng/mL at entry compared to trials including participants with vitamin D levels of 20 ng/mL or more at entry; or of trials using concomitant calcium supplementation compared to trials without calcium. Vitamin D decreased all-cause mortality (1854/24,846 (7.5%) versus 2007/25,020 (8.0%); RR 0.93 (95% CI 0.88 to 0.98); P = 0.009; I² = 0%; 15 trials; 49,866 participants; moderate quality evidence), but TSA indicates that this finding could be due to random errors. Cancer occurrence was observed in 1918/24,908 (7.7%) recipients of vitamin D₃ versus 1933/24,983 (7.7%) in recipients of control interventions (RR 1.00 (95% CI 0.94 to 1.06); P = 0.88; I² = 0%; 14 trials; 49,891 participants; moderate quality evidence). TSA of the vitamin D₃ trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. Vitamin D₃ decreased cancer mortality (558/22,286 (2.5%) versus 634/22,206 (2.8%); RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I² = 0%; 4 trials; 44,492 participants; low quality evidence), but TSA indicates that this finding could be due to random errors. Vitamin D₃ combined with calcium increased nephrolithiasis (RR 1.17 (95% CI 1.03 to 1.34); P = 0.02; I² = 0%; 3 trials; 42,753 participants; moderate quality evidence). TSA, however, indicates that this finding could be due to random errors. We did not find any data on health-related quality of life or health economics in the randomised trials included in this review. There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women. Vitamin D₃ supplementation decreased cancer mortality and vitamin D supplementation decreased all-cause mortality, but these estimates are at risk of type I errors due to the fact that too few participants were examined, and to risks of attrition bias originating from substantial dropout of participants. Combined vitamin D₃ and calcium supplements increased nephrolithiasis, whereas it remains unclear from the included trials whether vitamin D₃, calcium, or both were responsible for this effect. We need more trials on vitamin D supplementation, assessing the benefits and harms among younger participants, men, and people with low vitamin D status, and assessing longer duration of treatments as well as higher dosages of vitamin D. Follow-up of all participants is necessary to reduce attrition bias.
Twenty-eight studies (reporting a total of thirty-two comparisons) were included. Computer reminders achieved a median improvement in process adherence of 4.2% (interquartile range (IQR): 0.8% to 18.8%) across all reported process outcomes, 3.3% (IQR: 0.5% to 10.6%) for medication ordering, 3.8% (IQR: 0.5% to 6.6%) for vaccinations, and 3.8% (IQR: 0.4% to 16.3%) for test ordering. In a sensitivity analysis using the best outcome from each study, the median improvement was 5.6% (IQR: 2.0% to 19.2%) across all process measures and 6.2% (IQR: 3.0% to 28.0%) across measures of medication ordering. In the eight comparisons that reported dichotomous clinical endpoints, intervention patients experienced a median absolute improvement of 2.5% (IQR: 1.3% to 4.2%). Blood pressure was the most commonly reported clinical endpoint, with intervention patients experiencing a median reduction in their systolic blood pressure of 1.0 mmHg (IQR: 2.3 mmHg reduction to 2.0 mmHg increase). Point of care computer reminders generally achieve small to modest improvements in provider behaviour. A minority of interventions showed larger effects, but no specific reminder or contextual features were significantly associated with effect magnitude. Further research must identify design features and contextual factors consistently associated with larger improvements in provider behaviour if computer reminders are to succeed on more than a trial and error basis.
We included 18 RCTs with a total of 2738 participants. Fourteen studies had participants with nasal polyps and four studies had participants without nasal polyps. Only one study was conducted in children. Intranasal corticosteroids versus placebo or no intervention Only one study (20 adult participants without polyps) measured our primary outcome disease-specific HRQL  using the Rhinosinusitis Outcome Measures-31 (RSOM-31). They reported no significant difference (numerical data not available) (very low quality evidence). Our second primary outcome, disease severity  , was measured using the Chronic Sinusitis Survey in a second study (134 participants without polyps), which found no important difference (mean difference (MD) 2.84, 95% confidence interval (CI) -5.02 to 10.70; scale 0 to 100). Another study (chronic rhinosinusitis with nasal polyps) reported an increased chance of improvement in the intranasal corticosteroids group (RR 2.78, 95% CI 1.76 to 4.40; 109 participants). The quality of the evidence was low. Six studies provided data on at least two of the individualsymptoms  used in the EPOS 2012 criteria to define chronic rhinosinusitis (nasal blockage, rhinorrhoea, loss of sense of smell and facial pain/pressure). When all four symptoms in the EPOS criteria were available on a scale of 0 to 3 (higher = more severe symptoms), the average MD in change from baseline was -0.26 (95% CI -0.37 to -0.15; 243 participants; two studies; low quality evidence). Although there were more studies and participants when only nasal blockage and rhinorrhoea were considered (MD -0.31, 95% CI -0.38 to -0.24; 1702 participants; six studies), the MD was almost identical to when loss of sense of smell was also considered (1345 participants, four studies; moderate quality evidence). When considering the results for the individual symptoms, benefit was shown in the intranasal corticosteroids group. The effect size was larger for nasal blockage (MD -0.40, 95% CI -0.52 to -0.29; 1702 participants; six studies) than for rhinorrhoea (MD -0.25, 95% CI -0.33 to -0.17; 1702 participants; six studies) or loss of sense of smell (MD -0.19, 95% CI -0.28 to -0.11; 1345 participants; four studies). There was heterogeneity in the analysis for facial pain/pressure (MD -0.27, 95% CI -0.56 to 0.02; 243 participants; two studies). The quality of the evidence was moderate for nasal blockage, rhinorrhoea and loss of sense of smell, but low for facial pain/pressure. There was an increased risk of epistaxis  with intranasal corticosteroids (risk ratio (RR) 2.74, 95% CI 1.88 to 4.00; 2508 participants; 13 studies; high quality evidence). Considering our secondary outcome, general HRQL, one study (134 participants without polyps) measured this using the SF-36 and reported a statistically significant benefit only on the general health subscale. The quality of the evidence was very low. It is unclear whether there is a difference in the risk of local irritation (RR 0.94, 95% CI 0.53 to 1.64; 2124 participants; 11 studies) (low quality evidence). None of the studies treated or followed up patients long enough to provide meaningful data on the risk of osteoporosis or stunted growth (children). Other comparisons We identified no other studies that compared intranasal corticosteroids plus co-intervention A versus placebo plus co-intervention A. Most of the evidence available was from studies in patients with chronic rhinosinusitis with nasal polyps. There is little information about quality of life (very low quality evidence). For disease severity, there seems to be improvement for all symptoms (low quality evidence), a moderate-sized benefit for nasal blockage and a small benefit for rhinorrhoea (moderate quality evidence). The risk of epistaxis is increased (high quality evidence), but these data included all levels of severity; small streaks of blood may not be a major concern for patients. It is unclear whether there is a difference in the risk of local irritation (low quality evidence).
Eleven studies including a total of 422 participants contributed to data analyses. Most studies had a small population size (average 38 people per study) and were of short duration. We also detected a high risk of bias for selective outcome reporting in just under 50% of the trials. We therefore rated the overall methodological quality of the included studies as low. We considered seven main outcomes of interest: clinically important change in overall mental state, clinically important change in cognitive functioning, incidence of a clinically important adverse effect/event, clinically important change in global state, leaving the study early for any reason, clinically important change in quality of life, and hospital admission. All studies assessed the effects of adding modafinil to participants' usual antipsychotic treatment compared to adding placebo to usual antipsychotic treatment. Six studies found that adding modafinil to antipsychotic treatment may have little or no effect on overall mental state of people with schizophrenia, specifically the risk of worsening psychosis (RR 0.91, 95% CI 0.28 to 2.98; participants = 209; studies = 6, low-quality evidence). Regarding the effect of modafinil on cognitive function, the trials did not report clinically important change data, but one study reported endpoint scores on the MATRICS Consensus Cognitive Battery (MCCB): in this study we found no clear difference in scores between modafinil and placebo treatment groups (MD −3.10, 95% CI −10.9 to 4.7; participants = 48; studies = 1, very low-quality evidence). Only one study (N = 35) reported adverse effect/event data. In this study one serious adverse event occurred in each group (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). One study measured change in global state using the Clinical Global Impression - Improvement Scale. This study found that adding modafinil to antipsychotic treatment may have little or no effect on global state (RR 6.36, 95% CI 0.94 to 43.07, participants = 21; studies = 1, very low-quality evidence). Nine studies found that modafinil has no effect on numbers of participants leaving the study early (RR 1.26, 95% CI 0.63 to 2.52 participants = 357; studies = 9, moderate-quality evidence). None of the trials reported clinically important change in quality of life, but one study did report quality of life using endpoint scores on the Quality of Life Inventory, finding no clear difference between treatment groups (MD −0.2, 95% CI −1.18 to 0.78; participants = 20; studies = 1, very low-quality evidence). Finally, one study reported data for number of participants needing hospitalisation: one participant in each group was hospitalised (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). Due to methodological issues, low sample size, and short duration of the clinical trials as well as high risk of bias for outcome reporting, most of the evidence available for this review is of very low or low quality. For results where quality is low or very low, we are uncertain or very uncertain if the effect estimates are true effects, limiting our conclusions. Specifically, we found that modafinil is no better or worse than placebo at preventing worsening of psychosis; however, we are uncertain about this result. We have more confidence that participants receiving modafinil are no more likely to leave a trial early than participants receiving placebo. However, we are very uncertain about the remaining equivocal results between modafinil and placebo for outcomes such as improvement in global state or cognitive function, incidence of adverse events, and changes in quality of life. More high-quality data are needed before firm conclusions regarding the effects of modafinil for people with schizophrenia or related disorders can be made.
Thirty-five placebo-controlled trials (4060 participants) provided data in a form suitable for inclusion in the meta-analyses. When compared with placebo, the use of IS was shown to reduce ARTIs measured as the total numbers of ARTIs (MD -1.24; 95% CI -1.54 to -0.94) and the difference in ARTI rates (MD -38.84%; 95% CI -46.37% to -31.31%). Trial quality was generally poor and a high level of statistical heterogeneity was evident. The subgroup analysis of bacterial IS, D53 and OM-85 studies produced similar results, with lower heterogeneity. No difference in adverse events was evident between the placebo and IS groups. This review shows that IS reduce the incidence of ARTIs by 40% on average in susceptible children. Studies in healthy children are not available. Although the safety profile in the studies was good, some IS may be unsafe. ARTI-susceptible children may benefit from IS treatment. Further high-quality trials are needed and we encourage national health authorities to conduct large, multicentre, double-blind, placebo-controlled RCTs on the role of IS in preventing ARTIs in children.
With this current update, a total of five eligible studies (215 patients) were identified. Only one outcome, the proportion of patients with Expanded Disability Status Scale (EDSS) improvement at four weeks, was common to three trials, while two trials examined magnetic resonance imaging (MRI) outcomes. The results of this review shows there is no significant difference in relapse recovery at week four (MD -0.22, 95% confidence interval (95% CI), 0.71 to 0.26, P = 0.20) nor differences in magnetic resonance imaging (MRI) gadolinium enhancement activity based on oral versus intravenous steroid treatment. However, only two of the five studies employed more current and rigorous methodological techniques, so these results must be taken with some caution. The Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial and the "Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses" (COPOUSEP) trial, designed to address such limitations, are currently underway. The analysis of the five included trials comparing intravenous versus oral steroid therapy for MS relapses do not demonstrate any significant differences in clinical (benefits and adverse events), radiological or pharmacological outcomes. Based on the evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy in the treatment of MS relapses.
We identified three trials that met the inclusion criteria for this review. In these, a total of 47 people with MRSA-positive diabetic foot infections were randomised to six different antibiotic regimens. While these trials included 925 people with multiple pathogens, they reported the information on outcomes for people with MRSA infections separately (MRSA prevalence: 5.1%). The only outcome reported for people with MRSA infection in these trials was the eradication of MRSA. The three trials did not report the review's primary outcomes (death and quality of life) and secondary outcomes (length of hospital stay, use of healthcare resources and time to complete wound healing). Two trials reported serious adverse events in people with infection due to any type of bacteria (i.e. not just MRSA infections), so the proportion of patients with serious adverse events was not available for MRSA-infected wounds. Overall, MRSA was eradicated in 31/47 (66%) of the people included in the three trials, but there were no significant differences in the proportion of people in whom MRSA was eradicated in any of the comparisons, as shown below. 1. Daptomycin compared with vancomycin or semisynthetic penicillin: RR of MRSA eradication 1.13; 95% CI 0.56 to 2.25 (14 people). 2. Ertapenem compared with piperacillin/tazobactam: RR of MRSA eradication 0.71; 95% CI 0.06 to 9.10 (10 people). 3. Moxifloxacin compared with piperacillin/tazobactam followed by amoxycillin/clavulanate: RR of MRSA eradication 0.87; 95% CI 0.56 to 1.36 (23 people). We found no trials comparing the use of antibiotics with no antibiotic for treating MRSA-colonised non-surgical wounds and therefore can draw no conclusions for this population. In the trials that compared different antibiotics for treating MRSA-infected non surgical wounds, there was no evidence that any one antibiotic was better than the others. Further well-designed RCTs are necessary.
Fourteen studies met the inclusion criteria, randomly assigning 2313 people with acute asthma to the comparisons of interest in this review. Most studies were double-blinded trials comparing a single infusion of 1.2 g or 2 g IV MgSO4 over 15 to 30 minutes versus a matching placebo. Eleven were conducted at a single centre, and three were multi-centre trials. Participants in almost all of the studies had already been given at least oxygen, nebulised short-acting beta2-agonists and IV corticosteroids in the ED; in some studies, investigators also administered ipratropium bromide. Ten studies included only adults, and four included both adults and children; these were included because the mean age of participants was over 18 years. Intravenous MgSO4 reduced hospital admissions compared with placebo (odds ratio (OR) 0.75, 95% confidence interval (CI) 0.60 to 0.92; I2 = 28%, P value 0.18; n = 972; high-quality evidence). In absolute terms, this odds ratio translates into a reduction of seven hospital admissions for every 100 adults treated with IV MgSO4 (95% CI two to 13 fewer). The test for subgroup differences revealed no statistical heterogeneity between the three severity subgroups (I2 = 0%, P value 0.73) or between the four studies that administered nebulised ipratropium bromide as a co-medication and those that did not (I2 = 0%, P value 0.82). Sensitivity analyses in which unpublished data and studies at high risk for blinding were removed from the primary analysis did not change conclusions. Within the secondary outcomes, high- and moderate-quality evidence across three spirometric indices suggests some improvement in lung function with IV MgSO4. No difference was found between IV MgSO4and placebo for most of the non-spirometric secondary outcomes, all of which were rated as low or moderate quality (intensive care admissions, ED treatment duration, length of hospital stay, readmission, respiration rate, systolic blood pressure). Adverse events were inconsistently reported and were not meta-analysed. The most commonly cited adverse events in the IV MgSO4 groups were flushing, fatigue, nausea and headache and hypotension (low blood pressure). This review provides evidence that a single infusion of 1.2 g or 2 g IV MgSO4 over 15 to 30 minutes reduces hospital admissions and improves lung function in adults with acute asthma who have not responded sufficiently to oxygen, nebulised short-acting beta2-agonists and IV corticosteroids. Differences in the ways the trials were conducted made it difficult for the review authors to assess whether severity of the exacerbation or additional co-medications altered the treatment effect of IV MgSO4. Limited evidence was found for other measures of benefit and safety. Studies conducted in these populations should clearly define baseline severity parameters and systematically record adverse events. Studies recruiting participants with exacerbations of varying severity should consider subgrouping results on the basis of accepted severity classifications.
35 short-term (14 weeks or less) RCTs were included in the analysis (4597 participants). Symptom severity for 17 trials was significantly reduced in the medication groups, relative to placebo (weighted mean difference -5.76, 95% confidence intervals (CI) -8.16 to -3.36, number of participants (N) = 2507). Similarly, summary statistics for responder status from 13 trials demonstrated overall superiority of a variety of medication agents to placebo (relative risk 1.49, 95% CI 1.28 to 1.73, number needed to treat = 4.85, 95% CI 3.85 to 6.25, N = 1272). Medication and placebo response occurred in 59.1% (N = 644) and 38.5% (628) of patients, respectively. Of the medication classes, evidence of treatment efficacy was most convincing for the SSRIs. Medication was superior to placebo in reducing the severity of PTSD symptom clusters, comorbid depression and disability. Medication was also less well tolerated than placebo. A narrative review of 3 maintenance trials suggested that long term medication may be required in treating PTSD. Medication treatments can be effective in treating PTSD, acting to reduce its core symptoms, as well as associated depression and disability. The findings of this review support the status of SSRIs as first line agents in the pharmacotherapy of PTSD, as well as their value in long-term treatment. However, there remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.
We included 30 studies, which evaluated 3D exercise (Tai Chi and yoga), balance training or strength and resistance training. Two of these were cluster-randomised trials, two were cross-over trials and one was quasi-randomised. The studies included a total of 2878 participants with a mean age ranging from 68 to 85 years. Most studies included more women than men, with four studies recruiting women only. Twelve studies recruited participants at increased risk of falls; three of these recruited participants who also had fear of falling. Poor reporting of the allocation methods in the trials made it difficult to assess the risk of selection bias in most studies. All of the studies were at high risk of performance and detection biases as there was no blinding of participants and outcome assessors and the outcomes were self reported. Twelve studies were at high risk of attrition bias. Using GRADE criteria, we judged the quality of evidence to be 'low' for fear of falling immediately post intervention and 'very low' for fear of falling at short or long-term follow-up and all other outcomes. Exercise interventions were associated with a small to moderate reduction in fear of falling immediately post intervention (SMD 0.37 favouring exercise, 95% confidence interval (CI) 0.18 to 0.56; 24 studies; 1692 participants, low quality evidence). Pooled effect sizes did not differ significantly between the different scales used to measure fear of falling. Although none of the sensitivity analyses changed the direction of effect, the greatest reduction in the size of the effect was on removal of an extreme outlier study with 73 participants (SMD 0.24 favouring exercise, 95% CI 0.12 to 0.36). None of our subgroup analyses provided robust evidence of differences in effect in terms of either the study primary aim (reduction of fear of falling or other aim), the study population (recruitment on the basis of increased falls risk or not), the characteristics of the study exercise intervention or the study control intervention (no treatment or alternative intervention). However, there was some weak evidence of a smaller effect, which included no reduction, of exercise when compared with an alternative control. There was very low quality evidence that exercise interventions may be associated with a small reduction in fear of falling up to six months post intervention (SMD 0.17, 95% CI -0.05 to 0.38; four studies, 356 participants) and more than six months post intervention (SMD 0.20, 95% CI -0.01 to 0.41; three studies, 386 participants). Very low quality evidence suggests exercise interventions in these studies that also reported on fear of falling reduced the risk of falling measured either as participants incurring at least one fall during follow-up or the number of falls during follow-up. Very low quality evidence from four studies indicated that exercise interventions did not appear to reduce symptoms of depression or increase physical activity. The only study reporting the effects of exercise interventions on anxiety found no difference between groups. No studies reported the effects of exercise interventions on activity avoidance or costs. It is important to remember that our included studies do not represent the totality of the evidence of the effect of exercise interventions on falls, depression, anxiety or physical activity as our review only includes studies that reported fear of falling. Exercise interventions in community-dwelling older people probably reduce fear of falling to a limited extent immediately after the intervention, without increasing the risk or frequency of falls. There is insufficient evidence to determine whether exercise interventions reduce fear of falling beyond the end of the intervention or their effect on other outcomes. Although further evidence from well-designed randomised trials is required, priority should be given to establishing a core set of outcomes that includes fear of falling for all trials examining the effects of exercise interventions in older people living in the community.
One ongoing study (Pellicer 2003) was identified. One study comparing adrenaline with dopamine infusion was included but was published in abstract form only (Phillipos 1996). It enrolled hypotensive, predominately preterm infants in the first 24 hours. Only infants >1750g are included in this review (report for infants <=1750g appears incomplete). The study was reported as being randomised and double blinded, but methods were not reported. Both adrenaline and dopamine significantly increased heart rate and mean BP, with no statistically significant effect on left or right ventricular outputs. No other clinical outcomes were reported. No studies were identified that compared adrenaline to other inotropes, placebo or no treatment. There are insufficient data on the use of adrenaline infusions in preterm infants with cardiovascular compromise to make recommendations for practice. There is a need for larger trials to determine whether adrenaline is effective in reducing morbidity and mortality in preterm infants with cardiovascular compromise.
24 studies met the inclusion for the review (3907 participants). In non-oral steroid treated, mild to moderately severe asthma, no clinically worthwhile differences in FEV1, morning PEFR, symptom scores or rescue beta2 agonist use were apparent across a dose range of 200-1600 mcg/d. However, in moderate to severe asthma a significant reduction in the likelihood of trial withdrawal due to asthma exacerbation was apparent when treating patients with BUD 800 mcg/d compared to 200 mcg/d: Relative Risk 3.93 (95% confidence interval, 1.4 to 10.9). This result was weighted largely by a single, large, high quality RCT. In severe asthma significant improvements favouring high dose BUD (1600 mcg/d) over low dose (200 mcg/d) were apparent for FEV1 but not morning PEFR. This finding was based on two large RCTs of good quality. In oral steroid treated asthmatics no dose dependent oral steroid sparing effect was apparent for BUD 1600 mcg/d v 800 or 400 mcg/d. Statistically significant, dose dependent suppression of 24 hour urinary free cortisol excretion and serum cortisol post synthetic ACTH infusion over the dose range 800-3200 mcg/d was apparent but the clinical significance of these findings is unclear. Budesonide exhibits a significant dose response effect between low and high dose for improvement in FEV1 in severe asthma and reduction of exacerbations in moderate to severe asthma. No significant dose dependent improvements in FEV1, PEFR or symptoms are evident in non-oral steroid treated asthmatics with mild to moderate disease. Dose dependent alterations in sensitive measures of hypothalamic-pituitary-adrenal function were evident but the clinical significance of these changes is unclear.
Seven RCTs, involving 1671 women were identified for inclusion. The review found that giving women information about the procedure prior to the mammogram may reduce pain and discomfort. Increasing women's control over breast compression could reduce pain experienced during the procedure, though mammogram image quality was only maintained if the technologist controlled the first compression. If the technologist reduced compression force of the mammogram, discomfort experienced was unchanged. The use of breast cushions reduced pain of mammography; however, image quality was impaired in 2% of women in the intervention group. Acetoaminophen as a premedication did not affect discomfort of mammography. Differences in interventions, and inconsistency in measures, validation of pain scales, and in assessment of mammogram quality, mean that results of these studies cannot be combined. All results are based on single studies. Further research is required. Currently there are very few proven interventions to reduce pain and discomfort of screening mammography, especially procedures that can be readily introduced to screening programmes. With mammography continuing as the preferred method for breast screening, more research on such interventions is needed.
We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials). Non-platinum single-agent versus non-platinum combination therapy Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence). Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data. Non-platinum therapy versus platinum combination therapy Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs). Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.
We identified five new studies for this update, which now has information from 10,857 participants in 39 studies, a 41% increase in participants from the earlier review; 32 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size. In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2353 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis. There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence). Clinical success with carrier occurred commonly - in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo. A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed. Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that.
Twenty papers describing 17 unique trials met the inclusion criteria. Analysis of data from nine trials (1737 participants) showed that topiramate reduced headache frequency by about 1.2 attacks per 28 days as compared to placebo (MD -1.20; 95% confidence interval (CI) -1.59 to -0.80). Data from nine trials (1190 participants) show that topiramate approximately doubled the proportion of responders relative to placebo (RR 2.02; 95% CI 1.57 to 2.60; NNT 4; 95% CI 3 to 6). Separate analysis of different topiramate doses produced similar MDs versus placebo at 50 mg (-0.95; 95% CI -1.95 to 0.04; three studies; 520 participants), 100 mg (-1.15; 95% CI -1.58 to -0.71; six studies; 1620 participants), and 200 mg (-0.94; 95% CI -1.53 to -0.36; five studies; 804 participants). All three doses significantly increased the proportion of responders relative to placebo; ORs were as follows: for 50 mg, 2.35 (95% CI 1.60 to 3.44; three studies; 519 participants); for 100 mg, 3.49 (95% CI 2.23 to 5.45; five studies; 852 participants); and for 200 mg, 2.49 (95% CI 1.61 to 3.87; six studies; 1025 participants). All three doses also significantly improved three or more domains of quality of life as compared to placebo. Meta-analysis of the three studies that included more than one dose of topiramate suggests that 200 mg is no more effective than 100 mg. With regard to mean headache frequency and/or responder rate, seven trials using active comparators found (a) no significant difference between topiramate and amitriptyline (one study, 330 participants); (b) no significant difference between topiramate and flunarizine (one study, 83 participants); (c) no significant difference between topiramate and propranolol (two studies, 342 participants); (d) no significant difference between topiramate and relaxation (one study, 61 participants); but (e) a slight significant advantage of topiramate over valproate (two studies, 120 participants). Relaxation improved migraine-specific quality of life significantly more than topiramate. In trials of topiramate against placebo, seven adverse events (AEs) were reported by at least three studies. These were usually mild and of a non-serious nature. Except for taste disturbance and weight loss, there were no significant differences in the frequency of AEs in general, or of the seven specific AEs, between placebo and topiramate 50 mg. AEs in general and all of the specific AEs except nausea were significantly more common on topiramate 100 mg than on placebo, with NNHs varying from 3 to 25, and the RDs versus placebo were even higher for topiramate 200 mg, with NNHs varying from 2 to 17. Meta-analysis demonstrates that topiramate in a 100 mg/day dosage is effective in reducing headache frequency and reasonably well-tolerated in adult patients with episodic migraine. This provides good evidence to support its use in routine clinical management. More studies designed specifically to compare the efficacy or safety of topiramate versus other interventions with proven efficacy in the prophylaxis of migraine are needed.
The search strategy identified six potentially eligible studies. Two studies were excluded. We included four randomised controlled trials that randomised a total of 599 women (data were available for 595 women). Two trials (283 women) compared the effects of perineal HAase injection during the second stage of labour with placebo injection and were at low risk of bias. Three trials (one three-armed trial was analysed twice) (373 women) compared the effects of perineal HAase injection during second stage of labour with no intervention and two out of the three trials were at high risk of bias. Data from four trials involving 599 women suggested that perineal HAase injection during second stage of labour had a lower incidence of perineal trauma (average risk ratio (RR) 0.69, 95% confidence interval (CI) 0.50 to 0.95,Tau² = 0.08, I² = 82% compared with women in the control group, but there was no clear evidence of a reduction in the incidence of episiotomy (average RR 0.74, 95% CI 0.43 to 1.29, Tau² = 0.17, I² = 66%), first and second degree perineal lacerations (average RR 0.54, 95% CI 0.38 to 1.33, Tau² = 0.30 , I² = 85%) and third and fourth degree perineal lacerations (RR 0.12, 95% CI 0.01 to 2.13). Data from two trials involving 283 women indicated that there was no clear evidence of a reduction in the incidence of perineal trauma (RR 0.90, 95% CI 0.77 to 1.06, Tau²=1.07, I² = 7%), episiotomy (RR 0.77, 95% CI 0.32 to 1.89, Tau² = 0.27, I² = 54%), first and second degree perineal lacerations (RR 1.08, 95% CI 0.83 to 1.40, Tau² = 1.11, I² = 10%) and third and fourth degree perineal lacerations (RR 0.12, 95% CI 0.01 to 2.13) with perineal HAase injection. Data from three trials involving 373 women suggested that perineal HAase injection during second stage of labour had a lower incidence of perineal trauma (RR 0.61, 95% CI 0.42 to 0.88, Tau² = 0.08, I² = 78%) compared with no intervention, but had no clear effect on in the incidence of episiotomy (RR 0.79, 95% CI 0.44 to 1.42, Tau² = 0.16, I² = 70%) and first and second degree perineal lacerations (RR 0.58, 95% CI 0.31 to 1.10, Tau² = 0.18, I² = 59%). No side effects were reported in the included trials. No included trials reported on perineal pain and other pre-specified secondary outcomes: perineal trauma requiring suturing; blood loss; dyspareunia; urinary incontinence; faecal incontinence; assisted delivery rate; women's satisfaction; Apgar score less than seven at five minutes and need for admission to special care baby unit. Perineal HAase injection during second stage of labour had a lower incidence of perineal trauma compared with control or no intervention, but there was no clear evidence of benefit compared with placebo injection. The difference in incidence of perineal trauma may probably be due to bias and confounding in the non-placebo controlled comparison, this result should be interpreted cautiously. The potential use of perineal HAase injection as a method to reduce perineal trauma were yet to be determined as there was no appropriate established dose for HAase, no evidence of follow up, and the number of high-quality trials and outcomes reported were too limited to draw conclusions on its effectiveness and safety. Further rigorous randomised controlled trials are required to evaluate the role of perineal HAase injection in vaginal deliveries.
We included only one comparison of whole gland cryotherapy versus external beam radiotherapy, which was informed by two trials with a total of 307 randomised participants. The median age of the included studies was around 70 years. The median follow-up of included studies ranged from 100 to 105 months. Primary outcomes: we are uncertain about the effect of whole gland cryotherapy compared to radiation therapy on time to death from prostate cancer; hazard ratio (HR) of 1.00 (95% confidence interval (CI) 0.11 to 9.45; 2 trials, 293 participants; very low QoE); this would correspond to zero fewer death from prostate cancer per 1000 men (95% CI 85 fewer to 520 more). We are equally uncertain about the effect of quality of life-related urinary function and bowel function (QoL) at 36 months using the UCLA-Prostate Cancer Index score for which higher values (range: 0 to 100) reflect better quality of life using minimal clinically important differences (MCID) of 8 and 7 points, respectively; mean difference (MD) of 4.4 (95% CI −6.5 to 15.3) and 4.0 (95% CI −73.96 to 81.96), respectively (1 trial, 195 participants; very low QoE). We are also uncertain about sexual function-related QoL using a MCID of 8 points; MD of −20.7 (95% CI −36.29 to −5.11; 1 trial, 195 participants; very low QoE). Lastly, we are uncertain of the risk for major adverse events; risk ratio (RR): 0.91 (95% CI 0.47 to 1.78; 2 trials, 293 participants; very low QoE); this corresponds to 10 fewer major adverse events per 1000 men (95% CI 58 fewer to 86 more). Secondary outcomes: we are very uncertain about the effects of cryotherapy on time to death from any cause (HR 0.99, 95% CI 0.05 to 18.79; 2 trials, 293 participants; very low QoE), and time to biochemical failure (HR 2.15, 95% CI 0.07 to 62.12; 2 trials, 293 participants; very low QoE). Rates of secondary interventions for treatment failure and minor adverse events were either not reported in the trials, or the data could not be used for analyses. We found no trials that compared whole gland cryotherapy or focal cryotherapy to other treatment forms such as radical surgery, active surveillance, watchful waiting or other forms of radiotherapy. Based on very low quality evidence, primary whole gland cryotherapy has uncertain effects on oncologic outcomes, QoL, and major adverse events compared to external beam radiotherapy. Reasons for downgrading the QoE included serious study limitations, indirectness due to the use of lower doses of radiation in the comparison group than currently recommended, and serious or very serious imprecision.
Thirty four studies involving 4001 children were included. Interventions included; long-term low-dose antibiotics, surgical reimplantation of ureters, endoscopic injection treatment, probiotics, cranberry products, circumcision, and oxybutynin. Interventions were used alone and in combinations. The quality of conduct and reporting of these studies was variable, with many studies omitting crucial methodological information used to assess the risk of bias. Only four of the 34 studies were considered at low risk of bias across all fields of study quality. The majority of studies had many areas of uncertainty in the risk of bias fields, reflecting missing detail rather than stated poor design. Low-dose antibiotic prophylaxis compared to no treatment/placebo may make little or no difference to the risk of repeat symptomatic UTI (9 studies, 1667 children: RR 0.77, 95% CI 0.54 to 1.09; low certainty evidence) and febrile UTI (RR 0.83, 95% CI 0.56 to 1.21; low certainty evidence) at one to two years. At one to three years, antibiotic prophylaxis made little or no difference to the risk of new or progressive renal damage on DMSA scan (8 studies, 1503 children: RR 0.73, 95% CI 0.33 to 1.61; low certainty evidence). Adverse events were reported in four studies with little or no difference between treatment groups (1056 children: RR 0.94, 95% CI 0.81 to 1.08; ), but antibiotics increased the likelihood of bacterial drug resistance threefold (187 UTIs: RR 2.97, 95% CI 1.54 to 5.74; moderate certainty evidence). Seven studies compared long-term antibiotic prophylaxis alone with surgical reimplantation of ureters plus antibiotics, but only two reported the outcome febrile UTI (429 children). Surgery plus antibiotic treatment may reduce the risk of repeat febrile UTI by 57% (RR 0.43, 95% CI 0.27 to 0.70; moderate certainty evidence). There was little or no difference in the risk of new kidney defects detected using intravenous pyelogram at 4 to 5 years (4 studies, 572 children, RR 1.09, 95% CI 0.79 to 1.49; moderate certainty evidence) Four studies compared endoscopic injection with antibiotics alone and three reported the outcome febrile UTI. This analysis showed little or no difference in the risk of febrile UTI with endoscopic injection compared to antibiotics (RR 0.74, 95% CI 0.31 to 1.78; low certainty evidence). Four studies involving 425 children compared two different materials for endoscopic injection under the ureters (polydimethylsiloxane (Macroplastique) versus dextranomer/hyaluronic acid polymer (Deflux), glutaraldehyde cross-linked (GAX) collagen (GAX) 35 versus GAX 65 and Deflux versus polyacrylate polyalcohol copolymer (VANTRIS)) but only one study (255 children, low certainty evidence) had the outcome of febrile UTI and it reported no difference between the materials. All four studies reported rates of resolution of VUR, and the two studies comparing Macroplastique with Deflux showed that Macroplastique was probably superior to dextranomer/hyaluronic acid polymer (3 months: RR 0.50, 95% CI 0.33 to 0.78; 12 months: RR 0.54 95% CI 0.35 to 0.83; low certainty evidence) Two studies compared probiotic treatment with antibiotics and showed little or no difference in risk of repeat symptomatic UTI (RR 0.82 95% CI 0.56 to 1.21; low certainty evidence) Single studies compared circumcision with antibiotics, cranberry products with no treatment, oxybutynin with placebo, two different surgical techniques and endoscopic injection with no treatment. Compared with no treatment, the use of long-term, low-dose antibiotics may make little or no difference to the number of repeat symptomatic and febrile UTIs in children with VUR (low certainty evidence). Considerable variation in the study designs and subsequent findings prevented drawing firm conclusions on efficacy of antibiotic treatment. The added benefit of surgical or endoscopic correction of VUR over antibiotic treatment alone remains unclear since few studies comparing the same treatment and with relevant clinical outcomes were available for analysis.
In total we have identified 43 studies examining 4265 participants. The original review included 938 patients from 25 studies. The updated search identified an additional 18 studies with a combined total of 3327 participants between 1997 and June 2015. The results of these studies did not change the conclusions of the original review. No firm conclusions can be drawn from the many retrospective case series so the role of surgery in malignant bowel obstruction remains controversial. Clinical resolution varies from 26.7% to over 68%, though it is often unclear how this is defined. Despite being an inadequate proxy for symptom resolution or quality of life, the ability to feed orally was a popular outcome measure, with success rates ranging from 30% to 100%. Rates of re-obstruction varied, ranging from 0% to 63%, though time to re-obstruction was often not included. Postoperative morbidity and mortality also varied widely, although again the definition of both of these surgical outcomes differed between many of the papers. There were no data available for quality of life. The reporting of adverse effects was variable and this has been described where available. Where discussed, surgical procedures varied considerably and outcomes were not reported by specific intervention. Using the 'Risk of bias' assessment tool, most included studies were at high risk of bias for most domains. The role of surgery in malignant bowel obstruction needs careful evaluation, using validated outcome measures of symptom control and quality of life scores. Further information could include re-obstruction rates together with the morbidity associated with the various surgical procedures. Currently, bowel obstruction is managed empirically and there are marked variations in clinical practice by different units. In order to compare outcomes in malignant bowel obstruction, there needs to be a greater degree of standardisation of management. Since the last version of this review none of the new included studies have provided additional information to change the conclusions.
We included twelve randomised studies in this update of which five are additional studies. One trial compared fluspirilene and placebo and did not report important differences in the global improvement (n=60, 1 RCT, RR "no important improvement "0.97 CI 0.9 to 1.1). Though movement disorders (n=60, 1 RCT, RR 31.0 CI 1.9 to 495.6, NNH 4) were found only in the fluspirilene group, there were no convincing data showing the advantage of oral chlorpromazine or other depot antipsychotics over fluspirilene decanoate. We found no difference between depot fluspirilene and other oral antipsychotics with regard to relapses or to the number of people leaving the study early. Global state data (CGI) were not significantly different, in the short term when comparing fluspirilene with other depots (n=90, 2 RCTs, RR "no important improvement" 0.80 CI 0.2 to 2.8). No significant difference were apparent between fluspirilene and other depots with respect to the number of people leaving the trial early (n=83, 2 RCTs, RR 0.55 CI 0.1 to 2.3) or relapse rates (n=109, 3 RCTs, RR 0.55 CI 0.1 to 2.3). Extrapyramidal adverse effects were significantly less prevalent in the fluspirilene groups (n=164, 4 RCTs, RR 0.50 CI 0.3 to 0.8, NNH 5). Other adverse effects were not significantly different. Attrition in the one comparison between fluspirilene in weekly versus biweekly administration (n=34, RR 3.00 CI 0.1 to 68.8) and relapse rates (n=34 RR 3.18 CI 0.1 to 83.8) were not significantly different. There were no significant difference for movement disorders in one short term study. No study reported on hospital and service outcomes or commented on participants' overall satisfaction with care. Economic outcomes were not recorded by any of the included studies. Participant numbers in each comparison were small and we found no clear differences between fluspirilene and oral medication or other depots. The choice of whether to use fluspirilene as a depot medication and whether it has advantages over other depots cannot, at present, be informed by trial-derived data. Well-conducted and reported randomised trials are still needed to inform practice.
Fourteen trials were included. None of the included 2269 patients were previously treated for chronic hepatitis C. Peginterferon (either 2a, 180 microgram, or 2b, 1.5 microgram/kg, once weekly) plus ribavirin was more effective in achieving end of treatment and sustained virological response compared with interferon plus ribavirin (5 trials, 1340 patients) or peginterferon (2 trials, 714 patients). The benefit of peginterferon plus ribavirin was seen irrespective of HCV genotype although patients with genotype 1 or 4 had lower response rates (27%) than patients with genotype 2 or 3 (56%). The remaining trials compared different treatment regimens in patients who were treatment naive or had no virological response after three months of treatment, but overall they had not enough power to show any effect of increasing the dose of interferon or adding both amantadine or ribavirin. The overall mortality was 23/2111 patients with no significant differences between treatment regimens. Treatment increased the risk of adverse events including anaemia and flu-like symptoms, and several serious adverse events occurred including fatal lactic acidosis, liver failure, and suicide due to depression. Peginterferon plus ribavirin may be considered a treatment for patients with chronic hepatitis C and stable HIV who have not received treatment for hepatitis C as the intervention may clear the blood of HCV RNA. Supporting evidence comes mainly from the analysis of this non-validated surrogate outcome assessed in comparisons against other antiviral treatments. There is no evidence on treatment of patients who have relapsed or did not respond to previous therapy. Careful monitoring of adverse events is warranted.
We included 12 trials with 695 participants; five trials included participants awaiting elective cardiac surgery and seven trials included participants awaiting elective major abdominal surgery. All trials contained at least one domain judged to be at high or unclear risk of bias. Of greatest concern was the risk of bias associated with inadequate blinding, as it was impossible to blind participants due to the nature of the study designs. We could pool postoperative atelectasis in seven trials (443 participants) and postoperative pneumonia in 11 trials (675 participants) in a meta-analysis. Preoperative IMT was associated with a reduction of postoperative atelectasis and pneumonia, compared with usual care or non-exercise intervention (respectively; risk ratio (RR) 0.53, 95% confidence interval (CI) 0.34 to 0.82 and RR 0.45, 95% CI 0.26 to 0.77). We could pool all-cause mortality within postoperative period in seven trials (431 participants) in a meta-analysis. However, the effect of IMT on all-cause postoperative mortality is uncertain (RR 0.40, 95% CI 0.04 to 4.23). Eight trials reported the incidence of adverse events caused by IMT. All of these trials reported that there were no adverse events in both groups. We could pool the mean duration of hospital stay in six trials (424 participants) in a meta-analysis. Preoperative IMT was associated with reduced length of hospital stay (MD -1.33, 95% CI -2.53 to -0.13). According to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group guidelines for evaluating the impact of healthcare interventions, the overall quality of studies for the incidence of pneumonia was moderate, whereas the overall quality of studies for the incidence of atelectasis, all-cause postoperative death, adverse events, and duration of hospital stay was low or very low. We found evidence that preoperative IMT was associated with a reduction of postoperative atelectasis, pneumonia, and duration of hospital stay in adults undergoing cardiac and major abdominal surgery. The potential for overestimation of treatment effect due to lack of adequate blinding, small-study effects, and publication bias needs to be considered when interpreting the present findings.
For the primary outcome, pregnancy, two controlled studies of LAM users reported life table pregnancy rates at six months of 0.45% and 2.45%, one controlled study reported 5% pregnancies in the absence of life table rates per month, and eight uncontrolled studies of LAM users reported pregnancy rates of 0% to 7.5%. Life table pregnancy rates for fully breastfeeding women who were amenorrheic but not using any contraceptive method were 0.88% in one study and 0.9% to 1.2% (95% confidence interval 0.0 to 2.4) in a second study, depending on the definition of menstruation used. The life table menstruation rate at six months in all studies varied between 11.1% and 39.4%. We found no clear differences in life table pregnancy rates between women using LAM and being supported in doing so, and fully breastfeeding amenorrheic women not using any method. As the length of lactation amenorrhoea in women using LAM differed greatly between the populations studied, and was population specific, it is uncertain whether LAM extends lactational amenorrhoea.
We included nine studies that involved 735 people in this review. Four studies compared probiotic with placebo, two compared probiotic with no treatment, two compared probiotics with antibiotics in patients with UTI, and one study compared probiotic with placebo in healthy women. All studies aimed to measure differences in rates of recurrent UTI. Our risk of bias assessment found that most studies had small sample sizes and reported insufficient methodological detail to enable robust assessment. Overall, there was a high risk of bias in the included studies which lead to inability to draw firm conclusions and suggesting that any reported treatment effects may be misleading or represent overestimates. We found no significant reduction in the risk of recurrent symptomatic bacterial UTI between patients treated with probiotics and placebo (6 studies, 352 participants: RR 0.82, 95% CI 0.60 to 1.12; I2 = 23%) with wide confidence intervals, and statistical heterogeneity was low. No significant reduction in the risk of recurrent symptomatic bacterial UTI was found between probiotic and antibiotic treated patients (1 study, 223 participants: RR 1.12, 95% CI 0.95 to 1.33). The most commonly reported adverse effects were diarrhoea, nausea, vomiting, constipation and vaginal symptoms. None of the included studies reported numbers of participants with at least one asymptomatic bacterial UTI, all-cause mortality or those with at least one confirmed case of bacteraemia or fungaemia. Two studies reported study withdrawal due to adverse events and the number of participants who experienced at least one adverse event. One study reported withdrawal occurred in six probiotic participants (5.2%), 15 antibiotic participants (12.2%), while the second study noted one placebo group participant discontinued treatment due to an adverse event. No significant benefit was demonstrated for probiotics compared with placebo or no treatment, but a benefit cannot be ruled out as the data were few, and derived from small studies with poor methodological reporting. There was limited information on harm and mortality with probiotics and no evidence on the impact of probiotics on serious adverse events. Current evidence cannot rule out a reduction or increase in recurrent UTI in women with recurrent UTI who use prophylactic probiotics. There was insufficient evidence from one RCT to comment on the effect of probiotics versus antibiotics.
Forty studies (3764 patients) were included. Studies conducted earlier tended to have a higher risk of bias due to poor (or poorly reported) study design, broad inclusion criteria, less well developed disease definitions and low patient numbers. Later studies tend to have improved in all areas of quality, aided by the development of large international study groups. Induction therapy: Plasma exchange as adjunctive therapy may reduce the need for dialysis at three (2 studies: RR 0.43, 95% CI 0.23 to 0.78; I2 = 0%) and 12 months (6 studies: RR 0.45, 95% CI 0.29 to 0.72; I2 = 0%) (low certainty evidence). Plasma exchange may make little or no difference to death, serum creatinine (SCr), sustained remission or to serious or the total number of adverse events. Plasma exchange may increase the number of serious infections (5 studies: RR 1.26, 95% CI 1.03 to 1.54; I2 = 0%; low certainty evidence). Remission rates for pulse versus continuous cyclophosphamide (CPA) were equivalent but pulse treatment may increase the risk of relapse (4 studies: RR 1.79, 95% CI 1.11 to 2.87; I2 = 0%) (low certainty evidence) compared with continuous cyclophosphamide. Pulse CPA may make little or no difference to death at final follow-up, or SCr at any time point. More patients required dialysis in the pulse CPA group. Leukopenia was less common with pulse treatment; however, nausea was more common. Rituximab compared to CPA probably makes little or no difference to death, remission, relapse, severe adverse events, serious infections, or severe adverse events. Kidney function and dialysis were not reported. A single study reported no difference in the number of deaths, need for dialysis, or adverse events between mycophenolate mofetil (MMF) and CPA. Remission was reported to improve with MMF however more patients relapsed. A lower dose of steroids was probably as effective as high dose and may be safer, causing fewer infections; kidney function and relapse were not reported. There was little of no difference in death or remission between six and 12 pulses of CPA. There is low certainty evidence that there were less relapses with 12 pulses (2 studies: RR 1.57, 95% CI 0.96 to 2.56; I2 = 0%), but more infections (2 studies: RR 0.79, 95% CI 0.36 to 1.72; I2 = 45%). One study reported severe adverse events were less in patients receiving six compared to 12 pulses of CPA. Kidney function and dialysis were not reported. There is limited evidence from single studies about the effectiveness of intravenous immunoglobulin, avacopan, methotrexate, immunoadsorption, lymphocytapheresis, or etanercept. Maintenance therapy: Azathioprine (AZA) has equivalent efficacy as a maintenance agent to CPA with fewer episodes of leucopenia. MMF resulted in a higher relapse rate when tested against azathioprine in remission maintenance. Rituximab is an effective remission induction and maintenance agent. Oral co-trimoxazole did not reduce relapses in granulomatosis with polyangiitis. There were fewer relapses but more serious adverse events with leflunomide compared to methotrexate. There is limited evidence from single studies about the effectiveness of methotrexate versus CPA or AZA, cyclosporin versus CPA, extended versus standard AZA, and belimumab. Plasma exchange was effective in patients with severe AKI secondary to vasculitis. Pulse cyclophosphamide may result in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst CPA is standard induction treatment, rituximab and MMF were also effective. AZA, methotrexate and leflunomide were effective as maintenance therapy. Further studies are required to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.
We included 30 studies, analysing 14,835 participants, in this review. We assessed 10 studies (33%) as at low risk of bias, nine (30%) as at high risk of bias and 11 (37%) as unclear. Plaque Compared with control, after six to seven months of use, triclosan/copolymer toothpaste reduced plaque by 0.47 on a 0 to 5 scale (MD -0.47, 95% confidence interval (CI) -0.60 to -0.34, 20 studies, 2675 participants, moderate-quality evidence). The control group mean was 2.17, representing a 22% reduction in plaque. After six to seven months of use, it also reduced the proportion of sites scoring 3 to 5 on a 0 to 5 scale by 0.15 (MD -0.15, 95% CI -0.20 to -0.10, 13 studies, 1850 participants, moderate-quality evidence). The control group mean was 0.37, representing a 41% reduction in plaque severity. Gingivitis After six to nine months of use, triclosan/copolymer toothpaste reduced inflammation by 0.27 on a 0 to 3 scale (MD -0.27, 95% CI -0.33 to -0.21, 20 studies, 2743 participants, moderate-quality evidence). The control group mean was 1.22, representing a 22% reduction in inflammation. After six to seven months of use, it reduced the proportion of bleeding sites (i.e. scoring 2 or 3 on the 0 to 3 scale) by 0.13 (MD -0.13, 95% CI -0.17 to -0.08, 15 studies, 1998 participants, moderate-quality evidence). The control group mean was 0.27, representing a 48% reduction in bleeding. Periodontitis After 36 months of use, there was no evidence of a difference between triclosan/copolymer toothpaste and control in the development of periodontitis (attachment loss) (RR 0.92, 95% CI 0.67 to 1.27, one study, 480 participants, low-quality evidence). Caries After 24 to 36 months of use, triclosan/copolymer toothpaste slightly reduced coronal caries when using the decayed and filled surfaces (DFS) index (MD -0.16, 95% CI -0.31 to -0.02, four studies, 9692 participants, high-quality evidence). The control group mean was 3.44, representing a 5% reduction in coronal caries. After 36 months of use, triclosan/copolymer toothpaste probably reduced root caries (MD -0.31, 95% CI -0.39 to -0.23, one study, 1357 participants, moderate-quality evidence). Calculus After six months of use, triclosan/copolymer toothpaste may have reduced the mean total calculus per participant by 2.12 mm (MD -2.12 mm, 95% CI -3.39 to -0.84, two studies, 415 participants, low-quality evidence). The control group mean was 14.61 mm, representing a 15% reduction in calculus. Adverse effects There were no data available for meta-analysis regarding adverse effects, but 22 studies (73%) reported that there were no adverse effects caused by either the experimental or control toothpaste. There was considerable heterogeneity present in the meta-analyses for plaque, gingivitis and calculus. Plaque and gingivitis showed such consistent results that it did not affect our conclusions, but the reader may wish to interpret the results with more caution. There was moderate-quality evidence showing that toothpastes containing triclosan/copolymer, in addition to fluoride, reduced plaque, gingival inflammation and gingival bleeding when compared with fluoride toothpastes without triclosan/copolymer. These reductions may or may not be clinically important, and are evident regardless of initial plaque and gingivitis levels, or whether a baseline oral prophylaxis had taken place or not. High-quality evidence showed that triclosan/copolymer toothpastes lead to a small reduction in coronal caries. There was weaker evidence to show that triclosan/copolymer toothpastes may have reduced root caries and calculus, but insufficient evidence to show whether or not they prevented periodontitis. There do not appear to be any serious safety concerns regarding the use of triclosan/copolymer toothpastes in studies up to three years in duration.
Four trials were identified for inclusion in this review. All the trials were at high risk of bias. Three trials provided information for this review. Overall, this review included 280 people undergoing planned surgery. Participants were randomised to early dressing removal (removal of the wound dressing within the 48 hours following surgery) (n = 140) or delayed dressing removal (continued dressing of the wound beyond 48 hours) (n = 140) in the three trials. There were no statistically significant differences between the early dressing removal group and delayed dressing removal group in the proportion of people who developed superficial surgical site infection within 30 days (RR 0.64; 95% CI 0.32 to 1.28), superficial wound dehiscence within 30 days (RR 2.00; 95% CI 0.19 to 21.16) or serious adverse events within 30 days (RR 0.83; 95% CI 0.28 to 2.51). No deep wound infection or deep wound dehiscence occurred in any of the participants in the trials that reported this outcome. None of the trials reported quality of life. The hospital stay was significantly shorter (MD -2.00 days; 95% CI -2.82 to -1.18) and the total cost of treatment significantly less (MD EUR -36.00; 95% CI -59.81 to -12.19) in the early dressing removal group than in the delayed dressing removal group in the only trial that reported these outcomes. The early removal of dressings from clean or clean contaminated surgical wounds appears to have no detrimental effect on outcomes. However, it should be noted that the point estimate supporting this statement is based on very low quality evidence from three small randomised controlled trials, and the confidence intervals around this estimate were wide. Early dressing removal may result in a significantly shorter hospital stay, and significantly reduced costs, than covering the surgical wound with wound dressings beyond the first 48 hours after surgery, according to very low quality evidence from one small randomised controlled trial. Further randomised controlled trials of low risk of bias are necessary to investigate whether dressings are necessary after 48 hours in different types of surgery and levels of contamination and investigate whether antibiotic therapy influences the outcome
We identified 4 RCTs (1,194 adolescents). No RCT reported enough detail to assess whether a strong  randomisation method was used or allocation was concealed. Blinding was not possible as the intervention was mentoring. Three RCTs provided complete data. No selective reporting. Three RCTs provided evidence about mentoring and preventing alcohol use. We pooled two RCTs (RR for mentoring compared to no intervention = 0.71 (95% CI = 0.57 to 0.90, P value = 0.005). A third RCT found no significant differences. Three RCTs provided evidence about mentoring and preventing drug use, but could not be pooled. One found significantly less use of “illegal" drugs," one did not, and one assessed only marijuana use and found no significant differences. One RCT measured “substance use” without separating alcohol and drugs, and found no difference for mentoring. All four RCTs were in the US, and included “deprived” and mostly minority adolescents. Participants were young (in two studies age 12, and in two others 9-16). All students at baseline were non-users of alcohol and drugs. Two RCTs found mentoring reduced the rate of initiation of alcohol, and one of drug usage. The ability of the interventions to be effective was limited by the low rates of commencing alcohol and drug use during the intervention period in two studies (the use of marijuana in one study increased to 1% in the experimental and to 1.6% in the control group, and in another study drug usage rose to 6% in the experimental and 11% in the control group). However, in a third study there was scope for the intervention to have an effect as alcohol use rose to 19% in the experimental and 27% in the control group. The studies assessed structured programmes and not informal mentors.
The original review included six studies on tension-type headache. We now include eight studies with a total of 412 participants with chronic forms of tension-type headache. These studies evaluated five SSRIs (citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) and one SNRI (venlafaxine). The two new studies included in this update are placebo controlled trials, one evaluated sertraline and one venlafaxine. Six studies, already included in the previous version of this review, compared SSRIs to other antidepressants (amitriptyline, desipramine, sulpiride, mianserin). Most of the included studies had methodological and/or reporting shortcomings and lacked adequate power. Follow-up ranged between two and four months. Six studies explored the effect of SSRIs or SNRIs on tension-type headache frequency, the primary endpoint. At eight weeks of follow-up, we found no difference when compared to placebo (two studies, N = 127; mean difference (MD) -0.96, 95% confidence interval (CI) -3.95 to 2.03; I2= 0%) or amitriptyline (two studies, N = 152; MD 0.76, 95% CI -2.05 to 3.57; I2= 44%). When considering secondary outcomes, SSRIs reduce the symptomatic/analgesic medication use for acute headache attacks compared to placebo (two studies, N = 118; MD -1.87, 95% CI -2.09 to -1.65; I2= 0%). However, amitriptyline appeared to reduce the intake of analgesic more efficiently than SSRIs (MD 4.98, 95% CI 1.12 to 8.84; I2= 0%). The studies supporting these findings were considered at unclear risk of bias. We found no differences compared to placebo or other antidepressants in headache duration and intensity. SSRIs or SNRI were generally more tolerable than tricyclics. However, the two groups did not differ in terms of number of participants who withdrew due to adverse events or for other reasons (four studies, N = 257; odds ratio (OR) 1.04; 95% CI 0.41 to 2.60; I2= 25% and OR 1.55, 95% CI 0.71 to 3.38; I2= 0%). We did not find any study comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. botulinum toxin) or non-drug therapies (e.g. psycho-behavioural treatments, manual therapy, acupuncture). Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine (a SNRI) as preventive drugs for tension-type headache. Over two months of treatment, SSRIs or venlafaxine are no more effective than placebo or amitriptyline in reducing headache frequency in patients with chronic tension-type headache. SSRIs seem to be less effective than tricyclic antidepressants in terms of intake of analgesic medications. Tricyclic antidepressants are associated with more adverse events; however, this did not cause a greater number of withdrawals. No reliable information is available at longer follow-up. Our conclusion is that the use of SSRIs and venlafaxine for the prevention of chronic tension-type headache is not supported by evidence.
We included 41 randomised clinical trials with 6193 patients with chronic hepatitis C. All trials had high risk of bias. All included trials compared amantadine versus placebo or no intervention. Standard antiviral therapy was administered equally to the intervention and the control groups in 40 trials. The standard antiviral therapy, which was administered to both intervention groups, was interferon-alpha, interferon-alpha plus ribavirin, and peg interferon-alpha plus ribavirin, depending on the time when the trial was conducted. When we meta-analysed all trials together, the overall results demonstrated no significant effects of amantadine, when compared with placebo or no intervention, on our all-cause mortality or liver-related morbidity composite outcome (5/2353 (0.2%) versus 6/2264 (0.3%); RR 0.90, 95% CI 0.38 to 2.17; I² = 0%; 32 trials; very low quality). There was also no significant effect on adverse events (288/2869 (10%) versus 293/2777 (11%); RR 0.98, 95% CI 0.84 to 1.14; I² = 0%; 35 trials; moderate quality). We used both fixed-effect and random-effects meta-analyses. Amantadine, when compared with placebo or no intervention, did not significantly influence the number of patients who failed to achieve a sustained virological response (1821/2861 (64%) versus 1737/2721 (64%); RR 0.98, 95% CI 0.95 to 1.02; I² = 35%; 35 trials; moderate quality). However, in the subgroup using interferon plus ribavirin, amantadine decreased the number of patients who failed to achieve a sustained virological response (422/666 (63%) versus 447/628 (71%); RR 0.89, 95% CI 0.83 to 0.96; I² = 41%; 11 trials; low quality). Similar results were found for failure to achieve an end of treatment virological response. Amantadine, when compared with placebo or no intervention, significantly decreased the number of patients without normalisation of alanine aminotransferase (ALT) serum levels at the end of treatment (671/1141 (59%) versus 732/1100 (67%); RR 0.88, 95% CI 0.83 to 0.94; I² = 47%; 19 trials; low quality). Amantadine, when compared with placebo or no intervention, did not significantly influence the end of follow-up biochemical response (1133/1896 (60%) versus 1151/1848 (62%); RR 0.95, 95% CI 0.91 to 1.00; I² = 49%; 21 trials; low quality). The observed beneficial effects could be true effects but could also be due to both systematic errors (bias) and random errors (play of chance). The latter is due to the fact that trial sequential analyses could not confirm or refute our findings. We were not able to perform meta-analyses for failure of histological improvement or quality of life due to a lack of valid data. This systematic review does not demonstrate any significant effects of amantadine on all-cause mortality or liver-related morbidity composite outcome and on adverse events in patients with hepatitis C; however, the median trial duration was 12 months, with a median follow-up of six months, which is not long enough to assess the composite outcome sufficiently. Overall, we did not see an effect of amantadine on failure to achieve a sustained virological response. Subgroup analyses demonstrated that the combination of amantadine plus interferon-alpha and ribavirin seems to increase the number of patients achieving a sustained virological response. This finding may be caused by both systematic errors (bias) and risks of random errors (play of chance), but it could also be real. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine for patients with chronic hepatitis C will show strong benefits. Therefore, it is probably advisable to wait for the results of trials assessing other direct-acting antiviral drugs. In the absence of convincing evidence of benefit, the use of amantadine is justified in the context of randomised clinical trials assessing the effects of combination therapy. We found a lack of evidence on other aminoadamantanes than amantadine.
Eighteen trials are included in the review. The majority were in family care settings. For fourteen studies, FA was just one aspect of a broad multi-component programme of care. Assessing the effect of FA was compromised by ill-defined protocols for the duration of component parts of these programmes (i.e. frequency of the intervention or actual time spent). Therefore, establishing the real effect of the FA component was not possible. Overall, positive effects were noted at post-intervention for the frequency of reported challenging behaviour (but not for incidence or severity) and for caregiver reaction (but not burden or depression). These effects were not seen at follow-up. The delivery of FA has been incorporated within wide ranging multi-component programmes and study designs have varied according to setting - i.e. family care, care homes and hospital, with surprisingly few studies located in care homes. Our findings suggest potential beneficial effects of multi-component interventions, which utilise FA. Whilst functional analysis for challenging behaviour in dementia care shows promise, it is too early to draw conclusions about its efficacy.
Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis. One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low. In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points. The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low. Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non–cystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required. Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed.
Two randomized trials were included, enrolling 722 HIV-positive pregnant women from Malawi and Zambia. Both compared monthly regimens of sulfadoxine-pyrimethamine (SP) to the standard 2-dose regimen given in the second and third trimesters. In women in their first or second pregnancy, monthly SP may reduce both maternal parasitaemia (two trials, 463 participants, RR 0.25, 95% CI 0.14 to 0.43, low quality evidence), and placental parasitaemia at delivery (two trials, 459 participants, RR 0.38, 95% CI 0.21 to 0.70, low quality evidence). Monthly SP may have a small effect on the prevalence of maternal anaemia at delivery (two trials, 447 participants, RR 0.93, 95% CI 0.72 to 1.20, low quality evidence), and the number of babies born with low birth weight (two trials, 469 participants, RR 0.80, 95% CI 0.52 to 1.23, low quality evidence), but larger trials are necessary to reliably prove or exclude clinically important benefits on these outcomes. There is currently insufficient evidence to make conclusions regarding an effect on neonatal mortality (one study, 253 participants, very low quality evidence). In women in their third or higher pregnancy, there is insufficient evidence to make any conclusions on the benefits of monthly SP compared to the two dose regimen (one trial, 166 participants, very low quality evidence). There were no trials that assessed other treatment regimens for intermittent preventive treatment in HIV-positive pregnant women. Three or more doses of SP may have some advantages over the standard two doses in HIV-positive pregnant women, but larger trials would be necessary to confirm an effect on patient important outcomes. However, since SP cannot be administered concurrently with co-trimoxazole - a drug often recommended for infection prophylaxis in HIV-positive pregnant women, new drugs and research is needed to address needs of HIV-positive pregnant women.
We included 11 studies that randomly assigned 509 people with schizophrenia, schizoaffective disorder or psychotic depression. No trials were conducted in patients at their first episode of psychotic illness and none included populations at high risk for developing psychosis. Our pre-stated outcomes of interest were mental state, global state, general functioning, adverse effects and quality of life. Two trials compared antiglucocorticoid drugs (mifepristone) versus placebo as sole treatment. Limited data from one trial showed no difference in the proportion responding to mifepristone when mental state was assessed immediately post intervention using the Brief Psychiatric Rating Scale (BPRS) (n = 5, 1 RCT, MD -5.20, 95% CI -17.91 to 7.51; very low-quality evidence); depressive symptoms (Hamilton Rating Scale for Depression (HAMD) total) were also similar between groups (n = 5, 1 RCT, MD 1.67, 95% CI -16.44 to 19.78; very low-quality evidence). However, a significant difference favoured treatment at short-term follow-up for global state (30% reduction in total BPRS, n = 221, 1 RCT, RR 0.58, 95% CI 0.38 to 0.89; low-grade quality evidence). This effect was also seen for short-term positive psychotic symptoms (50% reduction in BPRS positive symptom subscale, n = 221, 1 RCT, RR 0.60, 95% CI 0.43 to 0.84; low-grade quality evidence). Participants receiving mifepristone experienced a similar overall number of adverse effects as those receiving placebo (n = 226, 2 RCTs, RR 0.92, 95% CI 0.77 to 1.09; moderate-quality evidence). No data on general functioning or quality of life were available. One trial compared an antiglucocorticoid, dehydroepiandrosterone (DHEA), as an adjunct to atypical antipsychotic treatment to adjunctive placebo. Data for main outcomes of interest were of low quality, and analysis of useable data showed no significant effects of treatment on mental state or adverse effects. Data on global state, general functioning and quality of life were not available. Data from six trials comparing antiglucocorticoid drugs as an adjunct to combination treatment versus adjunctive placebo showed no significant differences between groups in mean endpoint scores for overall psychotic symptoms (n = 171, 6 RCTs, SMD 0.01, 95% CI - 0.29 to 0.32) or positive psychotic symptoms (n = 151, 5 RCTs, SMD -0.07, 95% CI - 0.40 to 0.25). Data from three trials showed no differences between groups in mean endpoint scores for negative symptoms (n = 94, 3 RCTs, MD 2.21, 95% CI -0.14 to 4.55). One study found improvements in global state that were similar between groups (n = 30, 1 RCT, RR 0.58, 95% CI 0.32 to 1.06; very low-quality evidence). In this comparison, pooled results showed that antiglucorticoids caused a greater overall number of adverse events (n = 199, 7 RCTs, RR 2.66, 95% CI 1.33 to 5.32; moderate quality evidence), but no quality of life data were available. Good evidence is insufficient to conclude whether antiglucocorticoid drugs provide effective treatment for psychosis. Some global state findings suggest a favourable effect for mifepristone, and a few overall adverse effect findings favour placebo. Additional large randomised controlled trials are needed to justify findings.
We included one single blind study (total n = 24). The overall risk of bias in the study was considered to be unclear although the randomisation was adequate. It compared a package of horticultural therapy which consisted of one hour per day of horticultural activity plus standard care with standard care alone over two weeks (10 consecutive days) with no long-term follow-up. Only two people were lost to follow-up in the study, both in the horticultural therapy group (1 RCT n = 24,RR 5.00 95% CI 0.27 to 94.34, very low quality evidence). There was no clear evidence of a difference in Personal Wellbeing Index (PWI-C) change scores between groups, however confidence intervals were wide (1 RCT n = 22, MD -0.90 95% CI -10.35 to 8.55, very low quality evidence). At the end of treatment, the Depression Anxiety Stress Scale (DASS21) change scores in horticultural therapy group were greater than that in the control group (1 RCT n = 22, MD -23.70 CI -35.37 to - 12.03, very low quality evidence). The only included study did not report on adverse effects of interventions. Based on the current very low quality data, there is insufficient evidence to draw any conclusions on benefits or harms of horticultural therapy for people with schizophrenia. This therapy remains unproven and more and larger randomised trials are needed to increase high quality evidence in this area.
Fifty studies met the inclusion criteria. Six additional studies were identified since the original review. Only 31 of these studies involving 7104 participants were judged to have used a sufficiently robust measure of fatigue and thus were deemed suitable for detailed analysis. The drugs were still analysed by class (psychostimulants; haemopoietic growth factors; antidepressants and progestational steroids). Methylphenidate showed a small but significant improvement in fatigue over placebo (Z = 2.83; P = 0.005). Since the publication of the original review increased safety concerns have been raised regarding erythropoietin and this cannot now be recommended in practice.There was a very high degree of statistical and clinical heterogeneity in the trials and the reasons for this are discussed. There is increasing evidence that psychostimulant trials provide evidence for improvement in CRF at a clinically meaningful level. There is still a requirement for a large scale RCT of methylphenidate to confirm the preliminary results from this review. There is new safety data which indicates that the haemopoietic growth factors are associated with increased adverse outcomes. These drugs can no longer be recommended in the treatment of CRF. Readers of the first review should re-read the document in full.
Only two RCTs were eligible. One was a cross-over trial with 18 participants. The other randomised 400 participants to one of four treatments, of which two (L-carnitine and placebo) were relevant to this review, but the exact numbers of participants in these two treatment groups was not reported. All participants were young adults. Methodological details were poorly reported, and we considered the risk of bias in both studies to be unclear. The trials assessed different cognitive outcomes. We could extract cognitive data on approximately 200 participants from one trial. We found no evidence that L-carnitine has any effect on reaction time, vigilance, immediate memory, or delayed recall after three days of treatment. This trial report stated that there was a small number of adverse effects, none of which were serious. The small cross-over trial also reported no effect of L-carnitine on cognition, but did not provide data; no information was provided on adverse effects. We considered the available evidence to be of very low quality for all reported outcomes. Due to the limited number of included trials, short-term treatment, and inadequate reporting, we were unable to draw any conclusions about the efficacy or safety of L-carnitine for cognitive enhancement in healthy adults. Well-designed, randomised, placebo-controlled trials of L-carnitine for cognition enhancement in cognitively healthy people, with large samples and relatively long-term follow-up, are still needed.
We included 18 studies involving 549 relevant participants, of which 14 (421 participants) were included in the analysis (one within both comparisons). Four of the 14 studies compared the effects of bilateral training with usual care. Primary outcomes: results were not statistically significant for performance in ADL (standardised mean difference (SMD) 0.25, 95% confidence interval (CI) -0.14 to 0.63); functional movement of the arm (SMD -0.07, 95% CI -0.42 to 0.28) or hand (SMD -0.04, 95% CI -0.50 to 0.42). Secondary outcomes: no statistically significant results. Eleven of the 14 studies compared the effects of bilateral training with other specific upper limb (arm) interventions. Primary outcomes: no statistically significant results for performance of ADL (SMD -0.25, 95% CI -0.57 to 0.08); functional movement of the arm (SMD -0.20, 95% CI -0.49 to 0.09) or hand (SMD -0.21, 95% CI -0.51 to 0.09). Secondary outcomes: one study reported a statistically significant result in favour of another upper limb intervention for performance in extended ADL. No statistically significant differences were found for motor impairment outcomes. There is insufficient good quality evidence to make recommendations about the relative effect of simultaneous bilateral training compared to placebo, no intervention or usual care. We identified evidence that suggests that bilateral training may be no more (or less) effective than usual care or other upper limb interventions for performance in ADL, functional movement of the upper limb or motor impairment outcomes.
Six studies with a total of 1039 patients were eligible for inclusion. The two largest studies were rated as low risk of bias for all assessed items. Four studies were rated as unclear risk of bias for randomization and allocation concealment. Two studies were rated as high risk of bias for incomplete outcome data and selective reporting. There was a marginal significant benefit of n-3 therapy for maintenance of remission. Thirty-nine per cent of patients in the n-3 group relapsed at 12 months compared to 47% of placebo patients (6 studies, 1039 patients; RR 0.77, 95% CI 0.61 to 0.98). A GRADE analysis rated the overall quality of the evidence for the primary outcome (i.e. relapse) as very low due to unexplained heterogeneity (I2 = 58%), publication bias, and a high or unknown risk of bias in four studies in the pooled analysis. When two large studies at low risk of bias were considered the benefit was no longer statistically significant. Thirty-seven per cent of patients in the n-3 group relapsed at 12 months compared to 42% of placebo patients (2 studies, 738 patients; RR 0.88, 95% CI 0.74 to 1.05). No significant heterogeneity was identified for this pooled analysis ( I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (294 events). No serious adverse events were recorded in any of the studies but in a pooled analyses there was a significantly higher rate of diarrhea (4 studies, 862 patients; RR 1.36 95% CI 1.01 to 1.84) and upper gastrointestinal tract symptoms (5 studies, 999 patients; RR 1.65, 95% CI 1.25 to 2.18) in the n-3 treatment group. Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in CD. Omega 3 fatty acids appear to be safe although they may cause diarrhea and upper gastrointestinal tract symptoms.
Overall, more than 3500 references were considered and 19 original reports with a total of 3599 patients were included. There were 9 trials analysing antibiotics versus placebo/no treatment, with all outcomes significantly favouring antibiotic use (P < 0.05) (I2 = 0%), including bacteriuria (risk ratio (RR) 0.25 (95% confidence interval (CI) 0.15 to 0.42), bacteremia (RR 0.67, 95% CI 0.49 to 0.92), fever (RR 0.39, 95% CI 0.23 to 0.64), urinary tract infection (RR 0.37, 95% CI 0.22 to 0.62), and hospitalization (RR 0.13, 95% CI 0.03 to 0.55). Several classes of antibiotics were effective prophylactically for TRPB, while the quinolones, with the highest number of studies (5) and patients (1188), were the best analysed. For 'antibiotics versus enema', we analysed four studies with a limited number of patients. The differences between groups for all outcomes were not significant. For 'antibiotic versus antibiotic + enema', only the risk of bacteremia (RR 0.25, 95% CI 0.08 to 0.75) was diminished in the 'antibiotic + enema group'. Seven trials reported the effects of short-course (1 day) versus long-course (3 days) antibiotics. Long course was significantly better than short-course treatment only for bacteriuria (RR 2.09, 95% CI 1.17 to 3.73). For 'single versus multiple dose', there was significantly greater risk of bacteriuria for single-dose treatment (RR 1.98, 95% CI 1.18 to 3.33). Comparing oral versus systemic administration - intramuscular injection (IM), or intravenous (IV) - of antibiotics, there were no significant differences in the groups for bacteriuria, fever, UTI and hospitalization. Antibiotic prophylaxis is effective in preventing infectious complications following TRPB. There is no definitive data to confirm that antibiotics for long-course (3 days) are superior to short-course treatments (1 day), or that multiple-dose treatment is superior to single-dose.
Fifteen studies met the inclusion criteria, enrolling 1926 participants. The trial size varied from 20 to 598 patients. Most studies compared corticosteroids, particularly dexamethasone, to standard therapy. We included six studies with data at one week in the meta-analysis for pain intensity; no data were available at that time point for the remaining studies. Corticosteroid therapy resulted in less pain (measured on a scale of 0 to 10 with a lower score indicating less pain) compared to control at one week (MD 0.84 lower pain, 95% CI 1.38 to 0.30 lower; low quality evidence). Adverse events were poorly documented. Factors limiting statistical analysis included the lack of standardised measurements of pain and the use of different agents, dosages, comparisons and routes of drug delivery. Subgroup analysis according to type of cancer was not possible. The quality of this evidence was limited by the risk of bias of the studies and small sample size. The results were also compromised by attrition, with data missing for the enrolled patients. The evidence for the efficacy of corticosteroids for pain control in cancer patients is weak. Significant pain relief was noted in some studies, albeit only for a short period of time. This could be important for patients with poor clinical status. Further trials, with increased numbers of participants, are needed to evaluate the safety and effectiveness of corticosteroids for the management cancer pain in adults, and to establish an ideal dose, duration of therapy and route of administration.
We included four randomised trials (257 participants). The overall risk of bias in the included studies was low. Two trials compared the addition of intravenous acyclovir to a steroid (prednisolone). One included 43 participants, the other 70 patients. Neither demonstrated any hearing improvement with ISSHL. Another (84 patients) did not show any statistically significant difference between groups with the addition of valacyclovir to prednisolone (compared to steroid plus placebo) with respect to change in pure-tone audiogram. Comparing the addition of intravenous acyclovir to hydrocortisone with hydrocortisone alone, the final trial did not show any statistically significant difference between groups (60 patients). No trial documented any serious adverse effects related to the use of antiviral treatment. One study reported slight to moderate nausea equally in the acyclovir and placebo groups (one patient in each). Another reported insomnia, nervousness and weight gain with valacyclovir (number not specified). Even though no meta-analysis was possible, evidence from the four RCTs has demonstrated no statistically significant advantage in the use of antivirals in the treatment of ISSHL. There is currently no evidence to support the use of antiviral drugs in the treatment of ISSHL. The four trials included in this review were, however, small and with a low risk of bias. Further randomised controlled trials with larger patient populations, using standardised inclusion criteria, antiviral regimes and outcome measures, are needed in order for adequate meta-analysis to be performed to reach definitive conclusions. A uniform definition of ISSHL should also be established, together with what constitutes adequate recovery.
We found no RCTs or quasi-RCTs in the original review or updates in 20011 and 2012. Cure or improvement have been described in high quality observational studies:  (1) A single study describes spontaneous improvement of meralgia paraesthetica in 20 (69%) of 29 cases.  (2) Four studies evaluating the injection of corticosteroid and local anaesthetic found cure or improvement in 130 (83%) out of a combined total of 157 cases.  (3) Surgical treatments have been found to be beneficial in 264 (88%) out of 300 cases treated with decompression (nine studies); and 45 (94%) out of 48 cases treated with neurectomy (three studies).  (4) Ninety-nine (97%) out of 102 patients with iatrogenic meralgia paraesthetica recovered completely (three studies). In the absence of any published RCTs or quasi-RCTs, the objective evidence base for treatment choices in meralgia paraesthetica is weak. High quality observational studies report comparable high improvement rates for meralgia paraesthetica following local injection of corticosteroid and surgical interventions (either nerve decompression or neurectomy). However, a similar outcome has been reported without any intervention in a single natural history study.
No studies comparing CTG monitoring during labour with an ES to intermittent auscultation were identified. Two randomised controlled trials comparing CTG monitoring during labour with an ES versus CTG without an ES were identified and included in the qualitative synthesis of results, but only one trial (n = 220) provided data for quantitative analysis. Both trials were classified as low risk of bias. There was no strong evidence that CTG with an ES has an effect on the incidence of caesarean delivery (risk ratio (RR) 0.61; 95% confidence interval (CI) 0.35 to 1.04) when compared with CTG with fetal blood sampling.There was no strong evidence supporting a reduction in the incidence of neonatal seizures (RR 0.33; 95% CI 0.01 to 8.09) or fetal acidaemia (RR 0.50; 95% CI 0.09 to 2.67) in women monitored using a CTG with an ES versus a CTG without an ES. Overall perinatal mortality could not be ascertained for this trial since data on early neonatal deaths were unavailable. Although fetal deaths were recorded, no fetal deaths occurred in either arm of the trial, and thus no risk estimates could be derived. There was no strong evidence supporting a reduction in the incidence of forceps-assisted vaginal birth (RR 0.50; 95% CI 0.05 to 5.43), hypoxic ischaemic encephalopathy (RR 0.33; 95% CI 0.01 to 8.09), admission to the neonatal intensive care unit (RR 0.40; 95% CI 0.08 to 2.02) or an Apgar less than seven at five minutes (RR 0.50; 95% CI 0.13 to 1.95). The trial did not report on artificial rupture of amniotic membranes,oxytocin augmentation of labour ormaternal satisfaction with labour. Two trials met the inclusion criteria for this review but one trial did not provide data for any of this review's outcomes. The single trial that did contribute data was underpowered to evaluate the association between CTG monitoring with an ES and the primary outcomes of interest. No recommendations for clinical practice can be made at this time. Adequately powered trials are necessary before the impact of ESs for fetal assessment in labour can be determined.
We included 21 trials (2588 patients). The drugs did not reduce mortality significantly (relative risk 0.97, 95% confidence interval (CI) 0.75 to 1.25, for the trials with a low risk of bias, and 0.80, 95% CI 0.63 to 1.01, for the other trials). Units of blood transfused were 0.7 (0.2 to 1.1) less with drugs in the trials with a low risk of bias and 1.5 (0.9 to 2.0) less in the other trials. Number of patients failing initial haemostasis was reduced, relative risk 0.68 (0.54 to 0.87). Number of patients with rebleeding was not significantly reduced for the trials with a low risk of bias, relative risk 0.84 (0.52 to 1.37) while it was substantially reduced in the other trials, relative risk 0.36 (0.19 to 0.68). Use of balloon tamponade was rarely reported. The need for blood transfusions corresponded to one half unit of blood saved per patient. It is doubtful whether this effect is worthwhile. The findings do not suggest a need for further placebo-controlled trials of the type reviewed here. A large placebo controlled trial enrolling thousands of patients is needed if one wishes to rule out the possibility that a worthwhile effect on mortality might have been overlooked.
Of twenty eligible studies, ten evaluated breastfeeding and ten evaluated supplemental breast milk. Sixteen studies analysed used heel lance and four used venepuncture as procedure. We noted marked heterogeneity in control intervention and pain assessment measures among the studies. Neonates in the breastfeeding group had statistically a significantly lower increase in heart rate, reduced proportion of crying time and reduced duration of first cry and total crying time compared to positioning (swaddled and placed in a crib), holding by mother, placebo, pacifier use, no intervention or oral sucrose group, or both. Premature Infant Pain Profile (PIPP) scores were significantly lower in the breastfeeding group compared to positioning, placebo or oral sucrose group, or both. However, there was no statistically significant difference in PIPP scores when compared to no intervention. Douleur Aigue Nouveau-ne scores (DAN) were significantly lower in the breastfeeding group compared to the placebo group and the group held in mother's arms, but not when compared to the glucose group. Neonatal Infant Pain Scale (NIPS) was significantly lower in the breastfeeding group compared to the no intervention group, but there was no difference when compared to the oral sucrose group. The Neonatal Facial Coding System (NFCS) was significantly lower in the breastfeeding group when compared to oral glucose, pacifier use, holding by mother and no intervention, but no difference was found when compared to formula feeding. Supplemental breast milk yielded variable results. Neonates in the supplemental breast milk group had a significantly lower increase in heart rate, a reduction in duration of crying and a lower NFCS compared to the placebo group. Neonates in the supplemental breast milk group had a significantly higher increase in heart rate changes when compared to the sucrose group. Sucrose (in any concentration, i.e. 12.5%, 20%, 25%) was found to reduce the duration of cry when compared to breast milk, as did glycine, pacifier use, rocking, or no intervention. Breast milk was found not to be effective in reducing validated and non-validated pain scores such as NIPS, NFCS, and DAN; only being significantly better when compared to placebo (water) or massage. We did not identify any study that has evaluated safety/effectiveness of repeated administration of breastfeeding or supplemental breast milk for pain relief. If available, breastfeeding or breast milk should be used to alleviate procedural pain in neonates undergoing a single painful procedure rather than placebo, positioning or no intervention. Administration of glucose/sucrose had similar effectiveness as breastfeeding for reducing pain. The effectiveness of breast milk for painful procedure should be studied in the preterm population, as there are currently a limited number of studies in the literature that have assessed it's effectiveness in this population.
A total of 770 participants were involved in the 11 included studies. Data from five included randomised double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Quantitative analysis of these studies showed a significant reduction of mean pain intensity after administration of the antipsychotic compared to placebo or another active compound, weighted mean difference (WMD) -1.78 (95% CI -2.71 to -0.85) for the continuous data; and relative risk (RR) 0.43 (95% CI 0.25 to 0.73), number needed to treat to benefit (NNT) 2.6 for the dichotomous data. Nevertheless, the test for heterogeneity was significant for both the continuous data (P = 0.0007) and the dichotomous data (P = 0.04). Obviously this makes the calculated NNT less reliable and caution is warranted when interpreting these results. The most frequently reported adverse effects were extrapyramidal (that is involuntary movements, parkinsonism and akathisia) and sedating effects. The recent search found five new studies which were all excluded, so the review remains the same as previously. Antipsychotics might be used as an add-on therapy in the treatment of painful conditions. Nevertheless, extrapyramidal and sedating side effects have to be considered before using antipsychotics for treating painful conditions. Results for antipsychotics in the treatment of different painful conditions are mixed and most sample sizes in the reviewed RCTs are small. Further studies on atypical antipsychotics in larger double-blind placebo-controlled studies that include standardised pain assessment and documentation are warranted.
Two studies fitting the selection criteria were found for computer aided prescribing and one study for computer aided physiological monitoring. Computer-aided prescribing: one study (Cade 1997) examined the effects of computerised prescribing of parenteral nutrition ordering. No significant effects on short-term outcomes were found and longer term outcomes were not studied. The second study (Balaguer 2001) investigated the effects of a database program in aiding the calculation of neonatal drug dosages. It was found that the time taken for calculation was significantly reduced and there was a significant reduction in the number of calculation errors. Computer-aided physiological monitoring: one eligible study (Cunningham 1998) was found which examined the effects of computerised cot side physiological trend monitoring and display. There were no significant effects on mortality, volume of colloid infused, frequency of blood gases sampling (samples per day) or severe intraventricular haemorrhage (Papile Grade IV). Published data did not permit us to analyse effects on long-term neurodevelopmental outcome. There are very limited data from randomised trials on which to assess the effects of clinical decision support systems in neonatal care. Further evaluation of CDSS using randomised controlled trials is warranted.
We included 12 studies with a total of 1121 women. Ten studies enrolled healthy nulliparous women only and two studies enrolled healthy parous women at term as well. All studies excluded women with complicated pregnancies. There were variations in the technique of initiation of epidural analgesia. Seven studies utilized the combined spinal epidural (CSE) technique, and the other five studies only placed an epidural catheter without any intrathecal injection. Seven studies utilized ropivacaine: six with fentanyl and one with sufentanil. Two studies used levobupivacaine: one with sufentanil and one with fentanyl. Three used bupivacaine with or without fentanyl. The overall risk of bias of the studies was low. AMB probably reduces the risk of breakthrough pain compared with BI for maintaining epidural analgesia for labour (from 33% to 20%; risk ratio (RR) 0.60; 95% confidence interval (CI) 0.39 to 0.92, 10 studies, 797 women, moderate-certainty evidence). AMB may make little or no difference to the risk of caesarean delivery compared to BI (15% and 16% respectively; RR 0.92; 95% CI 0.70 to 1.21, 11 studies, 1079 women, low-certainty evidence). AMB may make little or no difference in the risk of instrumental delivery compared to BI (12% and 9% respectively; RR 0.75; 95% CI 0.54 to 1.06, 11 studies, 1079 women, low-certainty evidence). There is probably little or no difference in the mean duration of labour with AMB compared to BI (mean difference (MD) −10.38 min; 95% CI −26.73 to 5.96, 11 studies, 1079 women, moderate-certainty evidence). There is probably a reduction in the hourly consumption of local anaesthetic with AMB compared to BI for maintaining epidural analgesia during labour (MD −1.08 mg/h; 95% CI −1.78 to −0.38, 12 studies, 1121 women, moderate-certainty evidence). Five out of seven studies reported an increase in maternal satisfaction with AMB compared to BI for maintaining epidural analgesia for labour; however, we did not pool these data due to their ordinal nature. Seven studies reported Apgar scores, though there was significant heterogeneity in reporting. None of the studies showed any significant difference between Apgar scores between groups. There is predominantly moderate-certainty evidence that AMB is similar to BI for maintaining epidural analgesia for labour for all measured outcomes and may have the benefit of decreasing the risk of breakthrough pain and improving maternal satisfaction while decreasing the amount of local anaesthetic needed.
The searches identified 161 records; after de-duplication and title and abstract screening 90 full-text articles were retrieved. From these we included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality. P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; risk ratio (RR) 0.37, 95% confidence interval (CI) 0.24 to 0.57; I² = 0%; P < 0.00001; low-quality evidence). However, owing to the poor quality (high risk of bias) of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28, 95% CI 0.10 to 0.73; P = 0.01); therefore we consider this evidence to be of low quality. The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72, 95% CI 13.19 to 44.24; P = 0.0003; low-quality evidence); and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10, 95% CI 0.52 to 1.68; P = 0.0002; very low quality evidence). There were insufficient data to perform meta-analyses for toxicity, overall survival, drug resistance and reproductive outcomes. P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delays treatment of GTN and may expose women toxic side effects, this practice cannot currently be recommended.
Nine studies were included in this review which analysed 634 participants. Study duration ranged from 4 to 24 weeks. The interventions included calcium-enriched bread, low phosphorus intake, low protein intake, very low protein intake, post haemodialysis supplements and hypolipaemic diet. Only one study reported death; none of the included studies reported cardiovascular events or fractures. There was insufficient reporting of design and methodological aspects among the included studies to enable robust assessment of risk of bias. There was limited and low-quality evidence to indicate that calcium-enriched bread increased serum calcium (1 study, 53 participants: MD -0.16 mmol/L, 95% CI -0.51 to -0.31), decreased serum phosphorus (53 participants: MD -0.41 mmol/L, 95% CI -0.51 to -0.31) and decreased the calcium × phosphate product (53 participants: MD -0.62 mmol²/L², 95% CI -0.77 to -0.47). Very low protein intake was not superior to conventional low protein intake in terms of effect on serum phosphorus (2 studies, 41 participants: MD -0.12 mmol/L, 95% CI -0.50 to 0.25), serum calcium (MD 0.00 mmol/L, 95% CI -0.17 to 0.17), or alkaline phosphatase (MD -22.00 U/L, 95% CI -78.25 to 34.25). PTH was significantly lower in the very low protein intake group (2 studies, 41 participants: MD -69.64 pmol/L, 95% CI -139.83 to 0.54). One study reported no significant difference in the number of deaths between low phosphorus intake and normal diet (279 participants: RR 0.18, 95% CI 0.01 to 3.82). Low phosphorus intake decreased serum phosphorus (2 studies, 359 participants: MD -0.18 mmol/L, 95% CI -0.29 to -0.07; I2 = 0%). One study reported post-haemodialysis supplements did not increase serum phosphorus compared to normal diet (40 participants: MD 0.12 mmol/L, 95% CI -0.24 to 0.49). One study reported low phosphorus intake plus lanthanum carbonate significantly decreased FGF-23 (19 participants: MD -333.80 RU/mL, 95% CI -526.60 to -141.00), but did not decrease serum phosphorus (19 participants: MD -0.10 mg/dL, 95% CI -0.38 to 0.58) or PTH (19 participants: MD 31.60 pg/mL, 95% CI -29.82 to 93.02). There was limited low quality evidence to indicate that dietary interventions (calcium-enriched bread or low phosphorus/protein intake) may positively affect CKD-MBD by increasing serum calcium, decreasing serum phosphorus, the calcium × phosphate product and FGF-23. Large and well-designed RCTs are needed to evaluate the effects of various interventions for people with CKD-MBD.
We included eight studies, involving 809 participants, comparing oral dipyrone 500 mg (143 participants), oral dipyrone 1000 mg (57 participants), and intramuscular dipyrone 2000 mg (35 participants) with placebo (236 participants). In addition to placebo, all studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen; 338 participants). Seven studies used the oral route of administration, and one study used the intramuscular route. The mean age ranged from 23 to 62 years. Six studies included both men and women, and two studies included only women. All the studies were small, but were otherwise of moderate to good quality. Over 70% of participants experienced our primary outcome of at least 50% pain relief over four to six hours with oral dipyrone 500 mg compared to 30% with placebo (five studies, 288 participants; NNT 2.4 (95% CI 1.8 to 3.1)) (moderate quality evidence). There were insufficient data to assess other doses or routes of administration of dipyrone. Fewer participants needed rescue medication within four to six hours with dipyrone 500 mg than with placebo (7% with dipyrone versus 34% with placebo; four studies, 248 participants) (low quality evidence). The data on numbers of participants experiencing any adverse event was inconsistently reported and no analysis was possible. No serious adverse events or adverse event withdrawals were reported (very low quality evidence). There were too few data to compare dipyrone directly with other active treatments. Based on very limited information, a single dose of dipyrone 500 mg provides good pain relief to about 70% of people treated, compared to about 30% with placebo. For every five people given dipyrone 500 mg, two people would experience this level of pain relief over four to six hours who would not have done with placebo, and fewer people would need rescue medication. We were unable to compare dipyrone directly with other active treatments, or to assess the effects of different doses or routes of administration, or the number of participants experiencing adverse events, because of insufficient data and inadequate reporting.
Treatment with naftidrofuryl tended to show reduction of pain evaluated by both analogue score and analgesic consumption, but the effect was statistically non-significant (mean difference (MD): 0.42; 95% confidence interval (CI)1.19 to 0.35). Similarly, improvement in rest pain or skin necrosis occurred, but these effects were also non-significant. The effect on mean ankle systolic pressure was inconclusive. Based on the results of these trials, it cannot be confirmed that intravenous naftidrofuryl is effective in the treatment of people with critical limb ischaemia. However, these results were based on trials of generally low methodological quality which had only a small number of participants, the duration of treatment was extremely short, and the methods varied between the trials. The wide range of endpoints effectively precluded any meaningful pooling of the results. Intravenous naftidrofuryl was withdrawn as a treatment for severe peripheral arterial disease in 1995 because of reported side effects.
We found no trials assessing the effect of visibility aids on pedestrian and cyclist-motor vehicle collisions and injuries. To date we have identified 42 trials assessing the effect of visibility aids on drivers' responses. Fluorescent materials in yellow, red and orange colours improve detection and recognition in the daytime. For night-time visibility, lamps, flashing lights and retroreflective materials in red and yellow colours increase detection and recognition. Retroreflective materials enhance recognition, in particular when arranged in a 'biomotion' configuration, taking advantage of the motion from a pedestrian's limbs. Substantial heterogeneity between and within the trials limited the possibility for meta-analysis. Summary statistics and descriptive summaries of the outcomes were presented for individual trials when appropriate. Visibility aids have the potential to increase visibility and enable drivers to detect pedestrians and cyclists earlier. Biomotion markings, which highlight the movement and form of the pedestrian, showed evidence of improving pedestrians' conspicuity at night. Public acceptability of various effective strategies which improve visibility would merit further development. However, the effect of visibility aids on pedestrian and cyclist safety remains unknown. A cluster randomised controlled trial involving large communities may provide an answer to this question. It would, however, be a challenging trial to conduct. Studies that collect data of road traffic injuries relating to the use of visibility aids also warrant consideration.
Two prospective controlled clinical trials involving 167 patients were included. All of them were of low quality. Radioiodine treatment versus ATD showed benefits in achieving euthyroidism (relative risk (RR) 1.70, 95% confidence interval (CI) 1.29 to 2.24). Radioiodine treatment showed a higher incidence of hypothyroidism compared with ATD (RR 6.46, 95% CI 1.16 to 35.81). No significant differences in modifying Graves' opthalmopathy (worsening or appearance) between radioiodine treatment and ATD (RR 1.30, 95% CI 0.56 to 3.00) were observed. No trial evaluated mortality, health related quality of life, economic outcomes or compliance with treatments. The limited results in Chinese suggest that a gland specific lower dosage of radioiodine treatment is potentially effective for pediatric GD, but a significant higher incidence of hypothyroidism compared with ATD was observed. However, we could not identify a well-designed trial to provide strong evidence for radioiodine in the treatment of pediatric GD. High-quality randomised controlled clinical trials are needed to guide treatment choice.
Six studies compared optimal self-management allowing self-adjustment of medications according to an individualised written action plan to adjustment of medications by a doctor. These two styles of asthma management gave equivalent effects for hospitalisation, emergency room (ER) visits, unscheduled doctor visits and nocturnal asthma. Self-management using a written action plan based on peak expiratory flow (PEF) was found to be equivalent to self-management using a symptoms based written action plan in the six studies which compared these interventions. Three studies compared self-management options. In one, that provided optimal therapy but tested the omission of regular review, the latter was associated with more health centre visits and sickness days. In another, comparing high and low intensity education, the latter was associated with more unscheduled doctor visits. In a third, no difference in health care utilisation or lung function was reported between verbal instruction and written action plans. Optimal self-management allowing for optimisation of asthma control by adjustment of medications may be conducted by either self-adjustment with the aid of a written action plan or by regular medical review. Individualised written action plans based on PEF are equivalent to action plans based on symptoms. Reducing the intensity of self-management education or level of clinical review may reduce its effectiveness.
Thirteen studies from six countries covering over 33,400 children and adults in rural, urban, and school settings met the review's inclusion criteria. In all studies the intervention was allocated at the community level. While the studies reported a wide range of effects, 11 of the 13 studies found the intervention was protective against diarrhoea. Differences in study populations and settings, in baseline sanitation levels, water, and hygiene practices, in types of interventions, study methodologies, compliance and coverage levels, and in case definitions and outcome surveillance limit the comparability of results of the studies included in this review. The validity of most individual study results are further compromised by the non-random allocation of the intervention among study clusters, an insufficient number of clusters, the lack of adjustment for clustering, unclear loss to follow-up, potential for reporting bias and other methodological shortcomings. This review provides some evidence that interventions to improve excreta disposal are effective in preventing diarrhoeal disease. However, this conclusion is based primarily on the consistency of the evidence of beneficial effects. The quality of the evidence is generally poor and does not allow for quantification of any such effect. The wide range of estimates of the effects of the intervention may be due to clinical and methodological heterogeneity among the studies, as well as to other important differences, including exposure levels, types of interventions, and different degrees of observer and respondent bias. Rigorous studies in multiple settings are needed to clarify the potential effectiveness of excreta disposal on diarrhoea.
Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less likely to die if they received an IP component to chemotherapy (eight studies, 2026 women; HR = 0.81; 95% confidence interval (CI): 0.72 to 0.90). Intraperitoneal component chemotherapy prolonged the disease-free interval (five studies, 1311 women; HR = 0.78; 95% CI: 0.70 to 0.86). There was greater serious toxicity with regard to gastrointestinal effects, pain, fever and infection but less ototoxicity with the IP than the IV route. Intraperitoneal chemotherapy increases overall survival and progression-free survival from advanced ovarian cancer. The results of this meta-analysis provide the most reliable estimates of the relative survival benefits of IP over IV therapy and should be used as part of the decision making process. However, the potential for catheter related complications and toxicity needs to be considered when deciding on the most appropriate treatment for each individual woman. The optimal dose, timing and mechanism of administration cannot be addressed from this meta-analysis. This needs to be addressed in the next phase of clinical trials.
We included 11 studies (2635 women) in the review. Six trials compared carbetocin with oxytocin; four of these were conducted for women undergoing caesarean deliveries, one was for women following vaginal deliveries and one did not state the mode of delivery clearly. The carbetocin was administered as 100 µg intravenous dosage across the trials, while oxytocin was administered intravenously but at varied dosages. Four trials compared intramuscular carbetocin and intramuscular syntometrine for women undergoing vaginal deliveries. Three of the trials were on women with no risk factor for PPH, while one trial was on women with risk factors for PPH. One trial compared the use of intravenous carbetocin with placebo. Use of carbetocin resulted in a statistically significant reduction in the need for therapeutic uterotonics (risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44 to 0.88; four trials, 1173 women) compared to oxytocin for those who underwent caesarean section, but not for vaginal delivery. Compared to oxytocin, carbetocin was associated with a reduced need for uterine massage following both caesarean delivery (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739 women) and vaginal delivery (RR 0.70; 95% CI 0.51 to 0.94; one trial, 160 women). There were no statistically significant differences between carbetocin and oxytocin in terms of risk of any PPH (blood loss greater than 500 ml) or in risk of severe PPH (blood loss greater than 1000 ml). Comparison between carbetocin and syntometrine showed a lower mean blood loss in women who received carbetocin compared to syntometrine (mean difference (MD) -48.84 ml; 95% CI -94.82 to -2.85; four trials, 1030 women). There was no statistically significant difference in terms of the need for therapeutic uterotonic agents, but the risk of adverse effects such as nausea and vomiting were significantly lower in the carbetocin group: nausea (RR 0.24; 95% CI 0.15 to 0.40; four trials, 1030 women); vomiting (RR 0.21; 95% CI 0.11 to 0.39; four trials, 1030 women). The incidence of postpartum hypertension was also significantly lower in women who received carbetocin compared to those who received syntometrine. Cost-effectiveness of carbetocin was investigated by one study published as an abstract, with limited data. For women who undergo caesarean section, carbetocin resulted in a statistically significant reduction in the need for therapeutic uterotonics compared to oxytocin, but there is no difference in the incidence of postpartum haemorrhage. Carbetocin is associated with less blood loss compared to syntometrine in the prevention of PPH for women who have vaginal deliveries and is associated with significantly fewer adverse effects. Further research is needed to analyse the cost-effectiveness of carbetocin as a uterotonic agent.
We included three trials with 381 participants. We were unable to pool the data from the included studies due to the differences in interventions used; therefore we synthesised the trial findings narratively. Two trials were conducted in the USA and one was undertaken in Israel. All trials included participants who were admitted to hospital with myocardial infarction (MI), and one trial also included participants who had undergone coronary artery bypass grafting. All trials followed up participants for a minimum of three months post-intervention; the longest follow-up timepoint was five months. One trial (N = 92) tested an intensive (total five hours) psychotherapeutic sexual counselling intervention delivered by a sexual therapist. One trial (N = 115) used a 15-minute educational video plus written material on resuming sexual activity following a MI. One trial (N = 174) tested the addition of a component that focused on resumption of sexual activity following a MI within a hospital cardiac rehabilitation programme. The quality of the evidence for all outcomes was very low. None of the included studies reported any outcomes from partners. Two trials reported sexual function. One trial compared intervention and control groups on 12 separate sexual function subscales and used a repeated measures analysis of variance (ANOVA) test. They reported statistically significant differences in favour of the intervention. One trial compared intervention and control groups using a repeated measures analysis of covariance (ANCOVA), and concluded: "There were no significant differences between the two groups [for sexual function] at any of the time points". Two trials reported sexual satisfaction. In one trial, the authors compared sexual satisfaction between intervention and control and used a repeated measured ANOVA; they reported "differences were reported in favour of the intervention". One trial compared intervention and control with a repeated measures ANCOVA and reported: "There were no significant differences between the two groups [for sexual satisfaction] at any of the timepoints". All three included trials reported the number of patients returning to sexual activity following MI. One trial found some evidence of an effect of sexual counselling on reported rate of return to sexual activity (yes/no) at four months after completion of the intervention (relative risk (RR) 1.71, 95% confidence interval (CI) 1.26 to 2.32; one trial, 92 participants, very low quality of evidence). Two trials found no evidence of an effect of sexual counselling on rate of return to sexual activity at 12 week (RR 1.01, 95% CI 0.94 to 1.09; one trial, 127 participants, very low quality of evidence) and three month follow-up (RR 0.98, 95% CI 0.88 to 1.10; one trial, 115 participants, very low quality of evidence). Two trials reported psychological well-being. In one trial, no scores were reported, but the trial authors stated: "No treatment effects were observed on state anxiety as measured in three points in time". In the other trial no scores were reported but, based on results of a repeated measures ANCOVA to compare intervention and control groups, the trial authors stated: "The experimental group had significantly greater anxiety at one month post MI". They also reported: "There were no significant differences between the two groups [for anxiety] at any other time points". One trial reporting relationship satisfaction and one trial reporting quality of life found no differences between intervention and control. No trial reported on satisfaction in how sexual issues were addressed in cardiac rehabilitation services. We found no high quality evidence to support the effectiveness of sexual counselling for sexual problems in patients with cardiovascular disease. There is a clear need for robust, methodologically rigorous, adequately powered RCTs to test the effectiveness of sexual counselling interventions for people with cardiovascular disease and their partners.
We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low-quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low-quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low-quality evidence), non-relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low-quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low-quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low-quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low-quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low. The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant-associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high-quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions.
Only one randomised controlled trial of treatment was identified. This trial compared the effectiveness of thalidomide with placebo and included 22 patients, 12 in the treatment group and 10 in the placebo group. Patients on the treatment arm received thalidomide 200 mg twice daily for 5 days. The main end point was the measurement of the progression of skin detachment after seven days. Other end points were the overall mortality and severity of the disease evaluated with the simplified acute physiology score. The study was terminated as the mortality on the treatment arm was 83% compared to 30% on the control arm (relative risk 2.78, 95% confidence interval 1.04 to 7.40). No randomised controlled trials of the most commonly used current treatments i.e. systemic steroids, cyclosporin A and intravenous immunoglobulins were found. Treatment with thalidomide was not shown to be effective and was associated with significantly higher mortality than placebo. There is no reliable evidence on which to base treatment for toxic epidermal necrolysis, a disease commonly associated with mortality rates of around 30%. More research is required to understand the mechanisms of toxic epidermal necrolysis. International multi-centre studies are needed in the form of randomised controlled trials, to evaluate treatments for toxic epidermal necrolysis, especially those using high doses of steroid and intravenous immunoglobulins.
We included seven RCTs (667 women) in this updated review. Most studies were at a low or moderate risk of bias and all compared methotrexate with actinomycin D. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) actinomycin D (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV actinomycin D (75 women), one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV actinomycin D (49 women), and one study compared eight-day IM MTX-FA with bi-weekly pulsed IV actinomycin D. One study contributed no data. Moderate-certainty evidence indicates that actinomycin D is probably more likely to lead to primary cure than methotrexate (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.57 to 0.75; six trials, 577 participants; I2 = 26%), and first-line methotrexate treatment is probably more likely to fail than actinomycin D treatment (RR 3.55, 95% CI 1.81 to 6.95; six trials, 577 participants; I2 = 61%; moderate-certainty evidence) Low-certainty evidence suggests that there may be little or no difference between methotrexate and actinomycin D treatment with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too inconsistent to be conclusive. Low-certainty evidence suggests that there may be little or no difference in the risk of severe adverse events (SAEs) between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%); however, the direction of effect favours methotrexate and more evidence is needed. Furthermore, evidence from subgroup analyses suggests that actinomycin D may be associated with a greater risk of SAEs than methotrexate (low-certainty evidence). We found no evidence on the effect of these treatments on future fertility. Actinomycin D is probably more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, than a methotrexate regimen. There may be little or no difference between the pulsed actinomycin D regimen and the methotrexate regimen with regard to side-effects. However, actinomycin D may be associated with a greater risk of severe adverse events (SAEs) than a methotrexate regimen. Higher-certainty evidence is still needed on treating low-risk GTN and the four ongoing trials are likely to make a significant contribution to this field. Given the variety of treatment regimens, findings from these trials could facilitate a network meta-analysis in the next version of this review to help women and clinicians determine the best treatment options for low-risk GTN.
Five trials involving 187 women with an age range of 15 to 40 years were included. Oral isoxsuprine was compared with placebo in two trials; terbutaline oral spray, ritodrine chloride and oral hydroxyphenyl-orciprenalin were compared with placebo in a further three trials. Clinical diversity in the studies in terms of the interventions being evaluated, assessments at different time points and the use of different assessment tools mitigated against pooling of outcome data across studies in order to provide a summary estimate of effect for any of the comparisons. Only one study, with unclear risk of bias, reported pain relief with a combination of isoxsuprine, acetaminophen and caffeine. None of the other studies reported any significant clinical difference in effectiveness between the intervention and placebo. Adverse effects were reported with all of these medications in up to a quarter of the total number of participants. They included nausea, vomiting, dizziness, quivering, tremor and palpitations. The evidence presented in this review was based on a few relatively small-sized studies that were categorised to have unclear to high risk of bias, which does not allow confident decision-making at present about the use of beta2-adrenoceptor agonists for dysmenorrhoea. The benefits as reported in one study should be balanced against the wide array of unacceptable side effects documented with this class of medication. We have emphasised the lack of precision and limitations in the reported data where appropriate.
This review update did not reveal any new studies, so the number of included studies remained the same: 8 studies involving a total of 2100 participants with high blood pressure and a mean age of 45 to 66 years. Mean treatment duration was 6 to 36 months. We judged the risk of bias as unclear or high for all but two trials. No study included mortality as a predefined outcome. One RCT evaluated the effects of dietary weight loss on a combined endpoint consisting of the necessity of reinstating antihypertensive therapy and severe cardiovascular complications. In this RCT, weight-reducing diet lowered the endpoint compared to no diet: hazard ratio 0.70 (95% confidence interval (CI), 0.57 to 0.87). None of the studies evaluated adverse events as designated in our protocol. There was low-quality evidence for a blood pressure reduction in participants assigned to weight loss diets as compared to controls: systolic blood pressure: mean difference (MD) -4.5 mm Hg (95% CI -7.2 to -1.8 mm Hg) (3 of 8 studies included in analysis), and diastolic blood pressure: MD -3.2 mm Hg (95% CI -4.8 to -1.5 mm Hg) (3 of  8  studies included in analysis). There was moderate-quality evidence for weight reduction in dietary weight loss groups as compared to controls: MD -4.0 kg (95% CI -4.8 to -3.2) (5 of 8 studies included in analysis). Two studies used withdrawal of antihypertensive medication as their primary outcome. Even though we did not consider this a relevant outcome for our review, the results of these studies strengthen the finding of reduction of blood pressure by dietary weight loss interventions. In this update, the conclusions remain the same, as we found no new trials. In people with primary hypertension, weight loss diets reduced body weight and blood pressure, however the magnitude of the effects are uncertain due to the small number of participants and studies included in the analyses. Whether weight loss reduces mortality and morbidity is unknown. No useful information on adverse effects was reported in the relevant trials.
We included nine trials involving 3137 participants. We did not identify any new trials for inclusion in this updated review. None of the studies reported data on the primary outcome in sufficient detail to enable analysis for the review. Overall, there was a moderate risk of bias in the included studies. Compared with UFH, there was no evidence of an effect of LMWH or heparinoids on death from all causes during the treatment period (96/1616 allocated LMWH/heparinoid versus 78/1486 allocated UFH; odds ratio (OR) 1.06, 95% CI 0.78 to 1.47; 8 trials, 3102 participants, low quality evidence). LMWH or heparinoid were associated with a significant reduction in deep vein thrombosis (DVT) compared with UFH (OR 0.55, 95% CI 0.44 to 0.70, 7 trials, 2585 participants, low quality evidence). However, the number of the major clinical events such as pulmonary embolism (PE) and intracranial haemorrhage was too small to provide a reliable estimate of the effects. Treatment with a LMWH or heparinoid after acute ischaemic stroke appears to decrease the occurrence of DVT compared with standard UFH, but there are too few data to provide reliable information on their effects on other important outcomes, including functional outcome, death and intracranial haemorrhage.
A search of the databases identified a total of 735 unique, previously unreviewed studies, of which 731 were excluded to leave 4 new studies to incorporate into the review. Four additional studies were identified in conference proceedings, for a total of 8 studies addressing when to start treatment (n=2), what to start (n=3), whether to substitute lopinavir/ritonavir (LPV/r) with nevirapine (NVP) (n=1), whether to use an induction-maintenance ART strategy (n=1) and whether to interrupt treatment (n=1). Treatment initiation in asymptomatic infants with good immunological status was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller pilot trial, median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART. Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure at 24 weeks was 1.79 (95%CI 1.33, 2.41) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0001) with no clear difference in the effect observed for children younger or older than 1 year. The hazard for virological failure at 24 weeks was overall 1.84 (95%CI 1.29, 2.63) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0008) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life. Infants starting a LPV/r regimen and achieving sustained virological suppression who then substituted LPV/r with NVP after median 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (>1000 copies/mL) was greater among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002). Children undergoing an induction-maintenance ART approach with a 4-drug NNRTI-based regimen for 36 weeks, followed by 3-drug ART, had significantly greater CD4 rise than children receiving a standard 3-drug NNRTI-based ART at 36 weeks (mean difference 1.70 [95%CI 0.61, 2.79] p=0.002) and significantly better viral load response at 24 weeks (OR 1.99 [95%CI 1.09, 3.62] p=0.02). However, the immunological and virological benefits were short-term. The one trial of treatment interruption that compared children initiating continuous ART from infancy with children interrupting ART was terminated early because the duration of treatment interruption was less than 3 months in most infants. Children interrupting treatment had similar growth and occurrence of serious adverse events as those in the continuous arm. ART initiation in asymptomatic children under 1 year of age reduces morbidity and mortality, but it remains unclear whether there are clinical benefits to starting ART in asymptomatic children diagnosed with HIV infection between 1-3 years. The available evidence shows that a LPV/r-based first-line regimen is more efficacious than a NVP-based regimen, regardless of PMTCT exposure status. New formulations of LPV/r are urgently required to enable new WHO recommendations to be implemented. An alternative approach to long-term LPV/r is substituting LPV/r with NVP once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of routine viral load testing. A 4-drug induction-maintenance approach showed short-term virological and immunological benefits during the induction phase but, in the absence of sustained benefits, is not recommended as a routine treatment strategy. Treatment interruption following early ART initiation in infancy was challenging for children who were severely immunocompromised in the context of poor clinical immunological condition at ART initiation due to the short duration of interruption, and is therefore not practical in ART treatment programmes where close monitoring is not feasible.
We found 18 studies including 2268 participants: 12 in adults, 5 in children and one in individuals from both age groups. Studies generally recruited people with mild to moderate persistent asthma and followed them for between three and 12 months. People in the intervention group were given one of a variety of technologies to record and share their symptoms (text messaging, Web systems or phone calls), compared with a group of people who received usual care or a control intervention. Evidence from these studies did not show clearly whether asthma telemonitoring with feedback from a healthcare professional increases or decreases the odds of exacerbations that require a course of oral steroids (OR 0.93, 95% confidence Interval (CI) 0.60 to 1.44; 466 participants; four studies), a visit to the emergency department (OR 0.75, 95% CI 0.36 to 1.58; 1018 participants; eight studies) or a stay in hospital (OR 0.56, 95% CI 0.21 to 1.49; 1042 participants; 10 studies) compared with usual care. Our confidence was limited by imprecision in all three primary outcomes. Evidence quality ratings ranged from moderate to very low. None of the studies recorded serious or non-serious adverse events separately from asthma exacerbations. Evidence for measures of asthma control was imprecise and inconsistent, revealing possible benefit over usual care for quality of life (MD 0.23, 95% CI 0.01 to 0.45; 796 participants; six studies; I2 = 54%), but the effect was small and study results varied. Telemonitoring interventions may provide additional benefit for two measures of lung function. Current evidence does not support the widespread implementation of telemonitoring with healthcare provider feedback between asthma clinic visits. Studies have not yet proven that additional telemonitoring strategies lead to better symptom control or reduced need for oral steroids over usual asthma care, nor have they ruled out unintended harms. Investigators noted small benefits for quality of life, but these are subject to risk of bias, as the studies were unblinded. Similarly, some benefits for lung function are uncertain owing to possible attrition bias. Larger pragmatic studies in children and adults could better determine the real-world benefits of these interventions for preventing exacerbations and avoiding harms; it is difficult to generalise results from this review because benefits may be explained at least in part by the increased attention participants receive by taking part in clinical trials. Qualitative studies could inform future research by focusing on patient and provider preferences, or by identifying subgroups of patients who are more likely to attain benefit from closer monitoring, such as those who have frequent asthma attacks.
Twenty-nine trials were included (3227 participants), and nine were excluded. One study examined pelvic pain and found no evidence of a difference between use of hydroflotation agents and no treatment. We found no evidence that any of the antiadhesion agents significantly affected the live birth rate. When gels were compared with no treatment or with hydroflotation agents at second-look laparoscopy (SLL), fewer participants who received a gel showed a worsening adhesion score when compared with those who received no treatment (OR 0.16, 95% CI 0.04 to 0.57, P value 0.005, two studies, 58 women, I2 = 0%, moderate-quality evidence) and with those given hydroflotation agents (OR 0.28, 95% CI 0.12 to 0.66, P value 0.003, two studies, 342 women, I2 = 0%, high-quality evidence). Participants who received steroids were less likely to have a worsening adhesion score (OR 0.27, 95% CI 0.12 to 0.58, P value 0.0008, two studies, 182 women, I2 = 0%, low-quality evidence). Participants were less likely to have adhesions at SLL if they received a hydroflotation agent or gel than if they received no treatment (OR 0.34, 95% CI 0.22 to 0.55, P value < 0.00001, four studies, 566 participants, I2 = 0%, high-quality evidence; OR 0.25, 95% CI 0.11 to 0.56, P value 0.0006, four studies, 134 women, I2 = 0%, high-quality evidence, respectively). When gels were compared with hydroflotation agents, participants who received a gel were less likely to have adhesions at SLL than those who received a hydroflotation agent (OR 0.36, 95% CI 0.19 to 0.67, P value 0.001, two studies, 342 women, I2 = 0%, high-quality evidence). No studies evaluated quality of life. In all studies apart from one, investigators stated that they were going to assess serious adverse outcomes associated with treatment agents, and no adverse effects were reported. Results suggest that for a woman with a 77% risk of developing adhesions without treatment, the risk of developing adhesions after use of a gel would be between 26% and 65%. For a woman with an 83% risk of worsening of adhesions after no treatment at initial surgery, the chance when a gel is used would be between 16% and 73%. Similarly, for hydroflotation fluids for a woman with an 84% chance of developing adhesions with no treatment, the risk of developing adhesions when hydroflotation fluid is used would be between 53% and 73%. Several of the included studies could not be included in a meta-analysis: The findings of these studies broadly agreed with the findings of the meta-analyses. The quality of the evidence, which was assessed using the GRADE approach, ranged from low to high. The main reasons for downgrading of evidence included imprecision (small sample sizes and wide confidence intervals) and poor reporting of study methods. Gels and hydroflotation agents appear to be effective adhesion prevention agents for use during gynaecological surgery, but no evidence indicates that they improve fertility outcomes or pelvic pain, and further research is required in this area. Future studies should measure outcomes in a uniform manner, using the modified American Fertility Society (mAFS) score. Statistical findings should be reported in full.
We included 17 studies. Methodological quality of included studies was poor. Of these 17, only seven studies specifically addressed the discharge question; none found any delay in premedicated patients. Two other studies used clinical criteria to assess fitness for discharge, though times were not given. Again, there was no difference from placebo. Eleven studies used tests of psychomotor function with or without clinical measures as indicators of recovery from anaesthesia. In none of these studies did the premedication appear to delay discharge, although performance on tests of psychomotor function was sometimes still impaired. Three studies showed no impairment in psychomotor function, six showed some impairment which had resolved by three hours or time of discharge and two showed significant impairment. We found no evidence of a difference in time to discharge from hospital, assessed by clinical criteria, in patients who received anxiolytic premedication. However, in view of the age and variety of anaesthetic techniques used and clinical heterogeneity between studies, inferences for current day case practice should be made with caution.
Of the 364 records identified, 129 studies with 18,086 participants met the inclusion criteria. Half of the studies were judged at high risk of bias with the remainder judged at unclear risk. A wide range of different comparisons were evaluated across the 129 studies, 92 in total, with azoles accounting for the majority of the interventions. Treatment duration varied from one week to two months, but in most studies this was two to four weeks. The length of follow-up varied from one week to six months. Sixty-three studies contained no usable or retrievable data mainly due to the lack of separate data for different tinea infections. Mycological and clinical cure were assessed in the majority of studies, along with adverse effects. Less than half of the studies assessed disease relapse, and hardly any of them assessed duration until clinical cure, or participant-judged cure. The quality of the body of evidence was rated as low to very low for the different outcomes. Data for several outcomes for two individual treatments were pooled. Across five studies, significantly higher clinical cure rates were seen in participants treated with terbinafine compared to placebo (risk ratio (RR) 4.51, 95% confidence interval (CI) 3.10 to 6.56, number needed to treat (NNT) 3, 95% CI 2 to 4). The quality of evidence for this outcome was rated as low. Data for mycological cure for terbinafine could not be pooled due to substantial heterogeneity. Mycological cure rates favoured naftifine 1% compared to placebo across three studies (RR 2.38, 95% CI 1.80 to 3.14, NNT 3, 95% CI 2 to 4) with the quality of evidence rated as low. In one study, naftifine 1% was more effective than placebo in achieving clinical cure (RR 2.42, 95% CI 1.41 to 4.16, NNT 3, 95% CI 2 to 5) with the quality of evidence rated as low. Across two studies, mycological cure rates favoured clotrimazole 1% compared to placebo (RR 2.87, 95% CI 2.28 to 3.62, NNT 2, 95% CI 2 to 3). Data for several outcomes were pooled for three comparisons between different classes of treatment. There was no difference in mycological cure between azoles and benzylamines (RR 1.01, 95% CI 0.94 to 1.07). The quality of the evidence was rated as low for this comparison. Substantial heterogeneity precluded the pooling of data for mycological and clinical cure when comparing azoles and allylamines. Azoles were slightly less effective in achieving clinical cure compared to azole and steroid combination creams immediately at the end of treatment (RR 0.67, 95% CI 0.53 to 0.84, NNT 6, 95% CI 5 to 13), but there was no difference in mycological cure rate (RR 0.99, 95% CI 0.93 to 1.05). The quality of evidence for these two outcomes was rated as low for mycological cure and very low for clinical cure. All of the treatments that were examined appeared to be effective, but most comparisons were evaluated in single studies. There was no evidence for a difference in cure rates between tinea cruris and tinea corporis. Adverse effects were minimal - mainly irritation and burning; results were generally imprecise between active interventions and placebo, and between different classes of treatment. The pooled data suggest that the individual treatments terbinafine and naftifine are effective. Adverse effects were generally mild and reported infrequently. A substantial number of the studies were more than 20 years old and of unclear or high risk of bias; there is however, some evidence that other topical antifungal treatments also provide similar clinical and mycological cure rates, particularly azoles although most were evaluated in single studies.There is insufficient evidence to determine if Whitfield’s ointment, a widely used agent is effective. Although combinations of topical steroids and antifungals are not currently recommended in any clinical guidelines, relevant studies included in this review reported higher clinical cure rates with similar mycological cure rates at the end of treatment, but the quality of evidence for these outcomes was rated very low due to imprecision, indirectness and risk of bias. There was insufficient evidence to confidently assess relapse rates in the individual or combination treatments. Although there was little difference between different classes of treatment in achieving cure, some interventions may be more appealing as they require fewer applications and a shorter duration of treatment. Further, high quality, adequately powered trials focusing on patient-centred outcomes, such as patient satisfaction with treatment should be considered.
We included 32 RCTs (approximately 54,000 participants) and data from 25 cohorts. There is consistent evidence from RCTs in adults of a small weight-reducing effect of eating a smaller proportion of energy from fat; this was seen in almost all included studies and was highly resistant to sensitivity analyses. The effect of eating less fat (compared with usual diet) is a mean weight reduction of 1.5 kg (95% confidence interval (CI) -2.0 to -1.1 kg), but greater weight loss results from greater fat reductions. The size of the effect on weight does not alter over time and is mirrored by reductions in body mass index (BMI) (-0.5 kg/m2, 95% CI -0.7 to -0.3) and waist circumference (-0.3 cm, 95% CI -0.6 to -0.02). Included cohort studies in children and adults most often do not suggest any relationship between total fat intake and later measures of weight, body fatness or change in body fatness. However, there was a suggestion that lower fat intake was associated with smaller increases in weight in middle-aged but not elderly adults, and in change in BMI in the highest validity child cohort. Trials where participants were randomised to a lower fat intake versus usual or moderate fat intake, but with no intention to reduce weight, showed a consistent, stable but small effect of low fat intake on body fatness: slightly lower weight, BMI and waist circumference compared with controls. Greater fat reduction and lower baseline fat intake were both associated with greater reductions in weight. This effect of reducing total fat was not consistently reflected in cohort studies assessing the relationship between total fat intake and later measures of body fatness or change in body fatness in studies of children, young people or adults.
We found six prospective controlled trials relating to our question. Four of these were described as randomised controlled trials, one was a prospective controlled trial that did not specify allocation to comparison groups, and one was a repeated cross-sectional study comparing different interventions. Comparison interventions included non-iodised salt, iodised water, iodised oil, and salt iodisation with potassium iodide versus potassium iodate. Numbers of participants in the trials ranged from 35 to 334; over 20,000 people were included in the cross-sectional study. Three studies were in children only, two investigated both groups of children and adults and one investigated pregnant women. There was a tendency towards goitre reduction with iodised salt, although this was not significant in all studies. There was also an improved iodine status in most studies (except in small children in one of the studies), although urinary iodine excretion did not always reach the levels recommended by the WHO. None of the studies observed any adverse effects of iodised salt. The results suggest that iodised salt is an effective means of improving iodine status. No conclusions can be made about improvements in other, more patient-oriented outcomes, such as physical and mental development in children and mortality. None of the studies specifically investigated development of iodine-induced hyperthyroidism, which can be easily overlooked if just assessed on the basis of symptoms. High quality controlled studies investigating relevant long term outcome measures are needed to address questions of dosage and best means of iodine supplementation in different population groups and settings.
We included 26 studies (18 RCTs and 8 NRCTs) with sample sizes of 41 to 1012 participants, involving a total of 7654 adults with cancer. Two studies included only men or women; all other studies included both sexes. For most studies people with breast, lung, head and neck, colorectal, prostate cancer, or several of these diagnoses were included; some studies included people with a broader range of cancer diagnosis. Ten studies focused on a solitary screening intervention, while the remaining 16 studies evaluated a screening intervention combined with guided actions. A broad range of intervention instruments was used, and were described by study authors as a screening of health-related quality of life (HRQoL), distress screening, needs assessment, or assessment of biopsychosocial symptoms or overall well-being. In 13 studies, the screening was a self-reported questionnaire, while in the remaining 13 studies an interventionist conducted the screening by interview or paper-pencil assessment. The interventional screenings in the studies were applied 1 to 12 times, without follow-up or from 4 weeks to 18 months after the first interventional screening. We assessed risk of bias as high for eight RCTs, low for five RCTs, and unclear for the five remaining RCTs. There were further concerns about the NRCTs (1 = critical risk study; 6 = serious risk studies; 1 = risk unclear). Due to considerable heterogeneity in several intervention and study characteristics, we have reported the results narratively for the majority of the evidence. In the narrative synthesis of all included studies, we found very low-certainty evidence for the effect of screening on HRQoL (20 studies). Of these studies, eight found beneficial effects of screening for several subdomains of HRQoL, and 10 found no effects of screening. One study found adverse effects, and the last study did not report quantitative results. We found very low-certainty evidence for the effect of screening on distress (16 studies). Of these studies, two found beneficial effects of screening, and 14 found no effects of screening. We judged the overall certainty of the evidence for the effect of screening on HRQoL to be very low. We found very low-certainty evidence for the effect of screening on care needs (seven studies). Of these studies, three found beneficial effects of screening for several subdomains of care needs, and two found no effects of screening. One study found adverse effects, and the last study did not report quantitative results. We judged the overall level of evidence for the effect of screening on HRQoL to be very low. None of the studies specifically evaluated or reported adverse effects of screening. However, three studies reported unfavourable effects of screening, including lower QoL, more unmet needs, and lower satisfaction. Three studies could be included in a meta-analysis. The meta-analysis revealed no beneficial effect of the screening intervention on people with cancer HRQoL (mean difference (MD) 1.65, 95% confidence interval (CI) −4.83 to 8.12, 2 RCTs, 6 months follow-up); distress (MD 0.0, 95% CI −0.36 to 0.36, 1 RCT, 3 months follow-up); or care needs (MD 2.32, 95% CI −7.49 to 12.14, 2 RCTs, 3 months follow-up). However, these studies all evaluated one specific screening intervention (CONNECT) in people with colorectal cancer. In the studies where some effects could be identified, no recurring relationships were found between intervention characteristics and the effectiveness of screening interventions. We found low-certainty evidence that does not support the effectiveness of screening of psychosocial well-being and care needs in people with cancer. Studies were heterogeneous in population, intervention, and outcome assessment. The results of this review suggest a need for more uniformity in outcomes and reporting; for the use of intervention description guidelines; for further improvement of methodological certainty in studies and for combining subjective patient-reported outcomes with objective outcomes.
Eleven studies met the inclusion criteria. All were small, and randomised fewer than 30 people to each group. Most included people after the most acute phase of psychosis and investigated a wide range of antidepressants. The quality of reporting varied a great deal. For the outcome of 'no important clinical response' antidepressants were significantly better than placebo (n=209, 5 RCTs, summary risk difference fixed effects -0.26, 95% CI -0.39 to -0.13, NNT 4 95% CI 3 to 8). The depression score at the end of the trial, as assessed by the Hamilton Rating Scale (HAM-D), seemed to suggest that using antidepressants was beneficial, but this was only statistically significant when a fixed effects model was used (n=261, 6 RCTs, WMD fixed effects -2.2 95% CI -3.8 to -0.6; WMD random effects -2.1 95% CI -5.04 to 0.84). There was no evidence that antidepressant treatment led to a deterioration of psychotic symptoms in the included trials. Heterogeneous data on 'any adverse effect' are equivocal (n=110, 2 RCTs, RD fixed 0.11 CI -0.03 to 0.25, Chi square 7.5, df=1, p=0.0062). In one small study extrapyramidal adverse effects were reported less often by those allocated to antidepressant (n=52, 1 RCT, RD fixed -0.28 CI -0.5 to -0.04). Only about 10% of people left these studies by 12 weeks. There was no apparent difference between those allocated placebo and those given an antidepressant (n=426, 10 RCTs, RD fixed 0.04 CI -0.02 to 0.1). Overall, the literature was of poor quality, and only a small number of trials made useful contributions. Though our results provide some evidence to indicate that antidepressants may be beneficial for people with depression and schizophrenia, the results, at best, are likely to overestimate the treatment effect, and, at worst, could merely reflect selective reporting of statistically significant results and publication bias. At present, there is no convincing evidence to support or refute the use of antidepressants in treating depression in people with schizophrenia. We need further well-designed, conducted and reported research to determine the best approach towards treating depression in people with schizophrenia. Note: the 71 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.
We included six studies conducted in Germany (three studies), Iran, India, and China. Three studies were conducted in people undergoing high-risk keratoplasty and investigated three different comparisons: systemic mycophenolate mofetil (MMF) versus no MMF; systemic MMF versus systemic cyclosporine A (CsA); and topical CsA versus placebo. One study compared topical tacrolimus to topical steroid in people with normal-risk keratoplasty, and two studies compared topical CsA to placebo in people experiencing graft rejection after normal-risk keratoplasty. Overall, we considered the trials to be at unclear or high risk of bias. MMF may not improve clear graft survival (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.84 to 1.33, 1 RCT, 87 participants, low-quality evidence) but may reduce the risk of graft rejection (RR 0.49, 95% CI 0.22 to 1.08, 1 RCT, 87 participants, low-quality evidence) compared to no MMF. Visual acuity was not reported. In 1 study of 52 people comparing systemic MMF and systemic CsA, there were no graft failures in the first year of follow-up. Data from the longest follow-up (three years) suggest that there may be little difference in the effect of these two treatments on clear graft survival (RR 1.10, 95% CI 0.90 to 1.35, low-quality evidence). There was low-quality evidence of an increased risk of graft rejection with systemic MMF compared to systemic CsA, but with wide CIs compatible with increased risk with systemic CsA (RR 1.48, 95% CI 0.56 to 3.93, low-quality evidence). Visual acuity was not reported. One study of 84 people comparing topical CsA to placebo did not report clear graft survival at 1 year, which suggests that all grafts survived to 1 year. This study suggests that the use of topical CsA probably leads to little or no difference in graft rejection (RR 1.00, 95% CI 0.39 to 2.58, moderate-quality evidence). At one year, the mean difference (MD) between the two groups in visual acuity was 0.07 (95% CI -0.01 to 0.15, moderate-quality evidence). Topical CsA probably does not have an effect on clear graft survival in people experiencing graft rejection after normal-risk keratoplasty compared to placebo (RR 1.03, 95% CI 0.96 to 1.10, 2 RCTs, 283 participants, moderate-quality evidence). There were inconsistent findings on graft rejection, with one study reporting a reduced incidence of graft rejection in the CsA group (RR 0.35, 95% CI 0.14 to 0.87, 230 participants) but the other study reporting a higher average number of episodes of graft rejection in people treated with CsA (MD 1.30, 95% CI 0.39 to 2.21, 43 participants). Overall, we judged this to be low-quality evidence due to risk of bias and inconsistency. There was no evidence for a difference in visual acuity between the 2 groups at final follow-up (approximately 18 months, range 2 to 33 months) (MD 0.04, 95% CI -0.10 to 0.18, 1 RCT, 43 participants, low-quality evidence). In 1 study comparing topical tacrolimus to topical steroid, the graft survived in all of the 12 treated participants and 20 control participants at 6 months. Graft rejection was rare (0 out of 12 versus 2 out of 20) (RR 0.32, 95% CI 0.02 to 6.21, low-quality evidence). Visual acuity was not reported. None of the studies reported on quality of life. We identified an unpublished trial of basiliximab (Simulect) (NCT00409656), probably completed in 2005. Current evidence on the effect of immunosuppressants in the prevention of graft failure and rejection after high- and normal-risk keratoplasty is largely low quality because the number of trials was limited, and, in general, the trials were small and at risk of bias. Future trials should be large enough to detect important clinical effects, conducted with a view to minimising the risk of bias, and they should measure outcomes important to patients.
Ten randomised trials randomising 1709 patients were included. Tamoxifen versus placebo/no intervention had no significant effect on overall survival (hazard ratio 1.05; 95% CI 0.94 to 1.16; P = 0.4). This comparison showed no statistical heterogeneity (P = 0.2 and I2 = 25.9%). Subgroup analysis showed that tamoxifen tended to increase mortality in trials with three adequate/three methodological components (hazard ratio 1.15; 95% CI 0.99 to 1.34; P = 0.06), showed no significant effect in trials with two adequate/three methodological components (hazard ratio 1.00; 95% CI 0.84 to 1.18; P = 0.98), and tended to reduce mortality in trials with one or less adequate/three methodological components (hazard ratio 0.82; 95% CI 0.60 to 1.12; P = 0.2), although this may have been confounded by the use of higher doses of tamoxifen in the better quality trials. Tamoxifen was associated with adverse effects. One trial measured patient quality of life, but the results were not reported in detail. These data do not support the use of tamoxifen for patients with hepatocellular carcinoma. Further research on the effects of tamoxifen in hepatocellular carcinoma does not seem warranted.
We included 69 studies involving more than 15,000 health professionals. Twenty-eight studies (34 comparisons) contributed to the calculation of the median and interquartile range for the main comparison. The median adjusted risk difference (RD) in compliance with desired practice was 5.6% (interquartile range 3.0% to 9.0%). The adjusted RDs were highly consistent for prescribing (median 4.8%, interquartile range 3.0% to 6.5% for 17 comparisons), but varied for other types of professional performance (median 6.0%, interquartile range 3.6% to 16.0% for 17 comparisons). Meta-regression was limited by the large number of potential explanatory factors (eight) with only 31 comparisons, and did not provide any compelling explanations for the observed variation in adjusted RDs. There were 18 comparisons with continuous outcomes, with a median adjusted relative improvement of 21% (interquartile range 11% to 41%). There were eight trials (12 comparisons) in which the intervention included an EOV and was compared to another type of intervention, usually audit and feedback. Interventions that included EOVs appeared to be slightly superior to audit and feedback. Only six studies evaluated different types of visits in head-to-head comparisons. When individual visits were compared to group visits (three trials), the results were mixed. EOVs alone or when combined with other interventions have effects on prescribing that are relatively consistent and small, but potentially important. Their effects on other types of professional performance vary from small to modest improvements, and it is not possible from this review to explain that variation.
We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data. Overall survival (OS) and progression-free survival (PFS) was longer with adjuvant chemotherapy compared with adjuvant radiotherapy (OS: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.57 to 0.99, I² = 22%; and PFS: HR 0.74, 95% CI 0.59 to 0.92, I² = 0%). Sensitivity analysis using adjusted and unadjusted OS data, gave similar results. In subgroup analyses, the effects on survival in favour of chemotherapy were not different for stage III and IV, or stage IIIA and IIIC (tests for subgroup differences were not significant and I² = 0%). This evidence was of moderate quality. Data from one trial showed that women receiving adjuvant chemotherapy were more likely to experience haematological and neurological adverse events and alopecia, and more likely to discontinue treatment (33/194 versus 6/202; RR 5.73, 95% CI 2.45 to 13.36), than those receiving adjuvant radiotherapy. There was no statistically significant difference in treatment-related deaths between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00). There was no clear difference in PFS between intervention groups in the one trial that compared CDP versus CD (552 women; HR 0.90, 95% CI 0.69 to 1.17). We considered this evidence to be of moderate quality. Mature OS data from this trial were not yet available. Severe haematological and neurological adverse events occurred more frequently with CDP than CD. We found no trials to include of adjuvant chemotherapy versus chemoradiation in advanced endometrial cancer; however we identified one ongoing trial of this comparison. There is moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer. There is limited evidence that it is associated with more adverse effects. There is some uncertainty as to whether triplet regimens offer similar survival benefits over doublet regimens in the long-term. Further research is needed to determine which chemotherapy regimen(s) are the most effective and least toxic, and whether the addition of radiotherapy further improves outcomes. A large trial evaluating the benefits and risks of adjuvant chemoradiation versus chemotherapy in advanced endometrial cancer is ongoing.
We included two trials comparing planned caesarean section versus planned vaginal birth for twin pregnancies. Most of the data included in the review were from a multicentre trial where 2804 women were randomised in 106 centres in 25 countries. All centres had facilities to perform emergency caesarean section and had anaesthetic, obstetrical, and nursing staff available in the hospital at the time of planned vaginal delivery. In the second trial carried out in Israel, 60 women were randomised. We judged the risk of bias to be low for all categories except performance (high) and outcome assessment bias (unclear). There was no clear evidence of differences between women randomised to planned caesarean section or planned vaginal birth for maternal death or serious morbidity (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.67 to 1.11; 2844 women; two studies; moderate quality evidence). There was no significant difference between groups for perinatal or neonatal death or serious neonatal morbidity (RR 1.15, 95% CI 0.80 to 1.67; data for 5565 babies, one study, moderate quality evidence). No studies reported childhood disability. For secondary outcomes there was no clear evidence of differences between groups for perinatal or neonatal mortality (RR 1.41, 95% CI 0.76 to 2.62; 5685 babies; two studies, moderate quality evidence), serious neonatal morbidity (RR 1.03, 95% CI 0.65 to 1.64; 5644 babies; two studies, moderate quality evidence) or any of the other neonatal outcomes reported. The number of women undergoing caesarean section was reported in both trials. Most women in the planned caesarean group had treatment as planned (90.9% underwent caesarean section), whereas in the planned vaginal birth group 42.9% had caesarean section for at least one twin. For maternal mortality; no events were reported in one trial and two deaths (one in each group) in the other. There were no significant differences between groups for serious maternal morbidity overall (RR 0.86, 95% CI 0.67 to 1.11; 2844 women; two studies) or for different types of short-term morbidity. There were no significant differences between groups for failure to breastfeed (RR 1.14, 95% CI 0.95 to 1.38; 2570 women, one study; moderate quality evidence) or the number of women with scores greater than 12 on the Edinbugh postnatal depression scale (RR 0.95, 95% CI 0.78 to 1.14; 2570 women, one study; moderate quality evidence). Data mainly from one large, multicentre study found no clear evidence of benefit from planned caesarean section for term twin pregnancies with leading cephalic presentation. Data on long-term infant outcomes are awaited. Women should be informed of possible risks and benefits of labour and vaginal birth pertinent to their specific clinical presentation and the current and long-term effects of caesarean section for both mother and babies. There is insufficient evidence to support the routine use of planned caesarean section for term twin pregnancy with leading cephalic presentation, except in the context of further randomised trials.
Eight trials involving 3366 women and their 3175 children were included in the review. In these trials, women were supplemented with n-3 LCPUFA during pregnancy (five trials), lactation (two trials) or both pregnancy and lactation (one trial). All trials randomly allocated women to either a n-3 LCPUFA supplement or a control group. The risk of bias varied across the eight included trials in this review with only two trials with a low risk of selection, performance and attrition bias. N-3 LCPUFA supplementation showed a clear reduction in the primary outcome of any allergy (medically diagnosed IgE mediated) in children aged 12 to 36 months (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.98; two RCTs; 823 children), but not beyond 36 months (RR 0.86, 95% CI 0.61 to 1.20; one RCT, 706 children). For any allergy (medically diagnosed IgE mediated and/or parental report), no clear differences were seen in children either at 12 to 36 months (RR 0.89, 95% CI 0.71 to 1.11; two RCTs, 823 children) or beyond 36 months of age (RR 0.96, 95% CI 0.84 to 1.09; three RCTs, 1765 children). For the secondary outcomes of specific allergies there were no clear differences for food allergies at 12 to 36 months and beyond 36 months, but a clear reduction was seen for children in their first 12 months with n-3 LCPUFA (both for medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report). There was a clear reduction in medically diagnosed IgE-mediated eczema with n-3 LCPUFA for children 12 to 36 months of age, but not at any other time point for both medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report. No clear differences for allergic rhinitis or asthma/wheeze were seen at any time point for both medically diagnosed IgE mediated, and medically diagnosed IgE mediated and/or parental report. There was a clear reduction in children's sensitisation to egg and sensitisation to any allergen between 12 to 36 months of age when mothers were supplemented with n-3 LCPUFA. In terms of safety for the mother and child, n-3 LCPUFA supplementation during pregnancy did not show increased risk of postpartum haemorrhage or early childhood infections. Overall, there is limited evidence to support maternal n-3 LCPUFA supplementation during pregnancy and/or lactation for reducing allergic disease in children. Few differences in childhood allergic disease were seen between women who were supplemented with n-3 LCPUFA and those who were not.
We included 14 trials in this review. Individual participant data were available for 2572 participants out of 3787 eligible individuals from nine out of 14 trials: 68% of the potential data. For remission outcomes, a HR of less than one indicated an advantage for carbamazepine; and for first seizure and treatment failure outcomes, a HR of less than one indicated an advantage for lamotrigine. The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type: 0.71, 95% CI 0.62 to 0.82, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type: 0.55 (95% CI 0.45 to 0.66, moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants: 1.03 (95% CI 0.75 to 1.41), moderate-quality evidence) showing a significant advantage for lamotrigine compared to carbamazepine in terms of treatment failure for any reason related to treatment and treatment failure due to adverse events, but no different between drugs for treatment failure due to lack of efficacy. Time to first seizure (pooled HR adjusted for seizure type: 1.26, 95% CI 1.12 to 1.41, high-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type: 0.86, 95% CI 0.76 to 0.97, high-quality evidence), showed a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (pooled HR for all participants 0.91, 95% CI 0.77 to 1.07, high-quality evidence) or time to 24-month remission (HR for all participants 1.00, 95% CI 0.80 to 1.25, high-quality evidence), however only two trials followed up participants for more than one year so evidence is limited. The results of this review are applicable mainly to individuals with focal onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures. The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs. The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the treatment failure and withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment failure to be moderate for individuals with focal onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with focal onset seizures and moderate for individuals with generalised onset seizures. Moderate quality evidence indicates that treatment failure for any reason related to treatment or due to adverse events occurs significantly earlier on carbamazepine than lamotrigine, but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. The choice between these first-line treatments must be made with careful consideration. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.
Only one study was included. This time series study assessed the migration of Philippine nurses to the United States of America (USA) from 1954 to 1990. We re-analysed it as an interrupted time series study. The intervention was a modification of migratory law in the US, called the 'Act of October 1965', which decreased the restrictions on Eastern hemisphere immigrants to the USA. The analysis showed a significant immediate increase of 807.6 (95% confidence interval (CI) 480.9 to 1134.3) in the number of nurses migrating to the USA annually after the intervention. This represents a relative increase of 5000% over the underlying pre-intervention trend. There were no significant differences in the slopes of the underlying trends for the number of nurses migrating between the pre- and postintervention periods. There is an important gap in knowledge about the effectiveness of policy interventions in either HICs or LMICs that could regulate positively the movement of health professionals from LMICs. The only evidence found was from an intervention in a HIC that increased the movement of health professionals from a LMIC. New initiatives to improve records on the migration of health professionals from LMICs should be implemented, as a prerequisite to conducting more rigorous research in the field. This research should focus on whether the range of interventions outlined in the literature could be effective in retaining health professionals in LMICs. Such interventions include financial rewards, career development and continuing education, improving hospital infrastructure, resource availability, better hospital management and improved recognition of health professionals.
Five randomised clinical trials, including 330 patients, met the inclusion criteria. The majority of trials had adequate allocation concealment, but only one employed blinded outcome assessment. Mortality at 30-days (OR 1.00, 95% CI 0.10 to 10.06, P = 1.0) and 24-months (OR 1.29, 95% CI 0.65 to 2.56, P = 0.5) did not differ significantly between TIPS and paracentesis. Transjugular intrahepatic portosystemic stent-shunts significantly reduced the re-accumulation of ascites at 3-months (OR 0.07, 95% CI 0.03 to 0.18, P < 0.01) and 12-months (OR 0.14, 95% CI 0.06 to 0.28, P < 0.01). Hepatic encephalopathy occurred significantly more often in the TIPS group (OR 2.24, 95% CI 1.39 to 3.6, P < 0.01), but gastrointestinal bleeding, infection, and acute renal failure did not differ significantly between the two groups. The meta-analysis supports that TIPS was more effective at removing ascites as compared with paracentesis without a significant difference in mortality, gastrointestinal bleeding, infection, and acute renal failure. However, TIPS patients develop hepatic encephalopathy significantly more often.
From 29 identified references, 4 RCTs met inclusion criteria (169 patients). Mean change in forced expiratory volume in one second (FEV1) at 2 hours was similar in methylxanthine and placebo groups but transiently increased with methylxanthines at 3 days (WMD: 101 ml; 95% CI: 26 to 177). Data on clinical outcomes were sparse. Trends toward improvements in hospitalisation and length-of-stay were offset by a trend toward more relapses at one week. Changes in symptom scores were not significant. Methylxanthines caused more nausea and vomiting than placebo (OR: 4.6; 95% CI: 1.7 to 12.6) and trended toward more frequent tremor, palpitations, and arrhythmias. Given current evidence, methylxanthines should not be used for COPD exacerbations. Possible beneficial effects in lung function and clinical endpoints were modest and inconsistent, whereas adverse effects were significantly increased. More selective agents, tested in larger randomised trials, are necessary if methylxanthines are to have any role in the treatment of COPD exacerbations.
Two randomised controlled trials (142 infants) met the inclusion criteria of this review. We found no differences in the rates of mortality when the needle was removed immediately after aspiration (risk ratio (RR) 3.92, 95% confidence interval (CI) 0.88 to 17.58; participants = 70; studies = 1) or left in situ (RR 1.50, 95% CI 0.27 to 8.45; participants = 72; studies = 1) or complications related to the procedure. With immediate removal of the needle following aspiration, 30% of the newborns did not require the placement of an intercostal tube drainage. None of the 36 newborns treated with needle aspiration with the angiocatheter left in situ required the placement of an intercostal tube drainage. Overall, the quality of the evidence supporting this finding is very low. There is insufficient evidence to establish the efficacy and safety of needle aspiration and intercostal tube drainage in the management of neonatal pneumothorax. The two included trials showed no differences in mortality; however the information size is low. Needle aspiration reduces the need for intercostal tube drainage placement. Limited or no evidence is available on other clinically relevant outcomes.
We included nine trials enrolling 1733 patients; all trials were judged to be at risk of bias. Seven were randomised controlled trials; two were cluster-randomised controlled designs. Eight examined email as compared to standard methods of communication. One compared email with telephone for the delivery of counselling. When email was compared to standard methods, for the majority of patient/caregiver outcomes it was not possible to adequately assess whether email had any effect. For health service use outcomes it was not possible to adequately assess whether email has any effect on resource use, but some results indicated that an email intervention leads to an increased number of emails and telephone calls being received by healthcare professionals. Three studies reported some type of adverse event but it was not clear if the adverse event had any impact on the health of the patient or the quality of health care. When email counselling was compared to telephone counselling only patient outcomes were measured, and for the majority of measures there was no difference between groups. Where there were differences these showed that telephone counselling leads to greater change in lifestyle modification factors than email counselling. There was one outcome relating to harm, which showed no difference between the email and the telephone counselling groups. There were no primary outcomes relating to healthcare professionals for either comparison. The evidence base was found to be limited with variable results and missing data, and therefore it was not possible to adequately assess the effect of email for clinical communication between patients/caregivers and healthcare professionals. Recommendations for clinical practice could not be made. Future research should ideally address the issue of missing data and methodological concerns by adhering to published reporting standards. The rapidly changing nature of technology should be taken into account when designing and conducting future studies and barriers to trial development and implementation should also be tackled. Potential outcomes of interest for future research include cost-effectiveness and health service resource use.
We included five small trials that randomised a total of 234 participants. Two studies were assessed as low risk of bias; none of the included studies were adequately powered. Two studies used an attention control and three studies compared to an alternative intervention, which in all cases was one intervention versus usual care intervention. The searches we carried out did not find any trials comparing an intervention with no intervention. The searches did not find any trials of an intervention that compared variations in timing, dose, or intensity of treatment using the same intervention. Four studies included only people with stroke; one included mostly people with stroke, but also those with brain injury. Three studies delivered interventions in the first few months after stroke; two recruited people with chronic dysarthria. Three studies evaluated behavioural interventions, one investigated acupuncture and another transcranial magnetic stimulation. One study included people with dysarthria within a broader trial of people with impaired communication. Our primary analysis of a persisting (three to nine months post-intervention) effect at the activity level of measurement found no evidence in favour of dysarthria intervention compared with any control (SMD 0.18, 95% CI -0.18 to 0.55; 3 trials, 116 participants, GRADE: low quality, I² = 0%). Findings from sensitivity analysis of studies at low risk of bias were similar, with a slightly wider confidence interval and low heterogeneity (SMD 0.21, 95% CI -0.30 to 0.73, I² = 32%; 2 trials, 92 participants, GRADE: low quality). Subgroup analysis results for stroke were similar to the primary analysis because few non-stroke participants had been recruited to trials (SMD 0.16, 95% CI -0.23 to 0.54, I² = 0%; 3 trials, 106 participants, GRADE: low quality). Similar results emerged from most of the secondary analyses. There was no evidence of a persisting effect at the impairment (SMD 0.07, 95% CI -0.91 to 1.06, I² = 70%; 2 trials, 56 participants, GRADE: very low quality) or participation level (SMD -0.11, 95% CI -0.56 to 0.33, I² = 0%; 2 trials, 79 participants, GRADE: low quality) but substantial heterogeneity on the former. Analyses of immediate post-intervention outcomes provided no evidence of any short-term benefit on activity (SMD 0.29, 95% CI -0.07 to 0.66, I² = 0%; 3 trials, 117 participants, GRADE: very low quality); or participation (SMD -0.24, 95% CI -0.94 to 0.45; 1 study, 32 participants) levels of measurement. There was a statistically significant effect favouring intervention at the immediate, impairment level of measurement (SMD 0.47, 95% CI 0.02 to 0.92, P = 0.04, I² = 0%; 4 trials, 99 participants, GRADE: very low quality) but only one of these four trials had a low risk of bias. We found no definitive, adequately powered RCTs of interventions for people with dysarthria. We found limited evidence to suggest there may be an immediate beneficial effect on impairment level measures; more, higher quality research is needed to confirm this finding. Although we evaluated five studies, the benefits and risks of interventions remain unknown and the emerging evidence justifies the need for adequately powered clinical trials into this condition. People with dysarthria after stroke or brain injury should continue to receive rehabilitation according to clinical guidelines.
Nineteen randomised controlled trials with a total of 3382 participants were included. Three meta-analyses were possible. The overall quality of studies was low. Topical antimicrobials containing steroids were significantly more effective than placebo drops: OR 11 (95% CI 2.00 to 60.57; one trial). In general, no clinically meaningful differences were noted in clinical cure rates between the various topical interventions reviewed. One notable exception involved a trial of high quality which showed that acetic acid was significantly less effective when compared with antibiotic/steroid drops in terms of cure rate at two and three weeks (OR 0.29 (95% CI 0.13 to 0.62) and OR 0.25 (95% CI 0.11 to 0.58) respectively). One trial of low quality comparing quinolone with non-quinolone antibiotics did not find any difference in clinical cure rate. No trials evaluated the effectiveness of ear cleaning. Only two trials evaluated steroid-only drops. One trial of low quality suggested no significant difference between steroid and antibiotic/steroid but did not report the magnitude or precision of the result. Another trial of moderate quality comparing an oral antihistamine with topical steroid against topical steroid alone found that cure rates in both groups were high and comparable (100% (15/15) and 94% (14/15) respectively at three weeks). There is a paucity of high quality trials evaluating interventions for acute otitis externa. The results of this systematic review are largely based on odds ratios calculated from single trials, most of which have very broad 95% confidence intervals because of small to modest sample sizes. The findings may not be wholly generalisable to primary care for a variety of reasons; only two of the 19 trials included in the review were conducted in a primary care population setting, and in 11 of the 19 trials ear cleaning formed part of the treatment (an intervention unlikely to be available in primary care). Despite these reservations, some meaningful conclusions can be drawn from the evidence available: Topical treatments alone, as distinct from systemic ones, are effective for uncomplicated acute otitis externa. In most cases the choice of topical intervention does not appear to influence the therapeutic outcome significantly. Any observed differences in efficacy were usually minor and not consistently present at each follow-up visit. Acetic acid was effective and comparable to antibiotic/steroid at week 1. However, when treatment needed to be extended beyond this point it was less effective. In addition, patient symptoms lasted two days longer in the acetic acid group compared to antibiotic/steroid. The evidence for steroid-only drops is very limited and as yet not robust enough to allow us to reach a conclusion or provide recommendations. Further investigation is needed. Given that most topical treatments are equally effective, it would appear that in most cases the preferred choice of topical treatment may be determined by other factors, such as risk of ototoxicity, risk of contact sensitivity, risk of developing resistance, availability, cost and dosing schedule. Factors such as speed of healing and pain relief are yet to be determined for many topical treatments and may also influence this decision. Patients prescribed antibiotic/steroid drops can expect their symptoms to last for approximately six days after treatment has begun. Although patients are usually treated with topical medication for seven to 10 days it is apparent that this will undertreat some patients and overtreat others. It may be more useful when prescribing ear drops to instruct patients to use them for at least a week. If they have symptoms beyond the first week they should continue the drops until their symptoms resolve (and possibly for a few days after), for a maximum of a further seven days. Patients with persisting symptoms beyond two weeks should be considered treatment failures and alternative management initiated.
A total of seven studies (606 participants) met the inclusion criteria and measured the primary outcome of interest. All studies were at unclear to high risk of bias. Given the high degree of clinical and statistical heterogeneity of the included studies, no meta-analysis was completed. The results from individual studies that compared heparin at a dose of 1 to 2 IU/mL under continuous pressure were imprecise and do not provide definitive evidence of a difference. The observed difference with a dose of heparin increased to 4 IU/mL came from only one study of 30 participants, and the quality of the reported data was poor. Similarly. consistency in assessment and reporting of adverse events such as haematoma, insertion site infection and limb ischaemia was poor. Further research with well-defined primary and secondary outcome measures using a stratified sampling process that accommodates for the different heparin doses commonly used in clinical practice is needed to confirm the trends seen in research results now reported in the literature. The available evidence is of poor quality because of risk of bias and does not provide sufficient information to support the effects of adding heparin (1 to 2 IU/mL) to a maintenance solution (pressurized to deliver 3 mL of flush solution per hour) of 0.9% normal saline in maintaining the patency and functionality of arterial catheters.
We included nine RCTs (20,101 employees) and nine cohort studies (1280 employees) on the prevention of back pain in this updated review. Studies compared training to no intervention (4), professional education (2), a video (3), use of a back belt (3) or exercise (2). Other studies compared training plus lifting aids to no intervention (3) and to training only (1). The intensity of training ranged from a single educational session to very extensive personal biofeedback. Six RCTs had a high risk of bias. None of the included studies showed evidence of a preventive effect of training on back pain. There was moderate quality evidence from seven RCTs (19,317 employees) that those who received training reported levels of back pain similar to those who received no intervention, with an odds ratio of 1.17 (95% confidence intervals (CI) 0.68 to 2.02) or minor advice (video), with a relative risk of 0.93 (95% CI 0.69 to 1.25). Confidence intervals around the effect estimates were still wide due to the adjustment for the design effect of clustered studies. The results of the cohort studies were similar to those of the randomised studies. There is moderate quality evidence that MMH advice and training with or without assistive devices does not prevent back pain or back pain-related disability when compared to no intervention or alternative interventions. There is no evidence available from RCTs for the effectiveness of MMH advice and training or MMH assistive devices for treating back pain. More high quality studies could further reduce the remaining uncertainty.
Five randomised studies involving 1466 women met the inclusion criteria. All studies were classified as having an unclear risk of bias. Two studies (involving 1097 women) compared oral methylergometrine with a placebo, and one (involving 171 women) compared oral methylergometrine with Kyuki-chouketsu-in, a Japanese traditional herbal medicine. The remaining two studies (involving 198 women) did not report the outcomes of interest for this review. None of the included studies reported primary outcomes prespecified in the review protocol (blood loss of 1000 mL or more over the period of observation, maternal death or severe morbidity). Overall, there was no clear evidence of differences between groups in the following PPH outcomes: blood loss of 500 mL or more (risk ratio (RR) 1.45; 95% confidence interval (CI) 0.39 to 5.47, two studies), amount of lochia during the first 72 hours of the puerperium (mean difference (MD) -25.00 g; 95% CI -69.79 to 19.79, one study), or amount of lochia by four weeks postpartum (MD -7.00 g; 95% CI -23.99 to 9.99). The Japanese study with a relatively small sample size comparing oral methylergometrine with a Japanese traditional herbal medicine found that oral methylergometrine significantly increased the blood haemoglobin concentration at day one postpartum (MD 0.50 g/dL; 95% CI 0.11 to 0.89) compared to herbal medicine. Adverse events were not well-reported in the included studies. We did not find any studies comparing homeopathic remedies with either a placebo or no treatment. There was insufficient evidence to support the use of prophylactic oral methylergometrine given after delivery of the placenta for the prevention of PPH. Additionally, the effectiveness of prophylactic use of herbal medicine or homeopathic remedies for PPH is still unclear as we could not find any clear evidence. Trials to assess the effectiveness of herbal medicines and homeopathic remedies in preventing PPH are warranted.
We found no studies that compared multiple-micronutrient supplementation (with three or more micronutrients) versus supplementation with two or fewer micronutrients. Two small studies (involving a total of 52 women) were included. One study compared multiple micronutrients with placebo and the other study compared multiple micronutrients with a group who received no supplementation. The studies were carried out in Brazil (36 adolescent mothers) and the USA (16 women) and included women with a low socioeconomic status. A lack of information in the study reports meant that risk of bias could not be adequately assessed (unclear risk of bias for many domains). There were no quantitative data for any of this review's outcomes so meta-analysis was not possible. Neither of the studies reported on the primary outcomes of interest in this review: maternal morbidity (febrile illness, respiratory tract infection, diarrhoea), adverse effects of micronutrients within three days of receiving the supplement, infant mortality (defined as a child dying before completing the first year of age). One study reported qualitatively on maternal anaemia (a secondary outcome of this review) - the study found that multiple-micronutrient supplementation was effective for recuperating from anaemia but there were no data for inclusion in our analyses. Maternal satisfaction was not reported in the included studies. Similarly, none of this review's infant secondary outcomes were reported in the included studies: clinical micronutrient deficiency; morbidity episodes (febrile illness, respiratory tract infection, diarrhoea, other), adverse effects of micronutrients within three days of receiving the supplement. We found no evidence to quantitatively assess the effectiveness of multiple-micronutrient supplementation in improving health outcomes in mother and baby. The results of this review are limited by the small numbers of studies available, small sample sizes and the studies not reporting on the outcomes of interest in this review. There is no evidence to evaluate potential adverse effects of multiple-micronutrient supplements, particularly excess dosages. There is a need for high-quality studies to assess the effectiveness and safety of multiple-micronutrient supplementation for breastfeeding women for improving outcomes for the mother and her baby. Further research should focus on whether multiple-micronutrient supplementation during lactation compared with none, a placebo or supplementation with fewer than two micronutrients is beneficial to maternal and infant health outcomes. Future studies should collect data on outcomes beyond micronutrient concentrations, for example: maternal and infant morbidity, adverse effects, maternal satisfaction, the risks of excess supplementation, and potential adverse interactions between the micronutrients and the other outcomes. This would help to bridge the gap between research on intermediary outcomes and health outcomes in order to develop sound policy in this field. Future studies could more precisely assess a variety of multiple-micronutrient combinations and different dosages and look at how these affect maternal and infant health outcomes. Larger studies with longer follow-up would improve the quality of studies and provide stronger evidence. In most of the included studies, bias could not be adequately assessed due to lack of information, therefore attention should be given to adequate methods of randomisation and allocation concealment, adequate methods of blinding of the participants, providers and the outcome assessors to improve the methodological quality of studies in this field.
We identified 12 additional trials and included 22 trials with 8275 participants in this update. Oral oxycodone was studied in 10 trials, transdermal buprenorphine and oral tapentadol in four, oral codeine in three, oral morphine and oral oxymorphone in two, and transdermal fentanyl and oral hydromorphone in one trial each. All trials were described as double-blind, but the risk of bias for other domains was unclear in several trials due to incomplete reporting. Opioids were more beneficial in pain reduction than control interventions (SMD -0.28, 95% CI -0.35 to -0.20), which corresponds to a difference in pain scores of 0.7 cm on a 10-cm visual analogue scale (VAS) between opioids and placebo. This corresponds to a difference in improvement of 12% (95% CI 9% to 15%) between opioids (41% mean improvement from baseline) and placebo (29% mean improvement from baseline), which translates into a number needed to treat (NNTB) to cause one additional treatment response on pain of 10 (95% CI 8 to 14). Improvement of function was larger in opioid-treated participants compared with control groups (SMD -0.26, 95% CI -0.35 to -0.17), which corresponds to a difference in function scores of 0.6 units between opioids and placebo on a standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10. This corresponds to a difference in improvement of 11% (95% CI 7% to 14%) between opioids (32% mean improvement from baseline) and placebo (21% mean improvement from baseline), which translates into an NNTB to cause one additional treatment response on function of 11 (95% CI 7 to 14). We did not find substantial differences in effects according to type of opioid, analgesic potency, route of administration, daily dose, methodological quality of trials, and type of funding. Trials with treatment durations of four weeks or less showed larger pain relief than trials with longer treatment duration (P value for interaction = 0.001) and there was evidence for funnel plot asymmetry (P value = 0.054 for pain and P value = 0.011 for function). Adverse events were more frequent in participants receiving opioids compared with control. The pooled risk ratio was 1.49 (95% CI 1.35 to 1.63) for any adverse event (9 trials; 22% of participants in opioid and 15% of participants in control treatment experienced side effects), 3.76 (95% CI 2.93 to 4.82) for drop-outs due to adverse events (19 trials; 6.4% of participants in opioid and 1.7% of participants in control treatment dropped out due to adverse events), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials; 1.3% of participants in opioid and 0.4% of participants in control treatment experienced serious adverse events). Withdrawal symptoms occurred more often in opioid compared with control treatment (odds ratio (OR) 2.76, 95% CI 2.02 to 3.77; 3 trials; 2.4% of participants in opioid and 0.9% of participants control treatment experienced withdrawal symptoms). The small mean benefit of non-tramadol opioids are contrasted by significant increases in the risk of adverse events. For the pain outcome in particular, observed effects were of questionable clinical relevance since the 95% CI did not include the minimal clinically important difference of 0.37 SMDs, which corresponds to 0.9 cm on a 10-cm VAS.
Combining the results of six randomised clinical trials with high risk of bias which included 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.90, 95% CI 0.58 to 1.40), or complications of the liver disease. Although propylthiouracil was not associated with a significant increased risk of non-serious adverse events, there were occasional instances of serious adverse events such as leukopenia and generalised bullous eruption. We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, or liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Thus, the risk of random errors and systematic errors was high. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.
We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low. Primary outcomes In the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention. In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants). Secondary outcomes In the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants). With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here. Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.
Two RCTs (n = 40) were included in this review. The included trials compared rTMS with sham rTMS; no trials comparing rTMS with active treatments (electroconvulsive therapy (ECT), pharmacotherapy, psychotherapy) met our inclusion criteria. Both included studies used 1 Hz rTMS over the right dorso-lateral prefrontal cortex (DLPFC) for two or four weeks as an augmentation treatment for PD. However, in both studies the data for the primary outcome, panic symptoms as measured by the Panic Disorder Severity Scale (PDSS), were skewed and could not be pooled for a quantitative analysis. For this primary outcome one trial with 25 participants reported a superior effect of rTMS in reducing panic symptoms compared with sham rTMS (t = 3.04, df = 16.57, P = 0.007), but this trial had a 16% dropout rate and so was deemed as having a high risk of attrition bias. The other trial found that all 15 participants exhibited a reduction in panic symptoms but there was no significant difference between rTMS and sham rTMS (Mann Whitney U test, P > 0.05). Regarding the acceptability of rTMS, no significant difference was found between rTMS and sham rTMS in dropout rates or in reports of side effects. The quality of evidence contributing to this review was assessed as very low. Assessments of the risk of bias for the two studies were hampered by the lack of information provided in the reports, especially on methods of sequence generation and whether allocation concealment had been applied. Of the remaining sources of bias, we considered one of the studies to have been at risk of attrition bias. Only two RCTs of rTMS were available and their sample sizes were small. The available data were insufficient for us to draw any conclusions about the efficacy of rTMS for PD. Further trials with large sample sizes and adequate methodology are needed to confirm the effectiveness of rTMS for PD.
We identified 21 trials (19 trials of high risk of bias) involving 2348 people. There was no significant difference in the perioperative mortality (RR 0.80; 95% CI 0.56 to 1.16; n = 2210) or the number of people with drug-related adverse effects between the two groups (RR 2.09; 95% CI 0.83 to 5.24; n = 1199). Quality of life was not reported in any of the trials. The overall number of participants with postoperative complications was significantly lower in the somatostatin analogue group (RR 0.70; 95% CI 0.61 to 0.80; n = 1903) but there was no significant difference in the re-operation rate (RR 1.26; 95% CI 0.58 to 2.70; n = 687) or hospital stay (MD -1.29 days; 95% CI -2.60 to 0.03; n = 1314) between the groups. The incidence of pancreatic fistula was lower in the somatostatin analogue group (RR 0.66; 95% CI 0.55 to 0.79; n = 2206). The proportion of these fistulas that were clinically significant was not mentioned in most trials. On inclusion of trials that clearly distinguished clinically significant fistulas, there was no significant difference between the two groups (RR 0.69; 95% CI 0.38 to 1.28; n = 292). Somatostatin analogues may reduce perioperative complications but do not reduce perioperative mortality. Further adequately powered trials with low risk of bias are necessary. Based on the current available evidence, somatostatin and its analogues are recommended for routine use in people undergoing pancreatic resection.
The authors reviewed 1335 abstracts, and from these identified 21 potentially eligible abstracts. Upon detailed review, 12 studies fulfilled the entry criteria. Of these, eight were new studies that had been published since the previous version of this review. Two studies which were included in the previous version of this review were excluded because of potential for bias. The comparability of the included studies is extremely low because of differences in the specific diseases studied, differences in the therapeutic agents used, dosage, study design, and outcomes. The methodological quality of included studies was generally high, although risk of bias was unclear in random sequence generation and allocation concealment for most studies. Otherwise, the risk of bias was low for most studies in the other categories. Serious adverse events were uncommon, except for peripheral nerve toxicity in a long-term trial of dichloroacetate (DCA) in adults. One trial studied high-dose coenzyme Q10 without clinically meaningful improvement (although there were multiple biochemical, physiologic, and neuroimaging outcomes, in 30 participants). Three trials used creatine monohydrate alone, with one reporting evidence of improved measures of muscle strength and post-exercise lactate, but the other two reported no benefit (total of 38 participants). One trial studied the effects of a combination of coenzyme Q10, creatine monohydrate, and lipoic acid and reported a statistically significant improvement in biochemical markers and peak ankle dorsiflexion strength, but overall no clinical improvement in 16 participants. Five trials studied the effects of DCA: three trials in children showed a statistically significant improvement in secondary outcome measures of mitochondrial metabolism (venous lactate in three trials, and magnetic resonance spectroscopy (MRS) in one trial; total of 63 participants). One trial of short-term DCA in adults demonstrated no clinically relevant improvement (improved venous lactate but no change in physiologic, imaging, or questionnaire findings, in eight participants). One longer-term DCA trial in adults was terminated prematurely due to peripheral nerve toxicity without clinical benefit (assessments included the GATE score, venous lactate and MRS, in 30 participants). One trial using dimethylglycine showed no significant effect (measurements of venous lactate and oxygen consumption (VO2) in five participants). One trial using a whey-based supplement showed statistically significant improvement in markers of free radical reducing capacity but no clinical benefit (assessments included the Short Form 36 Health Survey (SF-36) questionnaire and UK Medical Research Council (MRC) muscle strength, in 13 participants). Despite identifying eight new trials there is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches. We suggest further research should identify novel agents to be tested in homogeneous study populations with clinically relevant primary endpoints.
We included two trials with 156 participants for this review. The comparisons included in these two trials were percutaneous cholecystostomy followed by early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy (1 trial; 70 participants) and percutaneous cholecystostomy versus conservative treatment (1 trial; 86 participants). Both trials had high risk of bias. Percutaneous cholecystostomy with early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy: There was no significant difference in mortality between the two intervention groups (0/37 versus 1/33; Fisher's exact test: P value = 0.47). There was no significant difference in overall morbidity between the two intervention groups (1/31 versus 2/30; Fisher's exact test: P value = 0.61). This trial did not report on quality of life. There was no significant difference in the proportion of participants requiring conversion to open cholecystectomy between the two intervention groups (2/31 percutaneous cholecystostomy followed by early laparoscopic cholecystectomy versus 4/30 delayed laparoscopic cholecystectomy; Fisher's exact test: P value = 0.43). The mean total hospital stay was significantly lower in the percutaneous cholecystostomy followed by early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group (1 trial; 61 participants; MD -9.90 days; 95% CI -12.31 to -7.49). The mean total costs were significantly lower in the percutaneous cholecystostomy followed by early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group (1 trial; 61 participants; MD -1123.00 USD; 95% CI -1336.60 to -909.40). Percutaneous cholecystostomy versus conservative treatment: Nine of the 44 participants underwent delayed cholecystectomy in the percutaneous cholecystostomy group. Seven of the 42 participants underwent delayed cholecystectomy in the conservative treatment group. There was no significant difference in mortality between the two intervention groups (6/44 versus 7/42; Fisher's exact test: P value = 0.77). There was no significant difference in overall morbidity between the two intervention groups (6/44 versus 3/42; Fisher's exact test: P value = 0.49). The number of participants who underwent laparoscopic cholecystectomy was not reported in this trial. Therefore, we were unable to calculate the proportion of participants who underwent conversion to open cholecystectomy. The other outcomes, total hospital stay, quality of life, and total costs, were not reported in this trial. Based on the current available evidence from randomised clinical trials, we are unable to determine the role of percutaneous cholecystostomy in the clinical management of high-risk surgical patients with acute cholecystitis. There is a need for adequately powered randomised clinical trials of low risk of bias on this issue.
Thirty-seven trials compared citalopram with other antidepressants (such as tricyclics, heterocyclics, SSRIs and other antidepressants, either conventional ones, such as mirtazapine, venlafaxine and reboxetine, or non-conventional, like hypericum). Citalopram was shown to be significantly less effective than escitalopram in achieving acute response (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.08 to 2.02), but more effective than paroxetine (OR 0.65, 95% CI 0.44 to 0.96) and reboxetine (OR 0.63, 95% CI 0.43 to 0.91). Significantly fewer patients allocated to citalopram withdrew from trials due to adverse events compared with patients allocated to tricyclics (OR 0.54, 95% CI 0.38 to 0.78) and fewer patients allocated to citalopram reported at least one side effect than reboxetine or venlafaxine (OR 0.64, 95% CI 0.42 to 0.97 and OR 0.46, 95% CI 0.24 to 0.88, respectively). Some statistically significant differences between citalopram and other antidepressants for the acute phase treatment of major depression were found in terms of efficacy, tolerability and acceptability. Citalopram was more efficacious than paroxetine and reboxetine and more acceptable than tricyclics, reboxetine and venlafaxine, however, it seemed to be less efficacious than escitalopram. As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings. Economic analyses were not reported in the included studies, however, cost effectiveness information is needed in the field of antidepressant trials.
We included 15 trials, with a total of 755 participants for analysis in the review. Fourteen trials compared prophylactic use of FFP against no FFP. One study compared therapeutic use of two types of plasma. The timing of intervention varied, including FFP transfusion at the time of heparin neutralisation and stopping cardiopulmonary bypass (CPB) (seven trials), with CPB priming (four trials), after anaesthesia induction (one trial) and postoperatively (two trials). Twelve trials excluded patients having emergency surgery and nine excluded patients with coagulopathies. Overall the trials were small, with only four reporting an a priori sample size calculation. No trial was powered to determine changes in mortality as a primary outcome. There was either high risk of bias, or unclear risk, in the majority of trials included in this review. There was no difference in the number of deaths between the intervention arms in the six trials (with 287 patients) reporting mortality (very low quality evidence). There was also no difference in blood loss in the first 24 hours for neonatal/paediatric patients (four trials with 138 patients; low quality evidence): mean difference (MD) -1.46 ml/kg (95% confidence interval (CI) -4.7 to 1.78 ml/kg); or adult patients (one trial with 120 patients): MD -12.00 ml (95% CI -101.16 to 77.16 ml). Transfusion with FFP was inferior to control for preventing patients receiving any red cell transfusion: Peto odds ratio (OR) 2.57 (95% CI 1.30 to 5.08; moderate quality evidence). There was a difference in prothrombin time within two hours of FFP transfusion in eight trials (with 210 patients; moderate quality evidence) favouring the FFP arm: MD -0.71 seconds (95% CI -1.28 to -0.13 seconds). There was no difference in the risk of returning to theatre for reoperation (eight trials with 398 patients; moderate quality evidence): Peto OR 0.81 (95% CI 0.26 to 2.57). Only one included study reported adverse events as an outcome and reported no significant adverse events following FFP transfusion. This review has found no evidence to support the prophylactic administration of FFP to patients without coagulopathy undergoing elective cardiac surgery. There was insufficient evidence about treatment of patients with coagulopathies or those who are undergoing emergency surgery. There were no reported adverse events attributable to FFP transfusion, although there was a significant increase in the number of patients requiring red cell transfusion who were randomised to FFP. Variability in outcome reporting between trials precluded meta-analysis for many outcomes across all trials, and there was evidence of a high risk of bias in most of the studies. Further adequately powered studies of FFP, or comparable pro-haemostatic agents, are required to assess whether larger reductions in prothrombin time translate into clinical benefits. Overall the evidence from randomised controlled trials for the safety and efficacy of prophylactic transfusion of FFP for cardiac surgery is insufficient.
We included five RCTs (2277 participants) that compared different frequencies of CVAD dressing changes. The studies were all conducted in Europe and published between 1995 and 2009. Participants were recruited from the intensive care and cancer care departments of one children's and four adult hospitals. The studies used a variety of transparent dressings and compared a longer interval between dressing changes (5 to15 days; intervention) with a shorter interval between changes (2 to 5 days; control). In each study participants were followed up until the CVAD was removed or until discharge from ICU or hospital. Confirmed catheter-related bloodstream infection (CRBSI) One trial randomised 995 people receiving central venous catheters to a longer or shorter interval between dressing changes and measured CRBSI. It is unclear whether there is a difference in the risk of CRBSI between people having long or short intervals between dressing changes (RR 1.42, 95% confidence interval (CI) 0.40 to 4.98) (low quality evidence). Suspected catheter-related bloodstream infection Two trials randomised a total of 151 participants to longer or shorter dressing intervals and measured suspected CRBSI. It is unclear whether there is a difference in the risk of suspected CRBSI between people having long or short intervals between dressing changes (RR 0.70, 95% CI 0.23 to 2.10) (low quality evidence). All cause mortality Three trials randomised a total of 896 participants to longer or shorter dressing intervals and measured all cause mortality. It is unclear whether there is a difference in the risk of death from any cause between people having long or short intervals between dressing changes (RR 1.06, 95% CI 0.90 to 1.25) (low quality evidence). Catheter-site infection Two trials randomised a total of 371 participants to longer or shorter dressing intervals and measured catheter-site infection. It is unclear whether there is a difference in risk of catheter-site infection between people having long or short intervals between dressing changes (RR 1.07, 95% CI 0.71 to 1.63) (low quality evidence). Skin damage One small trial (112 children) and three trials (1475 adults) measured skin damage. There was very low quality evidence for the effect of long intervals between dressing changes on skin damage compared with short intervals (children: RR of scoring ≥ 2 on the skin damage scale 0.33, 95% CI 0.16 to 0.68; data for adults not pooled). Pain Two studies involving 193 participants measured pain. It is unclear if there is a difference between long and short interval dressing changes on pain during dressing removal (RR 0.80, 95% CI 0.46 to 1.38) (low quality evidence). The best available evidence is currently inconclusive regarding whether longer intervals between CVAD dressing changes are associated with more or less catheter-related infection, mortality or pain than shorter intervals.
We included 21 trials with a total of 1197 women. They were mostly at moderate to high risk of bias. They assessed 11 different interventions resulting in 15 different comparisons. Compared with placebo, ursodeoxycholic acid (UDCA) showed improvement in pruritus in five (228 women) out of seven trials. There were no significant differences in instances of fetal distress in the UDCA groups compared with placebo (average risk ratio (RR) 0.67; 95% confidence interval (CI) 0.22 to 2.02; five trials, 304 women; random-effects analysis: Tau² = 0.74; I² = 48%). There were significantly fewer total preterm births with UDCA (RR 0.46; 95% CI 0.28 to 0.73; two trials, 179 women). The difference for spontaneous preterm births was not significant (RR 0.99; 95% CI 0.41 to 2.36, two trials, 109 women). Two trials (48 women) reported lower (better) pruritus scores for S-adenosylmethionine (SAMe) compared with placebo, while two other trials of 34 women reported no significant differences between groups. UDCA was more effective in improving pruritus than either SAMe (four trials; 133 women) or cholestyramine (one trial; 84 women), as was combined UDCA+SAMe when compared with placebo (one trial; 16 women) and SAMe alone (two trials; 68 women). However, combined UDCA+SAMe was no more effective than UDCA alone in regard to pruritus improvement (one trial; 53 women) and two trials (80 women) reported data were insufficient to draw any conclusions from. In one trial comparing UDCA and dexamethasone (83 women), a significant improvement with UDCA was seen only in a subgroup of women with severe obstetric cholestasis (23 women). Danxiaoling significantly improved pruritus in comparison to Yiganling. No significant differences were seen in pruritus improvement with other interventions. Eight trials reported fetal or neonatal deaths, with two deaths reported overall (both in the placebo groups). Women receiving UDCA and cholestyramine experienced nausea, vomiting and diarrhoea. Guar gum caused mild abdominal distress, diarrhoea and flatulence during the first days of treatment. Women found charcoal suspension unpleasant to swallow. Dexamethasone caused nausea, dizziness and stomach pain in one woman. One trial (62 women) looked at the timing of delivery intervention. There were no stillbirths or neonatal deaths in 'early delivery' or the 'await spontaneous labour' group. There were no significant differences in the rates of caesarean section, meconium passage or admission to neonatal intensive care unit between the two groups. Different approaches to assessing and reporting pruritus precluded pooling of trials comparing the effects of UDCA versus placebo on pruritus, but examination of individual trials suggests that UDCA significantly improves pruritus, albeit by a small amount. Fewer instances of fetal distress/asphyxial events were seen in the UDCA groups when compared with placebo but the difference was not statistically significant. Large trials of UDCA to determine fetal benefits or risks are needed. A single trial was too small to rule in or out a clinically important effect of early term delivery on caesarean section. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction (YCHD), Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy.
Four studies of a relatively small size, involving 144 participants, were included in this review. A combination of ranitidine with diphenhydramine was more effective at improving the resolution of urticaria than diphenhydramine administered alone (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.07 to 2.36). Although there was a similar improvement in itching, weal size, and intensity, cimetidine provided no statistically significant greater overall improvement in symptoms of urticaria when compared to diphenhydramine. However, a combination of these medications was more effective than diphenhydramine alone (RR 2.02, 95% CI 1.03 to 3.94). Adverse events were reported with several of the interventions, i.e. ranitidine and diphenhydramine, causing drowsiness and sedation, but there was no significant difference in the level of sedation from baseline with either famotidine or diphenhydramine. The very limited evidence provided by this review was based on a few old studies of a relatively small size, which we categorised as having high to unclear risk of bias. Thus, at present, the review does not allow confident decision-making about the use of H2-receptor antagonists for urticaria. Although some of these studies have reported a measure of relief of symptoms of urticaria and rather minimal clinical improvement in some of the participants, the evidence was weak and unreliable. We have emphasised the lack of precision and limitations in the reported data where appropriate in this review.
Two studies were included in the review. In the one study in HIV infected women, the IUD was compared with depot progestogen or the oral contraceptive, according to the women's choice. As the majority of women chose depot progestogen, we have included this study in the review, within a mixed hormonal contraception sub-group. Overall, the copper IUD was more effective than depot progestogens/hormonal contraception at preventing pregnancy (risk ratio (RR) 0.47; 95% confidence interval (CI) 0.26 to 0.85). HIV disease progression was reduced in the IUD group (RR 0.66; 95% CI 0.46 to 0.96). There was no significant difference in pelvic inflammatory disease rates between the two groups. Discontinuation of the allocated method was less frequent with the IUD in one study, and less frequent with hormonal contraception in the other study (in which women were allowed to switch between various hormonal methods). In the populations studied, the IUD was more effective than hormonal contraception with respect to pregnancy prevention. High quality research is urgently needed to compare the effects, if any, of these two commonly used contraception methods on HIV acquisition/seroconversion and HIV/AIDS disease progression.
We found 15 trials from 10 countries; the total number of participants was 2702. Nonsteroidal anti-inflammatory drugs (naproxen, suprofen, mefenamic acid, ibuprofen, indomethacin, flufenamic acid, alclofenac, and diclofenac) were effective in reducing menstrual blood loss associated with IUD use. This held true for women with and without complaints of heavy bleeding. Similarly, these drugs were effective in reducing pain associated with IUD use. In contrast, prophylactic use of nonsteroidal anti-inflammatory drugs had mixed results; studies with ibuprofen found no effect on pain after insertion on IUD discontinuation. No important differences emerged in the one trial comparing the effect of different NSAIDs on bleeding. Nonsteroidal anti-inflammatory drugs reduce bleeding and pain associated with IUD use. NSAIDs should be considered first-line therapy; if NSAIDs are ineffective, tranexamic acid may be considered as second-line therapy. Prophylactic ibuprofen administration with the first six menses after insertion appears unwarranted.
We included 10 RCTs (1458 participants), seven of which reported relevant outcomes for this review (1285 participants). All included trials had an overall high risk of bias, whilst two trials had a low risk of bias for all domains except blinding of participants and personnel. Meta-analysis indicated harm from higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation regarding mortality at the time point closest to three months (risk ratio (RR) 1.18, 95% confidence interval (CI) 1.01 to 1.37; I2 = 0%; 4 trials; 1135 participants; very low-certainty evidence). Meta-analysis indicated harm from higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation regarding serious adverse events at the time point closest to three months (estimated highest proportion of specific serious adverse events in each trial RR 1.13, 95% CI 1.04 to 1.23; I2 = 0%; 1234 participants; 6 trials; very low-certainty evidence). These findings should be interpreted with caution given that they are based on very low-certainty evidence. None of the included trials reported any data on quality of life at any time point. Meta-analysis indicated no evidence of a difference between higher fraction of inspired oxygen or targets as compared with lower fraction or targets of arterial oxygenation on lung injury at the time point closest to three months (estimated highest reported proportion of lung injury RR 1.03, 95% CI 0.78 to 1.36; I2 = 0%; 1167 participants; 5 trials; very low-certainty evidence). None of the included trials reported any data on acute myocardial infarction or stroke, and only one trial reported data on the effects on sepsis. We are very uncertain about the effects of higher versus lower fraction of inspired oxygen or targets of arterial oxygenation for adults admitted to the ICU on all-cause mortality, serious adverse events, and lung injuries at the time point closest to three months due to very low-certainty evidence. Our results indicate that oxygen supplementation with higher versus lower fractions or oxygenation targets may increase mortality. None of the trials reported the proportion of participants with one or more serious adverse events according to the ICH-GCP criteria, however we found that the trials reported an increase in the number of serious adverse events with higher fractions or oxygenation targets. The effects on quality of life, acute myocardial infarction, stroke, and sepsis are unknown due to insufficient data.
We included 41 fully published studies (2768 patients). Mortality was similar in the N-acetylcysteine group and the placebo group (RR 1.06, 95% CI 0.79 to 1.42; I2 = 0%). Neither did N-acetylcysteine show any significant effect on length of stay, duration of mechanical ventilation or incidence of new organ failure. Early application of N-acetylcysteine to prevent the development of an oxidato-inflammatory response did not affect the outcome, nor did late application that is after 24 hours of developing symptoms. Late application was associated with cardiovascular instability. Overall, this meta-analysis puts doubt on the safety and utility of intravenous N-acetylcysteine as an adjuvant therapy in SIRS and sepsis. At best, N-acetylcysteine is ineffective in reducing mortality and complications in this patient population. At worst, it can be harmful, especially when administered later than 24 hours after the onset of symptoms, by causing cardiovascular depression. Unless future RCTs provide evidence of treatment effect, clinicians should not routinely use intravenous N-acetylcysteine in SIRS or sepsis and academics should not promote its use.
We included 19 RCTs involving 13,209 women. Most studies concerned interval sterilisation; three RCTs involving 1632 women, concerned postpartum sterilisation. Comparisons included tubal rings versus clips (six RCTs, 4232 women); partial salpingectomy versus electrocoagulation (three RCTs, 2019 women); tubal rings versus electrocoagulation (two RCTs, 599 women); partial salpingectomy versus clips (four RCTs, 3627 women); clips versus electrocoagulation (two RCTs, 206 women); and Hulka versus Filshie clips (two RCTs, 2326 women). RCTs of clips versus electrocoagulation contributed no data to the review. One year after sterilisation, failure rates were low (< 5/1000) for all methods.There were no deaths reported with any method, and major morbidity related to the occlusion technique was rare. Minor morbidity was higher with the tubal ring than the clip (Peto OR 2.15, 95% CI 1.22 to 3.78; participants = 842; studies = 2; I² = 0%; high-quality evidence), as were technical failures (Peto OR 3.93, 95% CI 2.43 to 6.35; participants = 3476; studies = 3; I² = 0%; high-quality evidence). Major morbidity was significantly higher with the modified Pomeroy technique than electrocoagulation (Peto OR 2.87, 95% CI 1.13 to 7.25; participants = 1905; studies = 2; I² = 0%; low-quality evidence), as was postoperative pain (Peto OR 3.85, 95% CI 2.91 to 5.10; participants = 1905; studies = 2; I² = 0%; moderate-quality evidence). When tubal rings were compared with electrocoagulation, postoperative pain was reported significantly more frequently for tubal rings (OR 3.40, 95% CI 1.17 to 9.84; participants = 596; studies = 2; I² = 87%; low-quality evidence). When partial salpingectomy was compared with clips, there were no major morbidity events in either group (participants = 2198, studies = 1). The frequency of minor morbidity was low and not significantly different between groups (Peto OR 7.39, 95% CI 0.46 to 119.01; participants = 193; studies = 1, low-quality evidence). Although technical failure occurred more frequently with clips (Peto OR 0.18, 95% CI 0.08 to 0.40; participants = 2198; studies = 1; moderate-quality evidence); operative time was shorter with clips than partial salpingectomy (MD 4.26 minutes, 95% CI 3.65 to 4.86; participants = 2223; studies = 2; I² = 0%; high-quality evidence). We found little evidence concerning women's or surgeon's satisfaction. No RCTs compared tubal microinserts (hysteroscopic sterilisation) or chemical inserts (quinacrine) to other methods. Tubal sterilisation by partial salpingectomy, electrocoagulation, or using clips or rings, is a safe and effective method of contraception. Failure rates at 12 months post-sterilisation and major morbidity are rare outcomes with any of these techniques. Minor complications and technical failures appear to be more common with rings than clips. Electrocoagulation may be associated with less postoperative pain than the modified Pomeroy or tubal ring methods. Further research should include RCTs (for effectiveness) and controlled observational studies (for adverse effects) on sterilisation by minimally-invasive methods, i.e. tubal inserts and quinacrine.
Out of 1449 articles screened, seven studies were included. Three articles were awaiting classification, among them, two completed trials identified from the trial registry appeared to be unpublished so far. There were two major comparisons: IV fluid supplementation versus no fluid supplementation (six studies) and IV fluid supplementation versus oral fluid supplementation (one study). A total of 494 term, healthy newborn infants with unconjugated hyperbilirubinaemia were evaluated. All studies were at high risk of bias for blinding of care personnel, five studies had unclear risk of bias for blinding of outcome assessors, and most studies had unclear risk of bias in allocation concealment. There was low- to moderate-quality evidence for all major outcomes. In the comparison between IV fluid supplementation and no supplementation, no infant in either group developed bilirubin encephalopathy in the one study that reported this outcome. Serum bilirubin was lower at four hours postintervention for infants who received IV fluid supplementation (MD -34.00 μmol/L (-1.99 mg/dL), 95% CI -52.29 (3.06) to -15.71 (0.92); participants = 67, study = 1) (low quality of evidence, downgraded one level for indirectness and one level for suspected publication bias). Beyond eight hours postintervention, serum bilirubin was similar between the two groups. Duration of phototherapy was significantly shorter for fluid-supplemented infants, but the estimate was affected by heterogeneity which was not clearly explained (MD -10.70 hours, 95% CI -15.55 to -5.85; participants = 218; studies = 3; I² = 67%). Fluid-supplemented infants were less likely to require exchange transfusion (RR 0.39, 95% CI 0.21 to 0.71; RD -0.01, 95% CI -0.04 to 0.02; participants = 462; studies = 6; I² = 72%) (low quality of evidence, downgraded one level due to inconsistency, and another level due to suspected publication bias), and the estimate was similarly affected by unexplained heterogeneity. The frequencies of breastfeeding were similar between the fluid-supplemented and non-supplemented infants in days one to three based on one study (estimate on day three: MD 0.90 feeds, 95% CI -0.40 to 2.20; participants = 60) (moderate quality of evidence, downgraded one level for imprecision). One study contributed to all outcome data in the comparison of IV versus oral fluid supplementation. In this comparison, no infant in either group developed abnormal neurological signs. Serum bilirubin, as well as the rate of change of serum bilirubin, were similar between the two groups at four hours after phototherapy (serum bilirubin: MD 11.00 μmol/L (0.64 mg/dL), 95% CI -21.58 (-1.26) to 43.58 (2.55); rate of change of serum bilirubin: MD 0.80 μmol/L/hour (0.05 mg/dL/hour), 95% CI -2.55 (-0.15) to 4.15 (0.24); participants = 54 in both outcomes) (moderate quality of evidence for both outcomes, downgraded one level for indirectness). The number of infants who required exchange transfusion was similar between the two groups (RR 1.60, 95% CI 0.60 to 4.27; RD 0.11, 95% CI -0.12 to 0.34; participants = 54). No infant in either group developed adverse effects including vomiting or abdominal distension. There is no evidence that IV fluid supplementation affects important clinical outcomes such as bilirubin encephalopathy, kernicterus, or cerebral palsy in healthy, term newborn infants with unconjugated hyperbilirubinaemia requiring phototherapy. In this review, no infant developed these bilirubin-associated clinical complications. Low- to moderate-quality evidence shows that there are differences in total serum bilirubin levels between fluid-supplemented and control groups at some time points but not at others, the clinical significance of which is uncertain. There is no evidence of a difference between the effectiveness of IV and oral fluid supplementations in reducing serum bilirubin. Similarly, no infant developed adverse events or complications from fluid supplementation such as vomiting or abdominal distension. This suggests a need for future research to focus on different population groups with possibly higher baseline risks of bilirubin-related neurological complications, such as preterm or low birthweight infants, infants with haemolytic hyperbilirubinaemia, as well as infants with dehydration for comparison of different fluid supplementation regimen.
We included eight new studies (617 participants) in this updated review. In total we included 17 studies (1493 participants). A total of 15 trials provided data for the meta-analyses. We judged only two trials as low risk of bias. The majority of studies included participants undergoing cardiac surgery. We found six ongoing trials but were unable to retrieve any data from them. Compared with transfusion guided by any method, TEG or ROTEM seemed to reduce overall mortality (7.4% versus 3.9%; risk ratio (RR) 0.52, 95% CI 0.28 to 0.95; I2 = 0%, 8 studies, 717 participants, low quality of evidence) but only eight trials provided data on mortality, and two were zero event trials. Our analyses demonstrated a statistically significant effect of TEG or ROTEM compared to any comparison on the proportion of participants transfused with pooled red blood cells (PRBCs) (RR 0.86, 95% CI 0.79 to 0.94; I2 = 0%, 10 studies, 832 participants, low quality of evidence), fresh frozen plasma (FFP) (RR 0.57, 95% CI 0.33 to 0.96; I2 = 86%, 8 studies, 761 participants, low quality of evidence), platelets (RR 0.73, 95% CI 0.60 to 0.88; I2 = 0%, 10 studies, 832 participants, low quality of evidence), and overall haemostatic transfusion with FFP or platelets (low quality of evidence). Meta-analyses also showed fewer participants with dialysis-dependent renal failure. We found no difference in the proportion needing surgical reinterventions (RR 0.75, 95% CI 0.50 to 1.10; I2 = 0%, 9 studies, 887 participants, low quality of evidence) and excessive bleeding events or massive transfusion (RR 0.38, 95% CI 0.38 to 1.77; I2 = 34%, 2 studies, 280 participants, low quality of evidence). The planned subgroup analyses failed to show any significant differences. We graded the quality of evidence as low based on the high risk of bias in the studies, large heterogeneity, low number of events, imprecision, and indirectness. TSA indicates that only 54% of required information size has been reached so far in regards to mortality, while there may be evidence of benefit for transfusion outcomes. Overall, evaluated outcomes were consistent with a benefit in favour of a TEG- or ROTEM-guided transfusion in bleeding patients. There is growing evidence that application of TEG- or ROTEM-guided transfusion strategies may reduce the need for blood products, and improve morbidity in patients with bleeding. However, these results are primarily based on trials of elective cardiac surgery involving cardiopulmonary bypass, and the level of evidence remains low. Further evaluation of TEG- or ROTEM-guided transfusion in acute settings and other patient categories in low risk of bias studies is needed.
We included four trials (552 participants) that compared biphasic and monophasic waveform defibrillation in people with OHCA. Based on the assessment of five quality domains, we identified two trials that were at high risk of bias, one trial at unclear risk of bias and one trial at low risk of bias. The risk ratio (RR) for failure to achieve ROSC after biphasic compared to monophasic waveform defibrillation was 0.86 (95% CI 0.62 to 1.20; four trials, 552 participants). The RR for failure to defibrillate on the first shock following biphasic defibrillation compared to monophasic was 0.84 (95% CI 0.70 to 1.01; three trials, 450 participants); and 0.81 (95% CI 0.61 to 1.09; two trials, 317 participants) for one to three stacked shocks. The RR for failure to achieve ROSC after the first shock was 0.92 (95% CI 0.81 to 1.04; two trials, 285 participants). Biphasic waveforms did not reduce the risk of death before hospital admission (RR 1.05, 95% CI 0.90 to 1.23; three trials, 383 participants) or before hospital discharge (RR 1.05, 95% CI 0.78 to 1.42; four trials, 550 participants). There was no statistically significant heterogeneity in any of the pooled analyses. None of the included trials reported adverse events. It is uncertain whether biphasic defibrillators have an important effect on defibrillation success in people with OHCA. Further large studies are needed to provide adequate statistical power.
We screened 7674 citations, from which 14 trials with 1844 participants met our inclusion criteria. Ten RCTs were placebo-controlled, and four reported comparisons of different drugs. Drugs examined in these trials were the following: antipsychotics (n = 10), alpha2 agonists (n = 3; all dexmedetomidine), statins (n = 2), opioids (n = 1; morphine), serotonin antagonists (n = 1; ondansetron), and cholinesterase (CHE) inhibitors (n = 1; rivastigmine). Only one of these trials consistently used non-pharmacological interventions that are known to improve patient outcomes in both intervention and control groups. Eleven studies (n = 1153 participants) contributed to analysis of the primary outcome. Results of the NMA showed that the intervention with the smallest ratio of means (RoM) (i.e. most preferred) compared with placebo was the alpha2 agonist dexmedetomidine (0.58; 95% credible interval (CrI) 0.26 to 1.27; surface under the cumulative ranking curve (SUCRA) 0.895; moderate-quality evidence). In order of descending SUCRA values (best to worst), the next best interventions were atypical antipsychotics (RoM 0.80, 95% CrI 0.50 to 1.11; SUCRA 0.738; moderate-quality evidence), opioids (RoM 0.88, 95% CrI 0.37 to 2.01; SUCRA 0.578; very-low quality evidence), and typical antipsychotics (RoM 0.96, 95% CrI 0.64 to1.36; SUCRA 0.468; high-quality evidence). The NMAs of multiple secondary outcomes revealed that only the alpha2 agonist dexmedetomidine was associated with a shorter duration of mechanical ventilation (RoM 0.55, 95% CrI 0.34 to 0.89; moderate-quality evidence), and the CHE inhibitor rivastigmine was associated with a longer ICU stay (RoM 2.19, 95% CrI 1.47 to 3.27; moderate-quality evidence). Adverse events often were not reported in these trials or, when reported, were rare; pair-wise analysis of QTc prolongation in seven studies did not show significant differences between antipsychotics, ondansetron, dexmedetomidine, and placebo. We identified trials of varying quality that examined six different drug classes for treatment of delirium in critically ill adults. We found evidence that the alpha2 agonist dexmedetomidine may shorten delirium duration, although this small effect (compared with placebo) was seen in pairwise analyses based on a single study and was not seen in the NMA results. Alpha2 agonists also ranked best for duration of mechanical ventilation and length of ICU stay, whereas the CHE inhibitor rivastigmine was associated with longer ICU stay. We found no evidence of a difference between placebo and any drug in terms of delirium-free and coma-free days, days with coma, physical restraint use, length of stay, long-term cognitive outcomes, or mortality. No studies reported delirium relapse, resolution of symptoms, or quality of life. The ten ongoing studies and the six studies awaiting classification that we identified, once published and assessed, may alter the conclusions of the review.
Seven studies with 428 participants were included in this review; only two of these had published usable results. Individual patient data were obtained from one trial (Ballard 2002) and additional analyses performed. The additional analyses conducted using individual patient data from Ballard 2002 revealed a statistically significant treatment effect in favour of the aromatherapy intervention on measures of agitation (n = 71, MD -11.1, 95% CI -19.9 to -2.2) and behavioural symptoms (n = 71, MD -15.8, 95% CI -24.4 to -7.2). Burns 2011, however, found no difference in agitation (n = 63, MD 0.00, 95% CI -1.36 to 1.36), behavioural symptoms (n = 63, MD 2.80, 95% CI -5.84 to 11.44), activities of daily living (n = 63, MD -0.50, 95% CI -1.79 to 0.79) and quality of life (n = 63, MD 19.00, 95% CI -23.12 to 61.12). Burns 2011 and Fu 2013 found no difference in adverse effects (n = 124, RR 0.97, 95% CI 0.15 to 6.46) when aromatherapy was compared to placebo. The benefits of aromatherapy for people with dementia are equivocal from the seven trials included in this review. It is important to note there were several methodological difficulties with the included studies. More well-designed, large-scale randomised controlled trials are needed before clear conclusions can be drawn regarding the effectiveness of aromatherapy for dementia. Additionally, several issues need to be addressed, such as whether different aromatherapy interventions are comparable and the possibility that outcomes may vary for different types of dementia.
One double-blind cross-over RCT with 22 participants with SCD (aged 12 to 27 years) was eligible for inclusion. Following stratification into four pain crises severity grades, participants were then randomised to receive TENS or placebo (sham TENS). The trial was concluded after 60 treatment episodes (30 treatment episodes of each treatment group). There is a lack of clarity regarding the trial design and the analysis of the cross-over data. If a participant was allocated to TENS treatment for an episode of pain and subsequently returned with a further episode of a similar degree of pain, they would then receive the sham TENS treatment (cross-over design). For those experiencing a pain episode of a different severity, it is not clear whether they were re-randomised or given the alternate treatment. Reporting and analysis was based on the total number pain events and not on the number of participants. It is unclear how many participants were crossed over from the TENS group to the sham TENS group and vice versa. The trial had a high risk of bias regarding random sequence generation and allocation concealment; an unclear risk regarding the blinding of participants and personnel; and a low risk regarding the blinding of the outcome assessors and selective outcome reporting. The trial was small and of very low quality; furthermore, given the issue with trial design we were unable to quantitatively analyse the data. Therefore, we present only a narrative summary and caution is advised in interpreting the results. In relation to our pre-defined primary outcomes, the included trial did not report pain relief at two to four weeks post intervention. The trial authors reported that no difference was found in the changes in pain ratings (recorded at one hour and four hours post intervention) between the TENS and the placebo groups. In relation to our secondary outcomes, the analgesic usage during the trial also did not show any difference between groups. Given the quality of the evidence, we are uncertain whether TENS improves overall satisfaction as compared to sham TENS. The ability to cope with activities of daily living was not evaluated. Regarding adverse events, although one case of itching was reported in the TENS group, the site and nature of itching was not clearly stated; hence it cannot be clearly attributed to TENS. Also, two participants receiving 'sham' TENS reported a worsening of pain with the intervention. Since we have only included one small and very low-quality trial, with a high risk of bias across several domains, we are unable to conclude whether TENS is harmful or beneficial for managing pain in people with SCD. There is a need for a well-designed, adequately-powered, RCT to evaluate the role of TENS in managing pain in people with SCD.
Twenty-four double-blind trials with 4631 participants including a total of 33 comparisons of Echinacea preparations and placebo met the inclusion criteria. A variety of different Echinacea preparations based on different species and parts of plant were used. Evidence from seven trials was available for preparations based on the aerial parts of Echinacea purpurea. Ten trials were considered to have a low risk of bias, six to have an unclear risk of bias and eight to have a high risk of bias. Ten trials with 13 comparisons investigated prevention and 15 trials with 20 comparisons investigated treatment of colds (one trial addressed both prevention and treatment). Due to the strong clinical heterogeneity of the studies we refrained from pooling for the main analysis. None of the 12 prevention comparisons reporting the number of patients with at least one cold episode found a statistically significant difference. However a post hoc pooling of their results, suggests a relative risk reduction of 10% to 20%. Of the six treatment trials reporting data on the duration of colds, only two showed a significant effect of Echinacea over placebo. The number of patients dropping out or reporting adverse effects did not differ significantly between treatment and control groups in prevention and treatment trials. However, in prevention trials there was a trend towards a larger number of patients dropping out due to adverse events in the treatment groups. Echinacea products have not here been shown to provide benefits for treating colds, although, it is possible there is a weak benefit from some Echinacea products: the results of individual prophylaxis trials consistently show positive (if non-significant) trends, although potential effects are of questionable clinical relevance.
We included 10 studies (830 participants, 1387 eyes), published between 1998 and 2012. Prevalence of CSMO was 19% to 65% (median 50%) in nine studies with CSMO as the target condition. Study quality was often unclear or at high risk of bias for QUADAS 2 items, specifically regarding study population selection and the exclusion of participants with poor quality images. Applicablity was unclear in all studies since professionals referring patients and results of prior testing were not reported. There was a specific 'unit of analysis' issue because both eyes of the majority of participants were included in the analyses as if they were independent. In nine studies providing data on CSMO (759 participants, 1303 eyes), pooled sensitivity was 0.78 (95% confidence interval (CI) 0.72 to 0.83) and specificity was 0.86 (95% CI 0.76 to 0.93). The median central retinal thickness cut-off we selected for data extraction was 250 µm (range 230 µm to 300 µm). Central CSMO was the target condition in all but two studies and thus our results cannot be applied to non-central CSMO. Data from three studies reporting accuracy for detection of DMO (180 participants, 343 eyes) were not pooled. Sensitivities and specificities were about 0.80 in two studies and were both 1.00 in the third study. Since this review was conceived, the role of OCT has changed and has become a key ingredient of decision-making at all levels of ophthalmic care in this field. Moreover, disagreements between OCT and fundus examination are informative, especially false positives which are referred to as subclinical DMO and are at higher risk of developing clinical CSMO. Using retinal thickness thresholds lower than 300 µm and ophthalmologist's fundus assessment as reference standard, central retinal thickness measured with OCT was not sufficiently accurate to diagnose the central type of CSMO in patients with DR referred to retina clinics. However, at least OCT false positives are generally cases of subclinical DMO that cannot be detected clinically but still suffer from increased risk of disease progression. Therefore, the increasing availability of OCT devices, together with their precision and the ability to inform on retinal layer structure, now make OCT widely recognised as the new reference standard for assessment of DMO, even in some screening settings. Thus, this review will not be updated further.
We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (856/3643 (23.49%) versus 837/3549 (23.58%); RR 1.00, 95% confidence interval (CI) 0.88 to 1.14; I2 = 49%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I2 = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I2 = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I2 = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes. This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.
This updated review includes 20 studies, with 2641 participants. For oxycodone 15 mg alone compared with placebo, the NNT for at least 50% pain relief was 4.6 (95% Confidence Interval 2.9 to 11). For oxycodone 10 mg plus paracetamol 650 mg, the NNT was 2.7 (2.4 to 3.1). A dose response was demonstrated for this outcome with combination therapy. Duration of effect was 10 hours with oxycodone 10 mg plus paracetamol 650 mg, and 4 hours with half that dose. Fewer participants needed rescue medication over 6 hours at the higher dose. Adverse events occurred more frequently with combination therapy than placebo, but were generally described as mild to moderate in severity and rarely led to withdrawal. Single dose oxycodone is an effective analgesic in acute postoperative pain at doses over 5 mg; oxycodone is two to three times stronger than codeine. Efficacy increases when combined with paracetamol. Oxycodone 10 mg plus paracetamol 650 mg provides good analgesia to half of those treated, comparable to commonly used non-steroidal anti-inflammatory drugs, with the benefit of longer duration of action.
We included 15 trials, involving 1438 participants. The 2 trials (71 participants) comparing terbinafine and griseofulvin produced a pooled risk ratio (RR) of 2.26 (95% confidence interval (CI) 1.49 to 3.44) in favour of terbinafine's ability to cure infection. No significant difference was detected between terbinafine and itraconazole, fluconazole and itraconazole, fluconazole and ketoconazole, or between griseofulvin and ketoconazole, although the trials were generally small. Two trials showed that terbinafine and itraconazole were effective compared with placebo: terbinafine (31 participants, RR 24.54, 95% CI 1.57 to 384.32) and itraconazole (72 participants, RR 6.67, 95% CI 2.17 to 20.48). All drugs reported adverse effects, with gastrointestinal effects most commonly reported. Ten of the trials were published over 15 years ago, and this is reflected by the poor reporting of information from which to make a clear 'Risk of bias' assessment. Only one trial was at low risk of bias overall. The majority of the remaining trials were judged as 'unclear' risk of bias because of the lack of clear statements with respect to methods of generating the randomisation sequence and allocation concealment. More trials achieved blinding of participants and personnel than blinding of the outcome assessors, which was again poorly reported. The evidence suggests that terbinafine is more effective than griseofulvin, and terbinafine and itraconazole are more effective than no treatment. In order to produce more reliable data, a rigorous evaluation of different drug therapies needs to be undertaken with larger sample sizes to ensure they are large enough to show any real difference when two treatments are being compared. It is also important to continue to follow up and collect data, preferably for six months after the end of the intervention period, to establish whether or not the infection recurred.
Two studies met the inclusion criteria but only one contributed data for the prespecified outcomes. Caffeinated instant coffee (568 women) was compared with decaffeinated instant coffee (629 women) and it was found that reducing the caffeine intake of regular coffee drinkers (3+ cups/day) during the second and third trimester by an average of 182 mg/day did not affect birthweight (g) (mean difference (MD) 20.00, 95% confidence interval (CI) -48.68 to 88.68; one study, 1197 participants; low quality evidence), preterm birth (risk ratio (RR) 0.81, 95% CI 0.48 to 1.37; one study, 1153 participants; low quality evidence) or small-for-gestational age (RR 0.97, 95% 0.57 to 1.64; one study, 1150 participants). Risk of bias was moderate in both studies. Two outcomes were assessed and assigned a quality rating using the GRADE methods. Evidence for these two outcomes (birthweight and preterm birth) was assessed as of low quality, with downgrading decisions due to the relatively small sample sizes and the wide confidence interval of the one included trial that contributed data. Neither of the studies reported on any of the other primary outcomes (low birthweight; first trimester fetal loss; perinatal mortality; fetal hypoxia; fetal tachycardia) or on any of the reviews neonatal or maternal outcomes. There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high-quality, double-blinded RCTs to determine whether caffeine has any effect on pregnancy outcome.
Sixteen studies were included (n=3005). Four trials compared the effect of any type (mechanical and/or pharmacological) of prophylaxis versus no prophylaxis. Prophylaxis reduced the risk of DVT in people with trauma (RR 0.52; 95% CI 0.32 to 0.84). Mechanical prophylaxis reduced the risk of DVT (RR = 0.43; 95% CI 0.25 to 0.73). Pharmacological prophylaxis was more effective than mechanical methods at reducing the risk of DVT (RR 0.48; 95% CI 0.25 to 0.95). LMWH appeared to reduce the risk of DVT compared to UH (RR 0.68; 95% CI 0.50 to 0.94). People who received both mechanical and pharmacological prophylaxis had a lower risk of DVT (RR 0.34; 95% CI 0.19 to 0.60) We did not find evidence that thromboprophylaxis reduces mortality or PE in any of the comparisons assessed. However, we found some evidence that thromboprophylaxis prevents DVT. Although the strength of the evidence was not high, taking into account existing information from other related conditions such as surgery, we recommend the use of any DVT prophylactic method for people with severe trauma.
Four trials (163 participants) studied the effect of NSAIDs. Aspirin compared to placebo in a high quality trial produced no significant differences in clinical symptoms and signs. Naproxen produced significant short term pain reduction when compared to placebo, but not when compared to diflunisal. Laser therapy to stimulate blood flow in tender areas led to more satisfied participants than tenoxicam, though not significantly. Two high quality RCTs (84 participants) studied the effect of glycosaminoglycan polysulphate (GAGPS). Twelve intramuscular injections in six weeks led to significantly more participants with a good overall therapeutic effect after one year, and to significantly better pain reduction during one of two activities. Five weekly intra-articular injections of GAGPS and lidocaine were compared with intra-articular injections of saline and lidocaine or no injections, all with concurrent quadriceps training. Injected participants showed better function after six weeks, though only the difference between GAGPS injected participants and non-injected participants was significant. The differences had disappeared after one year. One trial (43 participants) found that intramuscular injections of the anabolic steroid nandrolone phenylpropionate significantly improved both pain and function compared to placebo injections. There is only limited evidence for the effectiveness of NSAIDs for short term pain reduction in PFPS. The evidence for the effect of glycosaminoglycan polysulphate is conflicting and merits further investigation. The anabolic steroid nandrolone may be effective, but is too controversial for treatment of PFPS.
Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal (GI) adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose or the course of asymptomatic influenza. Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Resistance of influenza viruses to amantadine is a serious worldwide problem as shown by recent virological surveillances. Both drugs have adverse gastrointestinal (stomach and gut) effects, but amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.
We included 10 trials involving 878 participants, among which 28 participants in two trials did not provide complete data due to loss to follow-up. We judged all trials to be at high risk of bias. Semi-recumbent position (30º to 60º) versus supine position (0° to 10°) A semi-recumbent position (30º to 60º) significantly reduced the risk of clinically suspected VAP compared to a 0º to 10º supine position (eight trials, 759 participants, 14.3% versus 40.2%, RR 0.36; 95% CI 0.25 to 0.50; risk difference (RD) 25.7%; 95% CI 20.1% to 30.1%; GRADE: moderate quality evidence). There was no significant difference between the two positions in the following outcomes: microbiologically confirmed VAP (three trials, 419 participants, 12.6% versus 31.6%, RR 0.44; 95% CI 0.11 to 1.77; GRADE: very low quality evidence), ICU mortality (two trials, 307 participants, 29.8% versus 34.3%, RR 0.87; 95% CI 0.59 to 1.27; GRADE: low quality evidence), hospital mortality (three trials, 346 participants, 23.8% versus 27.6%, RR 0.84; 95% CI 0.59 to 1.20; GRADE: low quality evidence), length of ICU stay (three trials, 346 participants, MD -1.64 days; 95% CI -4.41 to 1.14 days; GRADE moderate quality evidence), length of hospital stay (two trials, 260 participants, MD -9.47 days; 95% CI -34.21 to 15.27 days; GRADE: very low quality evidence), duration of ventilation (four trials, 458 participants, MD -3.35 days; 95% CI -7.80 to 1.09 days), antibiotic use (three trials, 284 participants, 84.8% versus 84.2%, RR 1.00; 95% CI 0.97 to 1.03) and pressure ulcers (one trial, 221 participants, 28% versus 30%, RR 0.91; 95% CI 0.60 to 1.38; GRADE: low quality evidence). No other adverse events were reported. Semi-recumbent position (45°) versus 25° to 30° We found no statistically significant differences in the following prespecified outcomes: clinically suspected VAP (two trials, 91 participants, RR 0.74; 95% CI 0.35 to 1.56; GRADE: very low quality evidence), microbiologically confirmed VAP (one trial, 30 participants, RR 0.61; 95% CI 0.20 to 1.84: GRADE: very low quality evidence), ICU mortality (one trial, 30 participants, RR 0.57; 95% CI 0.15 to 2.13; GRADE: very low quality evidence), hospital mortality (two trials, 91 participants, RR 1.00; 95% CI 0.38 to 2.65; GRADE: very low quality evidence), length of ICU stay (one trial, 30 participants, MD 1.6 days; 95% CI -0.88 to 4.08 days; GRADE: very low quality evidence) and antibiotic use (two trials, 91 participants, RR 1.11; 95% CI 0.84 to 1.47). No adverse events were reported. A semi-recumbent position (≧ 30º) may reduce clinically suspected VAP compared to a 0° to 10° supine position. However, the evidence is seriously limited with a high risk of bias. No adequate evidence is available to draw any definitive conclusion on other outcomes and the comparison of alternative semi-recumbent positions. Adverse events, particularly venous thromboembolism, were under-reported.
One open-label randomised controlled trial of 63 neonates was eligible for inclusion. Thirty-three neonates in the propofol group were compared to 30 infants in the morphine-atropine-suxamethonium group. There was no statistically significant difference in the number of infants who required multiple intubation attempts (39% in the propofol group versus 57% in the morphine-atropine-suxamethonium group; RR 1.40, 95% CI 0.85 to 2.29). Times required to prepare medication, to complete the procedure and for recovery to previous clinical status were shorter in the propofol group. No difference in clinically significant side effects was observed; however, the number of events was small. No practice recommendation can be made based on the available evidence regarding the use of propofol in neonates. Further research is needed on the pharmacokinetics of propofol in neonates and once a relatively safe dose is identified, randomised controlled trials assessing the safety and efficacy of propofol are needed.
Three trials including 360 women and their infants were identified as eligible for inclusion in this review. Two trials were rated as low risk of bias for random sequence generation and concealment of allocation. A third trial was assessed as unclear risk of bias for these domains but did not report data for any of the outcomes examined in this review. No trials were rated to be of high quality overall. Intravenous magnesium sulphate was administered according to low-dose regimens (4 g loading dose followed by 2 g/hour continuous infusion and/or increased by 1 g/hour hourly until successful tocolysis or failure of treatment), or high-dose regimens (4 g loading dose followed by 5 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment, or 6 g loading dose followed by 2 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment). There were no differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the primary outcome of fetal, neonatal and infant death (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.12 to 1.56; one trial, 100 infants). Using the GRADE approach, the evidence for fetal, neonatal and infant death was considered to be VERY LOW quality. No data were reported for any of the other primary maternal and infant health outcomes (birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome). There were no clear differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the secondary infant health outcomes of fetal death; neonatal death; and rate of hypocalcaemia, osteopenia or fracture; and secondary maternal health outcomes of rate of caesarean birth; pulmonary oedema; and maternal self-reported adverse effects. Pulmonary oedema was reported in two women given high-dose magnesium sulphate, but not in any of the women given low-dose magnesium sulphate. In a single trial of high and low doses of magnesium sulphate for tocolysis including 100 infants, the risk of respiratory distress syndrome was lower with use of a high-dose regimen compared with a low-dose regimen (RR 0.31, 95% CI 0.11 to 0.88; one trial, 100 infants). Using the GRADE approach, the evidence for respiratory distress syndrome was judged to be LOW quality. No difference was seen in the rate of admission to the neonatal intensive care unit. However, for those babies admitted, a high-dose regimen was associated with a reduction in the length of stay in the neonatal intensive care unit compared with a low-dose regimen (mean difference -3.10 days, 95% confidence interval -5.48 to -0.72). We found no data for the majority of our secondary outcomes. There are limited data available (three studies, with data from only two studies) comparing different dosing regimens of magnesium sulphate given as single agent tocolytic therapy for the prevention of preterm birth. There is no evidence examining duration of therapy, timing of therapy and the role for repeat dosing. Downgrading decisions for our primary outcome of fetal, neonatal and infant death were based on wide confidence intervals (crossing the line of no effect), lack of blinding and a limited number of studies. No data were available for any of our other important outcomes: birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome. The data are limited by volume and the outcomes reported. Only eight of our 45 pre-specified primary and secondary maternal and infant health outcomes were reported on in the included studies. No long-term outcomes were reported. Downgrading decisions for the evidence on the risk of respiratory distress were based on wide confidence intervals (crossing the line of no effect) and lack of blinding. There is some evidence from a single study suggesting a reduction in the length of stay in the neonatal intensive care unit and a reduced risk of respiratory distress syndrome where a high-dose regimen of magnesium sulphate has been used compared with a low-dose regimen. However, given that evidence has been drawn from a single study (with a small sample size), these data should be interpreted with caution. Magnesium sulphate has been shown to be of benefit in a wide range of obstetric settings, although it has not been recommended for tocolysis. In clinical settings where health benefits are established, further trials are needed to address the lack of evidence regarding the optimal dose (loading dose and maintenance dose), duration of therapy, timing of therapy and role for repeat dosing in terms of efficacy and safety for mothers and their children. Ongoing examination of different regimens with respect to important health outcomes is required.
8 trials included in the review for a total 424 patients who were randomised to Cisapride or placebo, of which 157 were children and 284 were female. Intervention duration was 8 to 12 weeks. Dosage of Cisapride in the adult and children trials were 5mg TDS and 0.2mg/kg/dose TDS respectively. Cisapride showed significant benefit in investigators’ assessment of clinical improvement (OR: 0.45, P=0.03), likelihood of passing daily stools (OR: 0.22, P<0.001), passage of normal stools (OR: 0.06, P<0.001) and total gastrointestinal transit time (MD: -19.47, P<0.00001). However Cisapride showed no benefit in global improvement of symptoms (MD: 0.11, P=0.99), abdominal pain (MD: 1.94, P=0.56), stool frequency: weekly (MD: 3.36, P=0.11), visual analogue scale (MD: -0.23, P=0.66), stool consistency (MD: 0.32, P=0.50), bloating (MD: 3.93, P=0.44), persistent bloating(OR: 1.11, P=0.83), ‘feeling of incomplete evacuation’ (MD: -3.80, P=0.08), straining (MD -0.95, p=0.19). No clear benefit can be demonstrated with cisapride. We do not feel that cisapride can be justifiably used for chronic constipation or irritable bowel disease given its side effects of arrhythmia and associated 175 recorded deaths.
We included 11 studies with a total of 596 participants. Two studies assessed fish oil versus olive oil or corn oil placebo. The following were all looked at in single studies: oral zinc sulphate compared to placebo, selenium versus selenium plus vitamin E versus placebo, vitamin D versus placebo, vitamin D versus vitamin E versus vitamins D plus vitamin E together versus placebo, pyridoxine versus placebo, sea buckthorn seed oil versus sea buckthorn pulp oil versus placebo, hempseed oil versus placebo, sunflower oil (linoleic acid) versus fish oil versus placebo, and DHA versus control (saturated fatty acids of the same energy value). Two small studies on fish oil suggest a possible modest benefit, but many outcomes were explored. A convincingly positive result from a much larger study with a publicly-registered protocol is needed before clinical practice can be influenced. There is no convincing evidence of the benefit of dietary supplements in eczema, and they cannot be recommended for the public or for clinical practice at present. Whilst some may argue that at least supplements do not do any harm, high doses of vitamin D may give rise to serious medical problems, and the cost of long-term supplements may also mount up.
Six published randomised controlled trials were identified, with a total of 1177 infants. Study quality varied for the comparison 'Inositol supplementation to preterm infants (repeat doses in any amount and any duration of treatment) versus control' and interim analyses had occurred in several trials for the outcomes of interest. In this comparison, neonatal death was found to be significantly reduced (typical RR 0.53, 95% CI 0.31 to 0.91; typical RD −0.09, 95% CI −0.16 to −0.01; NNTB 11, 95% CI 6 to 100; 3 trials, 355 neonates). Infant deaths were not reduced (typical RR 0.89, 95% CI 0.71 to 1.13; typical RD −0.02, 95% CI −0.07 to 0.02; 5 trials, 1115 infants) (low-quality evidence). ROP stage 2 or higher or stage 3 or higher was not significantly reduced (typical RR 0.89, 95% CI 0.75 to 1.06; typical RD −0.04, 95% CI −0.10 to 0.02; 3 trials, 810 infants) (moderate-quality evidence). There were no significant findings for ROP (any stage), NEC (suspected or proven), sepsis, IVH grade greater than II (moderate-quality evidence). For the comparison 'Inositol supplementation IV initially followed by enteral administration (repeat doses of 80 mg/kg/day) in preterm infants born at less than 30 weeks' postmenstrual age (PMA) compared to placebo for preterm infants at risk for or having respiratory distress syndrome' the results from two studies of high quality were included (N = 760 neonates). Recruitment to the larger study (N = 638) was terminated because of a higher rate of deaths in the inositol group. We did not downgrade the quality of the study. The meta-analyses of the outcomes of 'Type 1 ROP or death before determination of ROP outcome using the adjudicated ROP outcome', 'Type 1 ROP including adjudicated ROP outcome', 'All-cause mortality (outcome collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)' and 'Severe IVH (grade 3 or 4)' did not show significant findings (moderate-quality evidence). There were no significant findings for the outcomes 'BPD or death by it prior to 37 weeks' postmenstrual age (outcomes collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)', 'Late onset sepsis (> 72 hours of age)', and 'Suspected or proven NEC' (high-quality evidence). Based on the evidence from randomised controlled trials to date, inositol supplementation does not result in important reductions in the rates of infant deaths, ROP stage 3 or higher, type 1 ROP, IVH grades 3 or 4, BPD, NEC, or sepsis. These conclusions are based mainly on two recent randomised controlled trials in neonates less than 30 weeks' postmenstrual age (N = 760), the most vulnerable population. Currently inositol supplementation should not be routinely instituted as part of the nutritional management of preterm infants with or without RDS. It is important that infants who have been enrolled in the trials included in this review are followed to assess any effects of inositol supplementation on long-term outcomes in childhood. We do not recommend any additional trials in neonates.
The five trials that met our criteria included 698 patients: data from 499 (71.5%) were available for analysis of relapse frequency at one year's, from 488 (70%) at two years' and from 415 (59.5%) at three years' follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years' (RRR =23%; 95% CI = 12% to 33%) and three years' (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies.  Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years' follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials.  Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%).  Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g. Azathioprine is an appropriate maintenance treatment for patients with MS who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating MS. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in MS has not been made.
We included five RCTs (2840 women or couples) comparing timed intercourse versus intercourse without ovulation prediction. Unfortunately one large study (n = 1453) reporting live birth and pregnancy had not published outcome data by randomised group and therefore could not be analysed. Consequently, four RCTs (n = 1387) were included in the meta-analysis. The evidence was of low to very low quality. Main limitations for downgrading the evidence included imprecision, lack of reporting clinically relevant outcomes and the high risk of publication bias. One study reported live birth, but the sample size was too small to draw any relevant conclusions on the effect of timed intercourse (RR 0.75, 95% CI 0.16 to 3.41, 1 RCT, n = 17, very low quality). One study reported stress as an adverse event. There was no evidence of a difference in levels of stress (mean difference 1.98, 95 CI% -0.87 to 4.83, 1 RCT, n = 77, low level evidence). No other studies reported adverse events. Two studies reported clinical pregnancy. There was no evidence of a difference in clinical pregnancy rates (RR 1.10, 95% CI 0.57 to 2.12, 2 RCTs, n = 177, I2 = 0%, low level evidence). This suggested that if the chance of a clinical pregnancy following intercourse without ovulation prediction is assumed to be 16%, the chance of success following timed intercourse would be between 9% and 33%.Four studies reported pregnancy rate (clinical or self-reported pregnancy). Timed intercourse was associated with higher pregnancy rates compared to intercourse without ovulation prediction in couples trying to conceive (RR 1.35, 95% CI 1.06 to 1.71, 4 RCTs, n = 1387, I2 = 0%, very low level evidence). This suggests that if the chance of a pregnancy following intercourse without ovulation prediction is assumed to be 13%, the chance following timed intercourse would be between 14% and 23%. Subgroup analysis by duration of subfertility showed no difference in effect between couples trying to conceive for < 12 months versus couples trying for ≥ 12 months. One trial reported time to conception data and showed no evidence of a difference in time to conception. There are insufficient data available to draw conclusions on the effectiveness of timed intercourse for the outcomes of live birth, adverse events and clinical pregnancy. Timed intercourse may improve pregnancy rates (clinical or self-reported pregnancy, not yet confirmed by ultrasound) compared to intercourse without ovulation prediction. The quality of this evidence is low to very low and therefore findings should be regarded with caution. There is a high risk of publication bias, as one large study remains unpublished 8 years after recruitment finished. Further research is required, reporting clinically relevant outcomes (live birth, clinical pregnancy rates and adverse effects), to determine if timed intercourse is safe and effective in couples trying to conceive.
We included a total of 12 trials with 854 women in the review, with 10 trials and 754 women in the meta-analysis. Nine of the 10 studies compared exercise with no treatment, and one study compared exercise with NSAIDs. No studies compared exercise with attention control or with the oral contraceptive pill. Studies used low-intensity exercise (stretching, core strengthening or yoga) or high-intensity exercise (Zumba or aerobic training); none of the included studies used resistance training.  Exercise versus no treatment Exercise may have a large effect on reducing menstrual pain intensity compared to no exercise (standard mean difference (SMD) -1.86, 95% confidence interval (CI) -2.06 to -1.66; 9 randomised controlled trials (RCTs), n = 632; I2= 91%; low-quality evidence). This SMD corresponds to a 25 mm reduction on a 100 mm visual analogue scale (VAS) and is likely to be clinically significant. We are uncertain if there is any difference in adverse event rates between exercise and no treatment. We are uncertain if exercise reduces overall menstrual symptoms (as measured by the Moos Menstrual Distress Questionnaire (MMDQ)), such as back pain or fatigue compared to no treatment (mean difference (MD) -33.16, 95% CI -40.45 to -25.87; 1 RCT, n = 120; very low-quality evidence), or improves mental quality of life (MD 4.40, 95% CI 1.59 to 7.21; 1 RCT, n = 55; very low-quality evidence) or physical quality of life (as measured by the 12-Item Short Form Health Survey (SF-12)) compared to no exercise (MD 3.40, 95% CI -1.68 to 8.48; 1 RCT, n = 55; very low-quality evidence) when compared to no treatment. No studies reported on any changes in restriction of daily life activities or on absence from work or school. Exercise versus NSAIDs We are uncertain if exercise, when compared with mefenamic acid, reduced menstrual pain intensity (MD -7.40, 95% CI -8.36 to -6.44; 1 RCT, n = 122; very low-quality evidence), use of rescue analgesic medication (risk ratio (RR) 1.77, 95% CI 1.21 to 2.60; 1 RCT, n = 122; very low-quality evidence) or absence from work or school (RR 1.00, 95% CI 0.49 to 2.03; 1 RCT, n = 122; very low-quality evidence). None of the included studies reported on adverse events, overall menstrual symptoms, restriction of daily life activities or quality of life. The current low-quality evidence suggests that exercise, performed for about 45 to 60 minutes each time, three times per week or more, regardless of intensity, may provide a clinically significant reduction in menstrual pain intensity of around 25 mm on a 100 mm VAS. All studies used exercise regularly throughout the month, with some studies asking women not to exercise during menstruation. Given the overall health benefits of exercise, and the relatively low risk of side effects reported in the general population, women may consider using exercise, either alone or in conjunction with other modalities, such as NSAIDs, to manage menstrual pain. It is unclear if the benefits of exercise persist after regular exercise has stopped or if they are similar in women over the age of 25. Further research is required, using validated outcome measures, adequate blinding and suitable comparator groups reflecting current best practice or accounting for the extra attention given during exercise.
Two trials (70 participants) were included. One trial (28 participants) compared treatment with desipramine for five weeks to placebo. The other trial (42 participants) compared treatment with paroxetine for twelve weeks to placebo. Both trials had a significant number of patients lost to follow-up or with missing outcome measurements. There was a trend towards efficacy of both treatments compared to placebo, but this difference was not statistically significant except for one outcome. Confidence intervals were wide in all analyses and our sensitivity analysis showed that the missing data may have had an important effect in both trials, with large differences between best-case and worst-case scenarios for all assessed outcomes. Both treatments were associated with adverse effects, with significantly more patients treated with paroxetine suffering from nausea or headache. Given the difference in trial duration and type of drug, we decided not to perform a meta-analysis. Both desipramine and paroxetine show a trend towards efficacy in depression in MS the short term, but both treatments were associated with adverse effects, with significantly more patients treated with paroxetine suffering from nausea or headache. Further clinical research on the treatment of depression in MS is clearly needed. Future trials should address the efficacy and tolerability in the long term and compare antidepressant treatments head-to-head.
We identified 10 trials that met the inclusion criteria with a total of 587 participants. We also identified another ongoing trial. These trials were conducted between 1975 and 2015. None of the studies included people with neutrophil dysfunction. The studies differed in the type of infections they included. Six studies included both children and adults, however data were not reported separately for children and adults. The two newest studies gave granulocyte colony stimulating factor (G-CSF) to donors; both were stopped early due to lack of recruitment. Three studies re-randomised participants and therefore quantitative analysis was unable to be performed. Overall the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcomes being imprecise. There may be no difference in all-cause mortality over 30 days between participants receiving therapeutic granulocyte transfusions and those that did not (six studies; 321 participants; RR 0.75, 95% CI 0.54 to 1.04; very low-quality evidence). There were no differences between the granulocyte dose subgroups (< 1 x 1010 per day versus ≥ 1 x 1010 per day) (test for subgroup differences P = 0.39). There was a difference in all-cause mortality between the studies based on the age of the study (published before 2000 versus published 2000 or later) (test for subgroup differences P = 0.03). There was no difference in all-cause mortality between participants receiving granulocyte transfusions and those that did not in the newest study (one study; 111 participants; RR 1.10, 95% CI 0.70 to 1.73, low-quality evidence). There may be a reduction in all-cause mortality in participants receiving granulocyte transfusions compared to those that did not in studies published before the year 2000 (five studies; 210 participants; RR 0.53, 95% CI 0.33 to 0.85; low-quality evidence). There may be no difference in clinical reversal of concurrent infection between participants receiving therapeutic granulocyte transfusions and those that did not (five studies; 286 participants; RR 0.98, 95% CI 0.81 to 1.19; low-quality evidence). There is insufficient evidence to determine whether there is a difference in pulmonary serious adverse events (1 study; 24 participants; RR 0.85, 95% CI 0.38 to 1.88; very low-quality evidence). None of the studies reported number of days on therapeutic antibiotics, number of adverse events requiring discontinuation of treatment, or quality of life. Six studies reported their funding sources and all were funded by governments or charities. In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is insufficient evidence to determine whether granulocyte transfusions affect all-cause mortality. To be able to detect a decrease in all-cause mortality from 35% to 30% would require a study containing at least 2748 participants (80% power, 5% significance). There is low-grade evidence that therapeutic granulocyte transfusions may not increase the number of participants with clinical resolution of an infection.
We included 22 RCTs and four quasi-RCTs on 2272 participants. We categorised the intervention components into four groups: educational and psychological; educational and physical; physical and psychological; and educational, physical and psychological. Most of the studies used usual care (routine medical follow-up services) as the comparator. A few studies used a lower level or different type of intervention (e.g. stress management or exercise) or attention control as the comparator. We used the Functional Assessment of Cancer Therapy-Breast (FACT B), European Organisation for Research and Treatment of Cancer Quality of Life C30 (EORTC C30), Quality of Life (QoL) Breast Cancer, and SF36 questionnaires to assess quality of life. HBMS programmes may increase breast cancer-specific quality of life and global quality of life immediately after the intervention, as measured by FACT-B and EORTC C30 (FACT-B: mean difference (MD) 4.55, 95% confidence interval (CI) 2.33 to 6.78, 7 studies, 764 participants; EORTC: MD 4.38, 95% CI 0.11 to 8.64, 6 studies; 299 participants; moderate-quality evidence). There was no evidence of a difference in quality of life as measured by QoL-Breast Cancer or SF-36 (QoL-Breast Cancer: MD 0.42, 95% CI -0.02 to 0.85, 2 studies, 111 participants, very low-quality evidence; physical composite score SF36: MD 0.55, 95% CI -3.52 to 4.63, 2 studies, 308 participants, low-quality evidence). We observed a similar pattern at one to three months after the intervention: FACT-B (MD 6.10, 95% CI 2.48 to 9.72, 2 studies, 426 participants), EORTC-C30 (MD 6.32, 95% CI 0.61 to 12.04, 2 studies; 172 participants) and QoL-Breast Cancer (MD 0.45, 95% CI -0.19 to 1.09, 1 study, 61 participants). At four to six months and 12 months, there was no evidence of a difference in quality of life between groups (four to six months: EORTC - MD 0.08, 95% CI -7.28 to 7.44, 2 studies; 117 participants; SF-36 - MD -1.05, 95% CI -5.60 to 3.51, 2 studies, 308 participants; 12 months: EORTC - MD 2.04, 95% CI -9.91 to 13.99, 1 study; 57 participants). Functional status was incorporated into the quality of life subscale findings. HBMS programmes may decrease anxiety (MD of Hospital Anxiety and Depression Scale (HADS) -1.01, 95% CI -1.94 to -0.08, 5 studies, 253 participants, low-quality evidence) compared to control immediately after the intervention but the effect did not persist at four to six months. There was no evidence of improvements in depression immediately after HBMS (MD of HADS -1.36, 95% CI -2.94 to 0.22, 4 studies, 213 participants, low-quality evidence) or at follow-up. HBMS programmes may also decrease fatigue (MD -1.11, 95% CI -1.78 to -0.45, 3 studies, 127 participants; low-quality evidence) and insomnia (MD -1.81, 95% CI -3.34 to -0.27, 3 studies, 185 participants, low-quality evidence). None of the included studies reported service needs and utilisation and cost of care, and therefore the effect of HBMS programmes on healthcare utilisation and cost is unknown. Due to the variations in assessment methods of adherence among the eight studies, we could not combine the results for meta-analysis. We synthesised the results narratively, with the reported adherence rates of 58% to 100%. The results of this systematic review and meta-analysis revealed that HBMS programmes in breast cancer survivors appear to have a short-term beneficial effect of improving breast cancer-specific quality of life and global quality of life as measured by FACT-B and EORTC-C30, respectively. In addition, HBMS programmes are associated with a reduction in anxiety, fatigue and insomnia immediately after the intervention. We assessed the quality of evidence across studies as moderate for some outcomes, meaning that we are fairly confident about the results, while we assessed other outcomes as being low-quality, meaning that we are uncertain about the result.
Twenty three trials were included with a total of 3685 participants, one was a cross-over trial and the other 22 were parallel group trials. The duration of follow up varied from two to 52 weeks. The trials were generally small and of poor methodological quality. During treatment, symptomatic improvement was more common amongst those participants on anticholinergic drugs compared with bladder training in seven small trials (73/174, 42% versus 98/172, 57% not improved: risk ratio 0.74, 95% confidence interval 0.61 to 0.91). Augmentation of bladder training with anticholinergics was also associated with more improvements than bladder training alone in three small trials (23/85, 27% versus 37/79, 47% not improved: risk ratio 0.57, 95% confidence interval 0.38 to 0.88). However, it was less clear whether an anticholinergic combined with bladder training was better than the anticholinergic alone, in three trials (for example 74/296, 25% versus 95/306, 31% not improved: risk ratio 0.80, 95% confidence interval 0.62 to 1.04). The other information on whether combining behavioural modification strategies with an anticholinergic was better than the anticholinergic alone was scanty and inconclusive. Similarly, it was unclear whether these complex strategies alone were better than anticholinergics alone. In this review, seven small trials comparing an anticholinergic to various types of electrical stimulation modalities such as Intravaginal Electrical Stimulation (IES), transcutaneous electrical nerve stimulation (TENS), the Stoller Afferent Nerve Stimulation System (SANS) neuromodulation and percutaneous posterior tibial nerve stimulation (PTNS) were identified. Subjective improvement rates tended to favour the electrical stimulation group in three small trials (54% not improved with the anticholinergic versus 28/86, 33% with electrical stimulation: risk ratio 0.64, 95% confidence interval 1.15 to 2.34). However, this was statistically significant only for one type of stimulation, percutaneous posterior tibial nerve stimulation (risk ratio 2.21, 95% confidence interval 1.13 to 4.33), and was not supported by significant differences in improvement, urinary frequency, urgency, nocturia, incontinence episodes or quality of life. The most commonly reported adverse effect among anticholinergics was dry mouth, although this did not necessarily result in withdrawal from treatment. For all comparisons there were too few data to compare symptoms or side effects after treatment had ended. However, it is unlikely that the effects of anticholinergics persist after stopping treatment. The use of anticholinergic drugs in the management of overactive bladder syndrome is well established when compared to placebo treatment. During initial treatment of overactive bladder syndrome there was more symptomatic improvement when (a) anticholinergics were compared with bladder training alone, and (b) anticholinergics combined with bladder training were compared with bladder training alone. Limited evidence from small trials might suggest electrical stimulation is a better option in patients who are refractory to anticholinergic therapy, but more evidence comparing individual types of electrostimulation to the most effective types of anticholinergics is required to establish this. These results should be viewed with caution in view of the different classes and varying doses of individual anticholinergics used in this review. Anticholinergics had well recognised side effects, such as dry mouth.
One unblinded, quasi-randomised controlled trial (RCT) assessing effects of carbohydrate supplementation of human milk in the form of a prebiotic in 75 preterm infants was eligible for inclusion in this review. We identified two publications of the same trial, which reported different methods regarding blinding and randomisation. Study authors confirmed that these publications pertain to the same trial, but they have not yet clarified which method is correct. We were unable to reproduce analyses from the data presented. At 30 days of age, the mean weight of preterm infants in the trial was greater in the prebiotic carbohydrate-supplemented group than in the unsupplemented group (MD 160.4 grams, 95% CI 12.4 to 308.4 grams; one RCT, N = 75; very low-quality evidence). We found no evidence of a clear difference in risk of feeding intolerance (RR 0.64, 95% CI 0.36 to 1.15; one RCT, N = 75 infants; very low-quality evidence) or necrotising enterocolitis (NEC) (RR 0.2, 95% CI 0.02 to 1.3; one RCT, N = 75 infants; very low-quality evidence) between the prebiotic-supplemented group and the unsupplemented group. Duration of hospital stay was shorter in the prebiotic group than in the control group at a median (range) of 16 (9 to 45) days (95% CI 15.34 to 24.09) and 25 (11 to 80) days (95% CI 25.52 to 34.39), respectively. No other data were available for assessing effects of carbohydrate supplementation on short- and long-term growth, body mass index, body composition, and neurodevelopmental or cardio-metabolic outcomes. We found insufficient evidence on the short- and long-term effects of carbohydrate supplementation of human milk in preterm infants. The only trial included in this review presented very low-quality evidence, and study authors provided uncertain information about study methods and analysis. The evidence may be limited in its applicability because researchers included a small sample of preterm infants from a single centre. However, the outcomes assessed are common to all preterm infants, and this trial demonstrates the feasibility of prebiotic carbohydrate supplementation in upper-middle-income countries. Future trials should assess the safety and efficacy of different types and concentrations of carbohydrate supplementation for preterm infants fed human milk. Although prebiotic carbohydrate supplementation in preterm infants is currently a topic of active research, we do not envisage that further trials of digestible carbohydrates will be conducted, as this is currently done as a component of multi-nutrient human milk fortification. Hence we do not plan to publish any further updates of this review.
We identified only one trial as relevant. Seventy-seven children in intensive care with burns involving more than 25% of the total body surface area were randomized to either enteral nutrition within 24 hours or after at least 48 hours. No statistically significant differences were observed for mortality, sepsis, ventilator days, length of stay, unexpected adverse events, resting energy expenditure, nitrogen balance, or albumin levels. We assessed the trial as having unclear risk of bias. We consider the quality of the evidence to be very low due to there being only one small trial. In the most recent search update we identified a protocol for a relevant randomized controlled trial examining the impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients; no results have been published. There was only one randomized trial relevant to the review question. Research is urgently needed to identify best practices regarding the timing and forms of nutrition for critically ill infants and children.
Six studies met the inclusion criteria; however, only five studies provided data for analysis. Four of the six included studies were small and had significant limitations in design. As each study reported outcomes differently, data for most outcomes were effectively contributed by a single study. Study authors reported no differences between co-bedded twins and twins receiving separate care in terms of rate of weight gain (MD 0.20 grams/kg/d, 95% CI -1.60 to 2.00; one study; 18 pairs of twins; evidence of low quality); apnea, bradycardia, and desaturation (A/B/D) episodes (RR 0.85, 95% CI 0.18 to 4.05; one study; 62 pairs of twins; evidence of low quality); episodes in co-regulated states (MD 0.96, 95% CI -3.44 to 5.36; one study; three pairs of twins; evidence of very low quality); suspected or proven infection (RR 0.84, 95% CI 0.30 to 2.31; three studies; 65 pairs of twins; evidence of very low quality); length of hospital stay (MD -4.90 days, 95% CI -35.23 to 25.43; one study; three pairs of twins; evidence of very low quality); and parental satisfaction measured on a scale of 0 to 55 (MD -0.38, 95% CI -4.49 to 3.73; one study; nine pairs of twins; evidence of moderate quality). Although co-bedded twins appeared to have lower pain scores 30 seconds after heel lance on a scale of 0 to 21 (MD -0.96, 95% CI -1.68 to -0.23; two studies; 117 pairs of twins; I2 = 75%; evidence of low quality), they had higher pain scores 90 seconds after the procedure (MD 1.00, 95% CI 0.14 to 1.86; one study; 62 pairs of twins). Substantial heterogeneity in the outcome of infant pain response after heel prick at 30 seconds post procedure and conflicting results at 30 and 90 seconds post procedure precluded clear conclusions. Evidence on the benefits and harms of co-bedding for stable preterm twins was insufficient to permit recommendations for practice. Future studies must be adequately powered to detect clinically important differences in growth and neurodevelopment. Researchers should assess harms such as infection, along with medication errors and caregiver satisfaction.
We included 66 RCTs in the review (> 24 weeks; 11,597 participants; age range 18 to 70 years) and 63 in the meta-analysis. For the primary outcome of treatment response, we found very low-quality evidence of treatment response for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984). On this outcome there was also evidence of benefit for monoamine oxidase inhibitors (MAOIs) (k = 4, RR 2.36; 95% CI 1.48 to 3.75, N = 235), reversible inhibitors of monoamine oxidase A (RIMAs) (k = 8, RR 1.83; 95% CI 1.32 to 2.55, N = 1270), and the benzodiazepines (k = 2, RR 4.03; 95% CI 2.45 to 6.65, N = 132), although the evidence was low quality. We also found clinical response for the anticonvulsants with gamma-amino butyric acid (GABA) analogues (k = 3, RR 1.60; 95% CI 1.16 to 2.20, N = 532; moderate-quality evidence). The SSRIs were the only medication proving effective in reducing relapse based on moderate-quality evidence. We assessed the SSRIs and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine on the basis of treatment withdrawal; this was higher for medication than placebo (SSRIs: k = 24, RR 2.59; 95% CI 1.97 to 3.39, N = 5131, low-quality evidence; venlafaxine: k = 4, RR 3.23; 95% CI 2.15 to 4.86, N = 1213, moderate-quality evidence), but there were low absolute rates of withdrawal for both these medications classes compared to placebo. We did not find evidence of a benefit for the rest of the medications compared to placebo. For the secondary outcome of SAnD symptom severity, there was benefit for the SSRIs, the SNRI venlafaxine, MAOIs, RIMAs, benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine in the reduction of SAnD symptoms, but most of the evidence was of very low quality. Treatment with SSRIs and RIMAs was also associated with a reduction in depression symptoms. The SSRIs were the only medication class that demonstrated evidence of reduction in disability across a number of domains. We observed a response to long-term treatment with medication for the SSRIs (low-quality evidence), for the MAOIs (very low-quality evidence) and for the RIMAs (moderate-quality evidence). We found evidence of treatment efficacy for the SSRIs, but it is based on very low- to moderate-quality evidence. Tolerability of SSRIs was lower than placebo, but absolute withdrawal rates were low. While a small number of trials did report treatment efficacy for benzodiazepines, anticonvulsants, MAOIs, and RIMAs, readers should consider this finding in the context of potential for abuse or unfavourable side effects.
We included three studies involving 470 participants. These trials were of limited comparability evaluating an OHC education training programme, a decontamination gel and a ventilator-associated pneumonia bundle of care augmented with an OHC component by comparing them to a deferred intervention, a placebo gel or standard care respectively. The OHC educational intervention demonstrated a significant reduction in denture plaque scores up to six months (P < 0.00001) after the intervention but not dental plaque. Staff knowledge (P = 0.0008) and attitudes (P = 0.0001) towards oral care also improved. The decontamination gel reduced the incidence of pneumonia amongst the intervention group (P = 0.03). Based on two trials involving a small number of stroke survivors, OHC interventions can improve staff knowledge and attitudes, the cleanliness of patients' dentures and reduce the incidence of pneumonia. Improvements in the cleanliness of patients teeth were not observed. Further evidence relating to staff-led oral care interventions is severely lacking.
We identified four trials, with 116 participants, investigating the effectiveness of compression therapy for treatment of PTS. The methodology used by each trial was too heterogeneous to perform a meta-analysis, so we reported our findings narratively. Two trials studied the effect of graduated elastic compression stockings (GECS) on improvement of PTS symptoms. One study reported beneficial haemodynamic effects, while the other found no benefits on PTS severity compared to placebo (very low-certainty evidence). There was very limited evidence available for adverse effects and quality of life (QoL). The two studies did not report on compliance rates during the study period. Two trials studied the effects of intermittent mechanical compression devices. Both reported improvement in PTS severity (low-certainty evidence). Improvement of the severity of PTS was defined by treatment 'success' or 'failure'. Only one study comparing compression devices evaluated adverse effects and QoL. Although 9% of the participants experienced adverse effects such as leg swelling, irritation, superficial bleeding, and skin itching (moderate-certainty evidence), QoL was improved (moderate-certainty evidence). Studies did not assess compliance using intermittent mechanical compression devices. None of the studies evaluated patient satisfaction. There is very low-certainty evidence regarding the use of GECS for treatment of PTS as assessed by two small studies of short duration. One study reported beneficial haemodynamic effects, while one found no benefits on PTS severity compared to control/placebo stockings. There is very limited evidence for adverse effects, patient satisfaction, QoL, and compliance rates. There is low-certainty evidence favouring use of intermittent pneumatic compression devices compared to a control device for the treatment of severity owing to different measurements used by the studies reporting on this outcome and small studies of short duration. There is moderate-certainty evidence of improved QoL but possible increased adverse effects related to compression device use owing to small studies of short duration. High-certainty evidence to support the use of compression therapy in prevention of PTS is lacking and any conclusions drawn from current evidence should be interpreted with care. Further research is needed to assess whether compression can result in long-term reduction and relief of the symptoms caused by PTS, or prevent deterioration and leg ulceration.
We identified 81 studies that comprised 9072 participants for inclusion in our review. We categorised many studies at high or unclear risk of the bias' assessed. There was statistical evidence that use of CG reduced TFF [overall reduction of 10.4 hours (95% CI: -11.9, -8.9): 12.5 hours (95% CI: -17.2, -7.8) in CRS, 7.9 hours (95% CI: –10.0, -5.8) in CS, 10.6 hours (95% CI: -12.7, -8.5) in OS]. There was also statistical evidence that use of CG reduced TBM [overall reduction of 12.7 hours (95% CI: -14.5, -10.9): 18.1 hours (95% CI: -25.3, -10.9) in CRS, 9.1 hours (95% CI: -11.4, -6.7) in CS, 12.3 hours (95% CI: -14.9, -9.7) in OS]. There was statistical evidence that use of CG slightly reduced LOHS [overall reduction of 0.7 days (95% CI: -0.8, -0.5): 1.0 days in CRS (95% CI: -1.6, -0.4), 0.2 days (95% CI: -0.3, -0.1) in CS, 0.8 days (95% CI: -1.1, -0.5) in OS]. There was statistical evidence that use of CG slightly reduced TBS [overall reduction of 5.0 hours (95% CI: -6.4, -3.7): 3.21 hours (95% CI: -7.0, 0.6) in CRS, 4.4 hours (95% CI: -5.9, -2.8) in CS, 6.3 hours (95% CI: -8.7, -3.8) in OS]. Effect sizes were largest in CRS and smallest in CS. There was statistical evidence of heterogeneity in all analyses other than TBS in CRS. There was little difference in mortality, infection risk and readmission rate between the groups. Some studies reported reduced nausea and vomiting and other complications in the intervention group. CG was generally well-tolerated by participants. There was little difference in cost between the groups in the two studies reporting this outcome. Sensitivity analyses by quality of studies and robustness of review estimates revealed no clinically important differences in effect estimates. Sensitivity analysis of ERAS studies showed a smaller effect size on TFF, larger effect size on TBM, and no difference between groups for LOHS. Meta-regression analyses indicated that surgical site is associated with the extent of the effect size on LOHS (all surgical subgroups), and TFF and TBM (CS and CRS subgroups only). There was no evidence that ROB score predicted the extent of the effect size on any outcome. Neither variable explained the identified heterogeneity between studies. This review identified some evidence for the benefit of postoperative CG in improving recovery of GI function. However, the research to date has primarily focussed on CS and CRS, and largely consisted of small, poor quality trials. Many components of the ERAS programme also target ileus, therefore the benefit of CG alongside ERAS may be reduced, as we observed in this review. Therefore larger, better quality RCTS in an ERAS setting in wider surgical disciplines would be needed to improve the evidence base for use of CG after surgery.
Twentyone reports have been found eligible for inclusion in the review, encompassing 31,698 women having had 6,028 CDs and 25,170 VDs as the index event prior to anal continence assessment . Only one report randomised women (with breech presentation) to CD or VD, but because of extensive crossing over, 52.1%, after randomisation, it was analysed along with the other 20 studies as treated, i.e. as a non-randomised trial. Only one of these reports demonstrated a significant benefit of CD in the preservation of anal continence, a report in which incontinence incidence was extremely high, 39% in CD and 48% in VD, questioning, relative to other reports, the timing and nature of continence assessment. The greater the quality of the report, the closer its Odds ratio approached 1.0. There was no difference in continence preservation in women have emergency versus elective CD. Without demonstrable benefit, preservation of anal continence should not be used as a criterion for choosing elective primary CD. The strength of this conclusion would be greatly strengthened if there were studies that randomised women with average risk pregnancies to CD versus VD.
One randomised clinical trial met inclusion criteria, including infants born more than 12 weeks preterm. The trial employed adequate methodologies and was assessed at low risk of bias. One hundred and sixty-six infants were randomised to start continuous cerebral NIRS monitoring less than 3 hours after birth until 72 hours after birth plus appropriate interventions if NIRS was out of normal range according to a guideline versus conventional monitoring with blinded NIRS. There was no effect of NIRS plus guideline of mortality until term-equivalent age (RR 0.50, 95% CI 0.29 to 1.00; one trial; 166 participants). There were no effects of NIRS plus guideline on intraventricular haemorrhages: all grades (RR 0.93, 95% CI 0.65 to 1.34; one trial; 166 participants); grade III/IV (RR 0.57, 95% CI 0.25 to 1.31; one trial; 166 participants); and cystic periventricular leukomalacia (which did not occur in either group). Likewise, there was no effect of NIRS plus guideline on the occurrence of a patent ductus arteriosus (RR 1.96, 95% CI 0.94 to 4.08; one trial; 166 participants); chronic lung disease (RR 1.27, 95% CI 0.94 to 1.50; one trial; 166 participants); necrotising enterocolitis (RR 0.83, 95% CI 0.33 to 1.94; one trial; 166 participants); and retinopathy of prematurity (RR 1.64, 95% CI 0.75 to 3.00; one trial; 166 participants). There were no serious adverse events in any of the intervention groups. NIRS plus guideline caused more skin marks from the NIRS sensor in the control group than in the experimental group (unadjusted RR 0.31, 95% CI 0.10 to 0.92; one trial; 166 participants). There are no data regarding neurodevelopmental outcome, renal impairment or air leaks. The quality of evidence for all comparisons discussed above was assessed as very low apart from all-cause mortality and adverse events: these were assessed as low and moderate, respectively. The validity of all comparisons is hampered by a small sample of randomised infants, risk of bias due to lack of blinding, and indirectness of outcomes. The only eligible randomised clinical trial did not demonstrate any consistent effects of NIRS plus a guideline on the assessed clinical outcomes. The trial was, however, only powered to detect difference in cerebral oxygenation, not morbidities or mortality. Our systematic review did not reach sufficient power to prove or disprove effects on clinical outcomes. Further randomised clinical trials with low risks of bias and low risks of random errors are needed.
Five trials were included. Four trials with 370 patients compared methotrexate with placebo or no intervention (three trials added an equal dose of ursodeoxycholic acid to the intervention groups). The bias risk of these trials was high. We did not find statistically significant effects of methotrexate on mortality (RR 1.32, 95% CI 0.66 to 2.64), mortality or liver transplantation combined, pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (MD - 0.17, 95% CI - 0.25 to - 0.09) was significantly lower in patients receiving methotrexate. The prothrombin time was significantly worsened in patients receiving methotrexate (MD 1.60 s, 95% CI 1.18 to 2.02). One trial with 85 patients compared methotrexate with colchicine. The trial had low risk of bias. Methotrexate, when compared to colchicine, did not significantly effect mortality, fatigue, liver biopsy, or adverse events. Methotrexate significantly benefited pruritus score (MD - 0.68, 95% CI - 1.11 to - 0.25), serum alkaline phosphatases (MD - 0.41 U/l, 95% CI - 0.70 to - 0.12), and plasma immunoglobulin M (MD - 0.47 mg/dl, 95% CI - 0.74 to - 0.20) compared with colchicine. Other outcomes showed no statistical difference. Methotrexate had no statistically significant effect on mortality in patients with primary biliary cirrhosis nor the need for liver transplantation. Although methotrexate may benefit other outcomes (pruritus score, serum alkaline phosphatase, immunoglobulin M levels), there is no sufficient evidence to support methotrexate for patients with primary biliary cirrhosis.
Three RCTs, involving 192 participants, met inclusion criteria for this review. No significant differences for overall survival (OS) were reported in any of the trials: in the first trial, 33 patients received whole brain radiation therapy and no significant difference was found between patients treated with topotecan and those not treated with topotecan. In a second trial, in which 120 patients were randomized to receive teniposide with or without brain radiation therapy, the authors reported that the median progression-free survival (brain-specific progression-free survival (PFS)) was 3.5 months in the combined modality arm and 3.2 in the teniposide alone arm. In a third trial, comparing sequential and concomitant chemoradiotherapy (teniposide plus cisplatin) in 39 participants, the survival difference between the two groups was not statistically significant. While the first trial reported no significant difference in PFS, the second RCT found a significant difference favoring combined therapy group. The second trial also found that patients receiving chemoradiotherapy (teniposide plus whole brain radiotherapy) had a higher complete response rate than those receiving only the topoisomerase inhibitor. Given the paucity of robust studies assessing the clinical effects of treatments, available evidence is insufficient to judge the effectiveness and safety of chemotherapy for the treatment of BM from SCLC. Published studies are insufficient to address the objectives of this review. According to the available evidence included in this review, chemotherapy does not improve specific brain PFS and OS in patients with SCLC. The combined treatment of teniposide and brain radiation therapy contributed to outcome in terms of increased complete remission and shorter time to progression (though not OS).
Four RCTs that included 365 participants after one year of treatment were included. Only one trial reported final height in 61 treated women to be 148 cm and 141 cm in 43 untreated women (mean difference (MD) seven cm, 95% CI 6 to 8). Short-term growth velocity was greater in treated than untreated girls after one year (two trials, MD three cm per year, 95% CI 2 to 4) and after two years (one trial, MD two cm per year, 95% CI 1 to 2.3). Skeletal maturity was not accelerated by treatment with recombinant growth hormone (hGH). Adverse effects were minimally reported. Recombinant human growth hormone (hGH) doses between 0.3 to 0.375 mg/kg/wk increase short-term growth in girls with Turner syndrome by approximately three (two) cm in the first (second) year of treatment. Treatment in one trial increased final height by approximately six cm over an untreated control group. Despite this increase, the final height of treated women was still outside the normal range. Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.
We included 39 trials that recruited 16,082 participants, assessing 22 different interventions or comparisons. Fourteen trials were placebo-controlled, 15 evaluated a delirium prevention intervention against usual care, and 10 compared two different interventions. Thirty-two studies were conducted in patients undergoing surgery, the majority in orthopaedic settings. Seven studies were conducted in general medical or geriatric medicine settings. We found multi-component interventions reduced the incidence of delirium compared to usual care (RR 0.69, 95% CI 0.59 to 0.81; seven studies; 1950 participants; moderate-quality evidence). Effect sizes were similar in medical (RR 0.63, 95% CI 0.43 to 0.92; four studies; 1365 participants) and surgical settings (RR 0.71, 95% CI 0.59 to 0.85; three studies; 585 participants). In the subgroup of patients with pre-existing dementia, the effect of multi-component interventions remains uncertain (RR 0.90, 95% CI 0.59 to 1.36; one study, 50 participants; low-quality evidence). There is no clear evidence that cholinesterase inhibitors are effective in preventing delirium compared to placebo (RR 0.68, 95% CI, 0.17 to 2.62; two studies, 113 participants; very low-quality evidence). Three trials provide no clear evidence of an effect of antipsychotic medications as a group on the incidence of delirium (RR 0.73, 95% CI, 0.33 to 1.59; 916 participants; very low-quality evidence). In a pre-planned subgroup analysis there was no evidence for effectiveness of a typical antipsychotic (haloperidol) (RR 1.05, 95% CI 0.69 to 1.60; two studies; 516 participants, low-quality evidence). However, delirium incidence was lower (RR 0.36, 95% CI 0.24 to 0.52; one study; 400 participants, moderate-quality evidence) for patients treated with an atypical antipsychotic (olanzapine) compared to placebo (moderate-quality evidence). There is no clear evidence that melatonin or melatonin agonists reduce delirium incidence compared to placebo (RR 0.41, 95% CI 0.09 to 1.89; three studies, 529 participants; low-quality evidence). There is moderate-quality evidence that Bispectral Index (BIS)-guided anaesthesia reduces the incidence of delirium compared to BIS-blinded anaesthesia or clinical judgement (RR 0.71, 95% CI 0.60 to 0.85; two studies; 2057 participants). It is not possible to generate robust evidence statements for a range of additional pharmacological and anaesthetic interventions due to small numbers of trials, of variable methodological quality. There is strong evidence supporting multi-component interventions to prevent delirium in hospitalised patients. There is no clear evidence that cholinesterase inhibitors, antipsychotic medication or melatonin reduce the incidence of delirium. Using the Bispectral Index to monitor and control depth of anaesthesia reduces the incidence of postoperative delirium. The role of drugs and other anaesthetic techniques to prevent delirium remains uncertain.
We included 46 trials with 3850 women and their infants; 38 trials with 3472 women and infants contributed data to our analyses. Trials took place in 21 countries, and most recruited small samples (just 12 trials randomized more than 100 women). Eight trials included women who had SSC after cesarean birth. All infants recruited to trials were healthy, and the majority were full term. Six trials studied late preterm infants (greater than 35 weeks' gestation). No included trial met all criteria for good quality with respect to methodology and reporting; no trial was successfully blinded, and all analyses were imprecise due to small sample size. Many analyses had statistical heterogeneity due to considerable differences between SSC and standard care control groups. Results for women SSC women were more likely than women with standard contact to be breastfeeding at one to four months post birth, though there was some uncertainty in this estimate due to risks of bias in included trials (average risk ratio (RR) 1.24, 95% confidence interval (CI) 1.07 to 1.43; participants = 887; studies = 14; I² = 41%; GRADE: moderate quality). SSC women also breast fed their infants longer, though data were limited (mean difference (MD) 64 days, 95% CI 37.96 to 89.50; participants = 264; studies = six; GRADE:low quality); this result was from a sensitivity analysis excluding one trial contributing all of the heterogeneity in the primary analysis. SSC women were probably more likely to exclusively breast feed from hospital discharge to one month post birth and from six weeks to six months post birth, though both analyses had substantial heterogeneity (from discharge average RR 1.30, 95% CI 1.12 to 1.49; participants = 711; studies = six; I² = 44%; GRADE: moderate quality; from six weeks average RR 1.50, 95% CI 1.18 to 1.90; participants = 640; studies = seven; I² = 62%; GRADE: moderate quality). Women in the SCC group had higher mean scores for breastfeeding effectiveness, with moderate heterogeneity (IBFAT (Infant Breastfeeding Assessment Tool) score MD 2.28, 95% CI 1.41 to 3.15; participants = 384; studies = four; I² = 41%). SSC infants were more likely to breast feed successfully during their first feed, with high heterogeneity (average RR 1.32, 95% CI 1.04 to 1.67; participants = 575; studies = five; I² = 85%). Results for infants SSC infants had higher SCRIP (stability of the cardio-respiratory system) scores overall, suggesting better stabilization on three physiological parameters. However, there were few infants, and the clinical significance of the test was unclear because trialists reported averages of multiple time points (standardized mean difference (SMD) 1.24, 95% CI 0.76 to 1.72; participants = 81; studies = two; GRADE low quality). SSC infants had higher blood glucose levels (MD 10.49, 95% CI 8.39 to 12.59; participants = 144; studies = three; GRADE: low quality), but similar temperature to infants in standard care (MD 0.30 degree Celcius (°C) 95% CI 0.13 °C to 0.47 °C; participants = 558; studies = six; I² = 88%; GRADE: low quality). Women and infants after cesarean birth Women practicing SSC after cesarean birth were probably more likely to breast feed one to four months post birth and to breast feed successfully (IBFAT score), but analyses were based on just two trials and few women. Evidence was insufficient to determine whether SSC could improve breastfeeding at other times after cesarean. Single trials contributed to infant respiratory rate, maternal pain and maternal state anxiety with no power to detect group differences. Subgroups We found no differences for any outcome when we compared times of initiation (immediate less than 10 minutes post birth versus early 10 minutes or more post birth) or lengths of contact time (60 minutes or less contact versus more than 60 minutes contact). Evidence supports the use of SSC to promote breastfeeding. Studies with larger sample sizes are necessary to confirm physiological benefit for infants during transition to extra-uterine life and to establish possible dose-response effects and optimal initiation time. Methodological quality of trials remains problematic, and small trials reporting different outcomes with different scales and limited data limit our confidence in the benefits of SSC for infants. Our review included only healthy infants, which limits the range of physiological parameters observed and makes their interpretation difficult.
Three small published studies (88 participants) met the inclusion criteria, but one had been retracted from publication because of ethical problems concerned with confidentiality and financial irregularities. Since these did not affect the data, the study was retained in this review. Despite the search including any intervention, only two types were represented in the eligible studies: two trials used cognitive behavioural therapy (CBT) with biofeedback versus waiting list on unspecified persistent pain (58 participants completed treatment), and one examined the effect of complex manual therapy versus self-treatment on low back pain (30 participants completed treatment). Excluded studies were largely either not RCTs or did not report pain as an outcome. There was no difference for the outcome of pain relief at the end of treatment between CBT and waiting list (two trials, 58 participants; SMD -0.05, 95% CI -1.23 to 1.12) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD -0.03, 95% CI -0.28 to 0.23) (very low quality evidence). The manual therapy trial also reported no difference between complex manual therapy and self-treatment (30 participants; SMD -0.48, 95% CI -9.95 to 0.35) (very low quality evidence). Two studies reported dropouts, one with partial information on reasons; none of the studies reported adverse effects. There was no information from any study on the outcomes of use of analgesics or quality of life. Reduction in disability showed no difference at the end of treatment between CBT and waiting list (two trials, 57 participants; SMD -0.39, 95% CI -1.17 to 0.39) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD 0, 95% CI -0.74 to 0.74) (very low quality evidence). The manual therapy trial reported superiority of complex manual therapy over self-treatment for reducing disability (30 participants; SMD -1.10, 95% CI - 1.88 to -0.33) (very low quality evidence). Reduction in distress showed no difference at the end of treatment between CBT and waiting list (two trials, 58 participants; SMD 0.07, 95% CI -0.46 to 0.60) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD -0.24, 95% CI -0.50 to 0.99) (very low quality evidence). The manual therapy trial reported superiority of complex manual therapy over self-treatment for reducing distress (30 participants; SMD -1.26, 95% CI - 2.06 to -0.47) (very low quality evidence). The risk of bias was considered high given the small number of trials, small size of trials, and the likelihood that each was underpowered for the comparisons it reported. We primarily downgraded the quality of the evidence due to small numbers in trials, lack of intention-to-treat analyses, high unaccounted dropout, lack of detail on study methods, and CIs around effect sizes that included no effect, benefit, and harm. There is insufficient evidence to support or refute the use of any intervention for persistent pain in survivors of torture.
The search identified 25 studies for consideration but only 10 studies met the inclusion criteria. These included a total of 1015 participants. Generally the studies were poorly designed and underpowered, with low numbers of participants and short durations. Only two studies used our predetermined primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow meta-analysis.  In the individual studies, no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily by subcutaneous infusion; a combination of L-methionine 2 g, vitamin E 400 international units, and selenium (Alsemet) 0.03 mg three times daily; or coenzyme Q10 1800 mg/day and 2700 mg/day. No significant effect was observed on the primary outcome measure in a meta-analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. The antioxidants were generally well tolerated, without serious side effects. There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect but this was not supported in our analysis. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trials. The high tolerance and safety, and relatively low cost of vitamins C and E, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.
73 outreach interventions were identified covering many specialties, countries and settings. Nine studies met the inclusion criteria. Most comparative studies came from urban non-disadvantaged populations in developed countries. Simple 'shifted outpatients' styles of specialist outreach were shown to improve access, but there was no evidence of impact on health outcomes. Specialist outreach as part of more complex multifaceted interventions involving collaboration with primary care, education or other services wasassociated with improved health outcomes, more efficient and guideline-consistent care, and less use of inpatient services. The additional costs of outreach may be balanced by improved health outcomes. This review supports the hypothesis that specialist outreach can improve access, outcomes and service use, especially when delivered as part of a multifaceted intervention. The benefits of simple outreach models in urban non-disadvantaged settings seem small. There is a need for good comparative studies of outreach in rural and disadvantaged settings where outreach may confer most benefit to access and health outcomes.
Through the search, we identified 10 trials enrolling a total of 1431 infants and comparing extubation of infants to NIPPV or NCPAP. Three trials had methodological limitations and possible selection bias. Five trials used the synchronised form of NIPPV, four used the non-synchronised form and one used both methods. Eight studies used NIPPV delivered by a ventilator, one used a bilevel device and one used both methods. When all studies were included, meta-analysis demonstrated a statistically and clinically significant reduction in the risk of meeting extubation failure criteria (typical RR 0.70, 95% CI 0.60 to 0.80; typical RD -0.13, 95% CI -0.17 to -0.08; NNTB 8, 95% CI 6 to 13; 10 trials, 1431 infants) and needing re-intubation (typical RR 0.76, 95% CI 0.65 to 0.88; typical RD -0.10, 95% CI -0.15 to -0.05; NNTB 10, 95% CI 7 to 20; 10 trials, 1431 infants). We graded evidence for these outcomes as moderate, as all trial interventions were unblinded. Although methods of synchronisation varied (Graseby capsule or pneumotachograph/flow-trigger), the five trials that synchronised NIPPV showed a statistically significant benefit for infants extubated to NIPPV in terms of prevention of extubation failure up to one week after extubation. Unsynchronised NIPPV also reduced extubation failure. NIPPV provided via a ventilator is more beneficial than that provided by bilevel devices in reducing extubation failure during the first week. When comparing interventions, investigators found no significant reduction in rates of chronic lung disease (typical RR 0.94, 95% CI 0.80 to 1.10; typical RD -0.02, 95% CI -0.08 to 0.03) or death, and no difference in the incidence of necrotising enterocolitis. Air leaks were reduced in infants randomised to NIPPV (typical RR 0.48, 95% CI 0.28 to 0.82; typical RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100). We graded evidence quality as moderate (unblinded studies) or low (imprecision) for secondary outcomes. Implications for practice NIPPV reduces the incidence of extubation failure and the need for re-intubation within 48 hours to one week more effectively than NCPAP; however, it has no effect on chronic lung disease nor on mortality. Synchronisation may be important in delivering effective NIPPV. The device used to deliver NIPPV may be important; however, data are insufficient to support strong conclusions. NIPPV does not appear to be associated with increased gastrointestinal side effects. Implications for research Large trials should establish the impact of synchronisation of NIPPV on safety and efficacy of the technique and should compare the efficacy of bilevel devices versus a ventilator for providing NIPPV.
We included four RCTs that randomly assigned 389 participants with acute respiratory failure. Risk of bias was low in three RCTs and high in one RCT. We found no statistically significant differences in all-cause mortality at six months (two RCTs) or before six months (during 30 days of randomization in one trial and during hospital stay in another RCT). The quality of the evidence was low to moderate, and further research is very likely to impact our confidence in the estimate of effects because significant changes have been noted in ECMO applications and treatment modalities over study periods to the present. Two RCTs supplied data on disability. In one RCT survival was low in both groups but none of the survivors had limitations in their daily activities six months after discharge. The other RCT reported improved survival without severe disability in the intervention group (transfer to an ECMO centre ± ECMO) six months after study randomization but no statistically significant differences in health-related quality of life. In three RCTs, participants in the ECMO group received greater numbers of blood transfusions. One RCT recorded significantly more non-brain haemorrhage in the ECMO group. Another RCT reported two serious adverse events in the ECMO group, and another reported three adverse events in the ECMO group. Clinical heterogeneity between studies prevented meta-analyses across outcomes. We found no completed RCT that had investigated ECMO in the context of cardiac failure or arrest. We found one ongoing RCT that examined patients with acute respiratory failure and two ongoing RCTs that included patients with acute cardiac failure (arrest). Extracorporeal membrane oxygenation remains a rescue therapy. Since the year 2000, patient treatment and practice with ECMO have considerably changed as the result of research findings and technological advancements over time. Over the past four decades, only four RCTs have been published that compared the intervention versus conventional treatment at the time of the study. Clinical heterogeneity across these published studies prevented pooling of data for a meta-analysis. We recommend combining results of ongoing RCTs with results of trials conducted after the year 2000 if no significant shifts in technology or treatment occur. Until these new results become available, data on use of ECMO in patients with acute respiratory failure remain inconclusive. For patients with acute cardiac failure or arrest, outcomes of ongoing RCTs will assist clinicians in determining what role ECMO and ECPR can play in patient care.
We found six publications involving a total of 47 participants requiring maxillary advancement of 4 mm to 10 mm. All of them related to a single trial performed between 2002 and 2008 at the University of Hong Kong, but not all of the publications reported outcomes from all 47 participants. The study compared maxillary distraction osteogenesis with orthognathic surgery, and included participants from 13 to 45 years of age. Results and conclusions should be interpreted with caution given the fact that this was a single trial at high risk of bias, with a small sample size. The main outcomes assessed were hard and soft tissue changes, skeletal relapse, effects on speech and velopharyngeal function, psychological status, and clinical morbidities. Both interventions produced notable hard and soft tissue improvements. Nevertheless, the distraction group demonstrated a greater maxillary advancement, evaluated as the advancement of Subspinale A-point: a mean difference of 4.40 mm (95% CI 0.24 to 8.56) was recorded two years postoperatively. Horizontal relapse of the maxilla was significantly less in the distraction osteogenesis group five years after surgery. A total forward movement of A-point of 2.27 mm was noted for the distraction group, whereas a backward movement of 2.53 mm was recorded for the osteotomy group (mean difference 4.8 mm, 95% CI 0.41 to 9.19). No statistically significant differences could be detected between the groups in speech outcomes, when evaluated through resonance (hypernasality) at 17 months postoperatively (RR 0.11, 95% CI 0.01 to 1.85) and nasal emissions at 17 months postoperatively (RR 3.00, 95% CI 0.14 to 66.53), or in velopharyngeal function at the same time point (RR 1.28, 95% CI 0.65 to 2.52). Maxillary distraction initially lowered social self-esteem at least until the distractors were removed, at three months postoperatively, compared to the osteotomy group, but this improved over time and the distraction group had higher satisfaction with life in the long term (two years after surgery) (MD 2.95, 95% CI 014 to 5.76). Adverse effects, in terms of clinical morbidities, included mainly occlusal relapse and mucosal infection, with the frequency being similar between groups (3/15 participants in the distraction osteogenesis group and 3/14 participants in the osteotomy group). There was no severe harm to any participant. This review found only one small randomised controlled trial concerning the effectiveness of distraction osteogenesis compared to conventional orthognathic surgery. The available evidence is of very low quality, which indicates that further research is likely to change the estimate of the effect. Based on measured outcomes, distraction osteogenesis may produce more satisfactory results; however, further prospective research comprising assessment of a larger sample size with participants with different facial characteristics is required to confirm possible true differences between interventions.
Six trials and 146 patients were included. The proportion improved was significantly better in the group on ketanserin with a Peto's odds ratio (OR) of 2.74 (95% CI 1.42, 5.11) (Cadranel 1986; Dormandy 1988; Kirch 1987; Lukac 1985; van de Wal 1987). When comparing ketanserin to placebo, the decrease in frequency of RP attacks favoured placebo and was statistically significant [WMD (fixed) 25.20 (95% CI 22.55,27.85)] (Kirch 1987). Side effects were significantly more common in the group using active treatment [Peto's OR 2.63 (95% CI 1.42, 4.88)] (Cadranel 1986; Kirch 1987; Lukac 1985; Ortonne 1989; van de Wal 1987). Duration of attacks significantly favoured the placebo group over the active treatment [WMD (fixed) 4.10 (95% CI 3.57, 4.63)] (Kirch 1987). Ketanserin may have some efficacy in the treatment of Raynaud's phenomenon secondary to scleroderma. Overall, ketanserin is not significantly different from placebo for the treatment of Raynaud's phenomenon except for some decrease in the duration of attacks and more subjects improved on ketanserin compared to placebo. However, there were more side effects, and the frequency of attacks actually favored placebo. It can be concluded that ketanserin treatment in Raynaud's phenomenon secondary to scleroderma is not clinically beneficial.
We included two RCTs in the review. One study focused on the primary prevention of CVD, and the other addressed secondary prevention. We evaluated both as being at high risk of bias. Our primary outcomes of interest were death (all-cause and CVD-related) and all cardiovascular events, measured at one-year follow-up or longer. For primary prevention of CVD in participants with periodontitis and metabolic syndrome, one study (165 participants) provided very low-certainty evidence. There was only one death in the study; we were unable to determine whether scaling and root planning plus amoxicillin and metronidazole could reduce incidence of all-cause death (Peto odds ratio (OR) 7.48, 95% confidence interval (CI) 0.15 to 376.98), or all CVD-related death (Peto OR 7.48, 95% CI 0.15 to 376.98). We could not exclude the possibility that scaling and root planning plus amoxicillin and metronidazole could increase cardiovascular events (Peto OR 7.77, 95% CI 1.07 to 56.1) compared with supragingival scaling measured at 12-month follow-up. For secondary prevention of CVD, one pilot study randomised 303 participants to receive scaling and root planning plus oral hygiene instruction (periodontal treatment) or oral hygiene instruction plus a copy of radiographs and recommendation to follow-up with a dentist (community care). As cardiovascular events had been measured for different time periods of between 6 and 25 months, and only 37 participants were available with at least one-year follow-up, we did not consider the data to be sufficiently robust for inclusion in this review. The study did not evaluate all-cause death and all CVD-related death. We are unable to draw any conclusions about the effects of periodontal therapy on secondary prevention of CVD. For primary prevention of cardiovascular disease (CVD) in people diagnosed with periodontitis and metabolic syndrome, very low-certainty evidence was inconclusive about the effects of scaling and root planning plus antibiotics compared to supragingival scaling. There is no reliable evidence available regarding secondary prevention of CVD in people diagnosed with chronic periodontitis and CVD. Further trials are needed to reach conclusions about whether treatment for periodontal disease can help prevent occurrence or recurrence of CVD.
We included thirty trials, all conducted in high income countries, involving 4691 participants. Median sample size per group was 21. We examined the quality of each trial against eight standard criteria, and all trials were inadequate in relation to three or more of these standards. Trials evaluated contracts in addiction (10 trials), hypertension (4 trials), weight control (3 trials) and a variety of other areas (13 trials). Fifteen trials reported at least one outcome that showed statistically significant differences favouring the contracts group, six trials reported at least one outcome that showed differences favouring the control group and 26 trials reported at least one outcome without differences between groups. Effects on adherence were not detected when measured over longer periods. There is limited evidence that contracts can potentially contribute to improving adherence, but there is insufficient evidence from large, good quality studies to routinely recommend contracts for improving adherence to treatment or preventive health regimens.
We included four RCTs (n = 1392 women) which administered the following interventions: bed rest (two trials), fibrin sealant (one trial), and mechanical closure of the cervix (one trial). Our primary outcome, live birth rate, was not reported in any of the included trials; nor were the data available from the corresponding authors. For the ongoing pregnancy rate, two trials comparing more bed rest with less bed rest showed no evidence of a difference between groups (odds ratio (OR) 0.88; 95% confidence interval (CI) 0.60 to 1.31, 542 women, I2 = 0%, low quality evidence). Secondary outcomes were sporadically reported with the exception of the clinical pregnancy rate, which was reported in all of the included trials. There was no evidence of a difference in clinical pregnancy rate between more bed rest and less bed rest (OR 0.88; 95% CI 0.60 to 1.31, 542 women, I2 = 0%, low quality evidence) or between fibrin sealant and usual care (OR 0.98; 95% CI 0.54 to 1.78, 211 women, very low quality evidence). However, mechanical closure of the cervix was associated with a higher clinical pregnancy rate than usual care (OR 1.92; 95% CI 1.40 to 2.63, very low quality evidence). The quality of the evidence was rated as low or very low for all outcomes. The main limitations were failure to report live births, imprecision and risk of bias. Overall, the risk of bias of the included trials was high. The use of a proper method of randomisation and allocation concealment was fairly well reported, while only one trial clearly reported blinding. There was no evidence that any of the interventions had an effect on adverse event rates but data were too few to reach any conclusions. There is insufficient evidence to support any specific length of time for women to remain recumbent, if at all, following embryo transfer, nor is there sufficient evidence to recommend the use of fibrin sealants added to the embryo transfer fluid. There is very limited evidence to support the use of mechanical pressure to close the cervical canal following embryo transfer. Further well-designed and powered studies are required to determine the true effectiveness and safety of these interventions.
We included 21 randomised trials (involving 2222 women) and the majority of them had unclear or high risk of bias. There were several different herbal preparations used within the included trials. The average treatment duration was three to six months. The primary outcome of uterine fibroid related symptoms was not reported in any of the included trials. The majority of the trials reported fibroid volume and size of the uterus. Compared with mifepristone, Tripterygium wilfordii extract was associated with a greater reduction in the fibroid volume (MD -23.03 cm3, 95% CI -28.39 to -17.67; 2 trials) and in uterine size (MD -51.25 cm3, 95% CI -77.70 to -24.80; 2 trials). There was no evidence of a significant difference between Nona Roguy herbal product and gonadotropin-releasing hormone (GnRH) agonist on the average fibroid volume or the uterine size. The combination of Guizhi Fuling formula and mifepristone was associated with a greater reduction in the fibroid volume (-1.72 [-2.42, -1.02] 7 trials) and in uterine size (MD -31.63 [95% CI -54.58, -8.68] 3 trials)) compared with mifepristone alone. Only 13/21 trials reported on adverse events and no serious adverse effects from herbal preparations were reported. Current evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies with large sample sizes and of high quality. Further high quality trials evaluating clinically relevant outcomes are warranted.
The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first-generation antipsychotic agents in terms of the primary outcome "clinically important response to treatment" (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69). Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first-generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.
Four studies at unclear to high risk of bias comprising 463 participants were included. The mean study duration was 7.5 months (range 3 to 18 months). One of our primary outcomes－'change from baseline in health related quality of life'－and two of our secondary outcomes－'change from baseline in LT4 replacement dosage at end of the study' and 'economic costs'－were not assessed in any of the studies. One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4 (relative risk (RR) 4.67, 95% confidence interval (CI) 1.61 to 13.50; P = 0.004; 36 participants; number needed to treat (NNT) = 2 (95% CI 2 to 3)). Selenomethionine 200 μg reduced the serum levels of anti-thyroid peroxidase antibodies compared with placebo in two studies (mean difference (MD) -917 U/mL, 95% CI -1056 to -778; P < 0.001; 85 participants) and (MD -345 IU/mL, 95% CI -359 to -331; P < 0.001; 169 participants). Pooling of the studies was not feasible due to marked clinical heterogeneity (I2 = 99%). In a further comparison within the first study where selenomethionine was combined with LT4 the reduction in TPO antibodies was even more noticeable (MD -1508 U/mL, 95% CI -1671 to -1345; P < 0.001; 86 participants). In a third study, where LT4 was added to both intervention arms, a reduction in serum levels of anti-thyroid peroxidase antibodies favoured the selenomethionine arm as well (MD -235 IU/mL, 95% CI -374 to -95; P = 0.001; 88 participants). Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear. Serum antibodies were not statistically significantly affected in the study comparing sodium selenite 200 μg plus titrated LT4 with placebo plus titrated LT4 (MD -25, 95% CI -181 to 131; P = 0.75; 36 participants). Adverse events were reported in two studies (1 of 85 and 1 of 88 participants, respectively). Selenium supplementation did not appear to have a statistically significant impact on the incidence of adverse events (RR 2.93, 95% CI 0.12 to 70.00; and RR 2.63, 95% CI 0.11 to 62.95). Results of these four studies show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete. The current level of evidence for the efficacy of selenium supplementation in the management of people with Hashimoto's thyroiditis is based on four randomised controlled trials assessed at unclear to high risk of bias; this does not at present allow confident decision making about the use of selenium supplementation for Hashimoto's thyroiditis. This review highlights the need for randomised placebo-controlled trials to evaluate the effects of selenium in people with Hashimoto's thyroiditis and can ultimately provide reliable evidence to help inform clinical decision making.
We did not identify any randomised controlled trials that evaluated the effectiveness of sleep positioning systems on hip migration. We did find two randomised cross-over trials that met the inclusion criteria in respect of secondary objectives relating to sleep quality and pain. Neither study reported any important difference between sleeping in sleep positioning systems and not for sleep patterns or sleep quality (two studies, 21 children, very low quality evidence) and pain (one study, 11 children, very low quality evidence). These were small studies with established users of sleep positioning systems and were judged to have high risk of bias. We found no eligible trials that explored the other secondary objectives (number or frequency of hip problems, quality of life of the child and family, physical functioning, and adverse effects). We found no randomised trials that evaluated the effectiveness of sleep positioning systems to reduce or prevent hip migration in children with cerebral palsy. Nor did we find any randomised trials that evaluated the effect of sleep positioning systems on the number or frequency of hip problems, quality of life of the child and family or on physical functioning. Limited data from two randomised trials, which evaluated the effectiveness of sleep positioning systems on sleep quality and pain for children with cerebral palsy, showed no significant differences in these aspects of health when children were using and not using a sleep positioning system. In order to inform clinical decision-making and the prescription of sleep positioning systems, more rigorous research is needed to determine effectiveness, cost-effectiveness, and the likelihood of adverse effects.
We included 33 trials with a total of 2293 participants from 0.9 to 12 (mean or median) years of age. Most trials were at low risk of selection, detection, attrition, and reporting bias, however the lack of blinding of participants and personnel caring for participants resulted in 25 trials being judged as at high or unclear risk of bias. We identified five ongoing trials. Ultrasound guidance probably reduces the risk of failed block (risk difference (RD) −0.16, 95% confidence interval (CI) −0.25 to −0.07; 22 trials; 1789 participants; moderate-quality evidence). When ultrasound guidance was used, there was a small to moderate reduction in pain one hour after surgery, equivalent to a reduction of 1.3 points on the revised Bieri FACES pain scale (scale; 0 = no pain, 10 = maximal pain) (standardized mean difference (SMD) −0.41, 95% CI −0.74 to −0.07 (medium effect size); 15 trials; 982 participants; moderate-quality evidence). Ultrasound guidance increases block duration by the equivalent of 42 minutes (SMD 1.24, 95% CI 0.72 to 1.75; 10 trials; 460 participants; high-quality evidence). There is probably little or no difference in the time taken to perform the block (SMD −0.46, 95% CI −1.06 to 0.13; 9 trials; 680 participants; moderate-quality evidence). It is uncertain whether the number of needle passes required is reduced with the use of ultrasound guidance (SMD −0.63, 95% CI −1.08 to −0.18; 3 trials; 256 participants; very low-quality evidence). There were no occurrences of major complications in either the intervention or control arms of the trials (cardiac arrest from local anaesthetic toxicity (22 trials; 1576 participants; moderate-quality evidence); lasting neurological injury (19 trials; 1250 participants; low-quality evidence)). There may be little of no difference in the risk of bloody puncture (RD −0.02, 95% CI −0.05 to 0.00; 13 trials; 896 participants; low-quality evidence) or transient neurological injury (RD −0.00, 95% CI −0.01 to 0.01; 18 trials; 1230 participants; low-quality evidence). There were no occurrences of seizure from local anaesthetic toxicity (22 trials; 1576 participants; moderate-quality evidence) or block infections without neurological injury (18 trials; 1238 participants; low-quality evidence). Ultrasound guidance for regional blockade in children probably decreases the risk of failed block. It increases the duration of the block and probably decreases pain scores at one hour after surgery. There may be little or no difference in the risks of some minor complications. The five ongoing studies may alter the conclusions of the review once published and assessed.
Six trials met the inclusion criteria. We have not found any new studies since the initial review. In the trial comparing the desogestrel versus levonorgestrel progestin-only pill, desogestrel was not associated with a significantly lower risk of accidental pregnancy; the rate ratio was 0.27 (95% CI 0.06 to 1.19). However, the desogestrel progestin-only pill caused more bleeding problems, although this difference was not statistically significant. The trial comparing low-dose mifepristone versus a levonorgestrel progestin-only pill found similar pregnancy rates. In the trial comparing ethynodiol diacetate versus a combined oral contraceptive, irregular cycles occurred in all women assigned to the progestin-only pill (odds ratio 135.96; 95% CI 7.61 to 2421.02). In a trial comparing two progestin-only and two combined oral contraceptives, the progestin-only pill containing levonorgestrel 30 μg had higher efficacy than did the pill containing norethisterone 350 μg. An early trial found megestrol acetate inferior to other progestin-only pills in terms of efficacy. A study of the timing of pill initiation after birth found no important differences, but high losses to follow up undermined the trial. Evidence is insufficient to compare progestin-only pills to each other or to combined oral contraceptives.
We included 38 studies (15,903 participants) in this review, 18 of which were cluster-randomised trials (11,995 participants) and two were quasi-randomised trials (399 participants). We included 33 studies in the meta-analyses. We included eight studies (3405 participants) in the meta-analysis assessing episodes of relationship violence. There was substantial heterogeneity (I2 = 57%) for this outcome. The risk ratio was 0.77 (95% confidence interval (CI) 0.53 to 1.13). We included 22 studies (5256 participants) in the meta-analysis assessing attitudes towards relationship violence. The standardised mean difference (SMD) was 0.06 (95% CI -0.01 to 0.15). We included four studies (887 participants) in the meta-analysis assessing behaviour related to relationship violence; the SMD was -0.07 (95% CI -0.31 to 0.16). We included 10 studies (6206 participants) in the meta-analysis assessing knowledge related to relationship violence; the results showed an increase in knowledge in favour of the intervention (SMD 0.44, 95% CI 0.28 to 0.60) but there was substantial heterogeneity (I2 = 52%). We included seven studies (1369 participants) in the meta-analysis assessing skills related to relationship violence. The SMD was 0.03 (95% CI -0.11 to 0.17). None of the included studies assessed physical health, psychosocial health or adverse outcomes. Subgroup analyses showed no statistically significant differences by intervention setting or type of participants. The quality of evidence for all outcomes included in our meta-analysis was moderate due to an unclear risk of selection and detection bias and a high risk of performance bias in most studies. Studies included in this review showed no evidence of effectiveness of interventions on episodes of relationship violence or on attitudes, behaviours and skills related to relationship violence. We found a small increase in knowledge but there was evidence of substantial heterogeneity among studies. Further studies with longer-term follow-up are required, and study authors should use standardised and validated measurement instruments to maximise comparability of results.
We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period. The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence). We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants. The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.
The one study included in this review is a small (n=30) randomised controlled trial lasting 24 weeks. It was followed-up by an open label study with a crossover design. No significant differences were found on any four validated outcomes including global functioning and three measures of cognitive abilities and behavioural problems. 6 out of 16 carers (37%) of participants on donepezil and 2 out of 15 (13%) on placebo reported improvement. No data were available for day to day skills, institutionalisation, reduction in carers' stress or economic outcomes. Half the intervention group and 20% of the placebo group reported adverse events; two participants left because of adverse events. To date there is only one small randomised controlled study on the effect of donepezil. This shows, at best, a modest, non statistically significant trend in favour of people with Down syndrome and Alzheimer's dementia who are able to tolerate donepezil (this drug is currently only dispensed in relatively large doses and is contraindicated for those with cardiac and respiratory problems).This study does not provide good evidence on which to base practice. Findings in an open-label follow up to this study suggest possible benefit in some individuals. Further, larger randomised controlled studies with longer-term follow up are required.
Updating the previous review through December 2009 identified 41 additional papers, for a grand total of 278 references. Two-hundred and fourty-two of them were excluded because they analyzed survival (n=27), were repetitive (n=29), letters/reviews (n=71) or had no data (n=115). Thirty-six studies on 12,127 patients remained included: 23 showed a detrimental effect of PBT; 22 used multivariable analyses, and 14 found an independent PBT effect. Pooled estimates of PBT effect on recurrence in randomised studies yielded an OR of 1.42 (95% CI, 1.20 to 1.67) against transfused patients. Stratified meta-analyses confirmed these findings also by site and stage of disease, regardless of timing, type, and in a dose-related fashion, although heterogeneity was detected. Data on surgical techniques was not available for further analysis. This updated meta-analysis confirms the previous findings and supports the association of PBT on the recurrence of curable colorectal cancers. However, since heterogeneity was detected and the effect of surgical technique could not be assessed, a causal relationship cannot still be claimed. Carefully restricted indications for PBT seems necessary.
We included four studies with 151 randomized participants. Two studies included participants who were mechanically ventilated, one study included a mix of ventilated and non-ventilated participants and in one study participants were being weaned from mechanical ventilation. Three studies reported admission diagnoses, which varied: these included sepsis, pneumonia and cardiac or cardiorespiratory arrest. All studies compared melatonin against no agent; three were placebo-controlled trials; and one compared melatonin with usual care. All studies administered melatonin in the evening. All studies reported adequate methods for randomization and placebo-controlled trials were blinded at the participant and personnel level. We noted high risk of attrition bias in one study and were unclear about potential bias introduced in two studies with differences between participants at baseline. It was not appropriate to combine data owing to differences in measurement tools, or methods used to report data. The effects of melatonin on subjectively rated quantity and quality of sleep are uncertain (very low certainty evidence). Three studies (139 participants) reported quantity and quality of sleep as measured through reports of participants or family members or by personnel assessments. Study authors in one study reported no difference in sleep efficiency index scores between groups for participant assessment (using Richards-Campbell Sleep Questionnaire) and nurse assessment. Two studies reported no difference in duration of sleep observed by nurses. The effects of melatonin on objectively measured quantity and quality of sleep are uncertain (very low certainty evidence). Two studies (37 participants) reported quantity and quality of sleep as measured by polysomnography (PSG), actigraphy, bispectral index (BIS) or electroencephalogram (EEG). Study authors in one study reported no difference in sleep efficiency index scores between groups using BIS and actigraphy. These authors also reported longer sleep in participants given melatonin which was not statistically significant, and improved sleep (described as "better sleep") in participants given melatonin from analysis of area under the curve (AUC) of BIS data. One study used PSG but authors were unable to report data because of a large loss of participant data. One study (82 participants) reported no evidence of a difference in anxiety scores (very low certainty evidence). Two studies (94 participants) reported data for mortality: one study reported that overall one-third of participants died; and one study reported no evidence of difference between groups in hospital mortality (very low certainty). One study (82 participants) reported no evidence of a difference in length of ICU stay (very low certainty evidence). Effects of melatonin on adverse events were reported in two studies (107 participants), and are uncertain (very low certainty evidence): one study reported headache in one participant given melatonin, and one study reported excessive sleepiness in one participant given melatonin and two events in the control group (skin reaction in one participant, and excessive sleepiness in another participant). The certainty of the evidence for each outcome was limited by sparse data with few participants. We noted study limitations in some studies due to high attrition and differences between groups in baseline data; and doses of melatonin varied between studies. Methods used to measure data were not consistent for outcomes, and use of some measurement tools may not be effective for use on the ICU patient. All studies included participants in the ICU but we noted differences in ICU protocols, and one included study used a non-standard sedation protocol with participants which introduced indirectness to the evidence. We found insufficient evidence to determine whether administration of melatonin would improve the quality and quantity of sleep in ICU patients. We identified sparse data, and noted differences in study methodology, in ICU sedation protocols, and in methods used to measure and report sleep. We identified five ongoing studies from database and clinical trial register searches. Inclusion of data from these studies in future review updates would provide more certainty for the review outcomes.
We identified 16 randomised controlled trials with 3578 participants that fitted our inclusion criteria. These studies included a wide spectrum of interventions covering clinic-based brief interventions, Internet-based interventions that could be used from home and mobile phone-based interventions. The mean age of participants was between 46 to 67 years old and mean time since diagnosis was 6 to 13 years. The duration of the interventions varied between 1 to 12 months. There were three reported deaths out of 3578 participants. Computer-based diabetes self-management interventions currently have limited effectiveness. They appear to have small benefits on glycaemic control (pooled effect on glycosylated haemoglobin A1c (HbA1c): -2.3 mmol/mol or -0.2% (95% confidence interval (CI) -0.4 to -0.1; P = 0.009; 2637 participants; 11 trials). The effect size on HbA1c was larger in the mobile phone subgroup (subgroup analysis: mean difference in HbA1c -5.5 mmol/mol or -0.5% (95% CI -0.7 to -0.3); P < 0.00001; 280 participants; three trials). Current interventions do not show adequate evidence for improving depression, health-related quality of life or weight. Four (out of 10) interventions showed beneficial effects on lipid profile. One participant withdrew because of anxiety but there were no other documented adverse effects. Two studies provided limited cost-effectiveness data - with one study suggesting costs per patient of less than $140 (in 1997) or 105 EURO and another study showed no change in health behaviour and resource utilisation. Computer-based diabetes self-management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control and the effect was larger in the mobile phone subgroup. There is no evidence to show benefits in other biological outcomes or any cognitive, behavioural or emotional outcomes.
We included two small trials involving 79 patients. One trial (20 patients) examined the efficacy of intravenous, adjusted dose unfractionated heparin. The other trial (59 patients) examined high dose, body weight adjusted, subcutaneous, low-molecular weight heparin (nadroparin). Anticoagulant therapy was associated with a pooled relative risk of death of 0.33 (95% confidence interval (CI) 0.08 to 1.21) and of death or dependency of 0.46 (95% CI 0.16 to 1.31). The absolute reduction in the risk of death or dependency was 13% (95% CI 30% to -3%). No new symptomatic intracerebral haemorrhages were observed. One major gastro-intestinal haemorrhage occurred after anticoagulant treatment. Two control patients (placebo) had a diagnosis of probable pulmonary embolism (one fatal). Based upon the limited evidence available, anticoagulant treatment for cerebral venous sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significance.
We included six studies with 350 participants followed for at least three months. All of these studies enrolled participants undergoing total knee replacement. Studies were at least partially blinded. Three studies had a high risk of performance bias and one a high risk of attrition bias, but the risk of bias was otherwise unclear or low. Only one study assessed joint function using a global score. Due to heterogeneity in outcome and reporting, we could only pool three out of six RCTs, with range of motion assessed at three months after surgery used as a surrogate for joint function. All studies had a high risk of detection bias. Using the random-effects model, there was no statistically significant difference between the experimental and control groups (mean difference 3.99 degrees, 95% confidence interval (CI) − 2.23 to 10.21; P value = 0.21, 3 studies, 140 participants, very low quality evidence). We did not perform further analyses because immediate adverse effects were not part of the explicit outcomes of any of these typically small studies, and long-term adverse events after regional anaesthesia are rare. None of the included studies elicited or reported long-term adverse effects like persistent nerve damage. More high-quality studies are needed to establish the effects of regional analgesia on function after major joint replacement, as well as on the risk of adverse events (falls).
When pipotiazine palmitate was compared with 'standard' oral antipsychotic no differences were found for outcomes of global impression (n=53, 1 RCT, RR 2.57, CI 0.8 to 8.6), relapse (n=124, 1 RCT, RR 1.55 CI 0.76 to 3.2), study attrition (n=219, 3 RCTs, RR 1.37 CI 0.8 to 2.4) and behaviour (n=124, 1 RCT, WMD 4.65, CI -1.1 to 10.4). There was also no reported difference in adverse effects such as tardive dyskinesia or the need for anticholinergic drugs.   Sixteen studies compared pipotiazine palmitate with other depot preparations (n=1123). Pipotiazine palmitate was consistently equivalent to other depots in terms of a range of outcomes, including global impression (n=217, 4 RCTs, RR not improved 0.99 CI 0.91 to 1.07), relapse (n=239, 5 RCTs, RR relapse by 1 year 0.98 CI 0.55 to 1.75), and adverse effects (n=337, 5 RCTs, RR needing anticholinergic medication 0.98 CI 0.84 to 1.15). Although well-conducted and reported randomised trials are still needed to fully inform practice (no trial data exists reporting hospital and services outcomes, satisfaction with care and economics) pipotiazine palmitate is a viable choice for both clinician and recipient of care.
Three trials involving 247 people were included. Two studies involving 151 people assessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale scores on average by a further 2.65 points (95% confidence interval 0.38 to 4.93). Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at ten weeks (relative risk (RR) 0.47, 95% CI 0.24 to 0.92) The number needed to treat with folate for one additional person to experience a 50% reduction on this scale was 5 (95% confidence interval 4 to 33). One study involving 96 people assessed the use of folate instead of the antidepressant trazodone and did not find a significant benefit from the use of folate. The trials identified did not find evidence of any problems with the acceptability or safety of folate. The limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency.
The review included nine studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut-off levels used (12 parts per billion (ppb) to 30 ppb), the way in which FeNO was used to adjust therapy and duration of study (6 to 12 months). Of 1426 children randomised, 1329 completed the studies. The inclusion criteria for the participants in each study varied but all had a diagnosis of asthma. There was a significant difference in the number of children having one or more asthma exacerbations over the study period, they were significantly lower in the FeNO group in comparison to the control group (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.49 to 0.80; 1279 participants; 8 studies). The number needed to treat for an additional beneficial outcome (NNTB) over 52 weeks was 10 (95% CI 7 to 20). There was no difference between the groups when comparing exacerbation rates (mean difference (MD) -0.37, 95% CI -0.8 to 0.06; 736 participants; 4 studies; I2 = 67%). The number of children in the FeNO group requiring oral corticosteroid courses was lower in comparison to the children in the control group (OR 0.63, 95% CI 0.48 to 0.83; 1169 participants; 7 studies; I2 = 0%). There was no statistically significant difference between the groups for exacerbations requiring hospitalisation (OR 0.75, 95% CI 0.41 to 1.36; 1110 participants; 6 studies; I2 = 0%). There were no significant differences between the groups for any of the secondary outcomes (forced expiratory volume in one second (FEV1), FeNO levels, symptom scores or inhaled corticosteroid doses at final visit). The included studies recorded no adverse events. Three studies had inadequate blinding and were thus considered to have a high risk of bias. However, when these studies were removed in subgroup analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'Number of participants who had one or more exacerbations over the study period') to very low (for the outcome 'Exacerbation rates'), based on lack of blinding, statistical heterogeneity and imprecision. In this updated review with five new included studies, tailoring asthma medications based on FeNO levels (in comparison with primarily guideline management) significantly decreased the number of children who had one or more exacerbations over the study period but did not impact on the day-to-day clinical symptoms or inhaled corticosteroid doses. Therefore, the use of FeNO to guide asthma therapy in children may be beneficial in a subset of children, it cannot be universally recommended for all children with asthma. Further RCTs need to be conducted and these should encompass different asthma severities, different settings including primary care and less affluent settings, and consider different FeNO cut-offs.
Twelve trials met the inclusion criteria. One trial is still ongoing, leaving a total of 11 trials eligible involving 653 participants. These trials were conducted between 1978 and 2006 and enrolled participants from fairly comparable patient populations. None of the studies included people with neutrophil dysfunction. Ten studies included only adults, and two studies included children and adults. Ten of these studies contained separate data for each arm and were able to be critically appraised. One study re-randomised people and therefore quantitative analysis was unable to be performed. Overall, the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcome estimates being imprecise. All-cause mortality was reported for nine studies (609 participants). There was no difference in all-cause mortality over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (seven studies; 437 participants; RR 0.92, 95% CI 0.63 to 1.36, very low-quality evidence). Mortality due to infection was reported for seven studies (398 participants). There was no difference in mortality due to infection over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (six studies; 286 participants; RR 0.69, 95% CI 0.33 to 1.44, very low-quality evidence). The number of people with localised or systemic bacterial or fungal infections was reported for nine studies (609 participants). There were differences between the granulocyte dose subgroups (test for subgroup differences P = 0.01). There was no difference in the number of people with infections over 30 days between people receiving prophylactic granulocyte transfusions and those that did not in the low-dose granulocyte group (< 1.0 x 1010 granulocytes per day) (four studies, 204 participants; RR 0.84, 95% CI 0.58 to 1.20; very low-quality evidence). There was a decreased number of people with infections over 30 days in the people receiving prophylactic granulocyte transfusions in the intermediate-dose granulocyte group (1.0 x 1010 to 4.0 x 1010 granulocytes per day) (4 studies; 293 participants; RR 0.40, 95% CI 0.26 to 0.63, low-quality evidence). There was a decreased number of participants with bacteraemia and fungaemia in the participants receiving prophylactic granulocyte transfusions (nine studies; 609 participants; RR 0.45, 95% CI 0.30 to 0.65, low-quality evidence). There was no difference in the number of participants with localised bacterial or fungal infection in the participants receiving prophylactic granulocyte transfusions (six studies; 296 participants; RR 0.75, 95% CI 0.50 to 1.14; very low-quality evidence). Serious adverse events were only reported for participants receiving granulocyte transfusions and donors of granulocyte transfusions. In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is low-grade evidence that prophylactic granulocyte transfusions decrease the risk of bacteraemia or fungaemia. There is low-grade evidence that the effect of prophylactic granulocyte transfusions may be dose-dependent, a dose of at least 1.0 x 1010 per day being more effective at decreasing the risk of infection. There is insufficient evidence to determine any difference in mortality rates due to infection, all-cause mortality, or serious adverse events.
Five randomised trials involving 664 participants were analysed. Five different herbal medicines were tested in these trials, including Huo-Xue-Tong-Fu decoction, Xiao-Cheng-Qi-Tang decoction, a combination of Xiao-Cheng-Qi-Tang and Si-Jun-Zi-Tang decoctions, Chang-Nian-Lian-Song-Jie-Tang decoction, and Fufang-Da-Cheng-Qi-Tang decoction. There were variations in the tested herbal compositions and methods of medicine administration. The main outcomes reported in the trials were effects on abdominal pain, abdominal distension, constipation defection, time of first defecation after treatment, and reoperation rate during the course of the disease. Secondary outcomes selected for this review were not available, including complications such as small bowel perfusion (bowel resection, system complications, and other possible complications), length of hospital stay, cost of hospitalisation, and time from admission to surgical intervention. The results of five trials showed that patients receiving TCM combined with conventional therapy seemed to have improved outcomes compared with patients receiving conventional treatment alone (OR 4.24, 95% CI 2.83 to 6.36). However, we cannot conclusively determine the efficacy of TCM in this review due to inadequate reporting, low methodological quality, and the prevalence of various biases in the reviewed studies. Furthermore, because none of the reviewed trials discussed adverse events, we could not evaluate the safety of TCM for adhesive SBO patients. All trials were conducted and published in China. Although many studies have assessed the use of TCM products for adhesive SBO, most were excluded from this review due to their methodological limitations. This systematic review did not find sufficient evidence to support the objective efficacy and safety of TCM for patients with adhesive SBO. The positive evidence should be interpreted with caution given the insufficient number of studies with large sample sizes, the absence of well-designed, high-quality trials, and the lack of safety information. Therefore, further studies with larger sample sizes and high-quality, randomised, and controlled trials are necessary to produce more accurate and meaningful data on the efficacy of Chinese herbal medicines for adhesive SBO.
We found 22 eligible studies that included a total of 11,450 women. With 6 NRS added to this update, the review includes 17 NRS and 5 RCTs. By contraceptive method, the review has 16 studies of depot medroxyprogesterone acetate (DMPA), 4 of levonorgestrel-releasing intrauterine contraception (LNG-IUC), 5 for implants, and 2 for progestin-only pills. Comparison groups did not differ significantly for weight change or other body composition measure in 15 studies. Five studies with moderate or low quality evidence showed differences between study arms. Two studies of a six-rod implant also indicated some differences, but the evidence was low quality. Three studies showed differences for DMPA users compared with women not using a hormonal method. In a retrospective study, weight gain (kg) was greater for DMPA versus copper (Cu) IUC in years one (MD 2.28, 95% CI 1.79 to 2.77), two (MD 2.71, 95% CI 2.12 to 3.30), and three (MD 3.17, 95% CI 2.51 to 3.83). A prospective study showed adolescents using DMPA had a greater increase in body fat (%) compared with a group not using a hormonal method (MD 11.00, 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD -4.00, 95% CI -6.93 to -1.07). A more recent retrospective study reported greater mean increases with use of DMPA versus Cu IUC for weight (kg) at years 1 (1.3 vs 0.2), 4 (3.5 vs 1.9), and 10 (6.6 vs 4.9). Two studies reported a greater mean increase in body fat mass (%) for POC users versus women not using a hormonal method. The method was LNG-IUC in two studies (reported means 2.5 versus -1.3; P = 0.029); (MD 1.60, 95% CI 0.45 to 2.75). One also studied a desogestrel-containing pill (MD 3.30, 95% CI 2.08 to 4.52). Both studies showed a greater decrease in lean body mass among POC users. We considered the overall quality of evidence to be low; more than half of the studies had low quality evidence. The main reasons for downgrading were lack of randomizations (NRS) and high loss to follow-up or early discontinuation. These 22 studies showed limited evidence of change in weight or body composition with use of POCs. Mean weight gain at 6 or 12 months was less than 2 kg (4.4 lb) for most studies. Those with multiyear data showed mean weight change was approximately twice as much at two to four years than at one year, but generally the study groups did not differ significantly. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain.
We included 36 studies (33 RCTs) with a total of 3523 participants. Included studies were conducted in sub-Saharan Africa, the Middle East and North Africa, and Asia. Studies were implemented in response to armed conflicts; disasters triggered by natural hazards; and other types of humanitarian crises. Together, the 33 RCTs compared eight psychological treatments against a control comparator. Four studies included children and adolescents between 5 and 18 years of age. Three studies included mixed populations (two studies included participants between 12 and 25 years of age, and one study included participants between 16 and 65 years of age). Remaining studies included adult populations (18 years of age or older). Included trials compared a psychological therapy versus a control intervention (wait list in most studies; no treatment; treatment as usual). Psychological therapies were categorised mainly as cognitive-behavioural therapy (CBT) in 23 comparisons (including seven comparisons focused on narrative exposure therapy (NET), two focused on common elements treatment approach (CETA), and one focused on brief behavioural activation treatment (BA)); eye movement desensitisation and reprocessing (EMDR) in two comparisons; interpersonal psychotherapy (IPT) in three comparisons; thought field therapy (TFT) in three comparisons; and trauma or general supportive counselling in two comparisons. Although interventions were described under these categories, several psychotherapeutic elements were common to a range of therapies (i.e. psychoeducation, coping skills). In adults, psychological therapies may substantially reduce endpoint PTSD symptoms compared to control conditions (standardised mean difference (SMD) -1.07, 95% confidence interval (CI) -1.34 to -0.79; 1272 participants; 16 studies; low-quality evidence). The effect is smaller at one to four months (SMD -0.49, 95% CI -0.68 to -0.31; 1660 participants; 18 studies) and at six months (SMD -0.37, 95% CI -0.61 to -0.14; 400 participants; five studies). Psychological therapies may also substantially reduce endpoint depression symptoms compared to control conditions (SMD -0.86, 95% CI -1.06 to -0.67; 1254 participants; 14 studies; low-quality evidence). Similar to PTSD symptoms, follow-up data at one to four months showed a smaller effect on depression (SMD -0.42, 95% CI -0.63 to -0.21; 1386 participants; 16 studies). Psychological therapies may moderately reduce anxiety at endpoint (SMD -0.74, 95% CI -0.98 to -0.49; 694 participants; five studies; low-quality evidence) and at one to four months' follow-up after treatment (SMD -0.53, 95% CI -0.66 to -0.39; 969 participants; seven studies). Dropout rates are probably similar between study conditions (19.5% with control versus 19.1% with psychological therapy (RR 0.98 95% CI 0.82 to 1.16; 2930 participants; 23 studies, moderate quality evidence)). In children and adolescents, we found very low quality evidence for lower endpoint PTSD symptoms scores in psychotherapy conditions (CBT) compared to control conditions, although the confidence interval is wide (SMD -1.56, 95% CI -3.13 to 0.01; 130 participants; three studies;). No RCTs provided data on major depression or anxiety in children. The effect on withdrawal was uncertain (RR 1.87 95% CI 0.47 to 7.47; 138 participants; 3 studies, low quality evidence). We did not identify any studies that evaluated psychological treatments on (symptoms of) somatoform disorders or MUPS in LMIC humanitarian settings. There is low quality evidence that psychological therapies have large or moderate effects in reducing PTSD, depressive, and anxiety symptoms in adults living in humanitarian settings in LMICs. By one to four month and six month follow-up assessments treatment effects were smaller. Fewer trials were focused on children and adolescents and they provide very low quality evidence of a beneficial effect of psychological therapies in reducing PTSD symptoms at endpoint. Confidence in these findings is influenced by the risk of bias in the studies and by substantial levels of heterogeneity. More research evidence is needed, particularly for children and adolescents over longer periods of follow-up.
One study was included. It involved 44 adults aged 60 to 80 years and compared a glucose drink with a saccharin drink, given on only a single occasion. Those receiving the glucose drink were significantly faster in completing the switching condition of the modified Stroop test (F 1, 41 = 10.47; P < 0.01) compared to those receiving the saccharin drink. Participants in the glucose group also showed a significantly smaller dual-task cost in a computerised test of divided attention compared to the placebo group (F 1, 38 = 8.49; P < 0.01, ƞ2 = 0.18). As a glucose drink was administered only once, safety, global function, behaviour disturbance, and activities of daily living were not investigated in the study. With only one RCT included, there is insufficient evidence to base any recommendations about the use of any form of carbohydrate for enhancing cognitive performance in older adults with normal cognition or mild cognitive impairment. More studies of many different carbohydrates are needed to tease out complex nutritional issues and to further evaluate memory improvement.
We identified six relevant studies involving 1088 participants. This included two new studies published after the date of our previous review (2011). There was substantial variation in participants, in the diagnostic criteria used to define an episode of pneumonia, in the interventions and in the reported outcomes. We found no evidence relating to patients with a high probability of HAP who were not mechanically ventilated. For patients with VAP, overall a short seven- or eight-day course of antibiotics compared with a prolonged 10- to 15-day course increased 28-day antibiotic-free days (two studies; N = 431; mean difference (MD) 4.02 days; 95% confidence interval (CI) 2.26 to 5.78) and reduced recurrence of VAP due to multi-resistant organisms (one study; N = 110; odds ratio (OR) 0.44; 95% CI 0.21 to 0.95), without adversely affecting mortality and other recurrence outcomes. However, for cases of VAP specifically due to non-fermenting Gram-negative bacilli (NF-GNB), recurrence was greater after short-course therapy (two studies, N = 176; OR 2.18; 95% CI 1.14 to 4.16), though mortality outcomes were not significantly different. One study found that a three-day course of antibiotic therapy for patients with suspected HAP but a low Clinical Pulmonary Infection Score (CPIS) was associated with a significantly lower risk of superinfection or emergence of antimicrobial resistance, compared with standard (prolonged) course therapy. On the basis of a small number of studies and appreciating the lack of uniform definition of pneumonia, we conclude that for patients with VAP not due to NF-GNB a short, fixed course (seven or eight days) of antibiotic therapy appears not to increase the risk of adverse clinical outcomes, and may reduce the emergence of resistant organisms, compared with a prolonged course (10 to 15 days). However, for patients with VAP due to NF-GNB, there appears to be a higher risk of recurrence following short-course therapy. These findings do not differ from those of our previous review and are broadly consistent with current guidelines. There are few data from RCTs comparing durations of therapy in non-ventilated patients with HAP, but on the basis of a single study, short-course (three-day) therapy for HAP appears not to be associated with worse clinical outcome, and may reduce the risk of subsequent infection or the emergence of resistant organisms when there is low probability of pneumonia according to the CPIS.
We included five randomised controlled trials (RCTs), one controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies, five time-series trials, one case cross-over trial, two ecological studies, six self controlled case series studies involving in all about 14,700,000 children and assessing effectiveness and safety of MMR vaccine. Based on the available evidence, one MMR vaccine dose is at least 95% effective in preventing clinical measles and 92% effective in preventing secondary cases among household contacts. Effectiveness of at least one dose of MMR in preventing clinical mumps in children is estimated to be between 69% and 81% for the vaccine prepared with Jeryl Lynn mumps strain and between 70% and 75% for the vaccine containing the Urabe strain. Vaccination with MMR containing the Urabe strain has demonstrated to be 73% effective in preventing secondary mumps cases. Effectiveness of Jeryl Lynn containing MMR in preventing laboratory-confirmed mumps cases in children and adolescents was estimated to be between 64% to 66% for one dose and 83% to 88% for two vaccine doses. We did not identify any studies assessing the effectiveness of MMR in preventing rubella. The highest risk of association with aseptic meningitis was observed within the third week after immunisation with Urabe-containing MMR (risk ratio (RR) 14.28; 95% confidence interval (CI) from 7.93 to 25.71) and within the third (RR 22.5; 95% CI 11.8 to 42.9) or fifth (RR 15.6; 95% CI 10.3 to 24.2) weeks after immunisation with the vaccine prepared with the Leningrad-Zagreb strain. A significant risk of association with febrile seizures and MMR exposure during the two previous weeks (RR 1.10; 95% CI 1.05 to 1.15) was assessed in one large person-time cohort study involving 537,171 children aged between three months and five year of age. Increased risk of febrile seizure has also been observed in children aged between 12 to 23 months (relative incidence (RI) 4.09; 95% CI 3.1 to 5.33) and children aged 12 to 35 months (RI 5.68; 95% CI 2.31 to 13.97) within six to 11 days after exposure to MMR vaccine. An increased risk of thrombocytopenic purpura within six weeks after MMR immunisation in children aged 12 to 23 months was assessed in one case-control study (RR 6.3; 95% CI 1.3 to 30.1) and in one small self controlled case series (incidence rate ratio (IRR) 5.38; 95% CI 2.72 to 10.62). Increased risk of thrombocytopenic purpura within six weeks after MMR exposure was also assessed in one other case-control study involving 2311 children and adolescents between one month and 18 years (odds ratio (OR) 2.4; 95% CI 1.2 to 4.7). Exposure to the MMR vaccine was unlikely to be associated with autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, bacterial or viral infections. The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with the MMR vaccine cannot be separated from its role in preventing the target diseases.
We identified seven completed trials (472 participants), and four ongoing trials (recruiting 837 participants) which are due to be completed by December 2020. Of the seven completed trials, five trials (456 participants) compared a TPO mimetic versus placebo (four romiplostim trials, and one eltrombopag trial), one trial (eight participants) compared DDAVP with placebo and one trial (eight participants) compared tranexamic acid with placebo. In the DDAVP trial, the only outcome reported was the bleeding time. In the tranexamic acid trial there were methodological flaws and bleeding definitions were subject to significant bias. Consequently, these trials could not be incorporated into the quantitative synthesis. No randomised trial of artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII, rIL6 or rIL11 was identified. We assessed all five trials of TPO mimetics included in this review to be at high risk of bias because the trials were funded by the manufacturers of the TPO mimetics and the authors had financial stakes in the sponsoring companies. The GRADE quality of the evidence was very low to moderate across the different outcomes. There was insufficient evidence to detect a difference in the number of participants with at least one bleeding episode between TPO mimetics and placebo (RR 0.86, 95% CI 0.56 to 1.31, four trials, 206 participants, low-quality evidence). There was insufficient evidence to detect a difference in the risk of a life-threatening bleed between those treated with a TPO mimetic and placebo (RR 0.31, 95% CI 0.04 to 2.26, one trial, 39 participants, low-quality evidence). There was insufficient evidence to detect a difference in the risk of all-cause mortality between those treated with a TPO mimetic and placebo (RR 0.74, 95%CI 0.52 to 1.05, five trials, 456 participants, very low-quality evidence). There was a significant reduction in the number of participants receiving any platelet transfusion between those treated with TPO mimetics and placebo (RR 0.76, 95% CI 0.61 to 0.95, four trials, 206 participants, moderate-quality evidence). There was no evidence for a difference in the incidence of transfusion reactions between those treated with TPO mimetics and placebo (pOR 0.06, 95% CI 0.00 to 3.44, one trial, 98 participants, very low-quality evidence). There was no evidence for a difference in thromboembolic events between TPO mimetics and placebo (RR 1.41, 95%CI 0.39 to 5.01, five trials, 456 participants, very-low quality evidence). There was no evidence for a difference in drug reactions between TPO mimetics and placebo (RR 1.12, 95% CI 0.83 to 1.51, five trials, 455 participants, low-quality evidence). No trial reported the number of days of bleeding per participant, platelet transfusion episodes, mean red cell transfusions per participant, red cell transfusion episodes, transfusion-transmitted infections, formation of antiplatelet antibodies or platelet refractoriness. In order to demonstrate a reduction in bleeding events from 26 in 100 to 16 in 100 participants, a study would need to recruit 514 participants (80% power, 5% significance). There is insufficient evidence at present for thrombopoietin (TPO) mimetics for the prevention of bleeding for people with thrombocytopenia due to chronic bone marrow failure. There is no randomised controlled trial evidence for artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII or rIL6 or rIL11, antifibrinolytics or DDAVP in this setting.
We included 57 trials in the first version of this review. For this update 1 of those trials was excluded and 12 new trials were added. The total number of included trials was, thus, 68, with 5578 participants, reporting on 50 different treatments, including placebo. Most trials were in primary impetigo or did not specify this. For many of the items that were assessed for risk of bias, most studies did not provide enough information. Fifteen studies reported blinding of participants and outcome assessors. Topical antibiotic treatment showed better cure rates than placebo (pooled risk ratio (RR) 2. 24, 95% confidence interval (CI) 1.61 to 3.13) in 6 studies with 575 participants. In 4 studies with 440 participants, there was no clear evidence that either of the most commonly studied topical antibiotics (mupirocin and fusidic acid) was more effective than the other (RR 1.03, 95% CI 0.95 to 1.11). In 10 studies with 581 participants, topical mupirocin was shown to be slightly superior to oral erythromycin (pooled RR 1.07, 95% CI 1.01 to 1.13). There were no significant differences in cure rates from treatment with topical versus other oral antibiotics. There were, however, differences in the outcome from treatment with different oral antibiotics: penicillin was inferior to erythromycin, in 2 studies with 79 participants (pooled RR 1.29, 95% CI 1.07 to 1.56), and cloxacillin, in 2 studies with 166 participants (pooled RR 1.59, 95% CI 1.21 to 2.08). There was a lack of evidence for the benefit of using disinfectant solutions. When 2 studies with 292 participants were pooled, topical antibiotics were significantly better than disinfecting treatments (RR 1.15, 95% CI 1.01 to 1.32). The reported number of side-effects was low, and most of these were mild. Side-effects were more common for oral antibiotic treatment compared to topical treatment. Gastrointestinal effects accounted for most of the difference. Worldwide, bacteria causing impetigo show growing resistance rates for commonly used antibiotics. For a newly developed topical treatment, retapamulin, no resistance has yet been reported. There is good evidence that topical mupirocin and topical fusidic acid are equally, or more, effective than oral treatment. Due to the lack of studies in people with extensive impetigo, it is unclear if oral antibiotics are superior to topical antibiotics in this group. Fusidic acid and mupirocin are of similar efficacy. Penicillin was not as effective as most other antibiotics. There is a lack of evidence to support disinfection measures to manage impetigo.
Two studies met criteria for this review. One compared dilation and evacuation (D&E) to intra-amniotic instillation of prostaglandin F2 α. The second study compared D&E to induction with mifepristone and misoprostol. Compared with prostaglandin instillation, the combined incidence of minor complications was lower with D&E (OR 0.17, 95% CI 0.04-0.65) as was the total number of minor and major complications (OR 0.12, 95% CI 0.03-0.46). The number of women experiencing adverse events was also lower with D&E than with mifepristone and misoprostol (OR 0.06, 95% CI 0.01-0.76). Although women treated with mifepristone and misoprostol reported significantly more pain than those undergoing D&E, efficacy and acceptability were the same in both groups. In both trials, fewer subjects randomised to D&E required overnight hospitalisation. Dilation and evacuation is superior to instillation of prostaglandin F2 α. The current evidence also appears to favour D&E over mifepristone and misoprostol, however larger randomised trials are needed.
We included 11 RCTs (3215 women). The quality of the evidence ranged from very low to low. The main limitations were risk of bias (associated with poor reporting of allocation concealment and other methods) and imprecision for the primary outcome of live birth rate. Live birth rates: Seminal plasma application made little or no difference in live birth rates (RR 1.10, 95% CI 0.86 to 1.43; 948 participants; 3 studies; I2 = 0%). Low-quality evidence suggested that if the live birth rate following standard ART was 19%, it would be between 16% and 27% with seminal plasma application. Miscarriage rate: Seminal plasma application made little or no difference in miscarriage rates (RR 1.01, 95% CI 0.57 to 1.79; 1209 participants; 4 studies; I2 = 0%). Low-quality evidence suggested that if the miscarriage rate following standard ART was 3.7%, the miscarriage rate following seminal plasma application would be between 2.1% and 6.6%. Live birth or ongoing pregnancy rates: Seminal plasma application made little or no difference in live birth or ongoing pregnancy rates (RR 1.19, 95% CI 0.95 to 1.49; 1178 participants; 4 studies; I2 = 4%, low-quality evidence). The evidence suggested that if the live birth or ongoing pregnancy rate following standard ART was 19.5%, it would be between 18.5% and 29% with seminal plasma application. Clinical pregnancy rates: We are uncertain whether seminal plasma application increases clinical pregnancy rates (RR 1.15, 95% CI 1.01 to 1.31; 2768 participants; 10 studies; I2 = 0%). Very low-quality evidence suggested that if the clinical pregnancy rate following standard ART was 22.0%, it would be between 22.2% and 28.8% with seminal plasma application. This finding should be regarded with caution, as a post hoc sensitivity analysis restricted to studies at overall low risk of bias did not find a significant difference between the groups (RR 1.06, 95% CI 0.81 to 1.39; 547 participants; 3 studies; I2 = 0%). Multiple pregnancy rate: Seminal plasma application may make little or no difference to multiple pregnancy rates (RR 1.11, 95% CI 0.76 to 1.64; 1642 participants; 5 studies; I2 = 9%). Low-quality evidence suggested that if the multiple pregnancy rate following standard ART was 7%, the multiple pregnancy rate following seminal plasma application would be between 5% and 11.4%. Ectopic pregnancy: There was insufficient evidence to determine whether seminal plasma application influenced the risk of ectopic pregnancy (RR 1.59, 95% CI 0.20 to 12.78, 1521 participants; 5 studies; I2 = 0%) . Infectious complications or other adverse events: No data were available on these outcomes In women undergoing ART, there was insufficient evidence to determine whether there was a difference between the seminal plasma and the standard ART group in rates of live birth (low-quality evidence) or miscarriage (low-quality evidence). There was low-quality evidence suggesting little or no difference between the groups in rates of live birth or ongoing pregnancy (composite outcome). We found low-quality evidence that seminal plasma application may be associated with more clinical pregnancies than standard ART. There was low-quality evidence suggesting little or no difference between the groups in rates of multiple pregnancy. There was insufficient evidence to reach any conclusions about the risk of ectopic pregnancy, and no data were available on infectious complications or other adverse events. We conclude that seminal plasma application is worth further investigation, focusing on live birth and miscarriage rates.
We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.
We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor β2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials. Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I2 = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I2 = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I2= 74%, five trials). In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I2 = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence) Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I2 = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated. This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.
Ten studies including 5056 participants met the inclusion criteria for this review and assessed the diagnostic accuracy of the index tests in people presenting to the emergency department with acute abdominal pain. The risk of bias was unclear or high for all of the included studies. The study that contributed approximately two-thirds of the participants included in this review was excluded from the results of the analysis presented below due to major concerns about the participants included in the study. We have presented only the results where at least two studies were included in the analysis. Serum amylase, serum lipase, and urinary trypsinogen-2 at the standard threshold levels of more than three times normal for serum amylase and serum lipase, and a threshold of 50 ng/mL for urinary trypsinogen-2 appear to have similar sensitivities (0.72 (95% CI 0.59 to 0.82); 0.79 (95% CI 0.54 to 0.92); and 0.72 (95% CI 0.56 to 0.84), respectively) and specificities (0.93 (95% CI 0.66 to 0.99); 0.89 (95% CI 0.46 to 0.99); and 0.90 (95% CI 0.85 to 0.93), respectively). At the median prevalence of 22.6% of acute pancreatitis in the studies, out of 100 people with positive test, serum amylase (more than three times normal), serum lipase (more than three times normal), and urinary trypsinogen (more than 50 ng/mL), 74 (95% CI 33 to 94); 68 (95% CI 21 to 94); and 67 (95% CI 57 to 76) people have acute pancreatitis, respectively; out of 100 people with negative test, serum amylase (more than three times normal), serum lipase (more than three times normal), and urinary trypsinogen (more than 50 ng/mL), 8 (95% CI 5 to 12); 7 (95% CI 3 to 15); and 8 (95% CI 5 to 13) people have acute pancreatitis, respectively. We were not able to compare these tests formally because of sparse data. As about a quarter of people with acute pancreatitis fail to be diagnosed as having acute pancreatitis with the evaluated tests, one should have a low threshold to admit the patient and treat them for acute pancreatitis if the symptoms are suggestive of acute pancreatitis, even if these tests are normal. About 1 in 10 patients without acute pancreatitis may be wrongly diagnosed as having acute pancreatitis with these tests, therefore it is important to consider other conditions that require urgent surgical intervention, such as perforated viscus, even if these tests are abnormal. The diagnostic performance of these tests decreases even further with the progression of time, and one should have an even lower threshold to perform additional investigations if the symptoms are suggestive of acute pancreatitis.
We identified seven new RCTs since publication of the original review in 2002. In total, we included 10 RCTs. Primary outcomes Early AST probably reduces the risk of death from any cause over time (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75 to 0.90; moderate-certainty evidence; 4767 participants). This corresponds to 57 fewer deaths (95% CI 80 fewer to 31 fewer) per 1000 participants at 5 years for the moderate risk group and 23 fewer deaths (95% CI 32 fewer to 13 fewer) per 1000 participants at 5 years in the low risk group. We downgraded for study limitations. Early versus deferred AST may have little or no effect on serious adverse events (risk ratio (RR) 1.05, 95% CI 0.95 to 1.16; low-certainty evidence; 10,575 participants) which corresponds to 6 more serious adverse events (6 fewer to 18 more) per 1000 participants. We downgraded the certainty of evidence for study limitations and selective reporting. Secondary outcomes Early AST probably reduces the risk of death from prostate cancer over time (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence). This corresponds to 62 fewer prostate cancer deaths per 1000 (95% CI 87 fewer to 31 fewer) at 5 years for the moderate risk group and 24 fewer death from prostate cancer (95% CI 34 fewer to 12 fewer) per 1000 men at 5 years in the low risk group. We downgraded the certainty of evidence for study limitations. Early AST may decrease the rate of skeletal events (RR 0.37, 95% CI 0.17 to 0.80; low-certainty evidence) corresponding to 23 fewer skeletal events per 1000 (95% CI 31 fewer to 7 fewer). We downgraded for study limitations and imprecision. It may also increase fatigue (RR 1.41, 95% CI 1.23 to 1.62; low-certainty evidence), corresponding to 31 more men with this complaint per 1000 (95% CI 18 more to 48 more). We downgraded for study limitations and imprecision. It may increase the risk of heart failure (RR 1.90, 95% CI 1.09 to 3.33; low-certainty evidence) corresponding to 27 more events per 1000 (95% CI 3 more to 69 more). We downgraded the certainty of evidence for study limitations and imprecision. Global quality of life is probably similar after two years as assessed with the EORTC QLQ-C30 (version 3.0) questionnaire (mean difference −1.56, 95% CI −4.50 to 1.38; moderate-certainty evidence) with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Early AST probably extends time to death of any cause and time to death from prostate cancer. It may slightly decrease the rate of skeletal events. Rates of serious adverse events and quality of life may be similar. It may increase fatigue and may increase the risk of heart failure. Better quality trials would be particularly important to better understand the outcomes related to possible treatment-related harm, for which we only found low-certainty evidence.
Five parallel and 26 crossover randomised controlled trials were identified. The quality of reporting was found to be poor. Pooled data from parallel studies shows a statistically non-significant preference for physiologic pacing (primarily dual chamber pacing) for the prevention of stroke, heart failure and mortality, and a statistically significant beneficial effect regarding the prevention of atrial fibrillation (odds ratio (OR) 0.79, 95% CI 0.68 to 0.93). Both parallel and crossover studies favour dual chamber pacing with regard to pacemaker syndrome (parallel: Peto OR 0.11, 95% CI 0.08 to 0.14; crossover: standardised mean difference (SMD) -0.74, 95% CI - 0.95 to -0.52). Pooled data from crossover studies shows a statistically significant trend towards dual chamber pacing being more favourable in terms of exercise capacity (SMD -0.24, 95% CI -0.03 to -0.45). No individual studies reported a significantly more favourable outcome with single chamber ventricular pacing. This review shows a trend towards greater effectiveness with dual chamber pacing compared to single chamber ventricular pacing, which supports the current British Pacing and Electrophysiology Group's Guidelines regarding atrioventricular block. Additional randomised controlled trial evidence from ongoing trials in this area will further inform the debate.
It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind. None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis. It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies. When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.
Ten trials involving 1205 participants were included. The duration of patient follow-up ranged from 2 days to 2 years after the intervention. Overall, the quality of the evidence generated by these trials was low, due to risk of bias in the included trials and inconsistency in the results. Manual lymph drainage In total, four studies used manual lymph drainage (MLD) in combination with usual care or other interventions. In one study, lymphoedema incidence was lower in patients receiving MLD and usual care (consisting of standard education or exercise, or both) compared to usual care alone. A second study reported no difference in lymphoedema incidence when MLD was combined with physiotherapy and education compared to physiotherapy alone. Two other studies combining MLD with compression and scar massage or exercise observed a reduction in lymphoedema incidence compared to education only, although this was not significant in one of the studies. Two out of the four studies reported on shoulder mobility where MLD combined with exercise gave better shoulder mobility for lateral arm movement (shoulder abduction) and forward flexion in the first weeks after breast cancer surgery, compared to education only (mean difference for abduction 22°; 95% confidence interval (CI) 14 to 30; mean difference for forward flexion 14°; 95% CI 7 to 22). Two of the studies on MLD reported on pain, with inconsistent results. Results on HRQoL in two studies on MLD were also contradictory. Exercise: early versus delayed start of shoulder mobilising exercises Three studies examined early versus late start of postoperative shoulder exercises. The pooled relative risk of lymphoedema after an early start of exercises was 1.69 (95% CI 0.94 to 3.01, 3 studies, 378 participants). Shoulder forward flexion was better at one and six months follow-up for participants who started early with mobilisation exercises compared to a delayed start (two studies), but no meta-analysis could be performed due to statistical heterogeneity. There was no difference in shoulder mobility or self-reported shoulder disability at 12 months follow-up (one study). One study evaluated HRQoL and reported difference at one year follow-up (mean difference 1.6 points, 95% CI -2.14 to 5.34, on the Trial Outcome Index of the FACT-B). Two studies collected data on wound drainage volumes and only one study reported higher wound drainage volumes in the early exercise group. Exercise: resistance training Two studies compared progressive resistance training to restricted activity. Resistance training after breast cancer treatment did not increase the risk of developing lymphoedema (RR 0.58; 95% CI 0.30 to 1.13, two studies, 358 participants) provided that symptoms are monitored and treated immediately if they occur. One out of the two studies measured pain where participants in the resistance training group reported pain more often at three months and six months compared to the control group. One study reported HRQoL and found no significant difference between the groups. Patient education, monitoring and early intervention One study investigated the effects of a comprehensive outpatient follow-up programme, consisting of patient education, exercise, monitoring of lymphoedema symptoms and early intervention for lymphoedema, compared to education alone. Lymphoedema incidence was lower in the comprehensive outpatient follow-up programme (at any time point) compared to education alone (65 people). Participants in the outpatient follow-up programme had a significantly faster recovery of shoulder abduction compared to the education alone group. Based on the current available evidence, we cannot draw firm conclusions about the effectiveness of interventions containing MLD. The evidence does not indicate a higher risk of lymphoedema when starting shoulder-mobilising exercises early after surgery compared to a delayed start (i.e. seven days after surgery). Shoulder mobility (that is, lateral arm movements and forward flexion) is better in the short term when starting shoulder exercises earlier compared to later. The evidence suggests that progressive resistance exercise therapy does not increase the risk of developing lymphoedema, provided that symptoms are closely monitored and adequately treated if they occur. Given the degree of heterogeneity encountered, limited precision, and the risk of bias across the included studies, the results of this review should be interpreted with caution.
Eighteen RCTs (14 dihydropyridines, 4 non-dihydropyridines) with a total of 141,807 participants were included. All-cause mortality was not different between first-line CCBs and any other first-line antihypertensive classes. CCBs reduced the following outcomes as compared to β-blockers: total cardiovascular events (RR 0.84, 95% CI [0.77, 0.92]), stroke (RR 0.77, 95% CI [0.67, 0.88]) and cardiovascular mortality (RR 0.90, 95% CI [0.81, 0.99]). CCBs increased total cardiovascular events (RR 1.05 , 95% CI [1.00, 1.09], p = 0.03) and congestive heart failure events (RR 1.37, 95% CI [1.25, 1.51]) as compared to diuretics. CCBs reduced stroke (RR 0.89, 95% CI [0.80, 0.98]) as compared to ACE inhibitors and reduced stroke (RR 0.85, 95% CI [0.73, 0.99]) and MI (RR 0.83, 95% CI [0.72, 0.96]) as compared to ARBs. CCBs also increased congestive heart failure events as compared to ACE inhibitors (RR 1.16, 95% CI [1.06, 1.27]) and ARBs (RR 1.20, 95% CI [1.06, 1.36]). The other evaluated outcomes were not significantly different. Diuretics are preferred first-line over CCBs to optimize reduction of cardiovascular events. The review does not distinguish between CCBs, ACE inhibitors or ARBs, but does provide evidence supporting the use of CCBs over β-blockers. Many of the differences found in the current review are not robust and further trials might change the conclusions. More well-designed RCTs studying the mortality and morbidity of patients taking CCBs as compared with other antihypertensive drug classes are needed for patients with different stages of hypertension, different ages, and with different co-morbidities such as diabetes.
One-hundred and eight trials (18 placebo-controlled and 90 before-and-after) evaluated the dose-related efficacy of rosuvastatin in 19,596 participants. Rosuvastatin 10 to 40 mg/day caused LDL-cholesterol decreases of 46% to 55%, when all the trials were combined using the generic inverse variance method. The quality of evidence for these effects is high. Log dose-response data over doses of 1 to 80 mg, revealed strong linear dose-related effects on blood total cholesterol, LDL-cholesterol and non-HDL-cholesterol. When compared to atorvastatin, rosuvastatin was about three-fold more potent at reducing LDL-cholesterol. There was no dose-related effect of rosuvastatin on blood HDL-cholesterol, but overall, rosuvastatin increased HDL by 7%. There is a high risk of bias for the trials in this review, which would affect WDAEs, but unlikely to affect the lipid measurements. WDAEs were not statistically different between rosuvastatin and placebo in 10 of 18 of these short-term trials (risk ratio 0.84; 95% confidence interval 0.48 to 1.47). The total blood total cholesterol, LDL-cholesterol and non-HDL-cholesterol-lowering effect of rosuvastatin was linearly dependent on dose. Rosuvastatin log dose-response data were linear over the commonly prescribed dose range. Based on an informal comparison with atorvastatin, this represents a three-fold greater potency. This review did not provide a good estimate of the incidence of harms associated with rosuvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 44% of the placebo-controlled trials.
We included four studies involving 644 pregnant women. Three studies were randomised controlled trials and one trial was a quasi-randomised study. A higher dose of oxytocin was associated with a significant reduction in length of labour reported from one trial (mean difference (MD) -3.50 hours; 95% confidence interval (CI) -6.38 to -0.62; one trial, 40 women). There was a decrease in the rate of caesarean section (risk ratio (RR) 0.62; 95% CI 0.44 to 0.86 four trials, 644 women) and an increase in the rate of spontaneous vaginal birth in the high-dose group (RR 1.35; 95% CI 1.13 to 1.62, three trials, 444 women), although for both of these outcomes there were inconsistencies between studies in the size of effect. When we carried out sensitivity analysis (temporarily removing a study at high risk of bias) the differences between groups were no longer statistically significant There were no significant differences between high- and low-dose regimens for instrumental vaginal birth, epidural analgesia, hyperstimulation, postpartum haemorrhage, chorioamnionitis or women's perceptions of experiences. For neonatal outcomes, there was no significant difference between groups for Apgar scores, umbilical cord pH, admission to special care baby unit, or neonatal mortality. The following outcomes were not evaluated in the included studies: perinatal mortality, uterine rupture, abnormal cardiotocography, women's pyrexia, dystocia and neonatal neurological morbidity. Higher-dose regimens of oxytocin (4 mU per minute or more) were associated with a reduction in the length of labour and in caesarean section, and an increase in spontaneous vaginal birth. However, there is insufficient evidence to recommend that high-dose regimens are advised routinely for women with delay in the first stage of labour. Further research should evaluate the effect of high-dose regimens of oxytocin for women delayed in labour and should include maternal and neonatal outcomes as well as the effects on women.
Despite extensive searching we found no randomised trials suitable for inclusion. Based on the available evidence a meaningful conclusion cannot be reached. The term "single brain metastasis" is used to describe a brain metastasis found in patients presenting with an inoperable lung cancer or from an uncontrolled primary tumour some time after diagnosis, and the term "solitary brain metastasis" is used when the brain metastasis is diagnosed some time after radical, potentially curative treatment. In the evaluated studies, we found that the criteria for the definition of solitary brain metastasis were not consistent. Some series combined patients with single and solitary brain metastasis. Some of the single arm or cohort studies came from single institutions where the availability of both techniques (radiosurgery and surgery) was not described. Therefore, it is possible that the most accessible technique might be used preferentially, reinforced by a general belief that the techniques are equivalent. This has prevented an appropriate treatment comparison, which should be made through a well designed phase III clinical trial.
We included five studies with 1601 children in the review. Pooled analysis demonstrated that the following outcomes were comparable between the two groups: clinical cure at the end of therapy (RR 1.03, 95% CI 0.99 to 1.07); during therapy (RR 1.06, 95% CI 0.85 to 1.33) and at follow-up (RR 1.02, 95% CI 0.95 to 1.09); recurrent AOM (RR 1.21, 95% CI 0.52 to 2.81); compliance rate (RR 1.04, 95% CI 0.98 to 1.10) and overall adverse events (RR 0.92, 95% CI 0.52 to 1.63). When we performed subgroup analysis separately for trials with amoxicillin only and amoxicillin/clavulanate only, it showed that all important outcomes were comparable between once or twice daily groups and the three times daily group. The risk of bias amongst the five included studies was as follows: for random sequence generation we graded two studies as low and three unclear risk of bias; for allocation concealment all studies were at unclear risk of bias; for blinding (performance and detection bias) we graded four as high and one as unclear risk of bias; for incomplete outcome data (attrition bias) we graded two low, two high and one as unclear risk of bias; for reporting bias four were at low and one at high risk; and for ‘other’ bias four were at low and one at unclear risk of bias. This review showed that the results of using once or twice daily doses of amoxicillin, with or without clavulanate, were comparable with three doses for the treatment of AOM.
We included 15 trials involving a total of 3911 women and infant pairs. We judged the trials to have an overall moderate risk of bias. Maternal outcomes: No studies in this review reported on maternal death or on severe maternal morbidity. There were no significant differences between early versus late cord clamping groups for the primary outcome of severe postpartum haemorrhage (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.65 to 1.65; five trials with data for 2066 women with a late clamping event rate (LCER) of ˜3.5%, I2 0%) or for postpartum haemorrhage of 500 mL or more (RR 1.17 95% CI 0.94 to 1.44; five trials, 2260 women with a LCER of ˜12%, I2 0%). There were no significant differences between subgroups depending on the use of uterotonic drugs. Mean blood loss was reported in only two trials with data for 1345 women, with no significant differences seen between groups; or for maternal haemoglobin values (mean difference (MD) -0.12 g/dL; 95% CI -0.30 to 0.06, I2 0%) at 24 to 72 hours after the birth in three trials. Neonatal outcomes: There were no significant differences between early and late clamping for the primary outcome of neonatal mortality (RR 0.37, 95% CI 0.04 to 3.41, two trials, 381 infants with a LCER of ˜1%), or for most other neonatal morbidity outcomes, such as Apgar score less than seven at five minutes or admission to the special care nursery or neonatal intensive care unit. Mean birthweight was significantly higher in the late, compared with early, cord clamping (101 g increase 95% CI 45 to 157, random-effects model, 12 trials, 3139 infants, I2 62%). Fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR 0.62, 95% CI 0.41 to 0.96, data from seven trials, 2324 infants with a LCER of 4.36%, I2 0%). Haemoglobin concentration in infants at 24 to 48 hours was significantly lower in the early cord clamping group (MD -1.49 g/dL, 95% CI -1.78 to -1.21; 884 infants, I2 59%). This difference in haemoglobin concentration was not seen at subsequent assessments. However, improvement in iron stores appeared to persist, with infants in the early cord clamping over twice as likely to be iron deficient at three to six months compared with infants whose cord clamping was delayed (RR 2.65 95% CI 1.04 to 6.73, five trials, 1152 infants, I2 82%). In the only trial to report longer-term neurodevelopmental outcomes so far, no overall differences between early and late clamping were seen for Ages and Stages Questionnaire scores. A more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. Delayed cord clamping is likely to be beneficial as long as access to treatment for jaundice requiring phototherapy is available.
We included nine RCTs involving 3253 nursing home residents in this review; seven of these trials used cluster randomisation. The mean resident age ranged from 78 to 86 years across studies, and most participants were women (more than 66% in all studies). The proportion of residents with dental protheses ranged from 62% to 87%, and the proportion of edentulous residents ranged from 32% to 90% across studies. Eight studies compared educational interventions with information and practical components versus (optimised) usual care, while the ninth study compared educational interventions with information only versus usual care. All interventions included educational sessions on oral health for nursing staff (five trials) or for both staff and residents (four trials), and used more than one active component. Follow-up of included studies ranged from three months to five years. No study showed overall low risk of bias. Four studies had a high risk of bias, and the other five studies were at unclear risk of bias. None of the trials assessed our predefined primary outcomes 'oral health' and 'oral health-related quality of life'. All trials assessed our third primary outcome, 'dental or denture plaque'. Meta-analyses showed no evidence of a difference between interventions and usual care for dental plaque (mean difference -0.04, 95% confidence interval (CI) -0.26 to 0.17; six trials; 437 participants; low quality evidence) or denture plaque (standardised mean difference -0.60, 95% CI -1.25 to 0.05; five trials; 816 participants; low quality evidence). None of the studies assessed adverse events of the intervention. We found insufficient evidence to draw robust conclusions about the effects of oral health educational interventions for nursing home staff and residents. We did not find evidence of meaningful effects of educational interventions on any measure of residents' oral health; however, the quality of the available evidence is low. More adequately powered and high-quality studies using relevant outcome measures are needed.
Five studies met the criteria for inclusion in the review. Two of these were multi-intervention studies where the dietary intervention was one component of a wider programme of prevention, but where data on dietary behaviour change were reported. One of the single intervention studies was concerned with dental caries prevention. The other two concerned general health outcomes. There were no studies concerned with dietary change aimed at preventing tooth erosion. In four out of the five included studies a significant change in dietary behaviour was found for at least one of the primary outcome variables. There is some evidence that one-to-one dietary interventions in the dental setting can change behaviour, although the evidence is greater for interventions aiming to change fruit/vegetable and alcohol consumption than for those aiming to change dietary sugar consumption. There is a need for more studies, particularly in the dental practice setting, as well as greater methodological rigour in the design, statistical analysis and reporting of such studies.
Two trials randomised in total 106 patients to piggy-back method (n = 53) versus conventional method with veno-venous bypass (n = 53). Both trials were at high risk of bias. There was no significant difference in post-operative mortality, primary graft non-function, vascular complications, renal failure, transfusion requirements, intensive therapy unit (ITU) stay, or hospital stay between the two groups. The warm ischaemic time was significantly shorter in the piggy-back method than the conventional method (MD -11.50 minutes; 95% CI -19.35 to -3.65; P < 0.01). The proportion of patients who developed chest complications were significantly higher in the the piggy-back method than the conventional method (75.8% versus 44.1%; P = 0.01). One trial randomised 80 patients to piggy-back with porto-caval bypass (n = 40) versus piggy-back without porto-caval bypass (n = 40). This trial was at high risk of bias. There was no significant difference in post-operative mortality, re-transplantation due to primary graft non-function, vascular complications, renal failure, or hospital stay between the two groups. Fewer patients required blood transfusion in the piggy-back with porto-caval bypass group (55%) than the piggy-back without porto-caval bypass group (75%) (P = 0.02). There was no significant difference in the mean amount of blood transfused between the groups (MD -1.00 unit; 95% CI -2.19 to 0.19; P = 0.10). The ITU stay was significantly shorter in the piggy-back with porto-caval bypass group (2.9 days) than the piggy-back without porto-caval bypass group (4.9 days; MD -2.00 days; 95% CI -3.82 to -0.18; P = 0.03). There were no trials comparing piggy-back method with conventional method without veno-venous bypass or different techniques of piggy-back method. There is currently no evidence to recommend or refute the use of piggy-back method of liver transplantation.
Eleven suitable trials that tested vigabatrin doses between 1000 mg and 6000 mg were identified and included in the analysis. There were 982 observations on 747 patients in the primary ITT analysis of treatment efficacy. Patients treated with vigabatrin were significantly more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.58, 95% CI 1.87 to 3.57). Those treated with vigabatrin were also significantly more likely to have treatment withdrawn (RR 2.49, 95% CI 1.05 to 5.88), and were more likely to experience a number of side effects, significantly so for fatigue or drowsiness. There was some evidence of small study effect bias, with smaller studies tending to report greater estimates of RR than larger studies. It is possible, therefore, that the actual RR of obtaining 50% reduction in seizure frequency is less than that obtained by a meta-analysis of fully published studies. This review of randomised controlled trials showed that vigabatrin can reduce seizure frequency in people with drug-resistant partial epilepsy. Short-term follow-up of patients showed that some side effects were associated with its use. Further analysis of longer-term observational studies is required to evaluate how likely patients are to develop visual field defects and whether such side effects are associated with dose and duration of drug use.
Ten studies (440 subfertile couples) were included. Results of the meta-analysis demonstrated no difference in outcome measures and adverse events in the routine use of adjuvant growth hormone in in-vitro fertilisation protocols. However, meta-analysis demonstrated a statistically significant difference in both live birth rates and pregnancy rates favouring the use of adjuvant growth hormone in in-vitro fertilisation protocols in women who are considered poor responders without increasing adverse events, OR 5.39, 95% CI 1.89 to 15.35 and OR 3.28, 95% CI 1.74 to 6.20 respectively. Although the use of growth hormone in poor responders has been found to show a significant improvement in live birth rates, we were unable to identify which sub-group of poor responders would benefit the most from adjuvant growth hormone. The result needs to be interpreted with caution, the included trials were few in number and small sample size. Therefore, before recommending growth hormone adjuvant in in-vitro fertilisation further research is necessary to fully define its role.
A total of 55 trials were included for one or more outcomes for this review. In duodenal ulcer healing, eradication therapy was superior to ulcer healing drug (UHD) (34 trials, 3910 participants, RR of ulcer persisting = 0.66, 95% confidence interval (CI) 0.58 to 0.76; 381/2286 (adjusted proportion: 12.4%) in eradication therapy plus UHD versus 304/1624 (18.7%) in UHD; low quality evidence) and no treatment (two trials, 207 participants, RR 0.37, 95% CI 0.26 to 0.53; 30/125 (adjusted proportion: 21.7%) in eradication therapy versus 48/82 (58.5%) in no treatment; low quality evidence). In gastric ulcer healing, the differences were imprecise between eradication therapy and UHD (15 trials, 1974 participants, RR 1.23, 95% CI 0.90 to 1.68; 220/1192 (adjusted proportion: 16.0%) in eradication therapy plus UHD versus 102/782 (13.0%) in UHD; very low quality evidence). In preventing duodenal ulcer recurrence the differences were imprecise between maintenance therapy with H.pylori eradication therapy and maintenance therapy with UHD (four trials, 319 participants, RR of ulcer recurring 0.73; 95% CI 0.42 to 1.25; 19/159 (adjusted proportion: 11.9%) in eradication therapy versus 26/160 (16.3%) in UHD; very low quality evidence), but eradication therapy was superior to no treatment (27 trials 2509 participants, RR 0.20, 95% CI 0.15 to 0.26; 215/1501 (adjusted proportion: 12.9%) in eradication therapy versus 649/1008 (64.4%) in no treatment; very low quality evidence). In preventing gastric ulcer recurrence, eradication therapy was superior to no treatment (12 trials, 1476 participants, RR 0.31, 95% CI 0.22 to 0.45; 116/697 (adjusted proportion: 16.3%) in eradication therapy versus 356/679 (52.4%) in no treatment; very low quality evidence). None of the trials reported proportion of people with gastric ulcer not healed after initial therapy between H.pylori eradication therapy and no active treatment or the proportion of people with recurrent gastric ulcer or peptic ulcers during maintenance therapy between H.pylori eradication therapy and ulcer healing drug therapy. Adding a one to two-week course of H. pylori eradication therapy is an effective treatment for people with H. pylori-positive duodenal ulcer when compared to ulcer healing drugs alone and no treatment. H. pylori eradication therapy is also effective in preventing recurrence of duodenal and gastric ulcer compared to no treatment. There is currently no evidence that H. pylori eradication therapy is an effective treatment in people with gastric ulcer or that it is effective in preventing recurrence of duodenal ulcer compared to ulcer healing drug. However, confidence intervals were wide and significant benefits or harms of H. pylori eradication therapy in acute ulcer healing of gastric ulcers compared to no treatment, and in preventing recurrence of duodenal ulcers compared to ulcer healing drugs cannot be ruled out.
We included six RCTs, with a total of 449 patients. In four studies (267 patients) the CL intervention resulted in reduced medical costs (in two studies the outcomes could be pooled: MD -352.55 US Dollars (95% CI -522.32 to -182.78)) and improved physical functioning (three studies, MD 5.71 (95% CI 4.11 to 7.31)). In two studies (182 patients) the intervention was a joint consultation with a psychiatrist in presence of the physician, and resulted in reduced severity of somatization symptoms, reduced medical consumption and improved social functioning. There is limited evidence that a CL is effective in terms of medical costs and improvement of physical functioning for patients with MUPS in primary care. The results are even less pronounced in patients with clinically less severe, but more meaningful, forms of MUPS and the results vary for other patient-related outcomes. All studies, except one, were performed in the United States and therefore the results can not be generalized directly to countries with other healthcare systems. Furthermore all studies were small and of only moderate quality. There is very limited evidence that a joint consultation with the patient by a psychiatrist in the presence of the physician, together with the provision of a CL, reduces severity of somatization symptoms and medical consumption.
We included reports for six studies of 656 participants that compared high- and low-intensity exercise programs; five studies exclusively recruited people with symptomatic knee osteoarthritis (620 participants), and one study exclusively recruited people with hip or knee osteoarthritis (36 participants). The majority of the participants were females (70%). No studies evaluated physical activity programs. We found the overall quality of evidence to be low to very low due to concerns about study limitations and imprecision (small number of studies, large confidence intervals) for the major outcomes using the GRADE approach. Most of the studies had an unclear or high risk of bias for several domains, and we judged five of the six studies to be at high risk for performance, detection, and attrition bias. Low-quality evidence indicated reduced pain on a 20-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale (mean difference (MD) -0.84, 95% confidence interval (CI) -1.63 to -0.04; 4% absolute reduction, 95% CI -8% to 0%; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 14 to 22) and improved physical function on the 68-point WOMAC disability subscale (MD -2.65, 95% CI -5.29 to -0.01; 4% absolute reduction; NNTB 10, 95% CI 8 to 13) immediately at the end of the exercise programs (from 8 to 24 weeks). However, these results are unlikely to be of clinical importance. These small improvements did not continue at longer-term follow-up (up to 40 weeks after the end of the intervention). We are uncertain of the effect on quality of life, as only one study reported this outcome (0 to 200 scale; MD 4.3, 95% CI -6.5 to 15.2; 2% absolute reduction; very low level of evidence). Our subgroup analyses provided uncertain evidence as to whether increased exercise time (duration, number of sessions) and level of resistance (strength or effort) have an impact on the exercise program effects. Three studies reported withdrawals due to adverse events. The number of dropouts was small. Only one study systematically monitored adverse effects, but four studies reported some adverse effects related to knee pain associated with an exercise program. We are uncertain as to whether high intensity increases the number of adverse effects (Peto odds ratio 1.72, 95% CI 0.51 to 5.81; - 2% absolute risk reduction; very low level of evidence). None of the included studies reported serious adverse events. We found very low-quality to low-quality evidence for no important clinical benefit of high-intensity compared to low-intensity exercise programs in improving pain and physical function in the short term. There was insufficient evidence to determine the effect of different types of intensity of exercise programs. We are uncertain as to whether higher-intensity exercise programs may induce more harmful effects than those of lower intensity; this must be evaluated by further studies. Withdrawals due to adverse events were poorly monitored and not reported systematically in each group. We downgraded the evidence to low or very low because of the risk of bias, inconsistency, and imprecision. The small number of studies comparing high- and low-intensity exercise programs in osteoarthritis underscores the need for more studies investigating the dose–response relationship in exercise programs. In particular, further studies are needed to establish the minimal intensity of exercise programs needed for clinical effect and the highest intensity patients can tolerate. Larger studies should comply with the Consolidated Standards of Reporting Trials (CONSORT) checklist and systematically report harms data to evaluate the potential impact of highest intensities of exercise programs in people with joint damage.
Compared with the previous review, which was published in 2011, we included 14 additional studies (493 participants), excluded one study and included data for meta-analysis of HRQOL. In total, we included in this review 44 studies including 1195 participants, and we included 33 of these (901 participants)in the meta-analysis. We found that breathlessness during exercise or daily activities was reduced by oxygen compared with air (32 studies; 865 participants; SMD -0.31, 95% CI -0.43 to -0.20; I2 = 29%; low-quality evidence). This translates to a decrease in breathlessness of about 0.7 points on a 0 to 10 numerical rating scale. In contrast, we found no effect of short-burst oxygen given before exercise (four studies; 90 participants; SMD -0.03, 95% CI -0.28 to 0.22; I2 = 0%; low-quality evidence). Oxygen reduced breathlessness measured during exercise tests (30 studies; 591 participants; SMD -0.34, 95% CI -0.46 to -0.22; I2 = 29%; moderate-quality evidence), whereas evidence of an effect on breathlessness measured in daily life was limited (two studies; 274 participants; SMD -0.13, 95% CI, -0.37 to 0.11; I2 = 0%; low-quality evidence). Oxygen did not clearly affect HRQOL (five studies; 267 participants; SMD 0.12, 95% CI -0.04 to 0.28; I2 = 0%; low-quality evidence). Patient preference and adverse events could not be analysed owing to insufficient data. We are moderately confident that oxygen can relieve breathlessness when given during exercise to mildly hypoxaemic and non-hypoxaemic people with chronic obstructive pulmonary disease who would not otherwise qualify for home oxygen therapy. Most evidence pertains to acute effects during exercise tests, and no evidence indicates that oxygen decreases breathlessness in the daily life setting. Findings show that oxygen does not affect health-related quality of life.
We included two studies with 57 smokers with a diagnosis of rheumatoid arthritis (RA). We identified no studies including other IJDs. One pilot study compared a smoking cessation intervention specifically for people with RA with a less intensive, generic smoking cessation intervention. People included in the study had a mean age of 56.5 years and a disease duration of 7.7 years (mean). The second study tested effects of an eight-week cognitive-behavioural patient education intervention on cardiovascular disease (CVD) risk for people with RA and compared this with information on CVD risk only. The intervention encouraged participants to address multiple behaviours impacting CVD risk, including smoking cessation, but did not target smoking cessation alone. People included in the study had a mean age of 62.2 years (intervention group) and 60.8 years (control group), and disease duration of 11.6 years (intervention group) and 14.1 years (control group). It was not appropriate to perform a meta-analysis of abstinence data from the two studies due to clinical heterogeneity between interventions. Neither of the studies individually provided evidence to show benefit of the interventions tested. Only one study reported on adverse effects. These effects were non-serious, and numbers were comparable between trial arms. Neither of the studies assessed or reported disease activity or any of the predefined secondary outcomes. We assessed the overall certainty of evidence as very low due to indirectness, imprecision, and high risk of detection bias based on GRADE. We found very little research investigating the efficacy of smoking cessation intervention specifically in people with IJD. Included studies are limited by imprecision, risk of bias, and indirectness. Neither of the included studies investigated whether smoking cessation intervention reduced disease activity among people with IJD. High-quality, adequately powered studies are warranted. In particular, researchers should ensure that they measure disease markers and quality of life, in addition to long-term smoking cessation.
We included 14 trials with 1863 participants. Evidence from six studies showed that self management programmes improved quality of life in people with stroke (standardised mean difference (SMD) random effects 0.20, 95% confidence interval (CI) 0.00 to 0.41, P = 0.05; low quality evidence) and improved self efficacy (SMD, random effects 0.33, 95% CI 0.04 to 0.61, P = 0.03; low quality evidence) compared with usual care. Individual studies reported benefits for health-related behaviours such as reduced use of health services, smoking, and alcohol intake, as well as improved diet and attitude. However, there was no superior effect for such programmes in the domains of locus of control, activities of daily living, medication adherence, participation, or mood. Statistical heterogeneity was mostly low; however, there was much variation in the types and delivery of programmes. Risk of bias was relatively low for complex intervention clinical trials where participants and personnel could not be blinded. The current evidence indicates that self management programmes may benefit people with stroke who are living in the community. The benefits of such programmes lie in improved quality of life and self efficacy. These are all well-recognised goals for people after stroke. There is evidence for many modes of delivery and examples of tailoring content to the target group. Leaders were usually professionals but peers (stroke survivors and carers) were also reported - the commonality is being trained and expert in stroke and its consequences. It would be beneficial for further research to be focused on identifying key features of effective self management programmes and assessing their cost-effectiveness.
We have included nine trials, involving 2391 women and their babies in this review. Trials were at a moderate to high risk of bias overall. Results of primary outcomes revealed no significant differences in rates of vaginal delivery not achieved within 24 hours (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.78 to 1.14, two trials, 1339 women) or caesarean section (RR 0.96, 95% CI 0.81 to 1.14, eight trials, 2023 women). There was no difference in serious maternal morbidity or death (RR 1.24, 95% CI 0.55 to 2.82, one trial, 523 women), and no difference in serious neonatal morbidity or perinatal death (RR 0.84, 95% CI 0.23 to 3.12, one trial, 781 infants). Finally, no trials reported on the number of women who had uterine hyperstimulation with fetal heart rate changes. Results of secondary outcomes revealed no difference between time from induction to delivery (mean difference (MD) -0.90 hours, 95% CI -2.28 to +0.49 hours; five studies), uterine rupture (RR 3.10, 95% CI 0.50 to 19.33; three trials), epidural analgesia (RR 1.03, 95% CI 0.89 to 1.18; two trials), instrumental birth (RR 1.22, 95% CI 0.88 to 1.66; three trials), Apgar less than seven at five minutes (RR 1.25, 95% CI 0.77 to 2.01, five trials), perinatal death (RR 0.84, 95% CI 0.23 to 3.12; two trials), postpartum haemorrhage (RR 1.08, 95% CI 0.87 to 1.34; five trials), or endometritis (RR 1.35, 95% CI 0.53 to 3.43; three trials). Removal of high bias studies reveals a significant reduction of induction to delivery interval (MD -1.94 hours, 95% CI -0.99 to -2.89 hours, 489 women). A significant increase in hyperstimulation without specifying fetal heart rate changes was found in the high-dose group (RR 1.86, 95% CI 1.55 to 2.25). No other secondary outcomes were reported: unchanged/unfavourable cervix after 12 to 24 hours, meconium-stained liquor, neonatal intensive care unit admission, neonatal encephalopathy, disability in childhood, other maternal side-effects (nausea, vomiting, diarrhoea), maternal antibiotic use, maternal satisfaction, neonatal infection and neonatal antibiotic use. The findings of our review do not provide evidence that high-dose oxytocin increases either vaginal delivery within 24 hours or the caesarean section rate. There is no significant decrease in induction to delivery time at meta-analysis but these results may be confounded by poor quality trials. High-dose oxytocin was shown to increase the rate of uterine hyperstimulation but the effects of this are not clear. The conclusions here are specific to the definitions used in this review. Further trials evaluating the effects of high-dose regimens of oxytocin for induction of labour should consider all important maternal and infant outcomes.
In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics. We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias. For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias. There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.
Searching identified 113 records. We obtained the full text of 48 of these records for closer inspection. Sixteen trials, randomising a total of 919 participants are included. The majority of trials included adults with schizophrenia or similar illness who were inpatients, and while they were poorly characterised, most appeared to include patients with a chronic presentation. The intervention NRI in nine of the 16 trials was reboxetine, with atomoxetine and viloxazine used in the remaining trials. 14 trials compared NRIs with placebo. Only two trials provided data to compare NRIs against an active control and both compared reboxetine to citalopram but at 4 weeks and 24 weeks respectively so they could not be combined in a meta-analysis. One trial was described as 'open' and we considered it to be at high risk of bias for randomisation and blinding, three trials were at high risk of bias for attrition, six for reporting, and two for other sources of bias. Our main outcomes of interest were significant response or improvement in positive/negative mental state, global state and cognitive functioning, average cognitive functioning scores, significant response or improvement in quality of life and incidence of nausea. All data for main outcomes were short term. NRIs versus placebo Mental state results showed significantly greater rates of improvement in negative symptoms scores (1 RCT, n = 50; RR 3.17, 95% CI 1.52 to 6.58; very low quality evidence) with NRIs on the PANSS negative. No data were reported for significant response or improvement in positive symptoms, but average endpoint PANSS positive scores were available and showed no difference between NRIs and placebo (5 RCTs, n = 294; MD −0.16, 95% CI −0.96 to 0.63; low-quality evidence). Improvement in clinical global status was similar between groups (1 RCT, n = 28; RR 0.99, 95% CI 0.45 to 2.20; very low quality evidence). Significant response or improvement in cognitive functioning data were not reported. Average composite cognitive scores showed no difference between NRIs and placebo (4 RCTs, n = 180; SMD 0.04, 95% CI −0.28 to 0.36; low-quality evidence). Significant response or improvement in quality of life data were not reported, however average endpoint scores from the GQOLI-74 were reported. Those receiving NRIs had better quality of life scores compared to placebo (1 RCT, n = 114; MD 9.36, 95% CI 7.89 to 10.83; very low quality evidence). All-cause withdrawals did not differ between the treatment groups (8 RCTs, n = 401, RR 0.94 95% CI 0.63 to 1.39; moderate-quality evidence). Rates of nausea were not greater with NRIs (3 RCTs, n = 176; RR 0.49, 95% CI 0.10 to 2.41; low-quality evidence). Our results provide tentative very low quality evidence that compared to placebo, NRIs (specifically reboxetine) may have a benefit on the negative symptoms of schizophrenia. Limited evidence also suggests that NRIs have no effect on the positive symptoms of schizophrenia or cognitive functioning. NRIs appear generally well tolerated with no real differences in adverse effects such as nausea noted between NRIs and placebo. However, these results are based on short-term follow-up and are poor quality — there is need for more good-quality evidence. A large RCT of reboxetine over a longer period of time, focusing specifically on negative and cognitive symptoms as well as more detailed and comprehensive reporting of outcomes, including adverse events, is required.
Eleven studies met the criteria for inclusion in this review, all were randomised clinical trials, two were double-blind. There were a total number of 1969 participants. The sequence generation was inadequate in one study, adequate in five studies and unclear in the remaining studies. The allocation of concealment was adequate in three studies and unclear in the remaining studies. Methadone appeared statistically significantly more effective than non-pharmacological approaches in retaining patients in treatment and in the suppression of heroin use as measured by self report and urine/hair analysis (6 RCTs, RR = 0.66 95% CI 0.56-0.78), but not statistically different in criminal activity (3 RCTs, RR=0.39; 95%CI: 0.12-1.25) or mortality (4 RCTs, RR=0.48; 95%CI: 0.10-2.39). Methadone is an effective maintenance therapy intervention for the treatment of heroin dependence as it retains patients in treatment and decreases heroin use better than treatments that do not utilise opioid replacement therapy. It does not show a statistically significant superior effect on criminal activity or mortality.
We included eight RCTs (746 participants) in the review. The risk of bias in the studies was generally low. Five studies did not demonstrate any advantage in using a topical treatment prior to endoscopy. One study suggested that a vasoconstrictor alone should be used to reduce the general level of unpleasantness. Two studies did not compare treatment against placebo or no treatment, so it was not possible to draw meaningful conclusions from them. There may be some unpleasant side effects from the use of topical preparations, such as unpleasant taste. There was variation in the format of the outcome data and a lack of complete data; none of the included studies reported their results in a way that would allow pooling and we could not therefore perform meta-analysis. The included studies do not demonstrate any evidence to support the use of topical treatments prior to the use of a fibre-optic nasal endoscope. Some go as far as to suggest that these agents should not be used due to cost and unpleasant side effects. Five studies did not demonstrate any advantage in terms of reducing pain or discomfort when using a topical treatment prior to endoscopy. The absence of demonstrable effect may be due to relatively small patient groups. It is therefore possible that there is a small effect of using these sprays. Further research using standardised reporting methods is needed.
We pooled summary estimates from 10 trials evaluating SmartCare™ involving 654 participants. Overall, eight trials were judged to be at low or unclear risk of bias, and two trials were judged to be at high risk of bias. Compared with non-automated strategies, SmartCare™ decreased weaning time (mean difference (MD) -2.68 days, 95% confidence interval (CI) -3.99 to -1.37; P value < 0.0001, seven trials, 495 participants, moderate-quality evidence), time to successful extubation (MD -0.99 days, 95% CI -1.89 to -0.09; P value 0.03, seven trials, 516 participants, low-quality evidence), length of ICU stay (MD -5.70 days, 95% CI -10.54 to -0.85; P value 0.02, six trials, 499 participants, moderate-quality evidence) and proportions of participants receiving ventilation for longer than seven and 21 days (risk ratio (RR) 0.44, 95% CI 0.23 to 0.85; P value 0.01 and RR 0.39, 95% CI 0.18 to 0.86; P value 0.02). SmartCare™ reduced the total duration of ventilation (MD -1.68 days, 95% CI -3.33 to -0.03; P value 0.05, seven trials, 521 participants, low-quality evidence) and the number of participants receiving ventilation for longer than 14 days (RR 0.61, 95% CI 0.37 to 1.00; P value 0.05); however the estimated effects were imprecise. SmartCare™ had no effect on time to first successful SBT, mortality or adverse events, specifically reintubation. Subgroup analysis suggested that trials with protocolized (versus non-protocolized) control weaning strategies reported significantly shorter ICU stays. Sensitivity analysis excluded two trials with high risk of bias and supported a trend toward significant reductions in weaning time favouring SmartCare™. Compared with non-automated weaning strategies, weaning with SmartCare™ significantly decreased weaning time, time to successful extubation, ICU stay and proportions of patients receiving ventilation for longer than seven days and 21 days. It also showed a favourable trend toward fewer patients receiving ventilation for longer than 14 days; however the estimated effect was imprecise. Summary estimates from our review suggest that these benefits may be achieved without increasing the risk of adverse events, especially reintubation; however, the quality of the evidence ranged from low to moderate, and evidence was derived from 10 small randomized controlled trials.
We included eight RCTs with 1546 women. Five RCTs were included in our previous review and three new RCTs were added in this update of the review. They compared true acupuncture versus sham acupuncture (three RCTs), true acupuncture versus relaxation (one RCT), true acupuncture versus clomiphene (one RCT), low-frequency electroacupuncture versus physical exercise or no intervention (one RCT) and true acupuncture versus Diane-35 (two RCTs). Studies that compared true acupuncture versus Diane-35 did not measure fertility outcomes as they were focused on symptom control. Seven of the studies were at high risk of bias in at least one domain. For true acupuncture versus sham acupuncture, we could not exclude clinically relevant differences in live birth (RR 0.97, 95% CI 0.76 to 1.24; 1 RCT, 926 women; low-quality evidence); multiple pregnancy rate (RR 0.89, 95% CI 0.33 to 2.45; 1 RCT, 926 women; low-quality evidence); ovulation rate (SMD 0.02, 95% CI –0.15 to 0.19, I2 = 0%; 2 RCTs, 1010 women; low-quality evidence); clinical pregnancy rate (RR 1.03, 95% CI 0.82 to 1.29; I2 = 0%; 3 RCTs, 1117 women; low-quality evidence) and miscarriage rate (RR 1.10, 95% CI 0.77 to 1.56; 1 RCT, 926 women; low-quality evidence). Number of intermenstrual days may have improved in participants receiving true acupuncture compared to sham acupuncture (MD –312.09 days, 95% CI –344.59 to –279.59; 1 RCT, 141 women; low-quality evidence). True acupuncture probably worsens adverse events compared to sham acupuncture (RR 1.16, 95% CI 1.02 to 1.31; I2 = 0%; 3 RCTs, 1230 women; moderate-quality evidence). No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes. We were uncertain whether acupuncture improved ovulation rate (measured by ultrasound three months post treatment) compared to relaxation (MD 0.35, 95% CI 0.14 to 0.56; 1 RCT, 28 women; very low-quality evidence) or Diane-35 (RR 1.45, 95% CI 0.87 to 2.42; 1 RCT, 58 women; very low-quality evidence). Overall evidence ranged from very low quality to moderate quality. The main limitations were failure to report important clinical outcomes and very serious imprecision. For true acupuncture versus sham acupuncture we cannot exclude clinically relevant differences in live birth rate, multiple pregnancy rate, ovulation rate, clinical pregnancy rate or miscarriage. Number of intermenstrual days may improve in participants receiving true acupuncture compared to sham acupuncture. True acupuncture probably worsens adverse events compared to sham acupuncture. No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes as the women in these trials did not seek fertility. We are uncertain whether acupuncture improves ovulation rate (measured by ultrasound three months post treatment) compared to relaxation or Diane-35. The other comparisons did not report on this outcome. Adverse events were recorded in the acupuncture group for the comparisons physical exercise or no intervention, clomiphene and Diane-35. These included dizziness, nausea and subcutaneous haematoma. Evidence was very low quality with very wide CIs and very low event rates. There are only a limited number of RCTs in this area, limiting our ability to determine effectiveness of acupuncture for PCOS.
We included 28 trials (2681 children) investigating 17 interventions of interest; all trials were conducted in high-income countries. Overall we judged the trials to be at high risk of bias. Except for parental acupuncture (graded low), all other GRADE assessments of the primary outcomes of comparisons were very low, indicating a high degree of uncertainty about the overall findings. Parental presence: In five trials (557 children), parental presence at induction of anaesthesia did not reduce child anxiety compared with not having a parent present (standardized mean difference (SMD) 0.03, 95% confidence interval (CI) -0.14 to 0.20). In a further three trials (267 children) where we were unable to pool results, we found no clear differences in child anxiety, whether a parent was present or not. In a single trial, child anxiety showed no significant difference whether one or two parents were present, although parental anxiety was significantly reduced when both parents were present at the induction. Parental presence was significantly less effective than sedative premedication in reducing children's anxiety at induction in three trials with 254 children (we could not pool results). Child interventions (passive): When a video of the child's choice was played during induction, children were significantly less anxious than controls (median difference modified Yale Preoperative Anxiety Scale (mYPAS) 31.2, 95% CI 27.1 to 33.3) in a trial of 91 children. In another trial of 120 children, co-operation at induction did not differ significantly when a video fairytale was played before induction. Children exposed to low sensory stimulation were significantly less anxious than control children on introduction of the anaesthesia mask and more likely to be co-operative during induction in one trial of 70 children. Music therapy did not show a significant effect on children's anxiety in another trial of 51 children. Child interventions (mask introduction): We found no significant differences between a mask exposure intervention and control in a single trial of 103 children for child anxiety (risk ratio (RR) 0.59, 95% CI 0.31 to 1.11) although children did demonstrate significantly better co-operation in the mask exposure group (RR 1.27, 95% CI 1.06 to 1.51). Child interventions (interactive): In a three-arm trial of 168 children, preparation with interactive computer packages (in addition to parental presence) was more effective than verbal preparation, although differences between computer and cartoon preparation were not significant, and neither was cartoon preparation when compared with verbal preparation. Children given video games before induction were significantly less anxious at induction than those in the control group (mYPAS mean difference (MD) -9.80, 95% CI -19.42 to -0.18) and also when compared with children who were sedated with midazolam (mYPAS MD -12.20, 95% CI -21.82 to -2.58) in a trial of 112 children. When compared with parental presence only, clowns or clown doctors significantly lessened children's anxiety in the operating/induction room (mYPAS MD -24.41, 95% CI -38.43 to -10.48; random-effects, I² 75%) in three trials with a total of 133 children. However, we saw no significant differences in child anxiety in the operating room between clowns/clown doctors and sedative premedication (mYPAS MD -9.67, 95% CI -21.14 to 1.80, random-effects, I² 66%; 2 trials of 93 children). In a trial of hypnotherapy versus sedative premedication in 50 children, there were no significant differences in children's anxiety at induction (RR 0.59, 95% CI 0.33 to 1.04). Parental interventions: Children of parents having acupuncture compared with parental sham acupuncture were less anxious during induction (mYPAS MD -17, 95% CI -30.51 to -3.49) and were more co-operative (RR 1.59, 95% CI 1.01 to 2.53) in a single trial of 67 children. Two trials with 191 parents assessed the effects of parental video viewing but did not report any of the review's prespecified primary outcomes. This review shows that the presence of parents during induction of general anaesthesia does not diminish their child's anxiety. Potentially promising non-pharmacological interventions such as parental acupuncture; clowns/clown doctors; playing videos of the child's choice during induction; low sensory stimulation; and hand-held video games need further investigation in larger studies.
Five RCTs (295 participants) were included in this review. All were identified during the original review. The overall risk of bias was high for two RCTs and unclear for three. One RCT compared different proprietary alginate dressings (20 participants), three compared alginate and hydrocolloid dressings (215 participants), and one compared alginate and plain non-adherent dressings (60 participants). Follow-up periods were six weeks in three RCTs and 12 weeks in two. No statistically significant between-group differences were detected for any comparison, for any healing outcome. Meta-analysis was feasible for one comparison (alginate and hydrocolloid dressings), with data from two RCTs (84 participants) pooled for complete healing at six weeks: risk ratio 0.42 (95% confidence interval 0.14 to 1.21). Adverse event profiles were generally similar between groups (not assessed for alginate versus plain non-adherent dressings). The current evidence base does not suggest that alginate dressings are more or less effective in the healing of venous leg ulcers than hydrocolloid or plain non-adherent dressings, and there is no evidence to indicate a difference between different proprietary alginate dressings. However, the RCTs in this area are considered to be of low or unclear methodological quality. Further, good quality evidence is required from well designed and rigorously conducted RCTs that employ - and clearly report on - methods to minimise bias, prior to any definitive conclusions being made regarding the efficacy of alginate dressings in the management of venous leg ulcers.
We included two RCTs, both published in 2015 involving a total of 391 participants with treatment duration of 12 to 13 weeks. One RCT compared a quinolone (moxifloxacin pulsed, for 5 days every 4 weeks), with a tetracycline (doxycycline continuous) or a macrolide (azithromycin intermittent). The second RCT compared a tetracycline (doxycycline continuous) plus a macrolide (roxithromycin continuous), with roxithromycin (continuous) alone. The trials recruited participants with a mean age of 68 years, with moderate-severity COPD. Both trials included participants who had between two and five exacerbations in the previous one to two years. In one trial, 17% of patients had previously been using inhaled corticosteroids. In the other study, all patients were positive for Chlamydophila pneumoniae (C pneumoniae). Overall, we judged the evidence presented to be of very low-certainty, mainly due to imprecision, but we also had concerns about indirectness and methodological quality of the included studies. The primary outcome measures for this review included exacerbations, quality of life, drug resistance and serious adverse events. Macrolide + tetracycline versus macrolide There was no clear difference between treatments in improvement in quality of life as assessed by the Chronic Respiratory Questionnaire (CRQ). The CRQ scale ranges from 0 to 10 and higher scores on the scale indicate better quality of life. CRQ sub-scales for dyspnoea (mean difference (MD) 0.58, 95% confidence interval (CI) -0.84 to 2.00; 187 participants; very low-certainty evidence), fatigue (MD 0.02, 95% CI -1.08 to 1.12; 187 participants; very low-certainty evidence), emotional function (MD -0.37, 95% CI -1.74 to 1.00; 187 participants; very low-certainty evidence), or mastery (MD -0.79, 95% CI -1.86 to 0.28; 187 participants; very low-certainty evidence) at 12 weeks. For serious adverse events, it was uncertain if there was a difference between combined roxithromycin and doxycycline versus roxithromycin alone at 48 weeks follow-up after active treatment of 12 weeks (odds ratio (OR) 1.00, 95% CI 0.52 to 1.93; 198 participants; very low-certainty evidence). There were five deaths reported in the combined treatment arm, versus three in the single treatment arm at 48 weeks follow-up after active treatment of 12 weeks (OR 1.63, 95% CI 0.38 to 7.02; 198 participants; very low-certainty evidence). Quinolone versus tetracycline There was no clear difference between moxifloxacin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants, very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. Quinolone versus macrolide There was no clear difference between moxifloxacin and azithromycin for the number of participants experiencing one or more exacerbations (OR 1.00, 95% CI 0.32 to 3.10; 50 participants; very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. Marcolide versus tetracycline There was no clear difference between azithromycin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants; very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes. We did not find head-to-head evidence for impact of antibiotics on drug resistance. It is not clear from the evidence included in this review whether there is a difference in efficacy or safety between different classes or regimens of prophylactic antibiotic, given for 12 to 13 weeks to people with COPD. Whilst no head-to-head comparisons of antibiotic resistance were identified, concerns about this continue. The sample size in this review is small and both included studies are of short duration. Thus, there is considerable uncertainty in effects observed and the effects of different prophylactic antibiotics requires further research.
We included 16 trials, which all compared either vaginal or intramuscular (IM) progesterone with a placebo or no treatment, and involved a total of 4548 women. The risk of bias for the majority of included studies was low, with the exception of three studies that had inadequate blinding, or significant loss to follow-up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate. 1 IM progesterone versus no treatment or placebo More women delivered at less than 34 weeks' gestation in the IM progesterone group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low-quality evidence). Although the incidence of perinatal death in the progesterone group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high-quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate-quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I2 = 76%, moderate-quality evidence)). No childhood outcomes were reported in the trials. 2 Vaginal progesterone versus no treatment or placebo by dose There were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.90, 95% CI 0.66 to 1.23; women = 1503; studies = 5; I2 = 36%; low-quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate-quality evidence); preterm birth less than 28 weeks (RR 1.53, 95% CI 0.79 to 2.97; women = 1345; studies = 3; low-quality evidence); infant birthweight less than 2500 g (average RR 0.95, 95% CI 0.84 to 1.07; infants = 2640; studies = 3; I2 = 66%, moderate-quality evidence)). No childhood outcomes were reported in the trials. For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (8%) (RR 0.92, 95% CI 0.86 to 0.98; women = 1919; studies = 5; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.70, 95% CI 0.52 to 0.94; infants = 2695; studies = 4). Overall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes. Future research could focus on a comprehensive individual participant data meta-analysis including all of the available data relating to both IM and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high-risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).
Four randomised controlled trials were included. No unintended pregnancies were reported during the study periods. Only one trial was of good methodological quality. It compared the influence of a levonorgestrel-releasing intrauterine device (IUD) versus a copper IUD on carbohydrate metabolism in women with type 1 diabetes mellitus. No significant difference was found between the two groups. The other three trials were of limited methodological quality. Two compared progestogen-only pills with different estrogen and progestogen combinations, and one also included the levonorgestrel-releasing IUD and copper IUD. The trials reported that blood glucose levels remained stable during treatment with most regimens. Only high-dose combined oral contraceptives and 30 µg ethinylestradiol + 75 µg gestodene were identified as slightly impairing glucose homeostasis. The three studies found conflicting results regarding lipid metabolism. Some combined oral contraceptives appeared to have a minor adverse effect while others appeared to slightly improve lipid metabolism. The copper IUD and progestogen-only oral contraceptives also slightly improved lipid metabolism and no influence was seen while using the levonorgestel-releasing IUD. Only one study reported on micro- and macrovascular complications. It observed no signs or symptoms of thromboembolic incidents or visual disturbances, however study duration was short. Only minor adverse effects were reported in two studies. The four included randomised controlled trials in this systematic review provided insufficient evidence to assess whether progestogen-only and combined contraceptives differ from non-hormonal contraceptives in diabetes control, lipid metabolism and complications. Three of the four studies were of limited methodological quality, sponsored by pharmaceutical companies and described surrogate outcomes. Ideally, an adequately reported, high-quality randomised controlled trial analysing both intermediate outcomes (that is glucose and lipid metabolism) and true clinical endpoints (micro- and macrovascular disease) in users of combined, progestogen-only and non-hormonal contraceptives should be conducted. However, due to the low incidence of micro- and macrovascular disease and accordingly the large sample size and long follow-up period needed to observe differences in risk, a randomised controlled trial might not be the ideal design.
We included 24 studies (5577 women). There were no trials specifically of miscarriage treatment after 13 weeks' gestation. Three trials involving 335 women compared misoprostol treatment (all vaginally administered) with expectant care. There was no difference in complete miscarriage (average risk ratio (RR) 1.23, 95% confidence interval (CI) 0.72 to 2.10; 2 studies, 150 women, random-effects; very low-quality evidence), or in the need for surgical evacuation (average RR 0.62, 95% CI 0.17 to 2.26; 2 studies, 308 women, random-effects; low-quality evidence). There were few data on 'deaths or serious complications'. For unplanned surgical intervention, we did not identify any difference between misoprostol and expectant care (average RR 0.62, 95% CI 0.17 to 2.26; 2 studies, 308 women, random-effects; low-quality evidence). Sixteen trials involving 4044 women addressed the comparison of misoprostol (7 studies used oral administration, 6 studies used vaginal, 2 studies sublingual, 1 study combined vaginal + oral) with surgical evacuation. There was a slightly lower incidence of complete miscarriage with misoprostol (average RR 0.96, 95% CI 0.94 to 0.98; 15 studies, 3862 women, random-effects; very low-quality evidence) but with success rate high for both methods. Overall, there were fewer surgical evacuations with misoprostol (average RR 0.05, 95% CI 0.02 to 0.11; 13 studies, 3070 women, random-effects; very low-quality evidence) but more unplanned procedures (average RR 5.03, 95% CI 2.71 to 9.35; 11 studies, 2690 women, random-effects; low-quality evidence). There were few data on 'deaths or serious complications'. Nausea was more common with misoprostol (average RR 2.50, 95% CI 1.53 to 4.09; 11 studies, 3015 women, random-effects; low-quality evidence). We did not identify any difference in women's satisfaction between misoprostol and surgery (average RR 1.00, 95% CI 0.99 to 1.00; 9 studies, 3349 women, random-effects; moderate-quality evidence). More women had vomiting and diarrhoea with misoprostol compared with surgery (vomiting: average RR 1.97, 95% CI 1.36 to 2.85; 10 studies, 2977 women, random-effects; moderate-quality evidence; diarrhoea: average RR 4.82, 95% CI 1.09 to 21.32; 4 studies, 757 women, random-effects; moderate-quality evidence). Five trials compared different routes of administration, or doses, or both, of misoprostol. There was no clear evidence of one regimen being superior to another. Limited evidence suggests that women generally seem satisfied with their care. Long-term follow-up from one included study identified no difference in subsequent fertility between the three approaches. The available evidence suggests that medical treatment, with misoprostol, and expectant care are both acceptable alternatives to routine surgical evacuation given the availability of health service resources to support all three approaches. Further studies, including long-term follow-up, are clearly needed to confirm these findings. There is an urgent need for studies on women who miscarry at more than 13 weeks' gestation.
We included 20 trials using a variety of biomedical tests interventions; one trial included two interventions, for a total of 21 interventions. We included a total of 9262 participants, all of whom were adult smokers. All studies included both men and women adult smokers at different stages of change and motivation for smoking cessation. We judged all but three studies to be at high or unclear risk of bias in at least one domain. We pooled trials in three categories according to the type of biofeedback provided: feedback on risk exposure (five studies); feedback on smoking-related disease risk (five studies); and feedback on smoking-related harm (11 studies). There was no evidence of increased cessation rates from feedback on risk exposure, consisting mainly of feedback on CO measurement, in five pooled trials (RR 1.00, 95% CI 0.83 to 1.21; I2 = 0%; n = 2368). Feedback on smoking-related disease risk, including four studies testing feedback on genetic markers for cancer risk and one study with feedback on genetic markers for risk of Crohn's disease, did not show a benefit in smoking cessation (RR 0.80, 95% CI 0.63 to 1.01; I2 = 0%; n = 2064). Feedback on smoking-related harm, including nine studies testing spirometry with or without feedback on lung age and two studies on feedback on carotid ultrasound, also did not show a benefit (RR 1.26, 95% CI 0.99 to 1.61; I2 = 34%; n = 3314). Only one study directly compared multiple forms of measurement with a single form of measurement, and did not detect a significant difference in effect between measurement of CO plus genetic susceptibility to lung cancer and measurement of CO only (RR 0.82, 95% CI 0.43 to 1.56; n = 189). There is little evidence about the effects of biomedical risk assessment as an aid for smoking cessation. The most promising results relate to spirometry and carotid ultrasound, where moderate-certainty evidence, limited by imprecision and risk of bias, did not detect a statistically significant benefit, but confidence intervals very narrowly missed one, and the point estimate favoured the intervention. A sensitivity analysis removing those studies at high risk of bias did detect a benefit. Moderate-certainty evidence limited by risk of bias did not detect an effect of feedback on smoking exposure by CO monitoring. Low-certainty evidence, limited by risk of bias and imprecision, did not detect a benefit from feedback on smoking-related risk by genetic marker testing. There is insufficient evidence with which to evaluate the hypothesis that multiple types of assessment are more effective than single forms of assessment.
Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I2 = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I2 = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I2 = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error. The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.
Heparinization of the infusate decreases the incidence of catheter occlusion but does not affect the frequency of aortic thrombosis. Heparinization of the flush solution is not an adequate alternative.  There does not appear to be an effect on frequency of intraventricular hemorrhage, death or clinical ischemic phenomena. Heparinization of the fluid infused through an umbilical arterial catheter decreases the likelihood of umbilical arterial catheters occluding. The lowest concentration tested so far (0.25 units/mL) has been shown to be effective. Heparinization of flushes without heparinizing the infusate is ineffective. The frequency of aortic thrombosis has not been shown to be affected; however, the confidence intervals for this effect are very wide. The frequency of intraventricular hemorrhage has not been shown to be affected by heparinization of the infusate, but again the confidence intervals are very wide and even a major increase in the incidence of grade 3 and 4 intraventricular hemorrhage would not have been detected.
The initial search identified 1014 records which identified 13 publications for further examination. After screening the full text of the 13 selected papers, only one study evaluating 47 babies finally met the inclusion criteria. Using the same cohort at two different time periods, the study investigated the effects of high versus low dose thyroid hormone replacement in relation to (1) time taken to achieve euthyroid status and (2) neurodevelopmental outcome. The study reported that a high dose is more effective in rising serum thyroxine and free thyroxine concentrations to the target range and earlier normalisation of thyroid stimulating hormone compared to a lower dose. Similarly, full scale intelligence quotient was noted to be significantly higher in children who received the high dose compared to the lower dose. However, the verbal intelligence quotient and performance intelligence quotient were similar in both groups. Growth and adverse effects were not reported in the included trial. There is currently only one randomised controlled trial evaluating the effects of high versus low dose of initial thyroid hormone replacement for CHT. There is inadequate evidence to suggest that a high dose is more beneficial compared to a low dose initial thyroid hormone replacement in the treatment of CHT.
Seven studies enrolling 385 patients were included. There were substantial methodological concerns for most studies including the use of quasi-random allocation methods and sizeable, largely unexplained differences in reported numbers allocated to each group. One study reported phenobarbitone compared to supportive care alone did not reduce treatment failure or time to regain birthweight, but resulted in a significant reduction in duration of supportive care (MD -162.1 min/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone resulted in a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). Comparing phenobarbitone with chlorpromazine, one study reported no significant difference in treatment failure. In infants treated with an opiate, one study reported addition of clonidine resulted in no significant difference in treatment failure, seizures or mortality. In infants treated with an opiate, one study reported addition of phenobarbitone significantly reduced the proportion of time infants had a high abstinence severity score, duration of hospitalisation and maximal daily dose of opiate. Infants with NAS due to opiate withdrawal should receive initial treatment with an opiate. Where a sedative is used, phenobarbitone should be used in preference to diazepam. In infants treated with an opiate, the addition of phenobarbitone or clonidine may reduce withdrawal severity. Further studies are needed to determine the role of sedatives in infants with NAS due to opiate withdrawal and the safety and efficacy of adding phenobarbitone or clonidine in infants treated with an opiate for NAS.
We found one eligible trial that included 72 preterm infants. This trial was not blinded. We are uncertain as to the effect of re-feeding gastric residual on efficacy outcomes such as time to regain birth weight (mean difference (MD) 0.40 days, 95% confidence interval (CI) -2.89 to 3.69 days; very low quality evidence), time to reach enteral feeds ≥ 120 mL/kg/d (MD -1.30 days, 95% CI -2.93 to 0.33 days; very low quality evidence), number of infants with extrauterine growth restriction at discharge (risk ratio (RR) 1.29, 95% CI 0.38 to 4.34; very low quality evidence), duration of total parenteral nutrition (MD -0.30 days, 95% CI -2.07 to 1.47 days; very low quality evidence), and length of hospital stay (MD -1.90 days, 95% CI -25.27 to 21.47 days; very low quality evidence). Similarly, we are uncertain as to the effect of re-feeding gastric residual on safety outcomes such as incidence of stage 2 or 3 necrotising enterocolitis and/or spontaneous intestinal perforation (RR 0.71, 95% CI 0.25 to 2.04; very low quality evidence), number of episodes of feed interruption lasting ≥ 12 hours (RR 0.80, 95% CI 0.42 to 1.52; very low quality evidence), or mortality before discharge (RR 0.50, 95% CI 0.14 to 1.85; low-quality evidence). We are uncertain as to the effect of re-feeding gastric residual in the subgroups of human milk-fed and formula-fed infants. We found no data on other outcomes such as linear and head growth during hospital stay, postdischarge growth, number of infants with parenteral nutrition-associated liver disease, and neurodevelopmental outcomes. We found only limited data from one small unblinded trial on the efficacy and safety of re-feeding gastric residuals in preterm infants. The quality of evidence was low to very low. Hence, available evidence is insufficient to support or refute re-feeding of gastric residuals in preterm infants. A large, randomised controlled trial is needed to provide data of sufficient quality and precision to inform policy and practice.
We included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal. In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence). In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (23%) (RR 1.7 (95% CI 1.4 to 2.0); NNT 6.6 (5.0 to 10); 6 studies, 1331 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence). For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate-quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%). Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review.
Two RCTs including 172 patients with moderate to severe UC who failed conventional therapy met the inclusion criteria. Both studies were rated as low risk of bias. We did not pool efficacy data from the two included studies due to differences in dose and route of administration. The small phase I study found no statistically significant differences between etrolizumab and placebo in the proportion of patients who failed to enter remission (RR 1.04, 95% CI 1.04 to 1.69; participants = 23) or respond at week 10 (RR 1.67, 95% CI 0.26 to 10.82; participants = 23). The phase II study reported on failure to enter clinical remission at weeks 6 and 10. In the etrolizumab group 91% (71/78) of patients failed to enter remission at week 6 compared to 95% (39/41) of placebo patients (RR 0.96, 95% CI 0.87 to 1.06). Subgroup analysis revealed no statistically significant differences by dose. At week 10, there was a statistically significant difference in clinical remission rates favouring etrolizumab over placebo. Of the patients who received etrolizumab, 85% (66/78) failed to enter remission at week 10 compared to 100% (41/41) patients in the placebo group (RR 0.86, 95% CI 0.77 to 0.95). A subgroup analysis by dose found a statistically significant difference in clinical remission rates favoring 100 mg etrolizumab over placebo (RR 0.81 CI 95% 0.68 to 0.96), but not 300 mg etrolizumab over placebo (RR 0.91, 95% CI 0.80 to 1.03). No significant heterogeneity was detected for this comparison (P = 0.28, I2 = 13.5%). GRADE analyses indicated that the overall quality of evidence for the clinical remission outcomes was moderate due to sparse data. Both of the included studies reported on safety. The outcome adverse events was initially pooled, however this analysis was removed due to high heterogeneity (I2 = 88%). The phase I study found no statistically significant difference between etrolizumab and placebo in the proportion of patients who had at least one adverse event. Ninety-five per cent (36/38) of etrolizumab patients had at least one adverse event compared to 100% (10/10) of placebo patients (RR 0.98, 95% CI 0.84 to 1.14). Common adverse events reported in the phase I study included exacerbation of UC, headache, fatigue, abdominal pain, dizziness, nasopharyngitis, nausea, arthralgia and urinary tract infection. There was a statistically significant difference between etrolizumab and placebo in the proportion of patients who had at least one adverse event. Fifty-six per cent (44/78) of etrolizumab patients had at least one adverse event compared to 79% of placebo patients (RR 0.71, 95% CI 0.55 to 0.91). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data. Common adverse events reported in the phase II study included worsening UC, nasopharyngitis, nervous system disorders, headache and arthralgia . A pooled analysis of two studies indicates that there was no statistically significant difference in the proportion of patients who had a serious adverse event. Twelve per cent (14/116) of etrolizumab patients had a serious adverse event compared to 12% of placebo patients (6/49) (RR 0.92, 95% CI 0.36 to 2.34). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (20 events). Common serious adverse events included worsening of UC, impaired wound healing and bacterial peritonitis. Moderate quality evidence suggests that etrolizumab may be an effective induction therapy for some patients with moderate to severe ulcerative colitis who have failed conventional therapy. Due to small numbers of patients in dose subgroups the optimal dosage of etrolizumab is unclear. Due to sparse data we are uncertain regarding the risk of adverse events and serious adverse events. Further studies are needed to determine the efficacy and safety of etrolizumab in this patient population. There are five ongoing phase III etrolizumab trials and two ongoing open-label extension studies that will provide important new information on the efficacy, safety and optimal dose of this drug for the treatment of UC.
We identified 136 studies; 133 with 64,640 participants contributed to the primary comparison between any type of NRT and a placebo or non-NRT control group. The majority of studies were conducted in adults and had similar numbers of men and women. People enrolled in the studies typically smoked at least 15 cigarettes a day at the start of the studies. We judged the evidence to be of high quality; we judged most studies to be at high or unclear risk of bias but restricting the analysis to only those studies at low risk of bias did not significantly alter the result. The RR of abstinence for any form of NRT relative to control was 1.55 (95% confidence interval (CI) 1.49 to 1.61). The pooled RRs for each type were 1.49 (95% CI 1.40 to 1.60, 56 trials, 22,581 participants) for nicotine gum; 1.64 (95% CI 1.53 to 1.75, 51 trials, 25,754 participants) for nicotine patch; 1.52 (95% CI 1.32 to 1.74, 8 trials, 4439 participants) for oral tablets/lozenges; 1.90 (95% CI 1.36 to 2.67, 4 trials, 976 participants) for nicotine inhalator; and 2.02 (95% CI 1.49 to 2.73, 4 trials, 887 participants) for nicotine nasal spray. The effects were largely independent of the definition of abstinence, the intensity of additional support provided or the setting in which the NRT was offered. Adverse events from using NRT were related to the type of product, and include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. Attempts to quantitatively synthesize the incidence of various adverse effects were hindered by extensive variation in reporting the nature, timing and duration of symptoms. The odds ratio (OR) of chest pains or palpitations for any form of NRT relative to control was 1.88 (95% CI 1.37 to 2.57, 15 included and excluded trials, 11,074 participants). However, chest pains and palpitations were rare in both groups and serious adverse events were extremely rare. There is high-quality evidence that all of the licensed forms of NRT (gum, transdermal patch, nasal spray, inhalator and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50% to 60%, regardless of setting, and further research is very unlikely to change our confidence in the estimate of the effect. The relative effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. NRT often causes minor irritation of the site through which it is administered, and in rare cases can cause non-ischaemic chest pain and palpitations.
We identified 12 RCTs and one quasi-RCT (6923 participants), six for cardiac surgery (3359 participants) and seven for thoracic surgery (3564 participants). No study evaluated fondaparinux, the new oral direct thrombin, direct factor Xa inhibitors, or caval filters. All studies had major study design flaws and most lacked a placebo or no treatment control group. We typically graded the quality of the overall body of evidence for the various outcomes and comparisons as low, due to imprecise estimates of effect and risk of bias. We could not pool data because of the different comparisons and the lack of data. In cardiac surgery, 71 symptomatic VTEs occurred in 3040 participants from four studies. In a study of 2551 participants, representing 85% of the review population in cardiac surgery, the combination of unfractionated heparin with pneumatic compression stockings was associated with a 61% reduction of symptomatic VTE compared to unfractionated heparin alone (1.5% versus 4.0%; risk ratio (RR) 0.39; 95% confidence interval (CI) 0.23 to 0.64). Major bleeding was only reported in one study, which found a higher incidence with vitamin K antagonists compared to platelet inhibitors (11.3% versus 1.6%, RR 7.06; 95% CI 1.64 to 30.40). In thoracic surgery, 15 symptomatic VTEs occurred in 2890 participants from six studies. In the largest study evaluating unfractionated heparin versus an inactive control the rates of symptomatic VTE were 0.7% versus 0%, respectively, giving a RR of 6.71 (95% CI 0.40 to 112.65). There was insufficient evidence to determine if there was a difference in the risk of major bleeding from two studies evaluating fixed-dose versus weight-adjusted low molecular weight heparin (2.7% versus 8.1%, RR 0.33; 95% CI 0.07 to 1.60) and unfractionated heparin versus low molecular weight heparin (6% and 4%, RR 1.50; 95% CI 0.26 to 8.60). The evidence regarding the efficacy and safety of thromboprophylaxis in cardiac and thoracic surgery is limited. Data for important outcomes such as pulmonary embolism or major bleeding were often lacking. Given the uncertainties around the benefit-to-risk balance, no conclusions can be drawn and a case-by-case risk evaluation of VTE and bleeding remains preferable.
Fifteen studies (N= 2012) were included in analyses. We assessed the risk of bias for included studies as low overall. We identified nine high 'risk of bias' assessments, 22 unclear, and 59 low 'risk of bias' assessments. Most judgements of a high risk of bias were due to inadequate reporting. Analyses revealed seven effects. Participants with headache conditions receiving psychological therapies delivered via the Internet had reduced pain (number needed to treat to benefit = 2.72, risk ratio 7.28, 95% confidence interval (CI) 2.67 to 19.84, p < 0.01) and a moderate effect was found for disability post-treatment (standardised mean difference (SMD) ‒0.65, 95% CI ‒0.91 to ‒0.39, p < 0.01). However, only two studies could be entered into each analysis; hence, findings should be interpreted with caution. There was no clear evidence that psychological therapies improved depression or anxiety post-treatment (SMD −0.26, 95% CI −0.87 to 0.36, p > 0.05; SMD −0.48, 95% CI −1.22 to 0.27, p > 0.05), respectively. In participants with non-headache conditions, psychological therapies improved pain post-treatment (p < 0.01) with a small effect size (SMD −0.37, 95% CI −0.59 to −0.15), disability post-treatment (p < 0.01) with a moderate effect size (SMD −0.50, 95% CI −0.79 to −0.20), and disability at follow-up (p < 0.05) with a small effect size (SMD −0.15, 95% CI −0.28 to −0.01). However, the follow-up analysis included only two studies and should be interpreted with caution. A small effect was found for depression and anxiety post-treatment (SMD −0.19, 95% CI −0.35 to −0.04, p < 0.05; SMD −0.28, 95% CI −0.49 to −0.06, p < 0.01), respectively. No clear evidence of benefit was found for other follow-up analyses. Analyses of adverse effects were not possible. No data were presented on satisfaction/acceptability. Only one study could be included in an analysis of the effect of psychological therapies on quality of life in participants with headache conditions; hence, no analysis could be undertaken. Three studies presented quality of life data for participants with non-headache conditions; however, no clear evidence of benefit was found (SMD −0.27, 95% CI −0.54 to 0.01, p > 0.05). There is insufficient evidence to make conclusions regarding the efficacy of psychological therapies delivered via the Internet in participants with headache conditions. Psychological therapies reduced pain and disability post-treatment; however, no clear evidence of benefit was found for depression and anxiety. For participants with non-headache conditions, psychological therapies delivered via the Internet reduced pain, disability, depression, and anxiety post-treatment. The positive effects on disability were maintained at follow-up. These effects are promising, but considerable uncertainty remains around the estimates of effect. These results come from a small number of trials, with mostly wait-list controls, no reports of adverse events, and non-clinical recruitment methods. Due to the novel method of delivery, the satisfaction and acceptability of these therapies should be explored in this population. These results are similar to those of reviews of traditional face-to-face therapies for chronic pain.
Twenty six trials met inclusion criteria. Methodological quality was variable and trial populations were generally small (median sample size = 48, range 14 to 180). Exercise was demonstrated to be effective in terms of short term recovery in rotator cuff disease (RR 7.74 (1.97, 30.32), and longer term benefit with respect to function (RR 2.45 (1.24, 4.86). Combining mobilisation with exercise resulted in additional benefit when compared to exercise alone for rotator cuff disease. Laser therapy was demonstrated to be more effective than placebo for adhesive capsulitis (RR 8, 95%CI 2.11 to 30.34) but not for supraspinatus tendinitis (RR 2, 95%CI 0.98 to 4.09). Both ultrasound and pulsed electromagnetic field therapy resulted in improvement compared to placebo in pain in calcific tendinitis (RR 1.81 (1.26, 2.60) and RR 19 (1.16, 12.43) respectively). There is no evidence of the effect of ultrasound in shoulder pain (mixed diagnosis), adhesive capsulitis or rotator cuff tendinitis. When compared to exercises, ultrasound is of no additional benefit over and above exercise alone. There is some evidence that for rotator cuff disease, corticosteroid injections are superior to physiotherapy and no evidence that physiotherapy alone is of benefit for adhesive capsulitis The small sample sizes, variable methodological quality and heterogeneity in terms of population studied, physiotherapy intervention employed and length of follow up of randomised controlled trials of physiotherapy interventions results in little overall evidence to guide treatment. There is evidence to support the use of some interventions in specific and circumscribed cases. There is a need for trials of physiotherapy interventions for specific clinical conditions associated with shoulder pain, for shoulder pain where combinations of physiotherapy interventions, as well as, physiotherapy interventions as an adjunct to other, non physiotherapy interventions are compared. This is more reflective of current clinical practice. Trials should be adequately powered and address key methodological criteria such as allocation concealment and blinding of outcome assessor.
We include three new studies in this update, making a total of 11 included trials with 1387 participants. The average age was 69 years and all trials included men and women. Participants were followed for up to two years. There was an improvement in primary duplex patency at six and 12 months in participants treated with PTA plus stent over lesions treated with PTA alone (six months: odds ratio (OR) 2.90, 95% confidence interval (CI) 1.17 to 7.18, P = 0.02, six studies, 578 participants; 12 months: OR 1.78, 95% CI 1.02 to 3.10, P = 0.04, nine studies, 858 participants). This was lost by 24 months (P = 0.06). There was a significant angiographic patency benefit at six months (OR 2.49, 95% CI 1.49 to 4.17, P = 0.0005, four studies, 329 participants) which was lost by 12 months (OR 1.30, 95% CI 0.84 to 2.00, P = 0.24, five studies, 384 participants). Ankle brachial index (ABI) and treadmill walking distance showed no improvement at 12 months (P = 0.49 and P = 0.57 respectively) between participants treated with PTA alone or PTA with stent insertion. Three trials (660 participants) reported quality of life, which showed no significant difference between participants treated with PTA alone or PTA with stent insertion at any time interval. Antiplatelet therapy protocols and inclusion criteria regarding affected arteries between trials showed marked heterogeneity. Although there was a short-term gain in primary patency there was no sustained benefit from primary stenting of lesions of the superficial femoral artery in addition to angioplasty. Future trials should focus on quality of life for claudication and limb salvage for critical ischaemia.
We included 44 trials (5783 participants with HF) with a median of six months' follow-up. For this latest update, we identified 11 new trials (N = 1040), in addition to the previously identified 33 trials. Although the evidence base includes predominantly patients with HFrEF with New York Heart Association classes II and III receiving centre-based exercise-based CR programmes, a growing body of studies include patients with HFpEF and are undertaken in a home-based setting. All included studies included a no formal exercise training intervention comparator. However, a wide range of comparators were seen across studies that included active intervention (i.e. education, psychological intervention) or usual medical care alone. The overall risk of bias of included trials was low or unclear, and we downgraded results using the GRADE tool for all but one outcome. Cardiac rehabilitation may make little or no difference in all-cause mortality over the short term (≤ one year of follow-up) (27 trials, 28 comparisons (2596 participants): intervention 67/1302 (5.1%) vs control 75/1294 (5.8%); risk ratio (RR) 0.89, 95% confidence interval (CI) 0.66 to 1.21; low-quality GRADE evidence) but may improve all-cause mortality in the long term (> 12 months follow up) (6 trials/comparisons (2845 participants): intervention 244/1418 (17.2%) vs control 280/1427 (19.6%) events): RR 0.88, 95% CI 0.75 to 1.02; high-quality evidence). Researchers provided no data on deaths due to HF. CR probably reduces overall hospital admissions in the short term (up to one year of follow-up) (21 trials, 21 comparisons (2182 participants): (intervention 180/1093 (16.5%) vs control 258/1089 (23.7%); RR 0.70, 95% CI 0.60 to 0.83; moderate-quality evidence, number needed to treat: 14) and may reduce HF-specific hospitalisation (14 trials, 15 comparisons (1114 participants): (intervention 40/562 (7.1%) vs control 61/552 (11.1%) RR 0.59, 95% CI 0.42 to 0.84; low-quality evidence, number needed to treat: 25). After CR, a clinically important improvement in short-term disease-specific health-related quality of life may be evident (Minnesota Living With Heart Failure questionnaire - 17 trials, 18 comparisons (1995 participants): mean difference (MD) -7.11 points, 95% CI -10.49 to -3.73; low-quality evidence). Pooling across all studies, regardless of the HRQoL measure used, shows there may be clinically important improvement with exercise (26 trials, 29 comparisons (3833 participants); standardised mean difference (SMD) -0.60, 95% CI -0.82 to -0.39; I² = 87%; Chi² = 215.03; low-quality evidence). ExCR effects appeared to be consistent different models of ExCR delivery: centre vs. home-based, exercise dose, exercise only vs. comprehensive programmes, and aerobic training alone vs aerobic plus resistance programmes. This updated Cochrane Review provides additional randomised evidence (11 trials) to support the conclusions of the previous version (2014) of this Cochane Review. Compared to no exercise control, CR appears to have no impact on mortality in the short term (< 12 months' follow-up). Low- to moderate-quality evidence shows that CR probably reduces the risk of all-cause hospital admissions and may reduce HF-specific hospital admissions in the short term (up to 12 months). CR may confer a clinically important improvement in health-related quality of life, although we remain uncertain about this because the evidence is of low quality. Future ExCR trials need to continue to consider the recruitment of traditionally less represented HF patient groups including older, female, and HFpEF patients, and alternative CR delivery settings including home- and using technology-based programmes.
We included seven trials with 1521 participants in this review. The expectant-care group was more likely to have an incomplete miscarriage by two weeks (RR 3.98; 95% CI 2.94 to 5.38) or by six to eight weeks (RR 2.56; 95% CI 1.15 to 5.69). The need for unplanned surgical treatment was greater for the expectant-care group (RR 7.35; 95% CI 5.04 to 10.72). The mean percentage needing surgical management in the expectant-care group was 28%, while 4% of the surgical-treatment group needed additional surgery. The expectant-care group had more days of bleeding (MD 1.59; 95% CI 0.74 to 2.45). Further, more of the expectant-care group needed transfusion (RR 6.45; 95% CI 1.21 to 34.42). The mean percentage needing blood transfusion was 1.4% for expectant care compared with none for surgical management. Results were mixed for pain. Diagnosis of infection was similar for the two groups (RR 0.63; 95% CI 0.36 to 1.12), as were results for various psychological outcomes. Pregnancy data were limited. Costs were lower for the expectant-care group (MD -499.10; 95% CI -613.04 to -385.16; in UK pounds sterling). Expectant management led to a higher risk of incomplete miscarriage, need for unplanned (or additional) surgical emptying of the uterus, bleeding and need for transfusion. Risk of infection and psychological outcomes were similar for both groups. Costs were lower for expectant management. Given the lack of clear superiority of either approach, the woman's preference should be important in decision making. Pharmacological ('medical') management has added choices for women and their clinicians and has been examined in other reviews.
The review included three studies involving 112 participants. All the included studies performed the comparison breathing exercises as part of a more complex intervention versus control. There were no trials comparing breathing exercises alone with control. Asthma severity of participants from the included studies varied. The studies measured: quality of life, asthma symptoms, reduction in medication usage, number of acute exacerbations and lung function. Breathing exercise techniques used by the included studies consisted of lateral costal breathing, diaphragmatic breathing, inspiratory patterns and pursed lips. One study included in the review did not specify the type of breathing exercise used. The control groups received different interventions: one received placebo treatment, one an educational programme and doctor appointments, and one was not described. There were no reported between-group comparisons for any of the primary outcomes. We judged the included studies as having an unclear risk of bias. We could draw no reliable conclusions concerning the use of breathing exercises for children with asthma in clinical practice. The breathing exercises were part of a more comprehensive package of care, and could not be assessed on their own. Moreover, there were methodological differences among the three small included studies and poor reporting of methodological aspects and results in most of the included studies.
In total, 31 heterogeneous trials including 1690 participants with patellofemoral pain are included in this review. There was considerable between-study variation in patient characteristics (e.g. activity level) and diagnostic criteria for study inclusion (e.g. minimum duration of symptoms) and exercise therapy. Eight trials, six of which were quasi-randomised, were at high risk of selection bias. We assessed most trials as being at high risk of performance bias and detection bias, which resulted from lack of blinding. The included studies, some of which contributed to more than one comparison, provided evidence for the following comparisons: exercise therapy versus control (10 trials); exercise therapy versus other conservative interventions (e.g. taping; eight trials evaluating different interventions); and different exercises or exercise programmes. The latter group comprised: supervised versus home exercises (two trials); closed kinetic chain (KC) versus open KC exercises (four trials); variants of closed KC exercises (two trials making different comparisons); other comparisons of other types of KC or miscellaneous exercises (five trials evaluating different interventions); hip and knee versus knee exercises (seven trials); hip versus knee exercises (two studies); and high- versus low-intensity exercises (one study). There were no trials testing exercise medium (land versus water) or duration of exercises. Where available, the evidence for each of seven main outcomes for all comparisons was of very low quality, generally due to serious flaws in design and small numbers of participants. This means that we are very unsure about the estimates. The evidence for the two largest comparisons is summarised here. Exercise versus control. Pooled data from five studies (375 participants) for pain during activity (short-term) favoured exercise therapy: mean difference (MD) -1.46, 95% confidence interval (CI) -2.39 to -0.54. The CI included the minimal clinically important difference (MCID) of 1.3 (scale 0 to 10), indicating the possibility of a clinically important reduction in pain. The same finding applied for usual pain (short-term; two studies, 41 participants), pain during activity (long-term; two studies, 180 participants) and usual pain (long-term; one study, 94 participants). Pooled data from seven studies (483 participants) for functional ability (short-term) also favoured exercise therapy; standardised mean difference (SMD) 1.10, 95% CI 0.58 to 1.63. Re-expressed in terms of the Anterior Knee Pain Score (AKPS; 0 to 100), this result (estimated MD 12.21 higher, 95% CI 6.44 to 18.09 higher) included the MCID of 10.0, indicating the possibility of a clinically important improvement in function. The same finding applied for functional ability (long-term; three studies, 274 participants). Pooled data (two studies, 166 participants) indicated that, based on the 'recovery' of 250 per 1000 in the control group, 88 more (95% CI 2 fewer to 210 more) participants per 1000 recovered in the long term (12 months) as a result of exercise therapy. Hip plus knee versus knee exercises. Pooled data from three studies (104 participants) for pain during activity (short-term) favoured hip and knee exercise: MD -2.20, 95% CI -3.80 to -0.60; the CI included a clinically important effect. The same applied for usual pain (short-term; two studies, 46 participants). One study (49 participants) found a clinically important reduction in pain during activity (long-term) for hip and knee exercise. Although tending to favour hip and knee exercises, the evidence for functional ability (short-term; four studies, 174 participants; and long-term; two studies, 78 participants) and recovery (one study, 29 participants) did not show that either approach was superior. This review has found very low quality but consistent evidence that exercise therapy for PFPS may result in clinically important reduction in pain and improvement in functional ability, as well as enhancing long-term recovery. However, there is insufficient evidence to determine the best form of exercise therapy and it is unknown whether this result would apply to all people with PFPS. There is some very low quality evidence that hip plus knee exercises may be more effective in reducing pain than knee exercise alone. Further randomised trials are warranted but in order to optimise research effort and engender the large multicentre randomised trials that are required to inform practice, these should be preceded by research that aims to identify priority questions and attain agreement and, where practical, standardisation regarding diagnostic criteria and measurement of outcome.
We obtained and scrutinised 41 potentially relevant records, and from these we could include only six trials (n = 1835). Five of the six trials had high risk of attrition bias and all trials were sponsored by pharmaceutical companies. Results showed a clinically important change in global state (1 RCT, n = 336, RR 0.81, 95% CI 0.68 to 0.97, low-quality evidence) and mental state (1 RCT, n = 336, RR 0.72, 95% CI 0.59 to 0.86, very low-quality evidence) at short-term amongst people receiving asenapine. People receiving asenapine demonstrated significant reductions in negative symptoms (1 RCT, n = 336, MD -1.10, 95% CI -2.29 to 0.09, very low-quality evidence) at short-term. Individuals receiving asenapine demonstrated significantly fewer incidents of serious adverse effects (1 RCT, n = 386, RR 0.29, 95% CI 0.14 to 0.63, very low-quality evidence) at medium-term. There was no clear difference in people discontinuing the study for any reason between asenapine and placebo at short-term (5 RCTs, n = 1046, RR 0.91, 95% CI 0.80 to 1.04, very low-quality evidence). No trial reported data for extrapyramidal symptoms or costs. There is some, albeit preliminary, evidence that asenapine provides an improvement in positive, negative, and depressive symptoms, whilst minimising the risk of adverse effects. However due to the low-quality and limited quantity of evidence, it remains difficult to recommend the use of asenapine for people with schizophrenia. We identify a need for large-scale, longer-term, better-designed and conducted randomised controlled trials investigating the clinical effects and safety of asenapine.
Sixteen placebo controlled trials have been completed with atypical antipsychotics although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer reviewed journals. No trials of amisulpiride, sertindole or zotepine were identified which met the criteria for inclusion.  The included trials led to the following results:  1. There was a significant improvement in aggression with risperidone and olanzapine treatment compared to placebo.  2. There was a significant improvement in psychosis amongst risperidone treated patients.  3. Risperidone and olanzapine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extrapyramidal side effects and other important adverse outcomes.  4. There was a significant increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated patients.  5. The data were insufficient to examine impact upon cognitive function. Evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis, but both are associated with serious adverse cerebrovascular events and extrapyramidal symptoms. Despite the modest efficacy, the significant increase in adverse events confirms that neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is severe distress or risk of physical harm to those living and working with the patient. Although insufficient data were available from the considered trials, a meta-analysis of seventeen placebo controlled trials of atypical neuroleptics for the treatment of behavioural symptoms in people with dementia conducted by the Food and Drug Administration suggested a significant increase in mortality (OR 1.7). A peer-reviewed meta-analysis (Schneider 2005) of 15 placebo controlled studies (nine unpublished) found similarly increased risk in mortality (OR=1.54, 95% CI 0.004 to 0.02, p=0.01) for the atypical neuroleptics.
We identified 17 trials and included 12 RCTs (11 completed and one trial protocol - this trial was terminated early) (464 participants). Eight trials included only children, whilst four trials included both children and adults. Trial duration ranged from one to 12 months. Nine trials compared a probiotic (seven single strain and three multistrain preparations) with a placebo preparation, two trials compared a synbiotic (multistrain) with a placebo preparation and one trial compared two probiotic preparations. Overall we judged the risk of bias in the 12 trials to be low. Three trials had a high risk of performance bias, two trials a high risk of attrition bias and six trials a high risk of reporting bias. Only two trials were judged to have low or unclear risk of bias for all domains. Four trials were sponsored by grants only, two trials by industry only, two trials by both grants and industry and three trials had an unknown funding source. Combined data from four trials (225 participants) suggested probiotics may reduce the number of pulmonary exacerbations during a four to 12 month time-frame, mean difference (MD) -0.32 episodes per participant (95% confidence interval (CI) -0.68 to 0.03; P = 0.07) (low-certainty evidence); however, the 95% CI includes the possibility of both an increased and a reduced number of exacerbations. Additionally, two trials (127 participants) found no evidence of an effect on the duration of antibiotic therapy during the same time period. Combined data from four trials (177 participants) demonstrated probiotics may reduce faecal calprotectin, MD -47.4 µg/g (95% CI -93.28 to -1.54; P = 0.04) (low-certainty evidence), but the results for other biomarkers mainly did not show any difference between probiotics and placebo. Two trials (91 participants) found no evidence of effect on height, weight or body mass index (low-certainty evidence). Combined data from five trials (284 participants) suggested there was no difference in lung function (forced expiratory volume at one second (FEV1) % predicted) during a three- to 12-month time frame, MD 1.36% (95% CI -1.20 to 3.91; P = 0.30) (low-certainty evidence). Combined data from two trials (115 participants) suggested there was no difference in hospitalisation rates during a three- to 12-month time frame, MD -0.44 admissions per participant (95% CI -1.41 to 0.54; P = 0.38) (low-certainty evidence). One trial (37 participants) reported health-related quality of life and while the parent report favoured probiotics, SMD 0.87 (95% CI 0.19 to 1.55) the child self-report did not identify any effect, SMD 0.59 (95% CI -0.07 to 1.26) (low-certainty evidence). There were limited results for gastrointestinal symptoms and intestinal microbial profile which were not analysable. Only four trials and one trial protocol (298 participants) reported adverse events as a priori hypotheses. No trials reported any deaths. One terminated trial (12 participants and available as a protocol only) reported a severe allergic reaction (severe urticaria) for one participant in the probiotic group. Two trials reported a single adverse event each (vomiting in one child and diarrhoea in one child). The estimated number needed to harm for any adverse reaction (serious or not) is 52 people (low-certainty evidence). Probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately-powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and adults with CF.
We included two studies with 362 pregnant women. Both studies compared ampicillin-sulbactam (N = 183) versus normal saline (N = 179) in pregnant women with MSAF. Prophylactic antibiotics appeared to have no statistically significant reduction in the incidence of neonatal sepsis (risk ratio (RR) 1.00, 95% CI 0.21 to 4.76), neonatal intensive care unit (NICU) admission (RR 0.83, 95% CI 0.39 to 1.78) and postpartum endometritis (RR 0.50, 95% CI 0.18 to 1.38). However, there was a significant decrease in the risk of chorioamnionitis (RR 0.36, 95% CI 0.21 to 0.62). No serious adverse effects were reported. Drug resistance, duration of mechanical ventilation and duration of admission to NICU/hospital were not reported. Most of the domains for risk of bias were at low risk of bias for one study and at unclear risk of bias for the other study. The quality of the evidence using GRADE was low for neonatal sepsis, postpartum endometritis, and neonatal mortality and morbidity prior to discharge (Neonatal intensive care admissions) and of moderate quality for chorioamnionitis. Current evidence indicates that compared to placebo, antibiotics for MSAF in labour may reduce chorioamnionitis. There was no evidence that antibiotics could reduce postpartum endometritis, neonatal sepsis and NICU admission. This systematic review identifies the need for more well-designed, adequately powered RCTs to assess the effect of prophylactic antibiotics in the incidence of maternal and neonatal complications.
One RCT and nine observational studies were included in the review. These ten studies identified 2,112 episodes of HIV transmission, 1,016 among treated couples and 1,096 among untreated couples. The rate ratio for the single randomised controlled trial was 0.04 [95% CI 0.00, 0.27]. All index partners in this study had CD4 cell counts at baseline of 350-550 cells/µL. Similarly, the summary rate ratio for the nine observational studies was 0.58 [95% CI 0.35, 0.96], with substantial heterogeneity (I2=64%). After excluding two studies with inadequate person-time data, we estimated a summary rate ratio of 0.36 [95% CI 0.17, 0.75] with substantial heterogeneity (I2=62%). We also performed subgroup analyses among the observational studies to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had ≥350 CD4 cells/µL, we estimated a rate ratio of 0.12 [95% CI 0.01, 1.99]. In this subgroup, there were 247 transmissions in untreated couples and 30 in treated couples. ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has ≤550 CD4 cells/µL. A recent multicentre RCT confirms the suspected benefit seen in earlier observational studies and reported in more recent ones. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed. Counselling, support, and follow up, as well as mutual disclosure, may have a role in supporting adherence, so programmes should be designed with these components. In addition to ART provision, the operational aspects of delivering such programmes must be considered.
Four cluster-randomised controlled studies met the inclusion criteria. All of them investigated complex interventions comprising educational approaches. Three studies offered education and training for nursing staff, one study offered multidisciplinary team meetings as main component of the intervention. There was one high-quality study, but overall the methodological quality of studies was moderate.  The studies revealed consistent results for the primary end point. All studies documented a decrease of the proportion of residents with antipsychotic drug use or a reduction in days with antipsychotic use per 100 days per resident, respectively. In summary, the reviewed evidence on psychosocial interventions targeting professionals is consistent with a reduction of antipsychotic medication prescription in care home residents. However, owing to heterogeneous approaches, summary effect sizes cannot be determined. There is evidence to support the effectiveness of psychosocial interventions for reducing antipsychotic medication in care home residents. However, the review was based on a small number of heterogeneous studies with important methodological shortcomings. The most recent and methodologically most rigorous study showed the most pronounced effect.
We included 10 trials involving 26,865 high vascular risk patients. The trials were generally of high quality. Aspirin was compared with ticlopidine in nine trials (7633 patients) and with clopidogrel in one trial (19,185 patients). Compared with aspirin, allocation to a thienopyridine produced a modest, just statistically significant, reduction in the odds of a serious vascular event (11.6% versus 12.5%; odds ratio (OR) 0.92, 95% confidence interval (CI) 0.85 to 0.99), corresponding to the avoidance of 10 (95% CI 0 to 20) serious vascular events per 1000 patients treated for about two years. However, the wide confidence interval includes the possibility of negligible additional benefit. Compared with aspirin, thienopyridines significantly reduced gastrointestinal adverse effects. However, thienopyridines increased the odds of skin rash and diarrhoea, ticlopidine more than clopidogrel. Allocation to ticlopidine, but not clopidogrel, significantly increased the odds of neutropenia. In patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. The thienopyridine derivatives are at least as effective as aspirin in preventing serious vascular events in patients at high risk, and possibly somewhat more so. However, the size of any additional benefit is uncertain and could be negligible. Clopidogrel has a more favourable adverse effects profile than ticlopidine and so is the thienopyridine of choice. It should be used as an alternative to aspirin in patients genuinely intolerant of or allergic to aspirin.
Three short-term RCTs, which enrolled 277 randomised participants with acute phase GBS, were included. Risk of bias in the included studies was generally unclear due to insufficient information. None of the included studies reported the primary outcome selected for this review, which was number of patients with self reported pain relief of 50% or greater. One small study investigated seven-day regimens of gabapentin versus placebo. Pain was rated on a scale from 0 (no pain) to 10 (maximum pain). Amongst the 18 participants, significantly lower mean pain scores were found at the endpoint (day 7) in the gabapentin phase compared to the endpoint of the placebo phase (mean difference -3.61, 95% CI -4.12 to -3.10) (very low quality evidence). For adverse events, no significant differences were found in the incidence of nausea (risk ratio (RR) 0.50, 95% CI 0.05 to 5.04) or constipation (RR 0.14, 95% CI 0.01 to 2.54). A second study enrolling 36 participants compared gabapentin, carbamazepine and placebo, all administered over seven days. Participants in the gabapentin group had significantly lower median pain scores on all treatment days in comparison to the placebo and carbamazepine groups (P < 0.05). There were no statistically significant differences in the median pain scores between the carbamazepine and placebo groups from day 1 to day 3, but from day 4 until the end of the study significantly lower median pain scores were noted in the carbamazepine group (P < 0.05) (very low quality evidence). There were no adverse effects of gabapentin or carbamazepine reported, other than sedation. One large RCT (223 participants, all also treated with intravenous immunoglobulin), compared a five-day course of methylprednisolone with placebo and found no statistically significant differences in number of participants developing pain (RR 0.89, 95% CI 0.68 to 1.16), number of participants with decreased pain (RR 0.95, 95% CI 0.63 to 1.42) or number of participants with increased pain (RR 0.85, 95% CI 0.52 to 1.41) (low quality evidence). The study did not report whether there were any adverse events. Since the last version of this review we found no new studies. While management of pain in GBS is essential and pharmacotherapy is widely accepted as being an important component of treatment, this review does not provide sufficient evidence to support the use of any pharmacological intervention in people with pain in GBS. Although reductions in pain severity were found when comparing gabapentin and carbamazepine with placebo, the evidence was limited and its quality very low. Larger, well-designed RCTs are required to further investigate the efficacy and safety of potential interventions for patients with pain in GBS. Additionally, interventions for pain in the convalescent phase of GBS should be investigated.
Seven studies, 482 participants, met the inclusion criteria. - Comparing antidepressant with placebo, no statistically significant results for dropouts. Selecting studies with low risk of bias, 325 participants, results favour placebo, RR 1.40 (Cl 95% 1.00 to 1.96). For severity of depression, results from two studies, 183 participants, favour antidepressants utilising Clinical Global Impression Scale RR 1.92 (CI 95% 1.26 to 2.94), while another study, 95 participants, utilising the Hamilton Depression Rating Scale, did not find a statistically significant difference RR 0.96 (CI 95% 0.54 to 1.71). For adverse events, result favour placebo, four studies, 311 participants, RR 2.90 (Cl 95% 1.23 to 6.86). For drug use, three studies, 211 participants, it was not possible to pool data because outcomes' measures were not comparable. Looking at singular studies, no statistically significant difference was seen. - Comparing different classes of antidepressants, the results favour tricyclics for severity of depression, two studies, 183 participants, RR 1.92 (Cl 95% 1.26 to 2.94) and favour placebo for adverse events, two studies, 172 participants, RR 3.11 (Cl 95% 1.06 to 9.12). There is low evidence, at the present, supporting the clinical use of antidepressants for the treatment of depressed opioid addicts in treatment with opioid agonists. There is a need of larger randomised studies investigating relevant outcomes, safety issues and reporting data to allow comparison of results.
We identified eight trials published from 2004 to 2017 randomising a total of 1730 participants, with mean intervention duration of 12 weeks. All eight trials were judged to be at overall high risk of bias and effect estimates are reported at the end of the intervention with a follow-up range of eight to 24 weeks. Seven trials reported all-cause mortality, but deaths only occurred in one trial with no evidence of a difference between exercise-based cardiac rehabilitation and control (risk ratio (RR) 1.96, 95% confidence interval (CI) 0.18 to 21.26; participants = 196; trials = 1; quality of evidence: low). There was also no evidence of a difference in serious adverse events between exercise-based cardiac rehabilitation and control (RR 1.05, 95% CI 0.77 to 1.44; participants = 356; trials = 2; quality of evidence: low). Due to the variation in reporting of health-related quality of life outcomes, it was not possible to pool data. However, the five trials reporting health-related quality of life at the end of the intervention, each showed little or no evidence of a difference between exercise-based cardiac rehabilitation and control. For secondary outcomes, there was evidence of a higher pooled exercise capacity (peak VO2) at the end of the intervention (mean difference (MD) 0.91 mL/kg/min, 95% CI 0.60 to 1.21; participants = 1485; trials = 7; quality of evidence: very low) favouring exercise-based cardiac rehabilitation, albeit there was evidence of substantial statistical heterogeneity (I2 = 78%). There was no evidence of a difference in the risk of requiring antitachycardia pacing (RR 1.26, 95% CI 0.84 to 1.90; participants = 356; trials = 2; quality of evidence: moderate), appropriate shock (RR 0.56, 95% CI 0.20 to 1.58; participants = 428; studies = 3; quality of evidence: low) or inappropriate shock (RR 0.60, 95% CI 0.10 to 3.51; participants = 160; studies = 1; quality of evidence: moderate). Due to a lack of evidence, we were unable to definitively assess the impact of exercise-based cardiac rehabilitation on all-cause mortality, serious adverse events and health-related quality of life in adults with an ICD. However, our findings do provide very low-quality evidence that patients following exercise-based cardiac rehabilitation experience a higher exercise capacity compared with the no exercise control. Further high-quality randomised trials are needed in order to assess the impact of exercise-based cardiac rehabilitation in this population on all-cause mortality, serious adverse events, health-related quality of life, antitachycardia pacing and shock.
We extracted data from 53 studies. We included 24 studies with a total of 581 participants. Three studies used a parallel-group, randomised design which compared prone and supine positions only. The remaining 21 studies used a randomised cross-over design. These studies compared prone, supine, lateral, elevated and flat positions. Prone positioning was significantly more beneficial than supine positioning in terms of oxygen saturation (mean difference (MD) 1.97%, 95% CI 1.18 to 2.77), arterial oxygen (MD 6.24 mm Hg, 95% confidence interval (CI) 2.20 to 10.28), episodes of hypoxaemia (MD -3.46, 95% CI -4.60 to -2.33) and thoracoabdominal synchrony (MD -30.76, 95% CI -41.39 to -20.14). No adverse effects were identified. There were no statistically significant differences between any other positions. As the majority of studies did not describe how possible biases were addressed, the potential for bias in these findings is unclear. The prone position was significantly superior to the supine position in terms of oxygenation. However, as most participants were ventilated preterm infants, the benefits of prone positioning may be most relevant to these infants. In addition, although placing infants and children in the prone position may improve respiratory function, the association of SIDS with prone positioning means that infants should only be placed in this position while under continuous cardiorespiratory monitoring.
We included nine studies with data for 638 VOC events and 594 participants aged 17 to 42 years with SCD presenting to a hospital emergency department in a painful VOC. Three studies investigated a non-steroidal anti-inflammatory drug (NSAID) compared to placebo. One study compared an opioid with a placebo, two studies compared an opioid with an active comparator, two studies compared an anticoagulant with a placebo, and one study compared a combination of three drugs with a combination of four drugs. Risk of bias across the nine studies varied. Studies were primarily at an unclear risk of selection, performance, and detection bias. Studies were primarily at a high risk of bias for size with fewer than 50 participants per treatment arm; two studies had 50 to 199 participants per treatment arm (unclear risk). Non-steroidal anti-inflammatory drugs (NSAID) compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The efficacy was uncertain regarding PGIC very much improved, and PGIC much or very much improved (no difference; 1 study, 21 participants; very low-quality evidence). Very low-quality, uncertain results suggested similar rates of adverse events across both the NSAIDs group (16/45 adverse events, 1/56 serious adverse events, and 1/56 withdrawal due to adverse events) and the placebo group (19/45 adverse events, 2/56 serious adverse events, and 1/56 withdrawal due to adverse events). Opioids compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30%, PGIC, or adverse events (any adverse event, serious adverse events, and withdrawals due to adverse events). Opioids compared with active comparator No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The results were uncertain regarding PGIC very much improved (33% of the opioids group versus 19% of the placebo group). No data were reported regarding PGIC much or very much improved. Very low-quality, uncertain results suggested similar rates of adverse events across both the opioids group (9/66 adverse events, and 0/66 serious adverse events) and the placebo group (7/64 adverse events, 0/66 serious adverse events). No data were reported regarding withdrawal due to adverse events. Quality of the evidence We downgraded the quality of the evidence by three levels to very low-quality because there are too few data to have confidence in results (e.g. too few participants per treatment arm). Where no data were reported for an outcome, we had no evidence to support or refute (quality of the evidence is unknown). This review identified only nine studies, with insufficient data for all pharmacological interventions for analysis. The available evidence is very uncertain regarding the efficacy or harm from pharmacological interventions used to treat pain related to sickle cell VOC in adults. This area could benefit most from more high quality, certain evidence, as well as the establishment of suitable registries which record interventions and outcomes for this group of people.
Twelve trials, with 615 participants, met our inclusion criteria. The median number of participants in each trial was 27, and median trial duration was 16 weeks. The included studies were conducted over a 32-year time period, from 1983 to 2015. A single RCT that was underpowered to detect clinically meaningful differences investigated most interventions. There were four trials of anti-TNF-α (tumour necrosis factor-alpha) therapies, which included etanercept, infliximab, and adalimumab. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) score in participants with moderate to severe HS by 4.0 points relative to placebo (95% confidence interval (CI) -6.5 to -1.5 points), an effect size approximately equal to the DLQI minimal clinically important difference. We reduced the evidence quality to 'moderate' because the effect size was based on the results of only one study. In a meta-analysis of two studies with 124 participants, standard dose adalimumab 40 mg every other week was ineffective compared with placebo (moderate quality evidence). In a smaller study of 38 participants, of whom only 33 provided efficacy data, infliximab 5 mg/kg treatment improved DLQI by 8.4 DLQI points after eight weeks. Etanercept 50 mg twice weekly was well tolerated but ineffective. In a RCT of 200 participants, no difference was found in surgical complications (week one: risk ratio (RR) 0.78, 95% CI 0.58 to 1.05, moderate quality evidence) or risk of recurrence (after three months: RR 0.96, 95% CI 0.68 to 1.34, moderate quality evidence) in those randomised to receive a gentamicin-collagen sponge prior to primary closure compared with primary closure alone. RCTs of other interventions, including topical clindamycin 1% solution; oral tetracycline; oral ethinylestradiol 50 mcg with either cyproterone acetate 50 mg or norgestrel 500 mcg; intense pulsed light; neodymium-doped yttrium aluminium garnet (Nd:YAG) laser; methylene blue gel photodynamic therapy; and staphage lysate, were relatively small studies, preventing firm conclusions due to imprecision. Many knowledge gaps exist in RCT evidence for HS. Moderate quality evidence exists for adalimumab, which improves DLQI score when 40 mg is given weekly, twice the standard psoriasis dose. However, the 95% confidence interval includes an effect size of only 1.5 DLQI points, which may not be clinically relevant, and the safety profile of weekly dosing has not been fully established. Infliximab also improves quality of life, based on moderate quality evidence. More RCTs are needed in most areas of HS care, particularly oral treatments and the type and timing of surgical procedures. Outcomes should be validated, ideally, including a minimal clinically important difference for HS.
We included seven RCTs (1217 women) of varying methodological quality in the review; most trials were at moderate or high risk of bias. Three were multi-centre trials, two were single-centre trials, and in two trials it was unclear if they were single or multi-centre. These trials compared the following interventions for women with locally advanced cervical cancer (stages IB2 to III): hysterectomy (simple or radical) with radiotherapy (N = 194) versus radiotherapy alone (N = 180); hysterectomy (simple or radical) with chemoradiotherapy (N = 31) versus chemoradiotherapy alone (N = 30); hysterectomy (radical) with chemoradiotherapy (N = 111) versus internal radiotherapy with chemoradiotherapy (N = 100); hysterectomy (simple or radical) with upfront (neoadjuvant) chemotherapy (N = 298) versus radiotherapy alone (N = 273). One trial (N = 256) found no difference in the risk of death or disease progression between women who received attenuated radiotherapy followed by hysterectomy and those who received radiotherapy (external and internal) alone (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.61 to 1.29). This trial also reported no difference between the two groups in terms of adverse effects (18/129 grade 3 or 4 adverse effects in the hysterectomy and radiation group and 19 cases in 18/121 women in the radiotherapy alone group). There was no difference in 5-year tumour-free actuarial survival (representation of the probable years of survivorship of a defined population of participants) or severe complications (grade 3) in another trial (N = 118) which reported the same comparison (6/62 versus 6/56 in the radiation with surgery group versus the radiotherapy alone group, respectively). The quality of the evidence was low for all these outcomes. One trial (N = 61) reported no difference (P value > 0.10) in overall and recurrence-free survival at 3 years between chemoradiotherapy and hysterectomy versus chemoradiotherapy alone (low quality evidence). Adverse events and morbidity data were not reported. Similarly, another trial (N = 211) found no difference in the risk of death (HR 0.65, 95% CI 0.35 to 1.21, P value = 0.19, low quality evidence), disease progression (HR 0.70, 95% CI 0.31 to 1.34, P value = 0.24, low quality evidence) or severe late complications (P value = 0.53, low quality evidence) between women who received internal radiotherapy versus hysterectomy after both groups had received external-beam chemoradiotherapy. Meta analysis of three trials of neoadjuvant chemotherapy and hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received neoadjuvant chemotherapy plus hysterectomy had less risk of death than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93, I2 = 0%, moderate quality evidence). However, a significant number of the participants that received neoadjuvant chemotherapy plus hysterectomy had radiotherapy as well. There was no difference in the proportion of women with disease progression or recurrence between the two groups (RR 0.75, 95% CI 0.53 to 1.05, I2 = 20%, moderate quality evidence). Results of single trials reported no apparent (P value > 0.05) difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between the two groups (low quality evidence). Quality of life outcomes were not reported in any of the trials. From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with locally advanced cervical cancer who are treated with radiotherapy or chemoradiotherapy alone. The overall quality of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The quality of the evidence for neoadjuvant chemotherapy and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate, with evidence from other comparisons of low quality. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials that assess medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.
We identified 37 eligible studies involving over 15,000 participants who smoked tobacco. The majority of studies recruited participants with particular characteristics, often from groups of people who are less likely to seek support to stop smoking than the general population. Although a few studies recruited participants who intended to stop smoking soon or had no intentions to quit, most recruited a population without regard to their intention to quit. MI was conducted in one to 12 sessions, with the total duration of MI ranging from five to 315 minutes across studies. We judged four of the 37 studies to be at low risk of bias, and 11 to be at high risk, but restricting the analysis only to those studies at low or unclear risk did not significantly alter results, apart from in one case - our analysis comparing higher to lower intensity MI. We found low-certainty evidence, limited by risk of bias and imprecision, comparing the effect of MI to no treatment for smoking cessation (RR = 0.84, 95% CI 0.63 to 1.12; I2 = 0%; adjusted N = 684). One study was excluded from this analysis as the participants recruited (incarcerated men) were not comparable to the other participants included in the analysis, resulting in substantial statistical heterogeneity when all studies were pooled (I2 = 87%). Enhancing existing smoking cessation support with additional MI, compared with existing support alone, gave an RR of 1.07 (95% CI 0.85 to 1.36; adjusted N = 4167; I2 = 47%), and MI compared with other forms of smoking cessation support gave an RR of 1.24 (95% CI 0.91 to 1.69; I2 = 54%; N = 5192). We judged both of these estimates to be of low certainty due to heterogeneity and imprecision. Low-certainty evidence detected a benefit of higher intensity MI when compared with lower intensity MI (RR 1.23, 95% CI 1.11 to 1.37; adjusted N = 5620; I2 = 0%). The evidence was limited because three of the five studies in this comparison were at risk of bias. Excluding them gave an RR of 1.00 (95% CI 0.65 to 1.54; I2 = n/a; N = 482), changing the interpretation of the results. Mental health and quality of life outcomes were reported in only one study, providing little evidence on whether MI improves mental well-being. There is insufficient evidence to show whether or not MI helps people to stop smoking compared with no intervention, as an addition to other types of behavioural support for smoking cessation, or compared with other types of behavioural support for smoking cessation. It is also unclear whether more intensive MI is more effective than less intensive MI. All estimates of treatment effect were of low certainty because of concerns about bias in the trials, imprecision and inconsistency. Consequently, future trials are likely to change these conclusions. There is almost no evidence on whether MI for smoking cessation improves mental well-being.
Seven treatment studies of 257 infants with suspected systemic bacterial infection and three prophylaxis studies comprising 359 neonates are analysed.   Treatment studies: There is no evidence that the addition of G-CSF or GM-CSF to antibiotic therapy in preterm infants with suspected systemic infection reduces immediate all cause mortality. No significant survival advantage was seen at 14 days from the start of therapy [typical RR 0.71 (95% CI 0.38,1.33); typical RD -0.05 (95% CI -0.14, 0.04)]. However all seven of the treatment studies were small, the largest recruiting only 60 infants.  The subgroup analysis of 97 infants from three treatment studies who, in addition to systemic infection, had clinically significant neutropenia (< 1.7 x 109/l) at trial entry, does show a significant reduction in mortality by day 14 [RR 0.34 (95% CI 0.12, 0.92); RD -0.18 (95% CI -0.33, -0.03); NNT 6 (95% CI 3-33)]. Prophylaxis studies have not demonstrated a significant reduction in mortality in neonates receiving GM-CSF [RR 0.59 (95% CI 0.24,1.44); RD -0.03 (95% CI -0.08,0.02)]. The identification of sepsis as the primary outcome of prophylaxis studies has been hampered by inadequately stringent definitions of systemic infection. However, data from one study suggest that prophylactic GM-CSF may provide protection against infection when given to preterm infants who are neutropenic or at high risk of developing postnatal neutropenia. There is currently insufficient evidence to support the introduction of either G-CSF or GM-CSF into neonatal practice, either as treatment of established systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high risk neonates. No toxicity of CSF use was reported in any study included in this review. The limited data suggesting that CSF treatment may reduce mortality when systemic infection is accompanied by severe neutropenia should be investigated further in adequately powered trials which recruit sufficient infants infected with organisms associated with a significant mortality risk.
Only one additional RCT met the eligibility criteria (24 participants) for this updated review. Although this was a feasibility study, not designed to investigate intervention effect, it suggested that TENS may improve bone pain on movement in a cancer population. The initial review identified two RCTs (64 participants) therefore this review now includes a total of three RCTs (88 participants). These studies were heterogenous with respect to study population, sample size, study design, methodological quality, mode of TENS, treatment duration, method of administration and outcome measures used. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-type TENS and sham in palliative care patients; this study was underpowered. Despite the one additional RCT, the results of this updated systematic review remain inconclusive due to a lack of suitable RCTs. Large multi-centre RCTs are required to assess the value of TENS in the management of cancer-related pain in adults.
We identified 15 studies for possible inclusion in the review. Five studies reporting results from a total of 354 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One cross-over trial had 26 participants who received the first-arm treatment but only 15 received the second arm. One study had a low risk of bias for all criteria assessed; the remaining included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias. There was little or no difference between treatment groups in: forced expiratory volume in one second, mean difference (MD) 0.33 (95% confidence interval (CI) -2.81 to 3.48, moderate-quality evidence); forced vital capacity, MD 0.29 (95% CI -6.58 to 7.16, low-quality evidence); % weight for height, MD -0.82 (95% CI -3.77 to 2.13, low-quality evidence); body mass index, MD 0.00 (95% CI -0.42 to 0.42, low-quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% CI 0.04 to 7.96, moderate-quality evidence). Once-daily treatment in children probably improved the percentage change in creatinine, MD -8.20 (95% CI -15.32 to -1.08, moderate-quality evidence), but showed no difference in adults, MD 3.25 (95% CI -1.82 to 8.33, moderate-quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.
We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months. The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. Funding: nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.
We included three RCTs conducted in Australia, the United Kingdom, and the United States that enrolled a total of 225 eyes and analysed 219 eyes. The total number of people enrolled was not clear in two of the studies. Only adults were enrolled into these studies. Out of the eyes analysed, 119 had CXL (all using the epithelium-off technique) and 100 served as controls. One of these studies only reported comparative data on review outcomes. All three studies were at high risk for performance bias (lack of masking), detection bias (only one trial attempted to mask outcome assessment), and attrition bias (incomplete follow-up). It was not possible to pool data due to differences in measuring and reporting outcomes. We identified a further three unpublished trials that potentially had enrolled a total of 195 participants. There was limited evidence on the risk of progression. Analysis of the first few participants followed up to one year in one study suggested that eyes given CXL were less likely to have an increase in maximum keratometry of 1.5 D or more at 12 months compared to eyes given no treatment, but the confidence intervals (CI) were wide and compatible with no effect or more progression in the CXL group (risk ratio (RR) 0.12, 95% CI 0.01 to 2.00, 19 eyes). The same study reported the number of eyes with an increase of 2 D or more at 36 months in the whole cohort with a RR of 0.03 favouring CXL (95% CI 0.00 to 0.43, 94 eyes). Another study reported "progression" at 18 months using a different definition; people receiving CXL were less likely to progress, but again the effect was uncertain (RR 0.14, 95% CI 0.01 to 2.61, 44 eyes). We judged this to be very low-quality evidence due to the risk of bias of included studies, imprecision, indirectness and publication bias but noted that the size of the potential effect was large. On average, treated eyes had a less steep cornea (approximately 2 D less steep) (mean difference (MD) -1.92, 95% CI -2.54 to -1.30, 94 eyes, 1 RCT, very low-quality evidence) and better uncorrected visual acuity (approximately 2 lines or 10 letters better) (MD -0.20, 95% CI -0.31 to -0.09, 94 eyes, 1 RCT, very low-quality evidence) at 12 months. None of the studies reported loss of 0.2 logMAR acuity. The data on corneal thickness were inconsistent. There were no data available on quality of life or costs. Adverse effects were not uncommon but mostly transient and of low clinical significance. In one trial, 3 out of 12 participants treated with CXL had an adverse effect including corneal oedema, anterior chamber inflammation, and recurrent corneal erosions. In one trial at 3 years 3 out of 50 participants experienced adverse events including mild diffuse corneal oedema and paracentral infiltrate, peripheral corneal vascularisation, and subepithelial infiltrates and anterior chamber inflammation. No adverse effects were reported in the control groups. The evidence for the use of CXL in the management of keratoconus is limited due the lack of properly conducted RCTs.
We identified 18 studies (two RCTs and 16 non-randomized studies (NRSs)) comprising 11,043 women undergoing early medical abortion (≤ 9 weeks gestation) in 10 countries. Sixteen studies took place in low-to-middle income resource settings and two studies were in high-resource settings. One NRS study received analgesics from a pharmaceutical company. Five NRSs and one RCT did not report on funding; nine NRSs received all or partial funding from an anonymous donor. Five NRSs and one RCT received funding from government agencies, private foundations, or non-profit bodies. The intervention in the evidence is predominantly from women taking mifepristone in the presence of a healthcare provider, and subsequently taking misoprostol without healthcare provider supervision (e.g. at home). There is no evidence of a difference in rates of successful abortions between self-administered and provider-administered groups: for two RCTs, risk ratio (RR) 0.99, 95% confidence interval (CI) 0.97 to 1.01; 919 participants; moderate certainty of evidence. There is very low certainty of evidence from 16 NRSs: RR 0.99, 95% CI 0.97 to 1.01; 10,124 participants. For the outcome of ongoing pregnancy there may be little or no difference between the two groups: for one RCT: RR 1.69, 95% CI 0.41 to 7.02; 735 participants; low certainty of evidence; and very low certainty evidence for 11 NRSs: RR 1.28, 95% CI 0.65 to 2.49; 6691 participants. We are uncertain whether there are any differences in complications requiring surgical intervention, since we found no RCTs and evidence from three NRSs was of very low certainty: for three NRSs: RR 2.14, 95% CI 0.80 to 5.71; 2452 participants. This review shows that self-administering the second stage of early medical abortion procedures is as effective as provider-administered procedures for the outcome of abortion success. There may be no difference for the outcome of ongoing pregnancy, although the evidence for this is uncertain for this outcome. There is very low-certainty evidence for the risk of complications requiring surgical intervention. Data are limited by the scarcity of high-quality research study designs and the presence of risks of bias. This review provides insufficient evidence to determine the safety of self-administration when compared with administering medication in the presence of healthcare provider supervision. Future research should investigate the effectiveness and safety of self-administered medical abortion in the absence of healthcare provider supervision through the entirety of the medical abortion protocol (e.g. during administration of mifepristone or as part of a misoprostol-only regimen) and at later gestational ages (i.e. more than nine weeks). In the absence of any supervision from medical personnel, research is needed to understand how best to inform and support women who choose to self-administer, including when to seek clinical care.
This update of the 2010 review includes 96 studies, 57 from the previous update and 39 new studies, totalling 4512 participants. Most of the studies, covering a wide range of interventions, had fewer than 50 participants. All of the studies assessed repigmentation, however only five reported on all of our three primary outcomes which were quality of life, > 75% repigmentation and adverse effects. Of our secondary outcomes, six studies measured cessation of spread but none assessed long-term permanence of repigmentation resulting from treatment at two years follow-up. Most of the studies assessed combination therapies which generally reported better results. New interventions include seven new surgical interventions. We analysed the data from 25 studies which assessed our primary outcomes. We used the effect measures risk ratio (RR), and odds ratio (OR) with their 95% confidence intervals (CI) and where N is the number of participants in the study. We were only able to analyse one of nine studies assessing quality of life and this showed no statistically significant improvement between the comparators. Nine analyses from eight studies reported >75% repigmentation. In the following studies the repigmentation was better in the combination therapy group: calcipotriol plus PUVA (psoralen with UVA light) versus PUVA (paired OR 4.25, 95% CI 1.43 to 12.64, one study, N = 27); hydrocortisone-17-butyrate plus excimer laser versus excimer laser alone (RR 2.57, 95% CI 1.20 to 5.50, one study, N = 84); oral minipulse of prednisolone (OMP) plus NB-UVB (narrowband UVB) versus OMP alone (RR 7.41, 95% CI 1.03 to 53.26, one study, N = 47); azathioprine with PUVA versus PUVA alone (RR 17.77, 95% CI 1.08 to 291.82, one study, N = 58) and 8-Methoxypsoralen (8-MOP ) plus sunlight versus psoralen (RR 2.50, 95% CI 1.06 to 5.91, one study, N = 168). In these three studies ginkgo biloba was better than placebo (RR 4.40, 95% CI 1.08 to 17.95, one study, N = 47); clobetasol propionate was better than PUVAsol (PUVA with sunlight) (RR 4.70, 95% CI 1.14 to 19.39, one study, N = 45); split skin grafts with PUVAsol was better than minipunch grafts with PUVAsol (RR 1.89, 95% CI 1.25 to 2.85, one study, N = 64). We performed one meta-analysis of three studies, in which we found a non-significant 60% increase in the proportion of participants achieving >75% repigmentation in favour of NB-UVB compared to PUVA (RR 1.60, 95% CI 0.74 to 3.45; I² = 0%). Studies assessing topical preparations, in particular topical corticosteroids, reported most adverse effects. However, in combination studies it was difficult to ascertain which treatment caused these effects. We performed two analyses from a pooled analysis of three studies on adverse effects. Where NB-UVB was compared to PUVA, the NB-UVB group reported less observations of nausea in three studies (RR 0.13, 95% CI 0.02 to 0.69; I² = 0% three studies, N = 156) and erythema in two studies (RR 0.73, 95% CI 0.55 to 0.98; I² = 0%, two studies, N = 106), but not itching in two studies (RR 0.57, 95% CI 0.20 to 1.60; I² = 0%, two studies, N = 106). Very few studies only assessed children or included segmental vitiligo. We found one study of psychological interventions but we could not include the outcomes in our statistical analyses. We found no studies evaluating micropigmentation, depigmentation, or cosmetic camouflage. This review has found some evidence from individual studies to support existing therapies for vitiligo, but the usefulness of the findings is limited by the different designs and outcome measurements and lack of quality of life measures. There is a need for follow-up studies to assess permanence of repigmentation as well as high-quality randomised trials using standardised measures and which also address quality of life.
We found 23 potentially relevant trials, of which nine were eligible for inclusion in this review. The nine trials included in our meta-analysis had a total of 808 women. The overall risk of bias of included studies was low, as most studies properly reported their methods. Postoperative pain: Postoperative pain was measured on a visual analogue scale (VAS), with zero meaning 'no pain at all' and 10 signifying 'pain as bad as it could be.' Postoperative pain was significantly less, as determined by subjectively assessed pain score at six hours (MD -2.40, 95% CI -2.88 to -1.92, one study, 148 women, moderate-quality evidence) and 48 hours postoperatively (MD -1.90, 95% CI -2.80 to -1.00, two studies, 80 women, I² = 0%, moderate-quality evidence) in the laparoscopic myomectomy group compared with the open myomectomy group. This means that among women undergoing laparoscopic myomectomy, mean pain score at six hours and 48 hours would be likely to range from about three points lower to one point lower on a VAS zero-to-10 scale. No significant difference in postoperative pain score was noted between the laparoscopic and open myomectomy groups at 24 hours (MD -0.29, 95% CI -0.7 to 0.12, four studies, 232 women, I² = 43%, moderate-quality evidence). The overall quality of these findings is moderate; therefore further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. In-hospital adverse events: No evidence suggested a difference in unscheduled return to theatre (OR 3.04, 95% CI 0.12 to 75.86, two studies, 188 women, I² = 0%, low-quality evidence) and laparoconversion (OR 1.11, 95% CI 0.44 to 2.83, eight studies, 756 women, I² = 53%, moderate-quality evidence) when open myomectomy was compared with laparoscopic myomectomy. Only one study including 148 women reported injury to pelvic organs (no events were described in other studies), and no significant difference was noted between laparoscopic myomectomy and laparoscopically assisted mini-laparotomy myomectomy (OR 3.04, 95% CI 0.12 to 75.86). Significantly lower risk of postoperative fever was observed in the laparoscopic myomectomy group compared with groups treated with all types of open myomectomy (OR 0.44, 95% CI 0.26 to 0.77, I² = 0%, six studies, 635 women). This indicates that among women undergoing laparoscopic myomectomy, the risk of postoperative fever is 50% lower than among those treated with open surgery. No studies reported immediate hysterectomy, uterine rupture, thromboembolism or mortality. Six studies including 549 women reported haemoglobin drop, but these studies were not pooled because of extreme heterogeneity (I² = 97%) and therefore could not be included in the analysis. Laparoscopic myomectomy is a procedure associated with less subjectively reported postoperative pain, lower postoperative fever and shorter hospital stay compared with all types of open myomectomy. No evidence suggested a difference in recurrence risk between laparoscopic and open myomectomy. More studies are needed to assess rates of uterine rupture, occurrence of thromboembolism, need for repeat myomectomy and hysterectomy at a later stage.
We included five studies enrolling adults with frequent episodic TTH; 1812 participants took medication, of which 767 were included in comparisons of aspirin 1000 mg with placebo, and 405 in comparisons of aspirin 500 mg or 650 mg with placebo. Not all of these participants provided data for outcomes of interest in this review. Four studies specified using IHS diagnostic criteria; one predated commonly recognised criteria, but described comparable characteristics and excluded migraine. All participants treated headaches of at least moderate pain intensity. None of the included studies were at low risk of bias across all domains considered, although for most studies and domains this was likely to be due to inadequate reporting rather than poor methods. We judged one study to be at high risk of bias due to small size. There were no data for aspirin at any dose for the IHS preferred outcome of being pain free at two hours, or for being pain free at any other time, and only one study provided data equivalent to having no or mild pain at two hours (very low quality evidence). Use of rescue medication was lower with aspirin 1000 mg than with placebo (2 studies, 397 participants); 14% of participants used rescue medication with aspirin 1000 mg compared with 31% with placebo (NNTp 6.0, 95% confidence interval (CI) 4.1 to 12) (low quality evidence). Two studies (397 participants) reported a Patient Global Evaluation at the end of the study; we combined the top two categories for both studies to determine the number of participants who were 'satisfied' with treatment. Aspirin 1000 mg produced more satisfied participants (55%) than did placebo (37%) (NNT 5.7, 95% CI 3.7 to 12) (very low quality evidence). Adverse events were not different between aspirin 1000 mg and placebo (RR 1.1, 95% CI 0.8 to 1.5), or aspirin 500 mg or 650 mg and placebo (RR 1.3, 95% CI 0.8 to 2.0) (low quality evidence). Studies reported no serious adverse events. The quality of the evidence using GRADE comparing aspirin doses between 500 mg and 1000 mg with placebo was low or very low. Evidence was downgraded because of the small number of studies and events, and because the most important measures of efficacy were not reported. There were insufficient data to compare aspirin with any active comparator (paracetamol alone, paracetamol plus codeine, peppermint oil, or metamizole) at any of the doses tested. A single dose of aspirin between 500 mg and 1000 mg provided some benefit in terms of less frequent use of rescue medication and more participants satisfied with treatment compared with placebo in adults with frequent episodic TTH who have an acute headache of moderate or severe intensity. There was no difference between a single dose of aspirin and placebo for the number of people experiencing adverse events. The amount and quality of the evidence was very limited and should be interpreted with caution.
We included a total of five randomised studies (involving 805 women) evaluating different methods of analgesia for amniocentesis; there were no studies in women undergoing CVS. One RCT (N = 203) and one quasi-randomised study (N = 220) compared infiltrative local anaesthesia with no anaesthesia and found no statistical difference in experienced pain on the visual analogue scale (VAS) (mean differences (MD) -2.50 and 1.20; 95% confidence interval (CI) -6.98 to 1.98 and -2.67 to 5.07). One study (N = 200) compared light leg rubbing versus no intervention during amniocentesis and found no change in experienced anxiety (MD 0.2; 95% CI -0.63 to 1.03) or VAS pain score (MD 0.3; 95% CI -0.35 to 0.95) during amniocentesis. Another study with 62 patients did not find any benefit of using subfreezing temperature needle during amniocentesis in terms of decreased VAS pain score (MD -0.8; 95% CI -1.8 to 0.2). In addition, there was no difference between anticipated and actual pain (MD 0.4; 95% CI -0.82 to 1.62) (before/after comparison). There was also no difference in VAS pain scores in the study with 120 participants comparing lidocaine-prilocaine analgesic cream to placebo cream before amniocentesis (MD -0.6; 95% CI -1.44 to 0.24). In general, women who undergo amniocentesis could be informed that pain during procedure is minor and that there is currently insufficient evidence to support the use of local anaesthetics, leg rubbing or subfreezing the needle for pain reduction during procedure.
A total of 115 randomised controlled trials (26,134 participants) were included. In 54 studies paroxetine was compared with older ADs, in 21 studies with another SSRI, and in 40 studies with a newer or non-conventional antidepressant other than SSRIs. For the primary outcome (patients who responded to treatment), paroxetine was more effective than reboxetine at increasing patients who responded early to treatment (Odds Ratio (OR): 0.66, 95% Confidence Interval (CI) 0.50 to 0.87, number needed to treat to provide benefit (NNTb) = 16, 95% CI 10 to 50, at one to four weeks, 3 RCTs, 1375 participants, moderate quality of evidence), and less effective than mirtazapine (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, at one to four weeks, 3 RCTs, 726 participants, moderate quality of evidence). Paroxetine was less effective than citalopram in improving response to treatment (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, at six to 12 weeks, 1 RCT, 406 participants, moderate quality of evidence). We found no clear evidence that paroxetine was more or less effective compared with other antidepressants at increasing response to treatment at acute (six to 12 weeks), early (one to four weeks), or longer term follow-up (four to six months). Paroxetine was associated with a lower rate of adverse events than amitriptyline, imipramine and older ADs as a class, but was less well tolerated than agomelatine and hypericum. Included studies were generally at unclear or high risk of bias due to poor reporting of allocation concealment and blinding of outcome assessment, and incomplete reporting of outcomes. Some possibly clinically meaningful differences between paroxetine and other ADs exist, but no definitive conclusions can be drawn from these findings. In terms of response, there was a moderate quality of evidence that citalopram was better than paroxetine in the acute phase (six to 12 weeks), although only one study contributed data. In terms of early response to treatment (one to four weeks) there was moderate quality of evidence that mirtazapine was better than paroxetine and that paroxetine was better than reboxetine. However there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Even if some differences were identified, the findings from this review are better thought as hypothesis forming rather than hypothesis testing and it would be reassuring to see the conclusions replicated in future trials. Finally, most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.
We included six RCTs that fulfilled the above criteria, with a total of 119 participants. The beta blockers studied were atenolol, propranolol, pindolol and metoprolol. All trials were of poor quality with the drugs administered over a short time (10 days to two months). None of the primary outcomes were reported by more than one study. Similarly, secondary outcome measures, with the exception of vascular resistance (as reported by three studies), were reported, each by only one study. Pooling of such results was deemed inappropriate. None of the trials showed a statistically significant worsening effect of beta blockers on time to claudication, claudication distance and maximal walking distance as measured on a treadmill, nor on calf blood flow, calf vascular resistance and skin temperature, when compared with placebo. No reports described adverse events associated with the beta blockers studied. Currently, no evidence suggests that beta blockers adversely affect walking distance, calf blood flow, calf vascular resistance and skin temperature in people with intermittent claudication. However, because of the lack of large published trials, beta blockers should be used with caution, if clinically indicated.
Altogether 223 patients with DTC participated in four trials. Overall, studies had a high risk of bias. We found no statistically significant differences between rhTSH and THW treatment in terms of successful ablation rate but significant benefits in radiation exposure to blood and bone marrow. One trial reported on benefits in some domains of health-related quality of life. There were no deaths and no serious adverse effects in DTC patients treated with either rhTSH or THW. Maximum follow up was 12 months. None of the included trials investigated complete or partial remission of metastatic tumour, secondary malignancies or economic outcomes. We did not find sufficient data comparing rhTSH with THW-aided radioiodine treatment for metastatic DTC. Results from four randomised controlled clinical trials suggest that rhTSH is as effective as THW on iodine-131 thyroid remnant ablation, with limited data on significant benefits in decreased whole body radiation exposure and health-related quality of life. It is still uncertain whether lower iodine-131 doses (1110 MBq or 1850 MBq versus 3700 MBq) are equally effective for remnant ablation under rhTSH stimulation. Randomised controlled clinical trials are needed to guide treatment selection for metastatic differentiated thyroid cancer.
Fifteen studies on 425 participants were included in the review, one of which was in abstract form only. Twelve studies were included in the meta-analysis across one or more of the three comparisons. The sample size of the included studies was small (12 to 43 participants) and overall study quality was moderate to low given the imprecision and risk of bias issues (i.e. missing information on sequence generation and allocation concealment as well as no blinding of outcome assessment and incomplete data). When upper limb training was compared to either no training or sham training, there was a small significant improvement in symptoms of dyspnoea with a mean difference (MD) of 0.37 points (95% confidence interval (CI) 0.02 to 0.72 points; data from four studies on 129 people). However, there was no significant improvement in dyspnoea when the studies of endurance training only (MD 0.41 points, 95% CI −0.13 to 0.95 points; data from two studies on 55 people) or resistance training only (MD 0.34 points, 95% CI −0.11 to 0.80 points; data from two studies on 74 people) were analysed. When upper limb training combined with lower limb training was compared to lower limb training alone, no significant difference in dyspnoea was shown (MD 0.36 points, 95% CI −0.04 to 0.76 points; data from three studies on 86 people). There were no studies which examined the effects on dyspnoea of upper limb training compared to another upper limb training intervention. There was no significant improvement in HRQoL when upper limb training was compared to either no training or sham training with a standardised mean difference (SMD) of 0.05 (95% CI −0.31 to 0.40; four studies on 126 people) or when upper limb training combined with lower limb training was compared to lower limb training alone (SMD 0.01, 95% CI −0.40 to 0.43; three studies on 95 people). Only one study, in which endurance upper limb training was compared to resistance upper limb training, reported on HRQoL and showed no between-group differences (St George's Respiratory Questionnaire MD 2.0 points, 95% CI −9 to 12; one study on 20 people). Positive findings were shown for the effects of upper limb training on the secondary outcome of unsupported endurance upper limb exercise capacity. When upper limb training was compared to either no training or sham training, there was a large significant improvement in unsupported endurance upper limb capacity (SMD 0.66, 95% CI 0.19 to 1.13; six studies on 142 people) which remained significant when the studies in this analysis of endurance training only were examined (SMD 0.99, 95% CI 0.32 to 1.66; four studies on 85 people) but not when the studies of resistance training only were examined (SMD 0.23, 95% CI −0.31 to 0.76; three studies on 57 people, P = 0.08 for test of subgroup differences). When upper limb training combined with lower limb training was compared to lower limb training alone, there was also a large significant improvement in unsupported endurance upper limb capacity (SMD 0.90, 95% CI 0.12 to 1.68; three studies on 87 people). A single study compared endurance upper limb training to resistance upper limb training with a significant improvement in the number of lifts performed in one minute favouring endurance upper limb training (MD 6.0 lifts, 95% CI 0.29 to 11.71 lifts; one study on 17 people). Available data were insufficient to examine the impact of disease severity on any outcome. Evidence from this review indicates that some form of upper limb exercise training when compared to no upper limb training or a sham intervention improves dyspnoea but not HRQoL in people with COPD. The limited number of studies comparing different upper limb training interventions precludes conclusions being made about the optimal upper limb training programme for people with COPD, although endurance upper limb training using unsupported upper limb exercises does have a large effect on unsupported endurance upper limb capacity. Future RCTs require larger participant numbers to compare the differences between endurance upper limb training, resistance upper limb training, and combining endurance and resistance upper limb training on patient-relevant outcomes such as dyspnoea, HRQoL and arm activity levels.
In total, we included 31 studies (with 3231 participants) in our review. Of those 31 studies, 28 (2976 participants) provided data for the meta-analyses. For the 28 studies, 24 were used for the comparison of neuraxial block versus general anaesthesia. Based on 11 studies that included 2152 participants, we did not find a difference between the two anaesthetic techniques for mortality at one month: risk ratio (RR) 0.78, 95% confidence interval (CI) 0.57 to 1.06; I2 = 24% (fixed-effect model). Based on six studies that included 761 participants, we did not find a difference in the risk of pneumonia: RR 0.77, 95% CI 0.45 to 1.31; I2 = 0%. Based on four studies that included 559 participants, we did not find a difference in the risk of myocardial infarction: RR 0.89, 95% CI 0.22 to 3.65; I2 = 0%. Based on six studies that included 729 participants, we did not find a difference in the risk of cerebrovascular accident: RR 1.48, 95% CI 0.46 to 4.83; I2 = 0%. Based on six studies that included 624 participants, we did not find a difference in the risk of acute confusional state: RR 0.85, 95% CI 0.51 to 1.40; I2 = 49%. Based on laboratory tests, the risk of deep vein thrombosis was decreased when no specific precautions or just early mobilization was used: RR 0.57, 95% CI 0.41 to 0.78; I2 = 0%; (number needed to treat for an additional beneficial outcome (NNTB) = 3, 95% CI 2 to 7, based on a basal risk of 76%) but not when low molecular weight heparin was administered: RR 0.98, 95% CI 0.52 to 1.84; I2 for heterogeneity between the two subgroups = 58%. For neuraxial blocks compared to general anaesthesia, we rated the quality of evidence as very low for mortality (at 0 to 30 days), pneumonia, myocardial infarction, cerebrovascular accident, acute confusional state, decreased rate of deep venous thrombosis in the absence of potent thromboprophylaxis, and return of patient to their own home. The number of studies comparing other anaesthetic techniques was limited. We did not find a difference between the two techniques, except for deep venous thrombosis in the absence of potent thromboprophylaxis. The studies included a wide variety of clinical practices. The number of participants included in the review is insufficient to eliminate a difference between the two techniques in the majority of outcomes studied. Therefore, large randomized trials reflecting actual clinical practice are required before drawing final conclusions.
We included six randomised controlled trials with moderate or high risk of bias, involving 2123 participants. There is moderate quality evidence that involving consumers in the development of patient information material results in material that is more relevant, readable and understandable to patients, without affecting their anxiety. This 'consumer-informed' material can also improve patients' knowledge. There is low quality evidence that using consumer interviewers instead of staff interviewers in satisfaction surveys can have a small influence on the survey results. There is low quality evidence that an informed consent document developed with consumer input (potential trial participants) may have little if any impact on understanding compared to a consent document developed by trial investigators only. There is very low quality evidence that telephone discussions and face-to-face group meetings engage consumers better than mailed surveys in order to set priorities for community health goals. They also result in different priorities being set for these goals. There is little evidence from randomised controlled trials of the effects of consumer involvement in healthcare decisions at the population level. The trials included in this review demonstrate that randomised controlled trials are feasible for providing evidence about the effects of involving consumers in these decisions.
We included 20 RCTs, including one unpublished study with 1343 participants. Two studies were awaiting classification as the full text for these studies was not available. One study evaluated pre-emptive opioids, and 19 studies evaluated preventive opioids. We considered only one study to be at low risk of bias for most domains. The surgeries and opioids used varied, although roughly half of the included studies were conducted in abdominal hysterectomy, and around a quarter used morphine as the intervention. All studies were conducted in secondary care. Pre-emptive opioids compared to postincision opioids For pre-emptive opioids in dental surgery, there may be a reduction in early acute postoperative pain (mean difference (MD) -1.20, 95% confidence interval (CI) -1.75 to -0.65; 40 participants; 1 study; low-quality evidence). This study did not report on adverse events (respiratory depression, bradycardia, or hypotension). There may be a reduction in late acute postoperative pain (MD -2.10, 95% CI -2.57 to -1.63; 40 participants; 1 study; low-quality evidence). This study did not report 24-hour morphine consumption. Preventive opioids compared to postincision opioids For preventive opioids, there was probably no reduction in early acute postoperative pain (MD 0.11, 95% CI -0.32 to 0.53; 706 participants; 10 studies; I2 = 61%; moderate-quality evidence). There were no events of respiratory depression in four studies (433 participants). There was no important reduction in late acute postoperative pain (MD -0.06, 95% CI -0.13 to 0.01; 668 participants; 9 studies; I2 = 0%; moderate-quality evidence). There may be a small reduction in 24-hour morphine consumption (MD -4.91 mg, 95% CI -9.39 mg to -0.44 mg; 526 participants; 11 studies; I2 = 82%; very low-quality evidence). There may be similar rates of bradycardia (risk ratio (RR) 0.33, 95% CI 0.01 to 7.88; 112 participants; 2 studies; I2 = 0%; low-quality evidence) and hypotension (RR 1.08, 95% CI 0.25 to 4.73; 88 participants; 2 studies; I2 = 0%; low-quality evidence). Due to the low quality of the evidence, we are uncertain whether pre-emptive opioids reduce postoperative pain. Based on the trials conducted thus far, there was no clear evidence that preventive opioids result in reductions in pain scores. It was unclear if there was a reduction in morphine consumption due to very low-quality of evidence. Too few studies reported adverse events to be able to draw any definitive conclusions. Once assessed, the two studies awaiting classification may alter the conclusions of the review.
We did not identify any completed RCTs that met our inclusion criteria. However, three eligible studies are in progress: ADEPT is a phase III trial comparing postoperative radiotherapy with or without cisplatin in HPV-positive T1-4a OPSCC patients. Included patients must have received minimally invasive surgery and demonstrated extra-capsular spread from disease in the neck. ECOG-E3311 is a phase II trial of treatment for HPV-positive locally advanced OPSCC (stages III-IVa + IVb without distant metastasis). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy. PATHOS is a phase III trial of treatment for HPV-positive OPSCC (T1-3, N0-2b). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy. High-risk patients are randomised to radiotherapy with or without concurrent cisplatin. This review highlights the current lack of high-quality randomised controlled trials studying treatment de-escalation after minimally invasive surgery in patients with HPV-positive OPSCC. However, trials that will meet the inclusion criteria for this review are in progress with results expected between 2021 and 2023.
We included 19 trials with 19 different randomised dose comparisons. No studies reported data on relapse rates or quality of life and only one compared low dose (> 1.5 to 3 mg/day) haloperidol to higher dose ranges. Using standard lower dose (> 3 to 7.5 mg/day) did not result in loss of efficacy (no clinically important improvement in global state, versus standard higher dose (> 7.5 to 15 mg/day, n = 48, 1 RCT, RR 1.09, 95% CI 0.7 to 1.8, very-low-quality evidence); versus high dose (> 15 to 35 mg/day, n = 81, 2 RCTs, RR 0.95, 95% CI 0.8 to 1.2, very-low-quality evidence). Doses of haloperidol in the range of > 3 to 7.5 mg/day had a lower rate of development of clinically significant extrapyramidal adverse effects than higher doses (clinically significant extrapyramidal adverse effects, versus standard higher dose, n = 64, 2 RCTs, RR 0.12, 95% CI 0.01 to 2.1, very-low-quality evidence); versus high dose, n = 144, 3 RCTs, RR 0.59, 95% CI 0.5 to 0.8, very-low-quality evidence; versus very high dose (> 35 mg/day, n = 86, 2 RCTs, RR 0.70, 95% CI 0.5 to 1.1, very-low-quality evidence). None of the other comparisons between dose ranges yielded statistically significant differences, but several, particularly with lower dose ranges, were underpowered to detect clinically meaningful differences. Noresults were conclusive and all were based on small, short studies of limited quality. However, it would be understandable if clinicians were cautious in prescribing doses in excess of 7.5 mg/day of haloperidol to a person with uncomplicated acute schizophrenia, and if people with schizophrenia were equally reticent to take greater doses. Further research is needed regarding the efficacy and tolerability of the lower dose ranges, especially > 1.5 to 3 mg/day.
Eight trials met the inclusion criteria involving 504 patients in four cross-over and four parallel-group randomised controlled trials. Only two of the pre-stated six comparisons were addressed in these trials.   Four trials compared antibiotic prophylaxis with antibiotics when clinically indicated. For patients using intermittent catheterisation, there were inconsistent findings about the effect of antibiotic prophylaxis on symptomatic urinary tract infection (UTI). Only one study found a significant difference in the frequency of UTI favouring prophylaxis. For patients using indwelling urethral catheterisation, one small trial reported fewer episodes of symptomatic UTI in the prophylaxis group. Four trials compared antibiotic prophylaxis with giving antibiotics when microbiologically indicated. For patients using intermittent catheterisation, there was limited evidence that receiving antibiotics reduced the rate of bacteriuria (asymptomatic and symptomatic). There was weak evidence that prophylactic antibiotics were better in terms of fewer symptomatic bacteriuria. No eligible trials were identified that compared alternative routes of catheter insertion. The data from eight trials comparing different antibiotic policies were sparse, particularly when intermittent catheterisation was considered separately from indwelling catheterisation. Possible benefits of antibiotic prophylaxis must be balanced against possible adverse effects, such as development of antibiotic resistant bacteria. These cannot be reliably estimated from currently available trials.
We did not identify any studies for inclusion in the previous version of this review. For this update, the literature search identified one low-quality controlled clinical trial involving 106 participants. The findings from this study suggest 'low-level' evidence to support high-intensity ambulatory (outpatient) multidisciplinary rehabilitation in reducing short- and long-term motor disability (continence, mobility and locomotion, cognition), when compared with standard outpatient care. We found improvement in some domains of disability (continence, communication) and psychosocial gains were maintained at six months follow-up. We found no evidence for improvement in overall participation (quality of life and societal relationship). No adverse events were reported as a result of multidisciplinary rehabilitation. We found no evidence for improvement in quality of life or cost-effectiveness of rehabilitation. It was also not possible to suggest best 'dose' of therapy. Since the last version of this review, one new study has been identified for inclusion. The best evidence to date comes from this CCT, which provides low quality evidence that higher intensity ambulatory (outpatient) multidisciplinary rehabilitation reduces short- and long-term disability in people with brain tumour compared with standard outpatient care. Our conclusions are tentative at best, given gaps in current research in this area. Although the strength of evidence has increased with the identification of a new controlled clinical trial in this updated review, further research is needed into appropriate and robust study designs; outcome measurement; caregiver needs; evaluation of optimal settings; type, intensity, duration of therapy; and cost-effectiveness of multidisciplinary rehabilitation in the brain tumour population.
We included 17 RCTs involving 1297 participants. Participants were stroke survivors living in the community or receiving inpatient rehabilitation. Most could walk 10 metres without assistance. Ten studies (835 participants) measured walking capacity (measuring how far the participant could walk in six minutes) demonstrating that CCT was superior to the comparison intervention (Six-Minute Walk Test: mean difference (MD), fixed-effect, 60.86 m, 95% confidence interval (CI) 44.55 to 77.17, GRADE: moderate). Eight studies (744 participants) measured gait speed, again finding in favour of CCT compared with other interventions (MD 0.15 m/s, 95% CI 0.10 to 0.19, GRADE: moderate). Both of these effects are considered clinically meaningful. We were able to pool other measures to demonstrate the superior effects of CCT for aspects of walking and balance (Timed Up and Go: five studies, 488 participants, MD -3.62 seconds, 95% CI -6.09 to -1.16; Activities of Balance Confidence scale: two studies, 103 participants, MD 7.76, 95% CI 0.66 to 14.87). Two other pooled balance measures failed to demonstrate superior effects (Berg Blance Scale and Step Test). Independent mobility, as measured by the Stroke Impact Scale, Functional Ambulation Classification and the Rivermead Mobility Index, also improved more in CCT interventions compared with others. Length of stay showed a non-significant effect in favour of CCT (two trials, 217 participants, MD -16.35, 95% CI -37.69 to 4.99). Eight trials (815 participants) measured adverse events (falls during therapy): there was a non-significant effect of greater risk of falls in the CCT groups (RD 0.03, 95% CI -0.02 to 0.08, GRADE: very low). Time after stroke did not make a difference to the positive outcomes, nor did the quality or size of the trials. Heterogeneity was generally low; risk of bias was variable across the studies with poor reporting of study conduct in several of the trials. There is moderate evidence that CCT is effective in improving mobility for people after stroke - they may be able to walk further, faster, with more independence and confidence in their balance. The effects may be greater later after the stroke, and are of clinical significance. Further high-quality research is required, investigating quality of life, participation and cost-benefits, that compares CCT with standard care and that also investigates the influence of factors such as stroke severity and age. The potential risk of increased falls during CCT needs to be monitored.
We identified two eligible cohort studies including 60 children with newly diagnosed HR NBL. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible. In one study, the objective response rate (ORR) was 73% after surgery; the median overall survival was 15 months (95% confidence interval (CI) 7 to 23); five-year overall survival was 14.6%; median event-free survival was 10 months (95% CI 7 to 13); and five-year event-free survival was 12.2%. In the other study, the ORR was 56% after myeloablative therapy and autologous stem cell transplantation; 10-year overall survival was 6.25%; and event-free survival was not reported. With regard to short-term adverse effects, one study showed a prevalence of 2% (95% CI 0% to 13%; best-case scenario) for death due to myelosuppression. After the first cycle of 131I-MIBG therapy in one study, platelet toxicity occurred in 38% (95% CI 18% to 61%), neutrophil toxicity in 50% (95% CI 28% to 72%) and haemoglobin toxicity in 69% (95% CI 44% to 86%); after the second cycle this was 60% (95% CI 36% to 80%) for platelets and neutrophils and 53% (95% CI 30% to 75%) for haemoglobin. In one study, the prevalence of hepatic toxicity during or within four weeks after last the MIBG treatment was 0% (95% CI 0% to 9%; best-case scenario). Neither study reported cardiovascular toxicity and sialoadenitis. One study assessed long-term adverse events in some of the children: there was elevated plasma thyroid-stimulating hormone in 45% (95% CI 27% to 65%) of children; in all children, free T4 was within the age-related normal range (0%, 95% CI 0% to 15%). There were no secondary malignancies observed (0%, 95% CI 0% to 9%), but only five children survived more than four years. We identified no RCTs or CCTs comparing the effectiveness of treatment including 131I-MIBG therapy versus treatment not including 131I-MIBG therapy in patients with newly diagnosed HR NBL. We found two small observational studies including chilren. They had high risk of bias, and not all relevant outcome results were available. Based on the currently available evidence, we cannot make recommendations for the use of 131I-MIBG therapy in patients with newly diagnosed HR NBL in clinical practice. More high-quality research is needed.
In total, 65 trials (total number of patients = 11,237) were included in this review. Twenty-eight trials (42%) were considered high quality. Statistically significant effects were found in favour of NSAIDs compared to placebo, but at the cost of statistically significant more side effects. There is moderate evidence that NSAIDs are not more effective than paracetamol for acute low-back pain, but paracetamol had fewer side effects. There is moderate evidence that NSAIDs are not more effective than other drugs for acute low-back pain. There is strong evidence that various types of NSAIDs, including COX-2 NSAIDs, are equally effective for acute low-back pain. COX-2 NSAIDs had statistically significantly fewer side-effects than traditional NSAIDs. The evidence from the 65 trials included in this review suggests that NSAIDs are effective for short-term symptomatic relief in patients with acute and chronic low-back pain without sciatica. However, effect sizes are small. Furthermore, there does not seem to be a specific type of NSAID which is clearly more effective than others. The selective COX-2 inhibitors showed fewer side effects compared to traditional NSAIDs in the RCTs included in this review. However, recent studies have shown that COX-2 inhibitors are associated with increased cardiovascular risks in specific patient populations.
Twenty-nine RCTs were included: 28 were placebo-controlled, double-blind RCTs and one compared different doses of rFVIIa. In the 'Risk of bias' assessment, most studies were found to have some threats to validity although therapeutic RCTs were found to be less prone to bias than prophylactic RCTs. Sixteen trials involving 1361 participants examined the prophylactic use of rFVIIa; 729 received rFVIIa. There was no evidence of mortality benefit (risk ratio (RR) 1.04; 95% confidence interval (CI) 0.55 to 1.97). There was decreased blood loss (mean difference (MD) -297 mL; 95% CI -416 to -178) and decreased red cell transfusion requirements (MD -261 mL; 95% CI -367 to -154) with rFVIIa treatment; however, these values were likely overestimated due to the inability to incorporate data from trials (four RCTs in the outcome of blood loss and three RCTs in the outcome of transfusion requirements) showing no difference of rFVIIa treatment compared to placebo. There was a trend in favour of rFVIIa in the number of participants transfused (RR 0.85; 95% CI 0.72 to 1.01). However, there was a trend against rFVIIa with respect to thromboembolic adverse events (RR 1.35; 95% CI 0.82 to 2.25). Thirteen trials involving 2929 participants examined the therapeutic use of rFVIIa; 1878 received rFVIIa. There were no outcomes where any observed advantage or disadvantage of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality (RR 0.91; 95% CI 0.78 to 1.06). However, there was a trend against rFVIIa for increased thromboembolic adverse events (RR 1.14; 95% CI 0.89 to 1.47). When all trials were pooled together to examine the risk of thromboembolic events, a significant increase in total arterial events was observed (RR 1.45; 95% CI 1.02 to 2.05). The effectiveness of rFVIIa as a more general haemostatic drug, either prophylactically or therapeutically, remains unproven. The results indicate increased risk of arterial events in patients receiving rFVIIa. The use of rFVIIa outside its current licensed indications should be restricted to clinical trials.
We identified five RCTs with 5039 participants; two studies had a low risk of bias for all domains. Four studies evaluated the drug pioglitazone, and one study evaluated rosiglitazone. The participants in different studies were heterogeneous. Recurrent stroke Three studies evaluated the number of participants with recurrent stroke (4979 participants, a single study contributing 3876 of these). Peroxisome proliferator-activated receptor gamma agonists probably reduce the recurrence of stroke compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.99; moderate-quality evidence). Adverse events Evidence that adverse events occurred more frequently in participants treated with PPAR-γ agonists when compared with placebo was uncertain due to wide confidence interval and high levels of statistical heterogeneity: risk difference 10%, 95% CI -8% to 28%; low-quality evidence). Data were available on additional composite outcomes reflecting serious vascular events (all-cause death and other major vascular events; all-cause mortality, non-fatal myocardial infarction or non-fatal stroke) from one study in 984 people. This study provided low-quality evidence that PPAR-γ agonists led to fewer events (data not meta-analysed). Vascular events Peroxisome proliferator-activated receptor gamma agonists given over a mean duration of 34.5 months in a single trial of 984 participants may reduce serious vascular events expressed as a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99; low-quality evidence). Other outcomes One study in 20 people measured insulin sensitivity, and one study in 40 people measured the ubiquitin-proteasome activity in carotid plaques. Our confidence in the improvements observed with PPAR-γ agonists were limited by small sample sizes and risk of bias. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life. Peroxisome proliferator-activated receptor gamma agonists probably reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and may improve insulin sensitivity and the stabilisation of carotid plaques. Their effects on adverse events are uncertain. Our conclusions should be interpreted with caution considering the small number and the quality of the included studies. Further well-designed, double-blind RCTs with large samples are required to assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA.
We included five trials involving 639 clomiphene-resistant women with PCOS. Three studies compared UTND with LOD, and two compared UTND combined with gonadotropins with gonadotropins alone. The evidence was of low to very low quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency resulting from heterogeneity, imprecision induced by limited sample size, and lack of reporting of clinically relevant outcomes such as live birth and surgical complications. UTND versus LOD No studies reported on the main outcome live birth. One study reported on surgical complications; however, the evidence for this outcome was of very low quality because it was based on one study with small sample size and there were no events in either arm. Thus, we are uncertain whether there is any difference in surgical complications between UTND and LOD. We are also uncertain whether there is any difference in pregnancy rate when comparing UTND with LOD (OR 0.54, 95% CI 0.28 to 1.03; I2 = 56%; 3 RCTs, n = 473; very-low quality evidence). UTND may lead to a slight decrease in ovulation rate when compared to LOD (OR 0.66, 95% CI 0.45 to 0.97; I2 = 0%; 3 RCTs, n = 473; low-quality evidence). This suggests that among clomiphene-resistant women with PCOS using LOD with an expected ovulation rate of 69.5%, the ovulation rate among women using UTND may be between 50.6% and 68.8% No studies reported on the outcomes OHSS and multiple pregnancy. There was also insufficient evidence to reach a conclusion regarding miscarriage as there was only one study of very low quality. UTND combined with gonadotropins versus gonadotropins alone No studies reported on the main outcomes live birth and incidence of surgical complications. The evidence for the outcomes OHSS, pregnancy, ovulation, miscarriage, and multiple pregnancy in this comparison was of very low quality. Thus, we are uncertain whether there is any difference in these outcomes for women with clomiphene-resistant PCOS using UTND combined with gonadotropins as compared with gonadotropins. Based on very low-quality evidence, It is uncertain whether there is any difference in pregnancy rate, incidence of surgical complications, and miscarriage rate between UTND and LOD in women with clomiphene-resistant PCOS. UTND may lead to a slight decrease in ovulation rate when compared to LOD. No studies reported on the outcomes live birth rate, incidence of OHSS, and multiple pregnancy rate. No studies reported on the main outcomes live birth and surgical complications for the comparison UTND combined with gonadotrophins versus gonadotrophins alone. The evidence for the outcomes OHSS, pregnancy, ovulation, miscarriage, and multiple pregnancy in this comparison was of very low quality. Thus, it is unclear if there is a difference in any of the outcomes between UTND combined with gonadotrophins versus gonadotrophins alone.
We included 70 studies that compared an opioid with placebo or no treatment, another opioid administered intramuscularly or intravenously or compared with TENS applied to the back. Sixty-one studies involving more than 8000 women contributed data to the review and these studies reported on 34 different comparisons; for many comparisons and outcomes only one study contributed data. All of the studies were conducted in hospital settings, on healthy women with uncomplicated pregnancies at 37 to 42 weeks' gestation. We excluded studies focusing on women with pre-eclampsia or pre-existing conditions or with a compromised fetus. Overall, the evidence was graded as low- or very low-quality regarding the analgesic effect of opioids and satisfaction with analgesia; evidence was downgraded because of study design limitations, and many of the studies were underpowered to detect differences between groups and so effect estimates were imprecise. Due to the large number of different comparisons, it was not possible to present GRADE findings for every comparison. For the comparison of intramuscular pethidine (50 mg/100 mg) versus placebo, no clear differences were found in maternal satisfaction with analgesia measured during labour (number of women satisfied or very satisfied after 30 minutes: 50 women; 1 trial; risk ratio (RR) 7.00, 95% confidence interval (CI) 0.38 to 128.87, very low-quality evidence), or number of women requesting an epidural (50 women; 1 trial; RR 0.50, 95% CI 0.14 to 1.78; very low-quality evidence). Pain scores (reduction in visual analogue scale (VAS) score of at least 40 mm: 50 women; 1 trial; RR 25, 95% CI 1.56 to 400, low-quality evidence) and pain measured in labour (women reporting pain relief to be "good" or "fair" within one hour of administration: 116 women; 1 trial; RR 1.75, 95% CI 1.24 to 2.47, low-quality evidence) were both reduced in the pethidine group, and fewer women requested any additional analgesia (50 women; 1 trial; RR 0.71, 95% CI 0.54 to 0.94, low-quality evidence). There was limited information on adverse effects and harm to women and babies. There were few results that clearly showed that one opioid was more effective than another. Overall, findings indicated that parenteral opioids provided some pain relief and moderate satisfaction with analgesia in labour. Opioid drugs were associated with maternal nausea, vomiting and drowsiness, although different opioid drugs were associated with different adverse effects. There was no clear evidence of adverse effects of opioids on the newborn. We did not have sufficient evidence to assess which opioid drug provided the best pain relief with the least adverse effects. Though most evidence is of low- or very-low quality, for healthy women with an uncomplicated pregnancy who are giving birth at 37 to 42 weeks, parenteral opioids appear to provide some relief from pain in labour but are associated with drowsiness, nausea, and vomiting in the woman. Effects on the newborn are unclear. Maternal satisfaction with opioid analgesia was largely unreported. The review needs to be examined alongside related Cochrane reviews. More research is needed to determine which analgesic intervention is most effective, and provides greatest satisfaction to women with acceptable adverse effects for mothers and their newborn.
Sixteen studies involving 1233 participants with mean forced expiratory volume in one second (FEV1) 30% to 51% predicted were included. There was a significant improvement in six-minute walk distance after three months of yoga involving pranayama timed breathing techniques (mean difference to control 45 metres, 95% confidence interval 29 to 61 metres; two studies; 74 participants), with similar improvements in single studies of pursed lip breathing (mean 50 metres; 60 participants) and diaphragmatic breathing (mean 35 metres; 30 participants). Effects on dyspnoea and health-related quality of life were inconsistent across trials. Addition of computerised ventilation feedback to exercise training did not provide additional improvement in dyspnoea-related quality of life (standardised mean difference -0.03; 95% CI -0.43 to 0.49; two studies; 73 participants) and ventilation feedback alone was less effective than exercise training alone for improving exercise endurance (mean difference -15.4 minutes; 95% CI -28.1 to -2.7 minutes; one study; 32 participants). No significant adverse effects were reported. Few studies reported details of allocation concealment, assessor blinding or intention-to-treat analysis. Breathing exercises over four to 15 weeks improve functional exercise capacity in people with COPD compared to no intervention; however, there are no consistent effects on dyspnoea or health-related quality of life. Outcomes were similar across all the breathing exercises examined. Treatment effects for patient-reported outcomes may have been overestimated owing to lack of blinding. Breathing exercises may be useful to improve exercise tolerance in selected individuals with COPD who are unable to undertake exercise training; however, these data do not suggest a widespread role for breathing exercises in the comprehensive management of people with COPD.
Eight trials with 316 participants met the inclusion criteria. Most of the included studies were single-centre studies that were carried out in clinics or hospitals with a sample size ranging from 14 to 84. We generally considered the included studies to be at unclear or high risk of bias, as they had one domain at high risk of bias, or three or more domains at unclear risk of bias. We did not identify any studies that reported valid data for time to complete wound healing. Meta-analysis of four studies including 116 participants indicated that participants receiving phototherapy may experience a greater proportion of wounds completely healed during follow-up compared with those receiving no phototherapy/placebo (64.5% for the phototherapy group versus 37.0% for the no phototherapy/placebo group; risk ratio 1.57, 95% confidence interval 1.08 to 2.28; low-quality evidence, downgraded for study limitations and imprecision). Two studies mentioned adverse events in the results; one study with 16 participants suggested that there were no device-related adverse events, and the other study with 14 participants suggested that there was no clear difference between phototherapy and placebo group. Four studies reported change in ulcer size, but primarily due to high heterogeneity, they were not combined. Results from individual trials (including 16 participants to 84 participants) generally suggested that after two to four weeks of treatment phototherapy may result in a greater reduction in ulcer size but the quality of the evidence was low due to unclear risk of bias in the original trial and small sample size. We based the analyses for quality of life and amputations on only one study each (28 participants and 23 participants respectively); both outcomes showed no clear difference between the phototherapy group and the no phototherapy/placebo group. This systematic review of randomised trials suggested that phototherapy, when compared to no phototherapy/placebo, may increase the proportion of wounds completely healed during follow-up and may reduce wound size in people with diabetes, but there was no evidence that phototherapy improves quality of life. Due to the small sample size and methodological flaws in the original trials, the quality of the evidence was low, which reduces our confidence in these results. Large, well-designed randomised controlled trials are needed to confirm whether phototherapy could be an effective option for the treatment of foot ulcers in people with diabetes.
We included 15 eligible studies (n = 7976; effective sample size = 6630), four of which were cluster trials. Eight studies were conducted in Malawi, four in India, and one apiece in Kenya, Zambia, and Cambodia. Six studies received funding or donations from industry whereas eight did not, and one study did not report the funding source. The overall risk of bias was high for six studies, unclear for three studies, and low for six studies. Among the 14 studies that contributed to meta-analyses, none (n = 5), some (n = 5) or all (n = 4) children were stabilised in hospital prior to commencement of the study. One small study included only children known to be HIV-infected, another study stratified the analysis for 'recovery' according to HIV status, while the remaining studies included HIV-uninfected or untested children. Across all studies, the intervention lasted between 8 and 16 weeks. Only five studies followed up children postintervention (maximum of six months), and generally reported on a limited number of outcomes. We found seven studies with 2261 children comparing home-based RUTF meeting the World Health Organization (WHO) recommendations for nutritional composition (referred to in this review as standard RUTF) with an alternative dietary approach (effective sample size = 1964). RUTF probably improves recovery (risk ratio (RR) 1.33; 95% confidence interval (CI) 1.16 to 1.54; 6 studies, 1852 children; moderate-quality evidence), and may increase the rate of weight gain slightly (mean difference (MD) 1.12 g/kg/day, 95% CI 0.27 to 1.96; 4 studies, 1450 children; low-quality evidence), but we do not know the effects on relapse (RR 0.55, 95% CI 0.30 to 1.01; 4 studies, 1505 children; very low-quality evidence) and mortality (RR 1.05, 95% CI 0.51 to 2.16; 4 studies, 1505 children; very low-quality evidence). Two quasi-randomised cluster trials compared standard, home-based RUTF meeting total daily nutritional requirements with a similar RUTF but given as a supplement to the usual diet (213 children; effective sample size = 210). Meta-analysis showed that standard RUTF meeting total daily nutritional requirements may improve recovery (RR 1.41, 95% CI 1.19 to 1.68; low-quality evidence) and reduce relapse (RR 0.11, 95% CI 0.01 to 0.85; low-quality evidence), but the effects are unknown for mortality (RR 1.36, 95% CI 0.46 to 4.04; very low-quality evidence) and rate of weight gain (MD 1.21 g/kg/day, 95% CI - 0.74 to 3.16; very low-quality evidence). Eight studies randomised 5502 children (effective sample size = 4456) and compared standard home-based RUTF with RUTFs of alternative formulations (e.g. using locally available ingredients, containing less or no milk powder, containing specific fatty acids, or with added pre- and probiotics). For recovery, it made little or no difference whether standard or alternative formulation RUTF was used (RR 1.03, 95% CI 0.99 to 1.08; 6 studies, 4188 children; high-quality evidence). Standard RUTF decreases relapse (RR 0.84, 95% CI 0.72 to 0.98; 6 studies, 4188 children; high-quality evidence). However, it probably makes little or no difference to mortality (RR 1.00, 95% CI 0.80 to 1.24; 7 studies, 4309 children; moderate-quality evidence) and may make little or no difference to the rate of weight gain (MD 0.11 g/kg/day, 95% CI −0.32 to 0.54; 6 studies, 3807 children; low-quality evidence) whether standard or alternative formulation RUTF is used. Compared to alternative dietary approaches, standard RUTF probably improves recovery and may increase rate of weight gain slightly, but the effects on relapse and mortality are unknown. Standard RUTF meeting total daily nutritional requirements may improve recovery and relapse compared to a similar RUTF given as a supplement to the usual diet, but the effects on mortality and rate of weight gain are not clear. When comparing RUTFs with different formulations, the current evidence does not favour a particular formulation, except for relapse, which is reduced with standard RUTF. Well-designed, adequately powered, pragmatic RCTs with standardised outcome measures, stratified by HIV status, and that include diarrhoea as an outcome, are needed.
Our search strategy identified six reports for potential inclusion. Of those, we included one trial (four reports) involving 158 women, which was at low risk of bias. The one included trial examined the effect of prenatal repair versus postnatal repair. For the primary infant outcome of neonatal mortality, there was no clear evidence of a difference identified for prenatal versus postnatal repair (one study, 158 infants, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.05 to 5.54), however event rates were uncommon and so the analysis is likely to be underpowered to detect differences. Prenatal repair was associated with an earlier gestational age at birth (one study, 158 infants, mean difference (MD) -3.20 weeks, 95% CI -3.93 to -2.47) and a corresponding increase in both the risk of preterm birth before 37 weeks (one study, 158 infants, RR 5.30, 95% CI 3.11 to 9.04) and preterm birth before 34 weeks (one study, 158 infants, RR 9.23, 95% CI 3.45 to 24.71). Prenatal repair was associated with a reduction in shunt dependent hydrocephalus and moderate to severe hindbrain herniation. For women, prenatal repair was associated with increased preterm ruptured membranes (one study, 158 women, RR 6.15, 95% CI 2.75 to 13.78), although there was no clear evidence of difference in the risk of chorioamnionitis or blood transfusion, although again, event rates were uncommon. A number of this review's secondary infant and maternal outcomes were not reported. For the infant: days of hospital admission; survival to discharge; stillbirth; need for further surgery (e.g. skin grafting); neurogenic bladder dysfunction; childhood/infant quality of life. For the mother: admission to intensive care; women's emotional wellbeing and satisfaction with care. This review is based one small well-conducted study. There is insufficient evidence to recommend drawing firm conclusions on the benefits or harms of prenatal repair as an intervention for fetuses with spina bifida. Current evidence is limited by the small number of pregnancies that have been included in the single conducted randomised trial to date.
We identified six studies eligible for inclusion in this review; five RCTs and one NRS. Three completed RCTs (156 participants), one completed NRS (84 participants), and two ongoing RCTs. We identified one additional RCT awaiting classification. The completed studies were conducted between 1997 and 2015 and had a mean follow-up from 31 days to 2 years. One study included children receiving a HSCT (six participants), the other three studies only included adults: 218 participants with acute leukaemia receiving chemotherapy, and 16 with a haematological malignancy receiving a HSCT. The restrictive strategies varied from 70 g/L to 90 g/L. The liberal strategies also varied from 80 g/L to 120 g/L. Based on the GRADE rating methodology the overall quality of the included studies was very low to low across different outcomes. None of the included studies were free from bias for all 'Risk of bias' domains. One of the three RCTs was discontinued early for safety concerns after recruiting only six children, all three participants in the liberal group developed veno-occlusive disease (VOD). Evidence from RCTs A restrictive RBC transfusion policy may make little or no difference to: the number of participants who died within 100 days (two trials, 95 participants (RR: 0.25, 95% CI 0.02 to 2.69, low-quality evidence); the number of participants who experienced any bleeding (two studies, 149 participants; RR:0.93, 95% CI 0.73 to 1.18, low-quality evidence), or clinically significant bleeding (two studies, 149 participants, RR: 1.03, 95% CI 0.75 to 1.43, low-quality evidence); the number of participants who required RBC transfusions (three trials; 155 participants: RR: 0.97, 95% CI 0.90 to 1.05, low-quality evidence); or the length of hospital stay (restrictive median 35.5 days (interquartile range (IQR): 31.2 to 43.8); liberal 36 days (IQR: 29.2 to 44), low-quality evidence). We are uncertain whether the restrictive RBC transfusion strategy: decreases quality of life (one trial, 89 participants, fatigue score: restrictive median 4.8 (IQR 4 to 5.2); liberal median 4.5 (IQR 3.6 to 5) (very low-quality evidence); or reduces the risk of developing any serious infection (one study, 89 participants, RR: 1.23, 95% CI 0.74 to 2.04, very low-quality evidence). A restrictive RBC transfusion policy may reduce the number of RBC transfusions per participant (two trials; 95 participants; mean difference (MD) -3.58, 95% CI -5.66 to -1.49, low-quality evidence). Evidence from NRS We are uncertain whether the restrictive RBC transfusion strategy: reduces the risk of death within 100 days (one study, 84 participants, restrictive 1 death; liberal 1 death; very low-quality evidence); decreases the risk of clinically significant bleeding (one study, 84 participants, restrictive 3; liberal 8; very low-quality evidence); or decreases the number of RBC transfusions (adjusted for age, sex and acute myeloid leukaemia type geometric mean 1.25; 95% CI 1.07 to 1.47 - data analysis performed by the study authors) No NRS were found that looked at: quality of life; number of participants with any bleeding; serious infection; or length of hospital stay. No studies were found that looked at: adverse transfusion reactions; arterial or venous thromboembolic events; length of intensive care admission; or readmission to hospital. Findings from this review were based on four studies and 240 participants. There is low-quality evidence that a restrictive RBC transfusion policy reduces the number of RBC transfusions per participant. There is low-quality evidence that a restrictive RBC transfusion policy has little or no effect on: mortality at 30 to 100 days, bleeding, or hospital stay. This evidence is mainly based on adults with acute leukaemia who are having chemotherapy. Although, the two ongoing studies (530 participants) are due to be completed by January 2018 and will provide additional information for adults with haematological malignancies, we will not be able to answer this review's primary outcome. If we assume a mortality rate of 3% within 100 days we would need 1492 participants to have a 80% chance of detecting, as significant at the 5% level, an increase in all-cause mortality from 3% to 6%. Further RCTs are required in children.
37 studies fulfilled eligibility criteria, encompassing 5711 patients, 2866 randomised to routine tube use, and 2845 randomised to selective or No Tube use. Patients not having routine tube use had an earlier return of bowel function (p<0.00001), a decrease in pulmonary complications (p=0.09) and an insignificant trend toward increase in risk of wound infection (p=0.39) and ventral hernia (0.09). Anastomotic leak was no different between groups (p=0.70). Vomiting seemed to favour routine tube use, but with increased patient discomfort. Length of stay was shorter when no tube was used but the heterogeneity encountered in these analyses make rigorous conclusion difficult to draw for this outcome. No adverse events specifically related to tube insertion (direct tube trauma) were reported. Other outcomes were reported with insufficient frequency to be informative. Routine nasogastric decompression does not accomplish any of its intended goals and so should be abandoned in favour of selective use of the nasogastric tube.
Five trials involving 7391 women (2033 with a history of a pregnancy affected by a NTD and 5358 with no history of NTDs) were included. Four comparisons were made: 1) supplementation with any folate versus no intervention, placebo or other micronutrients without folate (five trials); 2) supplementation with folic acid alone versus no treatment or placebo (one trial); 3) supplementation with folate plus other micronutrients versus other micronutrients without folate (four trials); and 4) supplementation with folate plus other micronutrients versus the same other micronutrients without folate (two trials). The risk of bias of the trials was variable. Only one trial was considered to be at low risk of bias. The remaining studies lacked clarity regarding the randomisation method or whether the allocation to the intervention was concealed. All the participants were blinded to the intervention, though blinding was unclear for outcome assessors in the five trials. The results of the first comparison involving 6708 births with information on NTDs and other infant outcomes, show a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.17 to 0.58); five studies; 6708 births; high quality evidence). Only one study assessed the incidence of NTDs and showed no evidence of an effect (RR 0.07, 95% CI 0.00 to 1.32; 4862 births) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.34, 95% CI 0.18 to 0.64); four studies; 1846 births). Subgroup analyses suggest that the positive effect of folic acid on NTD incidence and recurrence is not affected by the explored daily folic acid dosage (400 µg (0.4 mg) or higher) or whether folic acid is given alone or with other vitamins and minerals. These results are consistent across all four review comparisons. There is no evidence of any preventive or negative effects on cleft palate (RR 0.73, 95% CI 0.05 to 10.89; three studies; 5612 births; low quality evidence), cleft lip ((RR 0.79, 95% CI 0.14 to 4.36; three studies; 5612 births; low quality evidence), congenital cardiovascular defects (RR 0.57, 95% CI 0.24 to 1.33; three studies; 5612 births; low quality evidence), miscarriages (RR 1.10, 95% CI 0.94 to 1.28; five studies; 7391 pregnancies; moderate quality evidence) or any other birth defects (RR 0.94, 95% CI 0.53 to 1.66; three studies; 5612 births; low quality evidence). There were no included trials assessing the effects of this intervention on neonatal death, maternal blood folate or anaemia at term. Folic acid, alone or in combination with vitamins and minerals, prevents NTDs, but does not have a clear effect on other birth defects.
One study (recruiting 48 women with idiopathic hyperprolactinemia) met our inclusion criteria; 46 women (42 pregnancies - 4/46 women did not conceive during the study period) were included in the analysis. The study compared the use of a dopamine agonist (bromocriptine, 2.5 mg to 5.0 mg/day until the end of the ninth week of gestation) versus a no-treatment control. The study was judged as being at a high risk of bias. It was not possible to carry out meta-analysis due to insufficient data. The study reported both of this review's primary outcomes of miscarriage and live birth. Results from this single study suggest that, compared to no treatment, oral bromocriptine was effective in preventing future miscarriage (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.09 to 0.87, 46 participants (low-quality evidence)) in women with idiopathic hyperprolactinemia. There was no clear difference with regard to the other primary outcome of live births (RR 1.50, 95% CI 0.93 to 2.42, 46 participants (very low-quality evidence)). There was no difference with regard to this review's secondary outcome of conception (RR 0.92, 95% CI 0.77 to 1.09, 46 participants (very low-quality evidence)) between the group of women who received dopamine (21 out of 24 women conceived) and women in the no-treatment group (21 out of 22 women conceived). The included study only reported the serum prolactin levels in pregnant women and therefore the data could not be analyzed in this review. No other secondary outcomes relevant to this review were reported; adverse effects for women (nausea, vomiting, headache, vertigo, fatigue, hypotension, arrhythmia, and psychotic symptoms) and infants (birth defects, low birthweight, and developmental disabilities) were not reported. We downgraded the quality of the evidence for risk of bias in the one trial contributing outcome data (no description of allocation concealment, lack of blinding and possible reporting bias) and for imprecision (all effect estimates were based on small sample size, miscarriage was based on few events, and the 95% CIs of live birth and conception cross the line of no effect). Currently, there is insufficient evidence (from a single randomized trial with a small sample size, and judged to be at high risk of bias) to evaluate the effectiveness of dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and a history of recurrent miscarriage. We assessed outcomes using GRADE methodology. Miscarriage was assessed as low quality due to risk of bias concerns in the one trial contributing data (no description of allocation concealment, lack of blinding and possible reporting bias) and to imprecision (effect estimates were based on small sample size and few events). Live births and conception were assessed as of very low quality due to the same risk of bias concerns in study design and to imprecision (with a wide 95% CI consistent with either benefit or harm), and a small sample size. There were no data relating to adverse effects of the intervention for either the mother or her baby. Futher high-quality research in this area is warranted. There is a need for well-designed, larger RCTs to confirm and extend the findings of the trial reviewed here. Many questions remain unanswered. Some important considerations for future research include, the need for well-designed RCTs with large sample sizes, and for those studies to consider important outcomes (including adverse effects for both the mother and her baby). Future studies should examine the effectiveness and safety of various dopamine agonists including bromocriptine, cabergoline and quinagolide.
We identified six randomised controlled trials with a total of 597 participants that were eligible for inclusion in the 2013 review. No new studies were eligible for inclusion in this update. Participants in the included studies, where dementia severity was reported, had mild to moderate severity of vascular dementia (four trials). The included studies tested varying doses and duration of Cerebrolysin treatment. Follow-up ranged from 15 days to three years. Five of included studies were conducted in China (three studies), Russia (one study), and Romania (one study), while relevant information of other study was unclear. Where details of funding were available, all studies were supported by the pharmaceutical industry (three studies). Cognitive function was measured using the Mini-Mental State Examination (MMSE) or Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog+). Combining the MMSE and ADAS-cog+ data (three studies, 420 people), there was a beneficial effect of Cerebrolysin (SMD 0.36, 95% CI 0.13 to 0.58; very low-quality evidence). Global function was measured by Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC+) or Investigator's Clinical Global Impression (CGI). We assessed response rates on these measures (the proportion of participants with a CIBIC+ score of < 3; or at least moderate improvement of the CGI rating at the last visit). There was a beneficial effect of Cerebrolysin (two studies, 379 participants, RR 2.69, 95% CI 1.82 to 3.98; very low-quality evidence). Only one trial described mortality and reported no deaths. Four studies reported adverse events; data from two studies (379 people) were in a format that permitted meta-analysis, and there was no difference in rates of adverse effects (RR 0.91, 95% CI 0.29 to 2.85; very low-quality evidence). No studies reported on quality of life or caregiver burden. Courses of intravenous Cerebrolysin improved cognition and general function in people living with vascular dementia, with no suggestion of adverse effects. However, these data are not definitive. Our analyses were limited by heterogeneity, and the included papers had high risk of bias. If there are benefits of Cerebrolysin, the effects may be too small to be clinically meaningful. There have been no new studies of Cerebrolysin in vascular dementia since the last Cochrane Review. Cerebrolysin continues to be used and promoted as a treatment for vascular dementia, but the supporting evidence base is weak. Adequately powered, methodologically robust trials are needed to properly assess the effects of Cerebrolysin in vascular dementia.
Two trials were included in this review. There was no significant difference between the two treatment groups for the frequency of discontinuation for either contraceptive, although the women on NET-EN were 4% more likely to discontinue for personal reasons than those on DPMA. Discontinuation because of accidental pregnancy did not differ between the groups. Although the duration of bleeding and spotting events was the same in each group, women on DPMA were 21% more likely to develop amenorrhoea. Mean changes in body weight at 12 and 24 months, and in systolic and diastolic blood pressure at 12 months did not differ significantly between the studies. While the choice between DPMA and NET-EN as injectable progestogen contraceptives may vary between both health providers and patients, data from randomized controlled trials indicate little difference between the effects of these methods, except that women on DMPA are more likely to develop amenorrhoea. There is inadequate data to detect differences in some non-menstrual major and minor clinical effects.
A total of 15 trials (n = 888 randomised participants) were included, 13 were placebo controlled and three were head to head (two trials had more than two treatment arms). Eleven of the trials were conducted in Turkey, two in Japan, one in Iran and one in the UK. Most trials used the International Study Group criteria for Behçet's disease. Eleven different interventions were assessed. The interventions were grouped into two categories, topical and systemic. Only one study was assessed as being at low risk of bias. It was not possible to carry out a meta-analysis. The quality of the evidence ranged from moderate to very low and there was insufficient evidence to support or refute the use of any included intervention with regard to pain, episode duration, or episode frequency associated with oral ulcers, or safety of the interventions. Due to the heterogeneity of trials including trial design, choice of intervention, choice and timing of outcome measures, it was not possible to carry out a meta-analysis. Several interventions show promise and future trials should be planned and reported according to the CONSORT guidelines. Whilst the primary aim of many trials for Behç̧et's disease is not necessarily reduction of oral ulceration, reporting of oral ulcers in these studies should be standardised and pre-specified in the methodology. The use of a core outcome set for oral ulcer trials would be beneficial.
Four studies, involving a total of 183 participants and 257 teeth were identified. Each of the interventions aimed to reduce infection or alter the inflammatory response or both at the time of or shortly after the tooth or teeth were replanted. Each study assessed a different intervention and therefore it was not appropriate or possible to numerically synthesise the data. All evidence was rated as being of very low quality due to problems with risk of bias and imprecision of results. This means that we are very uncertain about all of the results presented in this review. One study at high risk of bias with 69 participants (138 teeth) compared a 20-minute soak with gentamycin sulphate for both groups prior to replantation with the experimental group receiving daily hyperbaric oxygen for 80 minutes for the first 10 days. There was some evidence of a benefit for the hyperbaric oxygen group in respect of periodontal healing, tooth survival, and pulpal healing. One study at unclear risk of bias with 22 participants (27 teeth) compared the use of two root canal medicaments, Ledermix and Ultracal. There was insufficient evidence of a difference for periodontal healing or tooth survival. This was the only study to formally report adverse events with none identified. Study authors reported that Ledermix caused a greater level of patient dissatisfaction with the colour of avulsed and replanted teeth. A third study at high risk of bias with 19 participants compared extra- or intra-oral endodontics for avulsed teeth which were stored dry for longer than 60 minutes before replantation. There was insufficient evidence of a difference in periodontal healing. The fourth study at high risk of bias with 73 participants compared a 10-minute soak in either thymosin alpha 1 or saline before replantation followed by daily gingival injections with these same medicaments for the first 7 days. There was some evidence of a benefit for thymosin alpha 1 with respect to periodontal healing and tooth survival. Based on the results of the included studies, there is insufficient evidence to support or refute the effectiveness of different interventions for avulsed and replanted permanent front teeth. The overall quality of existing evidence was very low, and therefore great caution should be exercised when generalising the results of the included trials. There is urgent need for further well-designed randomised controlled trials.
We included eight trials involving 743 participants (369 children and 374 adults). All trials gave antibiotics to both placebo and corticosteroid groups; no trials assessed corticosteroids as standalone treatment for sore throat. In addition to any effect of antibiotics and analgesia, corticosteroids increased the likelihood of complete resolution of pain at 24 hours by more than three times (risk ratio (RR) 3.2, 95% confidence interval (CI) 2.0 to 5.1, P < 0.001, I2 statistic 44%) and at 48 hours by 1.7 times. Fewer than four people need to be treated to prevent one person continuing to experience pain at 24 hours. Corticosteroids also reduced the mean time to onset of pain relief and the mean time to complete resolution of pain by 6 and 14 hours, respectively, although significant heterogeneity was present. At 24 hours, pain (assessed by visual analogue scores) was reduced by an additional 14% by corticosteroids. No difference in rates of recurrence, relapse or adverse events were reported for participants taking corticosteroids compared to placebo, although reporting of adverse events was poor. Oral or intramuscular corticosteroids, in addition to antibiotics, increase the likelihood of both resolution and improvement of pain in participants with sore throat. Further trials assessing corticosteroids in the absence of antibiotics and in children are warranted.
Of 10 eligible studies eight were included in the analyses; two were of insufficient quality. Three trials (746 patients, low quality of evidence) of efficacy in acute bronchitis in adults showed effectiveness for most outcomes in the liquid preparation but not for tablets. Three other trials (819 children, low quality of evidence) showed similar results for acute bronchitis in children. For both meta-analyses, we did not pool subtotals due to relevant heterogeneity induced by type of preparation. One study in patients with sinusitis (n = 103 adults, very low quality of evidence) showed significant treatment effects (complete resolution at day 21; RR 0.43, 95% confidence interval (CI) 0.30 to 0.62). One study in the common cold demonstrated efficacy after 10 days, but not five days (very low quality of evidence). We rated the study quality as moderate for all studies (unvalidated outcome assessment, minor attrition problems, investigator-initiated trials only). Based on the funnel plot there was suspicion of publication bias. There were no valid data for the treatment of other acute respiratory tract infections. Adverse events were more common with P. sidoides, but none were serious. P. sidoides may be effective in alleviating symptoms of acute rhinosinusitis and the common cold in adults, but doubt exists. It may be effective in relieving symptoms in acute bronchitis in adults and children, and sinusitis in adults. The overall quality of the evidence was considered low for main outcomes in acute bronchitis in children and adults, and very low for acute sinusitis and the common cold. Reliable data on treatment for other ARIs were not identified.
We included 27 trials with 12,835 cases of sore throat. We did not identify any new trials in this 2013 update. 1. Symptoms Throat soreness and fever were reduced by about half by using antibiotics. The greatest difference was seen at day three. The number needed to treat to benefit (NNTB) to prevent one sore throat at day three was less than six; at week one it was 21. 2. Non-suppurative complications The trend was antibiotics protecting against acute glomerulonephritis but there were too few cases to be sure. Several studies found antibiotics reduced acute rheumatic fever by more than two-thirds within one month (risk ratio (RR) 0.27; 95% confidence interval (CI) 0.12 to 0.60). 3. Suppurative complications Antibiotics reduced the incidence of acute otitis media within 14 days (RR 0.30; 95% CI 0.15 to 0.58); acute sinusitis within 14 days (RR 0.48; 95% CI 0.08 to 2.76); and quinsy within two months (RR 0.15; 95% CI 0.05 to 0.47) compared to those taking placebo. 4. Subgroup analyses of symptom reduction Antibiotics were more effective against symptoms at day three (RR 0.58; 95% CI 0.48 to 0.71) if throat swabs were positive for Streptococcus, compared to RR 0.78; 95% CI 0.63 to 0.97 if negative. Similarly at week one the RR was 0.29 (95% CI 0.12 to 0.70) for positive and 0.73 (95% CI 0.50 to 1.07) for negative Streptococcus swabs. Antibiotics confer relative benefits in the treatment of sore throat. However, the absolute benefits are modest. Protecting sore throat sufferers against suppurative and non-suppurative complications in high-income countries requires treating many with antibiotics for one to benefit. This NNTB may be lower in low-income countries. Antibiotics shorten the duration of symptoms by about 16 hours overall.
We screened 574 records for eligibility and included 21 trials in the review. The 21 trials randomised 1490 women and addressed 11 comparisons. These were: differences in training supervision (amount, individual versus group), in approach (one versus another, the effect of an additional component) and the exercise training (type of contraction, frequency of training). In women with stress urinary incontinence, 10% of those who received weekly or twice-weekly group supervision in addition to individual appointments with the therapist did not report improvement post-treatment compared to 43% of the group who had individual appointments only (risk ratio (RR) for no improvement 0.29, 95% confidence interval (CI) 0.15 to 0.55, four trials). Looking at this another way, 90% of those who had combined group and individual supervision reported improvement versus 57% of women receiving individual supervision only. While women receiving the combination of frequent group supervision and individual supervision of pelvic floor muscle training were more likely to report improvement, the confidence interval was wide, and more than half of the 'control' group (the women who did not get the additional weekly or twice-weekly group supervision) reported improvement. This finding, of subjective improvement in both active treatment groups, with more improvement reported by those receiving more health professional contact, was consistent throughout the review. We feel there are several reasons why caution is needed when interpreting the results of the review: there were few data in any comparison; a number of trials were confounded by comparing two arms with multiple differences in the approaches to pelvic floor muscle training; there was a likelihood of a relationship between attention and reporting of more improvement in women who were not blind to treatment allocation; some trials chose interventions that were unlikely to have a muscle training effect; and some trials did not adequately describe their intervention. This review found that the existing evidence was insufficient to make any strong recommendations about the best approach to pelvic floor muscle training. We suggest that women are offered reasonably frequent appointments during the training period, because the few data consistently showed that women receiving regular (e.g. weekly) supervision were more likely to report improvement than women doing pelvic floor muscle training with little or no supervision.
In this review, we included data from 30 trials involving 7289 women. We excluded 11 trials, identified 16 ongoing/unpublished trials and two trials are awaiting classification. Overall risk of bias for the trials was mixed. Comparison 1. 601 IU/d or more versus 600 IU/d or less of vitamin D alone or with any other nutrient (19 trials; 5214 participants) Supplementation with 601 IU/d or more of vitamin D during pregnancy may make little or no difference to the risk of pre-eclampsia (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.42); 5 trials; 1553 participants,low-certainty evidence), may reduce the risk of gestational diabetes (RR 0.54, 95% CI 0.34 to 0.86; 5 trials; 1846 participants; moderate-certainty evidence), may make little or no difference to the risk of preterm birth (RR 1.25, 95% CI 0.92 to 1.69; 4 trials; 2294 participants; low-certainty evidence); and may make little or no difference to the risk of low birthweight (RR 0.90, 95% CI 0.66 to 1.24; 4 trials; 1550 participants; very low-certainty evidence) compared to women receiving 600 IU/d or less. Comparison 2. 4000 IU or more versus 3999 IU or less of vitamin D alone (15 trials; 4763 participants) Supplementation with 4000 IU/d or more of vitamin D during pregnancy may make little or no difference to the risk of: pre-eclampsia (RR 0.87, 95% CI 0.62 to 1.22; 4 trials, 1903 participants, low-certainty evidence); gestational diabetes (RR 0.89, 95% CI 0.56 to 1.42; 5 trials, 2276 participants; low-certainty evidence); preterm birth (RR 0.85, 95% CI 0.64 to 1.12; 6 trials, 2948 participants, low-certainty evidence); and low birthweight (RR 0.92, 95% CI 0.49 to 1.70; 2 trials; 1099 participants; low-certainty evidence) compared to women receiving 3999 IU/d or less. Adverse events (such as hypercalcaemia, hypocalcaemia, hypercalciuria, and hypovitaminosis D) were reported differently in most trials; however, in general, there was little to no side effects reported or similar cases between groups. Supplementing pregnant women with more than the current vitamin D recommendation may reduce the risk of gestational diabetes; however, it may make little or no difference to the risk of pre-eclampsia, preterm birth and low birthweight. Supplementing pregnant women with more than the current upper limit for vitamin D seems not to increase the risk of the outcomes evaluated. In general, the GRADE was considered low certainty for most of the primary outcomes due to serious risk of bias and imprecision of results. With respect to safety, it appears that vitamin D supplementation is a safe intervention during pregnancy, although the parameters used to determine this were either not reported or not consistent between trials. Future trials should be consistent in their reports of adverse events. There are 16 ongoing trials that when published, will increase the body of knowledge.
Forty-one trials involving 5449 women, met the inclusion criteria. These trials covered many interventions, including acupressure, acustimulation, acupuncture, ginger, chamomile, lemon oil, mint oil, vitamin B6 and several antiemetic drugs. There were no included studies of dietary and other lifestyle interventions. Evidence regarding the effectiveness of P6 acupressure, auricular (ear) acupressure and acustimulation of the P6 point was limited. Acupuncture (P6 or traditional) showed no significant benefit to women in pregnancy. The use of ginger products may be helpful to women, but the evidence of effectiveness was limited and not consistent, though three recent studies support ginger over placebo. There was only limited evidence from trials to support the use of pharmacological agents including vitamin B6, Doxylamine-pyridoxoine and other anti-emetic drugs to relieve mild or moderate nausea and vomiting. There was little information on maternal and fetal adverse outcomes and on psychological, social or economic outcomes. We were unable to pool findings from studies for most outcomes due to heterogeneity in study participants, interventions, comparison groups, and outcomes measured or reported. The methodological quality of the included studies was mixed. Risk of bias was low related to performance bias, detection bias and attrition bias for most studies. Selection bias risk was unclear for many studies and almost half of the studies did not fully or clearly report all pre-specified outcomes. Given the high prevalence of nausea and vomiting in early pregnancy, women and health professionals need clear guidance about effective and safe interventions, based on systematically reviewed evidence. There is a lack of high-quality evidence to support any particular intervention. This is not the same as saying that the interventions studied are ineffective, but that there is insufficient strong evidence for any one intervention. The difficulties in interpreting and pooling the results of the studies included in this review highlight the need for specific, consistent and clearly justified outcomes and approaches to measurement in research studies.
Of eleven studies identified, three (354 participants) were included: two with four-year follow up and one with 12-weeks follow up. Data were lacking on predefined outcomes; common outcomes were examined at different time-points and presented differently. Meta-analyses were not possible. In one study, oral corticosteroids at prednisolone-equivalent dose of 1 mg/kg alternate days slowed progression of lung disease; at two and four years, % predicted FEV1 in the 1 mg/kg group changed significantly more than in the placebo group (P < 0.02). During the first two years, the 2 mg/kg group was not significantly different from the placebo group. Linear growth retardation was observed from six months in the 2 mg/kg alternate days prednisolone group and from 24 months in the 1 mg/kg alternate days prednisolone group. Adverse events terminated one four-year study early. Year 10 follow up showed catch-up growth started two years after treatment ceased. Alternate-day treatment with oral corticosteroids may have impaired growth until adulthood in boys. Oral corticosteroids at prednisolone-equivalent dose of 1 to 2 mg/kg alternate days appear to slow progression of lung disease in CF; benefit should be weighed against occurrence of adverse events. Risk-benefit analysis of low-dose alternate days corticosteroids is important. No further trials of this intervention are anticipated, and hence the review will no longer be regularly updated. However, if any new data are published, these will be incorporate when available.
We included 10 trials reported in 9 publications (N = 1651). Only one trial out of 10 was assessed at low risk of bias. Five trials used the currently recommended daily dose for the drug, and two trials used lower daily doses available over the counter. Three trials investigated NSAIDs no longer approved for human use. The follow-up duration was short in all studies but one. Three trials (n = 918) compared the effects of NSAIDs to those of placebo on pain reduction. The pooled mean difference showed comparable pain reduction (visual analogue scale, 0 to 100) in the NSAIDs and placebo groups (MD -4.56, 95% CI -11.11 to 1.99). Heterogeneity was high (I2 = 82%), and the quality of the evidence was very low. When we excluded one trial with a short follow-up of eight hours, the mean difference further decreased (MD -0.09, 95% CI -9.89 to 9.71). Three trials (n = 753) compared NSAIDs to placebo regarding global improvement. We found low-quality evidence that NSAIDs are more effective than placebo with a risk ratio of 1.14 (95% CI 1.03 to 1.27). One trial (n = 214) studied the effect of NSAIDs on disability, finding very low-quality evidence that NSAIDs are no more effective than placebo on disability. Four trials (n = 967) comparing NSAIDs to placebo reported adverse effects, with low-quality evidence that the risk for adverse effects is higher in the NSAID group than in the placebo group (RR 1.40, 95% CI 1.02 to 1.93). The adverse effects reported in this review are consistent with those previously reported in the literature. This updated systematic review including 10 trials evaluating the efficacy of NSAIDs versus placebo or other drugs in people with sciatica reports low- to very low-level evidence using the GRADE criteria. The efficacy of NSAIDs for pain reduction was not significant. NSAIDs showed a better global improvement compared to placebo. These findings must be interpreted with caution, as the level of evidence according to the GRADE classification was very low for the outcome pain reduction and low for global improvement due to small study samples, inconsistent results, imprecision, and a high risk of bias in the included trials. While the trials included in the analysis were not powered to detect potential rare side effects, we found an increased risk for side effects in the short-term NSAIDs use. As NSAIDs are frequently prescribed, the risk-benefit ratio of prescribing the drug needs to be considered.
We included 12 studies with altogether 671 participants. Two high quality randomized controlled trials with altogether 141 participants demonstrated clinical improvement of carpal tunnel syndrome at one month or less following local corticosteroid compared to placebo injection (relative risk 2.58 (95% confidence intervals 1.72 to 3.87)). One trial compared local corticosteroid injection to oral corticosteroid and at 12 weeks after treatment there was significantly more improvement in the injection group (mean difference -7.10 (95% confidence intervals -11.68 to -2.52)). In one trial, the rate of improvement after one month was greater after local than systemic corticosteroid injection (relative risk 3.17 (95% confidence intervals 1.02 to 9.87)). In one trial, symptoms did not improve significantly more in the injection group at eight weeks after injection compared to treatment with anti-inflammatory medication and splinting (mean difference 0.10 (95% confidence intervals -0.33 to 0.53)). Two injections versus one injection of local corticosteroid did not provide further clinical improvement, mean difference -3.80 (95% CI -9.27 to 1.67). Local corticosteroid injection for carpal tunnel syndrome provides greater clinical improvement in symptoms one month after injection compared to placebo. Significant symptom relief beyond one month has not been demonstrated. Local corticosteroid injection provides significantly greater clinical improvement than oral corticosteroid for up to three months. Local corticosteroid injection does not significantly improve clinical outcome compared to either anti-inflammatory treatment and splinting after eight weeks or Helium-Neon laser treatment after six months. Two local corticosteroid injections do not provide significant added clinical benefit compared to one injection.
Three studies with 1306 women are included in the review and compared intramuscular versus intravenous oxytocin administered just after the birth of the anterior shoulder or soon after the birth of the baby. Studies were carried out in hospital settings in Turkey and Thailand and recruited women with singleton, term pregnancies. Overall, the included studies were at moderate risk of bias: none of the studies provided clear information on allocation concealment or attempted to blind staff or women. For GRADE outcomes the quality of the evidence was very low, with downgrading due to study design limitations and imprecision of effect estimates. Only one study reported severe postpartum haemorrhage (blood loss 1000 mL or more) and showed no clear difference between the intramuscular and intravenous oxytocin groups (risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.04; 256 women; very low-quality evidence). No woman required hysterectomy in either group in one study (no estimable data, very low-quality evidence), and in another study one woman in each group received a blood transfusion (RR 1.00, 95% CI 0.06 to 15.82; 256 women; very low-quality evidence). Other important outcomes (maternal death, hypotension, maternal dissatisfaction with the intervention and neonatal jaundice) were not reported by any of the included studies. There were no clear differences between groups for other prespecified secondary outcomes reported (postpartum haemorrhage 500 mL or more, use of additional uterotonics, retained placenta or manual removal of the placenta). Very low-quality evidence indicates no clear difference between the comparative benefits and risks of intramuscular and intravenous oxytocin when given to prevent excessive blood loss after vaginal birth. Appropriately designed randomised trials with adequate sample sizes are needed to assess whether the route of prophylactic oxytocin after vaginal birth affects maternal or infant outcomes. Such studies could be large enough to detect clinically important differences in major side effects that have been reported in observational studies and should also consider the acceptability of the intervention to mothers and providers as important outcomes.
Ten RCTs (361 participants) met our inclusion criteria. Five RCTs (152 participants, 134 analysed) with low to moderate quality of evidence compared standard recombinant interferon with placebo or control. There was no significant difference for mortality (5 studies (134 participants): RR 0.89, 95% CI 0.06 to 13.23), relapses (1 study (36 participants): RR 0.72, 95% CI 0.28 to 1.88), sustained virological response (4 studies (98 participants): RR 3.25, 95% CI 0.81 to 13.07), treatment discontinuation (4 studies (116 participants): RR 4.59, 95% CI 0.49 to 42.69) and number with adverse events (5 studies (143 participants): RR 3.56, 95% CI 0.98 to 13.01). End of treatment response was significantly more for standard interferon (5 studies (132 participants): RR 8.62, 95% CI 3.03 to 24.55). There was overall low to unclear risk of bias and no significant heterogeneity. One RCT (50 participants) with moderate quality of evidence compared PEG interferon and standard interferon. There was no significant difference in mortality (RR 0.33, 95% CI 0.01 to 7.81), relapses (RR 0.72, 95% CI 0.41 to 1.25), sustained virological response (RR 2.40, 95% CI 0.99 to 5.81), treatment discontinuation (RR 0.11, 95% CI 0.01 to 1.96) and number with major adverse events (RR 0.11, 95% CI 0.01 to 1.96). End of treatment response was significantly more for PEG interferon (RR 1.53, 95% CI 1.09 to 2.15). There was overall low risk of bias. Two RCTs (97 participants) with moderate quality of evidence compared two doses of two different preparations of PEG interferon. Subgroup analysis comparing high and low doses of PEG interferon alpha-2a (135 µg/week versus 90 µg/week) and PEG interferon alpha-2b (1 µg/kg versus 0.5 µg/kg body weight/week) found no significant difference in mortality (2 studies (97 participants): RR 4.30, 95% CI 0.76 to 24.33), relapses (1 study (81 participants): RR 1.11, 95% CI 0.45 to 2.77), end of treatment response (2 studies (97 participants): RR 1.42, 95% CI 0.51 to 3.90), sustained virological response (2 studies (97 participants): RR 1.19, 95% CI 0.68 to 2.07), treatment discontinuation (2 studies (97 participants): RR 1.20, 95% CI 0.63 to 2.28), patients with adverse events (2 studies (97 participants): RR 1.05, 95% CI 0.61 to 1.83) or serious adverse events (2 studies (97 participants): RR 1.24, 95% CI 0.72 to 2.14). Both had overall low risk of bias and no significant subgroup differences. Two RCTs (62 participants) with moderate quality of evidence compared standard or PEG interferon alone or in combination with ribavirin. The only reported outcome in both was treatment discontinuation which was significantly more with ribavirin in the one study (RR 0.34, 95% CI 0.14 to 0.84) and pooled 7/10 in the second. No RCTs had data on time to recovery, cost-effectiveness, quality of life, and other outcomes and in peritoneal dialysis. Our review demonstrated that in CKD patients on haemodialysis with HCV infection treatment with standard interferon brings about an end of treatment but not a sustained virological response and is relatively well tolerated. PEG interferon is more effective than standard interferon for end of treatment response but not for sustained response; both were equally tolerated. Increasing doses of PEG interferon did not improve responses but high and low doses are equally tolerated. Addition of ribavirin results in more treatment discontinuation.
The acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes. 1. Mental state - PANSS negative symptoms average end point score (2 RCTs, n = 31, MD -1.69 95% CI -2.80 to -0.57), PANSS General Psychopathology average end point score (2 RCTs, n = 31, MD -3.86 95% CI -5.40 to -2.32), and improvement in depressive symptoms showed at least by one short-term study as measured by CDSS scale (data skewed). 2. Cognitive domains - attention, (1 RCT, n = 73, MD 1.20 95% CI 0.14 to 2.26), visual memory (2 RCTs, n = 48 , MD 1.90 95% CI 0.52 to 3.28), verbal memory and language (3 RCTs, n = 42, MD 3.46 95% CI 0.67 to 6.26) and executive functioning (1 RCT, n = 24, MD 17.10 95% CI 0.70 to 33.50). 3. Tolerability - EPSE: AIMS, (1 RCT, n = 35, MD 1.50 95% CI 1.04 to 1.96). No difference was noted between the two arms in other outcomes. The overall rate of participants leaving studies early was low (13.6 %) and showed no clear difference between the two groups. The results seem to favour the use of acetylcholinesterase inhibitors in combination with antipsychotics on a few domains of mental state and cognition, but because of the various limitations in the studies as mentioned in the main text, the evidence is weak. This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies.
37 studies were included in the review (3551 participants). Antidepressants versus placebo: results for dropouts did not show evidence of difference, 31 studies, 2819 participants, RR 1.03 (Cl 95% 0.93 to 1.14). Looking at Abstinence from cocaine use, even though not statistically significant, the difference shown by the analysis in the three-weeks abstinence rate was in favour of antidepressants (eight studies, 942 participants, RR 1.22 (Cl 95% 0.99 to 1.51)). Considering only studies involving tricyclics, five studies, 367 participants, or only desipramine, four studies, 254 participants, the evidence was in favour of antidepressants. However, selecting only studies with operationally defined diagnostic criteria, statistical significance favouring antidepressants, as well as the trend for significance shown by the full sample, disappeared. Looking at safety issues, the results did not show evidence of differences (number of patients withdrawn for medical reasons, thirteen studies, 1396 participants, RR 1.39 (Cl 95% 0.91 to 2.12)). Subgroup analysis considering length of the trial, associated opioid dependence or associated psychosocial interventions as confounding factors, failed in showing consistent and statistically significant differences in favour of antidepressants. Antidepressants versus other drugs: Comparing antidepressants with dopamine agonists or with anticonvulsants, no evidence of differences was shown on dropouts and on other outcomes (abstinence from cocaine use, adverse events). At the current stage of evidence data do not support the efficacy of antidepressants in the treatment of cocaine abuse/dependence. Partially positive results obtained on secondary outcome measures, such as depression severity, do not seem to be associated with an effect on direct indicators of cocaine abuse/dependence. Antidepressants cannot be considered a mainstay of treatment for unselected cocaine abusers/dependents.
Two trials (one RCT and one CCT) (total 80 participants) met the review criteria. Both trials scored poorly on the methodological quality assessment. There was 'insufficient evidence' for VR programs for (a)‘competitive employment’, in altering rates of job retention, changes in employment, improvement in rates of re-entry into the labour force; (b) for altering ‘work ability' by improving participants’ confidence in the accommodation request process, or employability maturity or job seeking activity. No evidence could be assimilated for changes in proportions of persons in supported employment or on disability pensions, nor for cost-effectiveness. There was inconclusive evidence to support VR for pwMS. However, the review highlights some of the challenges in providing VR for pwMS. Clinicians need to be aware of vocational issues, and to understand and manage barriers for maintaining employment. Proactive and timely VR programs should incorporate practical solutions to deal with work disability, workplace accommodation and educate employers, and the wider community. Liaison with policy makers is imperative for government initiatives that encourage work focused VR programs. Future research in VR should focus on improving methodological and scientific rigour of clinical trials; on the development of appropriate and valid outcome measures; and on cost effectiveness of VR programs.
We included 18 trials (1463 participants) in the review. Thirteen trials involved people undergoing hip replacement, three involved people undergoing knee replacement and two included both people with hip and knee replacements. Only six trials reported using an adequate method of allocation concealment, and only two trials blinded participants. Few trials reported sufficient data to analyse the major outcomes of the review (pain, function, health-related quality of life, global assessment, postoperative anxiety, total adverse events and re-operation rate). There did not appear to be an effect of time on any outcome, so we chose to include only the latest time point available per outcome in the review. In people undergoing hip replacement, preoperative education may not offer additional benefits over usual care. The mean postoperative anxiety score at six weeks with usual care was 32.16 on a 60-point scale (lower score represents less anxiety) and was 2.28 points lower with preoperative education (95% confidence interval (CI) -5.68 to 1.12; 3 RCTs, 264 participants, low-quality evidence), an absolute risk difference of -4% (95% CI -10% to 2%). The mean pain score up to three months postoperatively with usual care was 3.1 on a 10-point scale (lower score represents less pain) and was 0.34 points lower with preoperative education (95% CI -0.94 to 0.26; 3 RCTs, 227 participants; low-quality evidence), an absolute risk difference of -3% (95% CI -9% to 3%). The mean function score at 3 to 24 months postoperatively with usual care was 18.4 on a 68-point scale (lower score represents better function) and was 4.84 points lower with preoperative education (95% CI -10.23 to 0.66; 4 RCTs, 177 participants; low-quality evidence), an absolute risk difference of -7% (95% CI -15% to 1%). The number of people reporting adverse events, such as infection and deep vein thrombosis, did not differ between groups, but the effect estimates are uncertain due to very low quality evidence (23% (17/75) reported events with usual care versus 18% (14/75) with preoperative education; risk ratio (RR) 0.79; 95% CI 0.19 to 3.21; 2 RCTs, 150 participants). Health-related quality of life, global assessment of treatment success and re-operation rates were not reported. In people undergoing knee replacement, preoperative education may not offer additional benefits over usual care. The mean pain score at 12 months postoperatively with usual care was 80 on a 100-point scale (lower score represents less pain) and was 2 points lower with preoperative education (95% CI -3.45 to 7.45; 1 RCT, 109 participants), an absolute risk difference of -2% (95% CI -4% to 8%). The mean function score at 12 months postoperatively with usual care was 77 on a 100-point scale (lower score represents better function) and was no different with preoperative education (0; 95% CI -5.63 to 5.63; 1 RCT, 109 participants), an absolute risk difference of 0% (95% CI -6% to 6%). The mean health-related quality of life score at 12 months postoperatively with usual care was 41 on a 100-point scale (lower score represents worse quality of life) and was 3 points lower with preoperative education (95% CI -6.38 to 0.38; 1 RCT, 109 participants), an absolute risk difference of -3% (95% CI -6% to 1%). The number of people reporting adverse events, such as infection and deep vein thrombosis, did not differ between groups (18% (11/60) reported events with usual care versus 13% (7/55) with preoperative education; RR 0.69; 95% CI 0.29 to 1.66; 1 RCT, 115 participants), an absolute risk difference of -6% (-19% to 8%). Global assessment of treatment success, postoperative anxiety and re-operation rates were not reported. Although preoperative education is embedded in the consent process, we are unsure if it offers benefits over usual care in terms of reducing anxiety, or in surgical outcomes, such as pain, function and adverse events. Preoperative education may represent a useful adjunct, with low risk of undesirable effects, particularly in certain patients, for example people with depression, anxiety or unrealistic expectations, who may respond well to preoperative education that is stratified according to their physical, psychological and social need.
60 studies recruiting 6542 participants met the inclusion criteria. CFC-BDP (57 studies): In non-oral steroid treated patients, at doses of 400mcg/day or less CFC-BDP produced significant improvements from baseline in a number of efficacy measures compared with placebo, including forced expiratory volume in one second (FEV1) 360 ml (95% CI 260 to 460); FEV1 (% predicted) WMD 12.41% (95% CI 8.18 to 16.64) and morning peak expiratory flow rate (am PEF) WMD 35.95 L/min (95% CI 27.85 to 44.04). BDP also led to reductions in rescue beta-2 agonist use compared with placebo of -2.32 puffs/d (95% CI -2.55 to -2.09) and reduced the relative risk (RR) of trial withdrawal due to an asthma exacerbation 0.25 (95% CI 0.12 to 0.51). Subgroup analyses based on treatment duration provide support to the proposal that a treatment period of greater than four weeks is required to realise a fuller treatment effect. In oral steroid treated patients BDP led to significantly greater reductions in oral prednisolone use WMD -4.91 mg/d (95% CI -5.88 to -3.94 mg/d) and greater likelihood of withdrawing oral steroid treatment RR 8.02 (95% CI 3.23 to 19.92). HFA-BDP (3 studies): In non-oral steroid-treated patients, HFA-BDP was significantly more effective than placebo in improving FEV1, morning and evening PEF, FEF25 to 75%, reduced asthma symptoms and beta2-agonists daily consumption. Significant effects for such outcomes were apparent after six weeks of treatment. In oral steroid treated patients, HFA-BDP improved significantly FEV1 and am PEF. The summary estimates for these outcomes suggested a high level of heterogeneity, and divergent aims of the studies may contribute to the variation we observed. Limited data on adverse events were reported. This review has quantified the efficacy of CFC-BDP and HFA-BDP in the treatment of chronic asthma and strongly supports its use. Current asthma guidelines recommend titration of dose to individual patient response, but the published data provide little support for dose titration above 400 mcg/d in patients with mild to moderate asthma. There are insufficient data to draw any conclusions concerning dose-response in people with severe asthma.
Fifteen studies (two with long term follow-up studies) were identified examining a range of interventions. In terms of main findings, twelve studies evaluated brief trauma focused cognitive behavioural interventions (TF-CBT). TF-CBT was more effective than a waiting list intervention (6 studies, 471 participants; SMD -0.64, 95% CI -1.06, -0.23) and supportive counselling (4 studies, 198 participants; SMD -0.67, 95% CI -1.12, -0.23). Effects against supportive counselling were still present at 6 month follow-up (4 studies, 170 participants; SMD -0.64, 95% CI -1.02, -0.25). There was no evidence of the effectiveness of a structured writing intervention when compared against minimal intervention (2 studies, 149 participants; SMD -0.15, 95% CI -0.48, 0.17). There was evidence that individual TF-CBT was effective for individuals with acute traumatic stress symptoms compared to both waiting list and supportive counselling interventions. The quality of trials included was variable and sample sizes were often small. There was considerable clinical heterogeneity in the included studies and unexplained statistical heterogeneity observed in some comparisons. This suggests the need for caution in interpreting the results of this review. Additional high quality trials with longer follow up periods are required to further test TF-CBT and other forms of psychological intervention.
None of the 1328 studies that were identified satisfied the inclusion criteria. Based on this review, we cannot make any new recommendations on the effectiveness of adrenaline auto-injectors for the treatment of anaphylaxis. Although randomized, double-blind, placebo-controlled clinical trials of high methodological quality are necessary to define the true extent of benefits from the administration of adrenaline in anaphylaxis via an auto-injector, such trials are unlikely to be performed in individuals experiencing anaphylaxis because of ethical concerns associated with randomization to placebo. There is, however, a need to consider trials in which, for example, auto-injectors of different doses of adrenaline and differing devices are compared in order to provide greater clarity on the dose and device of choice. Such trials would be practically challenging to conduct. In the absence of appropriate trials, we recommend that adrenaline administration by auto-injector should still be regarded as the most effective first-line treatment for the management of anaphylaxis in the community. In countries where auto-injectors are not commonly used, it may be possible to conduct trials to compare administration of adrenaline via auto-injector with adrenaline administered by syringe and ampoule, or comparing the effectiveness of two different types of auto-injector.
We identified 45 references out of 953 search results, of which 14 studies met the inclusion criteria involving 3528 rectal cancer patients. We did not consider the risk of bias of the included studies to have impacted on the quality of the evidence. Data were analysed according to an intention-to-treat principle with a mean conversion rate of 14.5% (range 0% to 35%) in the laparoscopic group. There was moderate quality evidence that laparoscopic and open TME had similar effects on five-year disease-free survival (OR 1.02; 95% CI 0.76 to1.38, 4 studies, N = 943). The estimated effects of laparoscopic and open TME on local recurrence and overall survival were similar, although confidence intervals were wide, both with moderate quality evidence (local recurrence: OR 0.89; 95% CI 0.57 to1.39 and overall survival rate: OR 1.15; 95% CI 0.87 to1.52). There was moderate to high quality evidence that the number of resected lymph nodes and surgical margins were similar between the two groups. For the short-term results, length of hospital stay was reduced by two days (95% CI -3.22 to -1.10), moderate quality evidence), and the time to first defecation was shorter in the LTME group (-0.86 days; 95% CI -1.17 to -0.54). There was moderate quality evidence that 30 days morbidity were similar in both groups (OR 0.94; 95% CI 0.8 to 1.1). There were fewer wound infections (OR 0.68; 95% CI 0.50 to 0.93) and fewer bleeding complications (OR 0.30; 95% CI 0.10 to 0.93) in the LTME group. There was no clear evidence of any differences in quality of life after LTME or OTME regarding functional recovery, bladder and sexual function. The costs were higher for LTME with differences up to GBP 2000 for direct costs only. We have found moderate quality evidence that laparoscopic total mesorectal excision (TME) has similar effects to open TME on long term survival outcomes for the treatment of rectal cancer. The quality of the evidence was downgraded due to imprecision and further research could impact on our confidence in this result. There is moderate quality evidence that it leads to better short-term post-surgical outcomes in terms of recovery for non-locally advanced rectal cancer. Currently results are consistent in showing a similar disease-free survival and overall survival, and for recurrences after at least three years and up to 10 years, although due to imprecision we cannot rule out superiority of either approach. We await long-term data from a number of ongoing and recently completed studies to contribute to a more robust analysis of long-term disease free, overall survival and local recurrence.
Very few studies directly assessed the effectiveness of corticosteroids for RA treatment and many were of poor methodologic quality. Only seven of 34 studies identified by our search met criteria for inclusion. Our results indicated that corticosteroids were significantly more effective than placebo controls for four of six outcomes assessed [standardized mean difference for tender joints = -0.37 (95%CI: -0.59, -0.14), swollen joints = -0.41 (-0.67, -0.16), pain = -0.43 (-0.74, -0.12), and functional status = -0.57 (-0.92, -0.22)]. The results for grip strength and ESR were not significant [GS = +0.30 (-0.19, +0.80), weighted mean difference (WMD) for ESR = -7.03 (-18.06, +4.01)]. The single trial that compared prednisone to aspirin indicated no statistically significant difference between these groups for joint tenderness (0.10 (-0.35, +0.55) and for ESR [0.00 (-11.09, +11.09]. Overall, the four outcomes assessed in the single trial that compared prednisone to chloroquine suggested that there was no statistically significant differenece in the effectiveness of these two agents [SMD for joint tenderness = +0.23 (-0.30, +0.75), swollen joints = +0.43 (-0.11, +0.96), functional status = -0.27 (-0.80, +0.26), and WMD for ESR = -16.00 (-30.58, -1.42)]. Based on the limited data available, moderate-term prednisone treatment of RA appears to be superior to placebo and comparable to treatment with aspirin or chloroquine in improving several common rheumatoid arthritis disease activity measures.
We identified nine studies meeting the inclusion criteria, including a Turkish study that is awaiting formal translation. There were 1244 participants randomised in classically designed RCTs, of whom 1197 had evaluable data, and 138 patients enrolled in an enriched enrolment, randomised withdrawal (EERW) trial. Overall, 600 participants were treated with transdermal fentanyl patches, 382 with various formulations of morphine, 36 with methadone, and 221 with paracetamol plus codeine. There were major sources of potential bias, including lack of blinding, small size, high levels of attrition, and inconsistent reporting. We could not compare data in a meaningful analysis regarding adverse events such as nausea, abdominal pain, gastrointestinal bleeding, and confusion. These events may have been attributable to the underlying disease process. There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNT) for the analgesic effect. In seven studies with 461 participants reporting pain intensity results after about two weeks, the mean or median pain scores were on the borderline of mild and moderate pain. Most participants would have had no worse than mild pain on treatment. Another reported that 77% of participants using transdermal fentanyl had an undefined successful outcome. Fewer participants experienced constipation with transdermal fentanyl (28%) than with oral morphine (46%), giving a risk ratio of 0.61 (95% CI 0.47 to 0.78); the NNT to prevent constipation was 5.5 (95% CI 3.8 to 10). The randomised trial literature for effectiveness of transdermal fentanyl is limited, but it is an important medicine. Most studies recruited fewer than 100 participants and did not provide data appropriate for meta-analysis. Only a few reported how many patients had good pain relief but, where data were reported, a majority had no worse than mild pain within a reasonably short time period. The evidence pointed to a useful and significant reduction in complaints about constipation for transdermal fentanyl compared with oral morphine.
We included 11 RCTs (962 participants). Eight RCTs (762 participants) were carried out on adults (18 to 80 years of age), two (128 participants) involved children (two to 16 years) and one RCT (72 participants) included patients aged 60 to 75 years. Of the 11 included studies, we judged three to be at low risk of bias, and the remaining eight RCTs at unclear or high risk of bias. Six RCTs (383 participants) estimated the primary outcome, time to awakening after stopping general anaesthesia, which was reduced in the entropy as compared to the standard practice group (mean difference (MD) -5.42 minutes, 95% confidence interval (CI) -8.77 to -2.08; moderate quality of evidence). We noted heterogeneity for this outcome; on performing subgroup analysis this was found to be due to studies that included participants undergoing major, long duration surgeries (off-pump coronary artery bypass grafting, major urological surgery). The MD for time to awakening with four studies on ambulatory procedures was -3.20 minutes (95% CI -3.94 to -2.45). No trial reported the second primary outcome, mortality at 24 hours, 30 days, and one year with the use of entropy monitoring. Eight trials (797 participants) compared the secondary outcome, postoperative recall of intraoperative events (awareness) in the entropy and standard practice groups. Awareness was reported by only one patient in the standard practice group, making meaningful estimation of benefit of entropy monitoring difficult; moderate quality of evidence. All 11 RCTs compared the amount of anaesthetic agent used between the entropy and standard practice groups. Six RCTs compared the amount of propofol, four compared the amount of sevoflurane and one the amount of isoflurane used between the groups. Analysis of three studies (166 participants) revealed that the MD of propofol consumption between the entropy group and control group was -11.56 mcg/kg/min (95% CI -24.05 to 0.92); low quality of evidence. Analysis of another two studies (156 participants) showed that the MD in sevoflurane consumption in the entropy group compared to the control group was -3.42 mL (95% CI -6.49 to -0.35); moderate quality of evidence. No trial reported on the secondary outcome of the cost of general anaesthesia. Three trials (170 participants) estimated MD in time to readiness to leave the PACU of the entropy group as compared to the control group (MD -5.94 minutes, 95% CI -16.08 to 4.20; low quality of evidence). Heterogeneity was noted, which was due to the difference in anaesthetic technique (propofol-based general anaesthesia) in one study. The remaining two studies had used volatile-based general anaesthesia. The MD in time to readiness to leave the PACU was -4.17 minutes (95% CI -6.84 to -1.51) with these two studies. The evidence as regards time to awakening, recall of intraoperative awareness and reduction in inhalational anaesthetic agent use was of moderate quality. The quality of evidence of as regards reduction in intravenous anaesthetic agent (propofol) use, as well as time to readiness to leave the PACU was found to be of low quality. As the data are limited, further studies consisting of more participants will be required for ascertaining benefits of entropy monitoring. Further studies are needed to assess the effect of entropy monitoring on focal issues such as short-term and long-term mortality, as well as cost of general anaesthesia.
Eight studies (11 study comparisons) were identified, all of which compared cognitive and/or behavioural treatments versus treatment as usual control groups. Seven studies (ten comparisons) had usable data for meta-analyses. These studies demonstrated that patients receiving any variant of cognitive behavioural treatment exhibited significantly fewer symptoms post-treatment than those receiving treatment as usual (SMD -1.24, 95% CI -1.61 to -0.87, I² test for heterogeneity 33.4%). Different types of cognitive and/or behavioural treatments showed similar differences in effect when compared with treatment as usual. The overall treatment effect appeared to be influenced by differences in baseline severity. The findings of this review suggest that psychological treatments derived from cognitive behavioural models are an effective treatment for adult patients with obsessive compulsive disorder. Larger high quality randomised controlled trials involving longer follow up periods are needed, to further test cognitive behavioural treatments, and other psychological approaches, in comparison to each other and control conditions. Future trials should examine the predictors of response to each treatment, and also conduct cost-effectiveness evaluations.
The primary outcome measures were complete clearance of lesions after the first treatment cycle and recurrence rate at 12 months. Our secondary outcomes included the number of lesions that cleared after each treatment cycle, the number of treatment cycles needed to achieve clearance, the recurrence rates at > 12 months, cosmetic outcome, quality of life assessment, and adverse outcomes as reported by both participant and clinician. We included 9 studies, with a total of 363 participants. One study demonstrated statistically significantly greater clearance of lesions of Bowen's disease with MAL-PDT (methyl aminolevulinate with photodynamic therapy) when compared with placebo-PDT (RR (risk ratio) 1.68, 95% CI (confidence interval) 1.12 to 2.52; n = 148) or cryotherapy (RR 1.17, 95% CI 1.01 to 1.37; n = 215), but there was no significant difference when MAL-PDT was compared to 5-FU (5-fluorouracil). One study demonstrated statistically significantly greater clearance of lesions with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) versus 5-FU (RR 1.83, 95% CI 1.10 to 3.06; n = 66), but no statistically significant difference in recurrence rates at 12 months (RR 0.33, 95% CI 0.07 to 1.53). Cryotherapy showed no statistically significant difference in clearance rates (RR 0.99, 95% CI 0.78 to 1.26) or recurrences at 1 year (RR 1.48, 95% CI 0.53 to 4.17) when compared to 5-FU in 1 study of 127 participants. One study compared imiquimod to placebo and demonstrated statistically significantly greater clearance rates in the imiquimod group (9/15 lesions) compared to placebo (0/16) (Fisher's Exact P value < 0.001). The imiquimod group did not report any recurrences at 12 months, but at 18 months, 2/16 participants in the placebo group had developed early invasive squamous cell carcinoma. Overall, there has been very little good-quality research on treatments for Bowen's disease. There is limited evidence from single studies to suggest MAL-PDT is an effective treatment. Although cosmetic outcomes appear favourable with PDT, five-year follow-up data are needed. Significantly more lesions cleared with MAL-PDT compared to cryotherapy. No significant difference in clearance was seen when MAL-PDT was compared with 5-FU, but one study found a significant difference in clearance in favour of ALA-PDT when compared to 5-FU. There was no significant difference in clearance when cryotherapy was compared to 5-FU. The lack of quality data for surgery and topical cream therapies has limited the scope of this review to one largely about PDT studies. The age group, number, and size of lesions and site(s) affected may all influence therapeutic choice; however, there was not enough evidence available to provide guidance on this. More studies are required in the immunosuppressed populations as different therapeutic options may be preferable. Specific recommendations cannot be made from the data in this review, so we cannot give firm conclusions about the comparative effectiveness of treatments.
We included 45 trials (involving 1619 participants) in this update of our review. Electromechanical and robot-assisted arm training improved activities of daily living scores (SMD 0.31, 95% confidence interval (CI) 0.09 to 0.52, P = 0.0005; I² = 59%; 24 studies, 957 participants, high-quality evidence), arm function (SMD 0.32, 95% CI 0.18 to 0.46, P < 0.0001, I² = 36%, 41 studies, 1452 participants, high-quality evidence), and arm muscle strength (SMD 0.46, 95% CI 0.16 to 0.77, P = 0.003, I² = 76%, 23 studies, 826 participants, high-quality evidence). Electromechanical and robot-assisted arm training did not increase the risk of participant dropout (RD 0.00, 95% CI -0.02 to 0.02, P = 0.93, I² = 0%, 45 studies, 1619 participants, high-quality evidence), and adverse events were rare. People who receive electromechanical and robot-assisted arm training after stroke might improve their activities of daily living, arm function, and arm muscle strength. However, the results must be interpreted with caution although the quality of the evidence was high, because there were variations between the trials in: the intensity, duration, and amount of training; type of treatment; participant characteristics; and measurements used.
We included 10 RCTs that involved a total of 300 participants whose mean age was 54.4 years. Women accounted for fewer than 25% of all study participants. Nine trials which randomised 284 participants to receive exercise-based rehabilitation (151 participants) or no exercise (133 participants) were included in the main analysis. One cross-over RCT compared high-intensity interval training with continued moderate-intensity training in 16 participants. We reported findings for all trials at their longest follow-up (median 12 weeks). Exercise-based cardiac rehabilitation increased exercise capacity (VO2peak) compared with no exercise control (MD 2.49 mL/kg/min, 95% CI 1.63 to 3.36; N = 284; studies = 9; moderate quality evidence). There was evidence from one trial that high-intensity interval exercise training was more effective in improving exercise capacity than continuous moderate-intensity exercise (MD 2.30 mL/kg/min, 95% CI 0.59 to 4.01; N = 16; 1 study). Four studies reported health-related quality of life (HRQoL) measured using SF-36, Profile of Quality of Life in the Chronically Ill (PLC) and the World Health Organization Quality Of Life (WHOQoL) - BREF. Due to the variation in HRQoL outcomes and methods of reporting we were unable to meta-analyse results across studies, but there was no evidence of a difference between exercise-based cardiac rehabilitation and control in 18 of 21 HRQoL domains reported, or between high and moderate intensity exercise in any of the 10 HRQoL domains reported. One adverse event was reported by one study. Exercise-based cardiac rehabilitation improves exercise capacity, but exercise was found to have no impact on health-related quality of life in the short-term (median 12 weeks follow-up), in heart transplant recipients whose health is stable. There was no evidence of statistical heterogeneity across trials for exercise capacity and no evidence of small study bias. The overall risk of bias in included studies was judged as low or unclear; more than 50% of included studies were assessed at unclear risk of bias with respect to allocation concealment, blinding of outcome assessors and declaration of conflicts of interest. Evidence quality was assessed as moderate according to GRADE criteria. We found moderate quality evidence suggesting that exercise-based cardiac rehabilitation improves exercise capacity, and that exercise has no impact on health-related quality of life in the short-term (median 12 weeks follow-up), in heart transplant recipients. Cardiac rehabilitation appears to be safe in this population, but long-term follow-up data are incomplete and further good quality and adequately-powered trials are needed to demonstrate the longer-term benefits of exercise on safety and impact on both clinical and patient-related outcomes, such as health-related quality of life, and healthcare costs.
We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine-dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo. All trials were published in peer-reviewed journals, and analysis was done by the intention-to-treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. Levosimendan may reduce short-term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low-quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short-term survival benefit with levosimendan vs. dobutamine is not confirmed on long-term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low-quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low-quality evidence). All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short-term mortality with very low-quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine-dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in-hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants). Apart from low quality of evidence data suggesting a short-term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug-based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS. Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well-designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal-directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support.
Ten trials involving 2412 participants were included. The vaccines investigated were calf-lymph derived first-generation vaccines (Dryvax, APVS, Lancy-vaxina, Lister), and cell-cultured second-generation vaccines (ACAM, CCSV). Vaccines were investigated in different dilutions. All undiluted vaccines induced a reaction in 95% of people vaccinated in terms of pustule and immunogenicity. Also 1:10 dilutions were fully efficient when the starting concentration was defined. Serious adverse events were reported in 1% to 2% of the volunteers. Fever was observed in 11% to 22% of participants, and headache in roughly half of the participants. Fever was less frequent when new vaccines were administered, but rates of headache were similar in new and old vaccines. The evidence shows that stockpiled vaccines have maintained their immunogenicity and new cell-cultured vaccines are similar to stockpiled vaccines in terms of vaccination success rate and immunogenicity. First- and second-generation vaccines diluted to at least 1:10 are as effective as undiluted vaccine in terms of clinical success rate and immunogenicity. Dilution did not reduce the frequency of adverse events. Success rate and immunogenicity were similar in naive and previously vaccinated persons, but there were fewer adverse events in previously vaccinated persons. The rate of adverse events found in this review reveals the need for further development and improvement of smallpox vaccines.
Three studies involving 170 participants compared the azapirone buspirone with placebo. No study provided enough usable information on our primary efficacy outcome (response). For our primary acceptability outcome, moderate-quality evidence indicated that azapirones had lower acceptability than placebo: risk ratio (RR) for dropouts for any reason 2.13 (95% confidence interval (CI) 1.11 to 4.07; 3 studies, 170 participants. Evidence for secondary efficacy outcomes were of low quality. Results on efficacy between azapirone and placebo in terms of agoraphobia (standardised mean difference (SMD) -0.01, 95% CI -0.56 to 0.53; 1 study, 52 participants), general anxiety (mean difference (MD) -2.20, 95% CI -5.45 to 1.06; 2 studies, 115 participants) and depression (MD -1.80, 95% CI -5.60 to 2.00; 1 study, 52 participants) were uncertain. None of the studies provided information for the assessment of allocation concealment or sequence generation. Conflicts of interest were not explicitly expressed. The risk of attrition bias was rated high for all three studies. Information on adverse effects other than dropouts for any reason was insufficient to include in the analyses. The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low-quality evidence for secondary efficacy outcomes. A small amount of moderate-quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo. However, only trials of one azapirone (namely buspirone) were included in this review; this, combined with the small sample size, limits our conclusions. If further research is to be conducted, studies with larger sample sizes, with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder.
We included 27 trials involving 1976 participants Trials were conducted in Europe, China, Brazil, Canada and New Zealand and involved patients undergoing elective abdominal surgery (18), orthopaedic surgery (4), cardiac surgery (4) and thyroidectomy (1). Twelve studies were limited to participants with an American Society of Anaesthesiologists grade of I-II or I-III. A total of 17 trials contained at least one domain judged to be at high risk of bias, and only two studies were judged to be at low risk of bias across all domains. Of greatest concern was the risk of bias associated with inadequate blinding, as most of the outcomes assessed by this review were subjective. Only six trials were judged to be at low risk of bias because of blinding. In 19 trials including 1351 participants, preoperative carbohydrate treatment was associated with shortened length of hospital stay compared with placebo or fasting (by 0.30 days; 95% confidence interval (CI) 0.56 to 0.04; very low-quality evidence). No significant effect on length of stay was noted when preoperative carbohydrate treatment was compared with placebo (14 trials including 867 participants; mean difference -0.13 days; 95% CI -0.38 to 0.12). Based on two trials including 86 participants, preoperative carbohydrate treatment was also associated with shortened time to passage of flatus when compared with placebo or fasting (by 0.39 days; 95% CI 0.70 to 0.07), as well as increased postoperative peripheral insulin sensitivity (three trials including 41 participants; mean increase in glucose infusion rate measured by hyperinsulinaemic euglycaemic clamp of 0.76 mg/kg/min; 95% CI 0.24 to 1.29; high-quality evidence). As reported by 14 trials involving 913 participants, preoperative carbohydrate treatment was not associated with an increase or a decrease in the risk of postoperative complications compared with placebo or fasting (risk ratio of complications 0.98, 95% CI 0.86 to 1.11; low-quality evidence). Aspiration pneumonitis was not reported in any patients, regardless of treatment group allocation. Preoperative carbohydrate treatment was associated with a small reduction in length of hospital stay when compared with placebo or fasting in adult patients undergoing elective surgery. It was found that preoperative carbohydrate treatment did not increase or decrease postoperative complication rates when compared with placebo or fasting. Lack of adequate blinding in many studies may have contributed to observed treatment effects for these subjective outcomes, which are subject to possible biases.
The present updated review included 25 RCTs involving 3278 participants. The small number of trials in each comparison group and the heterogeneity of outcome measures precluded quantitative analysis of data for all but one outcome: pain intensity. In two pooled studies, the mean self-reported visual analogue scale (VAS; 0 to 100 mm) score for topical prilocaine-phenylephrine (PP) was higher than the mean self-reported VAS (0 to 100 mm) score for topical tetracaine-epinephrine-cocaine (TAC) by 5.59 points (95% confidence interval (CI) 2.16 to 13.35). Most trials that compared infiltrated and topical anaesthetics were at high risk of bias, which is likely to have affected their results. Researchers found that several cocaine-free topical anaesthetics provided effective analgesic efficacy. However, data regarding the efficacy of each topical agent are based mostly on single comparisons in trials with unclear or high risk of bias. Mild, self-limited erythematous skin induration occurred in one of 1042 participants who had undergone application of TAC. Investigators reported no serious complications among any of the participants treated with cocaine-based or cocaine-free topical anaesthetics. The overall quality of the evidence according to the GRADE system is low owing to limitations in design and implementation, imprecision of results and high probability of publication bias (selective reporting of data). Additional well-designed RCTs with low risk of bias are necessary before definitive conclusions can be reached. We have found two new studies published since the last version of this review was prepared. We have added these studies to those previously included and have conducted an updated analysis, which resulted in the same review conclusions as were presented previously. Mostly descriptive analysis indicates that topical anaesthetics may offer an efficacious, non-invasive means of providing analgesia before suturing of dermal lacerations. Use of cocaine-based topical anaesthetics might be hard to justify, given the availability of other effective topical anaesthetics without cocaine. However, the overall quality of the evidence according to the GRADE system is low owing to limitations in design and implementation, imprecision of results and high probability of publication bias (selective reporting of data). Additional well-designed RCTs with low risk of bias are necessary before definitive conclusions can be reached.
We included seven RCTs that involved a total of 542 women; of these, five recruited post-menopausal women (aged from 56 to 70 years) (422 women). We assessed all studies to be at high risk of bias. Meta-analyses comparing the overall effectiveness of treatments during acute phases of infection and rates of recurrence were conducted. Analysis of three studies involving 282 women that looked at CHM versus antibiotics suggested that CHM had a higher rate of effectiveness for acute UTI (RR 1.21, 95% CI 1.11 to 33) and reduced recurrent UTI rates (RR 0.28, 95% CI 0.09 to 0.82). Analysis of two studies involving 120 women that compared CHM plus antibiotics versus antibiotics alone found the combined intervention had a higher rate of effectiveness for acute UTI (RR 1.24, 95% CI 1.04 to 1.47) and resulted in lower rates of recurrent infection six months after the study (RR 0.53, 95% CI 0.35 to 0.80). One study comparing different CHM treatments found Er Xian Tang was more effective in treating acute infection in post-menopausal women than San Jin Pian (80 women: RR 1.28, 95% CI 1.03 to 1.57). Analysis showed that active CHM treatments specifically formulated for recurrent UTI were more effective in reducing infection incidence than generic CHM treatments that were more commonly used for acute UTI (RR 0.40, 95% CI 0.21 to 0.77). Only two studies undertook to report adverse events; neither reported the occurrence of any adverse events. Evidence from seven small studies suggested that CHM as an independent intervention or in conjunction with antibiotics may be beneficial for treating recurrent UTIs during the acute phase of infection and may reduce the recurrent UTI incidence for at least six months post-treatment. CHM treatments specifically formulated for recurrent UTI may be more effective than herbal treatments designed to treat acute UTI. However, the small number and poor quality of the included studies meant that it was not possible to formulate robust conclusions on the use of CHM for recurrent UTI in women either alone or as an adjunct to antibiotics.
There was a significant reduction in the weekly hot flush frequency for HT compared to placebo (WMD -17.92, 95% CI -22.86 to -12.99). This was equivalent to a 75% reduction in frequency (95% CI 64.3 to 82.3) for HT relative to placebo. Symptom severity was also significantly reduced compared to placebo (OR 0.13, 95% CI 0.07 to 0.23). Withdrawal for lack of efficacy occurred significantly more often on placebo therapy (OR 10.51, 95% CI 5.00 to 22.09). Withdrawal for adverse events, commonly breast tenderness, oedema, joint pain and psychological symptoms, was not significantly increased (OR 1.25, 95% CI 0.83 to 1.90), although the occurrence of any adverse events was significantly increased for HT (OR 1.41, 95% CI 1.00 to 1.99). In women who were randomised to placebo treatment, a 57.7% (95% CI 45.1 to 67.7) reduction in hot flushes was observed between baseline and end of study. Oral HT is highly effective in alleviating hot flushes and night sweats. Therapies purported to reduce such symptoms must be assessed in blinded trials against a placebo or a validated therapy because of the large placebo effect seen in well conducted randomised controlled trials, and also because during menopause symptoms may fluctuate and after menopause symptoms often decline. Withdrawals due to side-effects were only marginally increased in the HT groups despite the inability to tailor HT in these fixed dose trials. Comparisons of hormonal doses, product types or regimens require analysis of trials with these specific "within study" comparisons.
Five trials comprising of 233 participants met our inclusion criteria. Each study described the use of a different rTMS device that delivered different waveforms at different frequencies. All five trials were relatively small studies but generally they demonstrated a low risk of bias. When considering the impact of tinnitus on patients' quality of life, the results of only one study demonstrated a statistically significant improvement in Tinnitus Handicap Inventory (THI) scores at four months follow-up (defined as a 'partial improvement' by the study authors (THI reduction of 21% to 80%)) when low-frequency rTMS was compared with a sham control treatment. However, no statistically significant improvement was demonstrated by another two studies that considered rTMS at the same frequency. Furthermore, this single positive finding should be taken in the context of the many different variables which were recorded at many different points in time by the study authors. In accordance with our pre-specified subgroup analysis we extracted the data from one study to consider the differential effectiveness between 'lower' low-frequency rTMS (1 Hz) and 'higher' low-frequency rTMS (10 Hz, 25 Hz). In doing this we were able to demonstrate a statistically significant difference between rTMS employing a frequency of 1 Hz and the sham group when considering tinnitus severity and disability after four months follow-up ('partial' improvement). However, no statistically significant difference was demonstrated between 10 Hz and 25 Hz rTMS, and the sham control group, when considering the severity and disability of tinnitus at four months follow-up. When considering tinnitus loudness in patients undergoing rTMS we were able to demonstrate a statistically significant reduction in tinnitus loudness when the results of two studies were pooled (risk ratio 4.17, 95% confidence interval 1.30 to 13.40). However, this finding was based on two small trials and consequently the confidence interval was particularly wide. No serious adverse effects were reported in any of the trials. There is very limited support for the use of low-frequency rTMS for the treatment of patients with tinnitus. When considering the impact of tinnitus on patients' quality of life, support is from a single study with a low risk of bias based on a single outcome measure at a single point in time. When considering the impact on tinnitus loudness, this is based on the analysis of pooled data with a large confidence interval. Studies suggest that rTMS is a safe treatment for tinnitus in the short-term, however there were insufficient data to provide any support for the safety of this treatment in the long-term. More prospective, randomised, placebo-controlled, double-blind studies with large sample sizes are needed to confirm the effectiveness of rTMS for tinnitus patients. Uniform, validated, tinnitus-specific questionnaires and measurement scales should be used in future studies.
Four trials (979 participants) were eligible for inclusion in this review. One trial in patients with recently healed venous ulcers (n = 153) compared recurrence rates with and without compression and found that compression significantly reduced ulcer recurrence at six months (Risk ratio (RR) 0.46, 95% CI 0.27 to 0.76). Two trials compared high-compression hosiery (equivalent to UK class 3) with moderate-compression hosiery (equivalent to UK class 2). The first study (n=300) found no significant reduction in recurrence at five years follow up with high-compression hosiery compared with moderate-compression (RR 0.82, 95% CI 0.61 to 1.12). The second study (n = 338) assessed ulcer recurrence at three years follow up and found that high-compression hosiery reduced recurrence compared with moderate-compression (RR 0.57, 95% CI 0.39 to 0.81). Statistically significant heterogeneity precluded meta-analysis of the results from these studies. Patient-reported compliance rates were reported in both trials;,there was significantly higher compliance with medium-compression than with high-compression hosiery in one and no significant difference in the second. A fourth trial (166 patients) found no statistically significant difference in recurrence between two types of medium (UK class 2) compression hosiery (Medi versus Scholl: RR 0.74, 95% CI 0.45 to 1.2). No trials of compression bandages for preventing ulcer recurrence were identified. There is evidence from one trial that compression hosiery reduces rates of reulceration of venous ulcers compared with no compression. Results from one trial suggest that recurrence is lower in high-compression hosiery than in medium-compression hosiery at three years whilst another trial found no difference at 5 years. Rates of patient intolerance of compression hosiery were high. There is insufficient evidence to aid selection of different types, brands, or lengths of compression hosiery.
We identified no new studies for inclusion in this update. In total we included one trial, excluded 18 trials, classed one trial as ongoing, and classed another as awaiting classification. The total number of participants in the included trial was 10, and the methodological quality of this trial was moderate because of high risk of bias in relation to two domains (random sequence generation and allocation concealment) but low risk of bias for the four remaining domains (blinding, incomplete outcome data, selective reporting, and any other bias). The included trial was a short-term cross-over randomised trial undertaken in Canada, which tested the effects of adding three seemingly identical prosthetic weights (150 g vs 770 g vs 1625 g) to the prostheses of a total of 10 participants with unilateral dysvascular transfemoral amputation. Eight participants were over 60 years of age. Trial authors found that four participants preferred the addition of the lightest weight (150 g), five preferred the middle weight (770 g), and one preferred the heaviest weight (1625 g). Researchers interpreted this as equating to user satisfaction (success) and reported no adverse effects. The limited evidence presented in this review is of very low quality and is insufficient to inform the choice of prosthetic rehabilitation, including the optimum weight of the prosthesis, after unilateral transfemoral amputation in older dysvascular people. A programme of research that includes randomised controlled trials to examine key interventions is urgently required in this area.
The updated search did not reveal any further studies that met our inclusion criteria. The number of included studies therefore remains at 10 with the number of participants randomised still 283. One study comparing carbamazepine with placebo as the sole treatment for schizophrenia was abandoned early due to high relapse rate with 26 out of 31 participants relapsing by three months. No effect of carbamazepine was evident with no difference in relapse between the two groups (1 RCT n = 31, RR 1.07 CI 0.78 to 1.45). Another study compared carbamazepine with antipsychotics as the sole treatment for schizophrenia. No differences in terms of mental state were found when comparing 50% reduction in Brief Psychiatric Rating Scale (BPRS) scores (1 RCT n = 38, RR 1.23 CI 0.78 to 1.92). A favourable effect for carbamazepine was found when more people who received the antipsychotic (perphenazine) had parkinsonism (1 RCT n = 38, RR 0.03 CI 0.00 to 0.043). Eight studies compared adjunctive carbamazepine versus adjunctive placebo, we were able use GRADE for quality of evidence for these results. Adding carbamazepine to antipsychotic treatment was as acceptable as adding placebo with no difference between the numbers leaving the study early from each group (8 RCTs n = 182, RR 0.47 CI 0.16 to 1.35, very low quality evidence). Carbamazepine augmentation was superior compared with antipsychotics alone in terms of overall global improvement, but participant numbers were low (2 RCTs n = 38, RR 0.57 CI 0.37 to 0.88). There were no differences for the mental state outcome of 50% reduction in BPRS scores (6 RCTs n = 147, RR 0.86 CI 0.67 to 1.12, low quality evidence). Less people in the carbamazepine augmentation group had movement disorders than those taking haloperidol alone (1 RCT n = 20, RR 0.38 CI 0.14 to 1.02). No data were available for the effects of carbamazepine on subgroups of people with schizophrenia and aggressive behaviour, negative symptoms or EEG abnormalities or with schizoaffective disorder. Based on currently available randomised trial-derived evidence, carbamazepine cannot be recommended for routine clinical use for treatment or augmentation of antipsychotic treatment of schizophrenia. At present large, simple well-designed and reported trials are justified - especially if focusing on people with violent episodes and people with schizoaffective disorders or those with both schizophrenia and EEG abnormalities.
The 12 included studies involved 10,953 residents in 355 (range 1 to 85) care homes in ten countries. Nine studies were cluster-randomised controlled trials and three studies were patient-randomised controlled trials. The interventions evaluated were diverse and often multifaceted. Medication review was a component of ten studies. Four studies involved multidisciplinary case-conferencing, five studies involved an educational element for health and care professionals and one study evaluated the use of clinical decision support technology. We did not combine the results in a meta-analysis due to heterogeneity across studies. Interventions to optimise prescribing may lead to fewer days in hospital (one study out of eight; low certainty evidence), a slower decline in health-related quality of life (one study out of two; low certainty evidence), the identification and resolution of medication-related problems (seven studies; low certainty evidence), and may lead to improved medication appropriateness (five studies out of five studies; low certainty evidence). We are uncertain whether the intervention improves/reduces medicine costs (five studies; very low certainty evidence) and it may make little or no difference on adverse drug events (two studies; low certainty evidence) or mortality (six studies; low certainty evidence). The risk of bias across studies was heterogeneous. We could not draw robust conclusions from the evidence due to variability in design, interventions, outcomes and results. The interventions implemented in the studies in this review led to the identification and resolution of medication-related problems and improvements in medication appropriateness, however evidence of a consistent effect on resident-related outcomes was not found. There is a need for high-quality cluster-randomised controlled trials testing clinical decision support systems and multidisciplinary interventions that measure well-defined, important resident-related outcomes.
Eight randomised controlled trials, enrolling 10,037 children, met our inclusion criteria. Seven of the trials were conducted in Africa. In general, the included studies were at a low risk of bias. There may have been a risk of performance bias as trial participants were aware which intervention group they were in, but we did not consider this likely to have biased the outcome measurement. We were unable to assess the risk of reporting bias in half of the trials and two trials were at high risk of attrition bias. Any specially formulated food versus standard care - the provision of food increased the recovery rate by 29% (RR 1.29, 95% CI 1.20 to 1.38; 2152 children, two trials; moderate quality evidence), decreased the number dropping out by 70% (RR 0.30, 95% CI 0.22 to 0.39; 1974 children, one trial; moderate quality evidence), and improved weight-for-height (MD 0.20 z-score, 95% CI 0.03 to 0.37; 1546 children, two trials; moderate quality evidence). The reduction in mortality did not reach statistical significance (RR 0.44; 95% CI 0.14 to 1.36; 1974 children, one trial; low quality evidence). Lipid-based nutrient supplements versus any blended foods (dry food mixtures, without high lipid content), at full doses - there was no significant difference in mortality (RR 0.93, 95% CI 0.54 to 1.62; 6367 children, five trials; moderate quality evidence), progression to severe malnutrition (RR 0.88, 95% CI 0.72 to 1.07; 4537 children, three trials; high quality evidence), or the number of dropouts from the nutritional programme (RR 1.14, 95% CI 0.62 to 2.11; 5107 children, four trials; moderate quality evidence). However, lipid-based nutrient supplements significantly increased the number of children recovered (RR 1.10, 95% CI 1.04 to 1.16; 6367 children, five trials; moderate quality evidence), and decreased the number of non-recovering children (RR 0.53, 95% CI 0.40 to 0.69; 4537 children, three trials; high quality evidence). LNS also improved weight gain, weight-for-height, and mid-upper arm circumference, although for these outcomes, the improvement was modest (moderate quality evidence). One trial observed more children with vomiting in the lipid-based nutrient supplements group compared to those receiving blended food (RR 1.43, 95% CI 1.11 to 1.85; 2712 children, one trial; low quality evidence). Foods at complementary doses - no firm conclusion could be drawn on the comparisons between LNS at complementary dose and blended foods at complementary or full dose (low quality evidence). Lipid-based nutrient supplements versus specific types of blended foods - a recently developed enriched blended food (CSB++) resulted in similar outcomes to LNS (4758 children, three trials; moderate to high quality evidence). Different types of blended foods - in one trial, CSB++ did not show any significant benefit over locally made blended food, for example, Misola, in number who recovered, number who died, or weight gain (moderate to high quality evidence). Improved adequacy of home diet - no study evaluated the impact of improving adequacy of local diet, such as local foods prepared at home according to a given recipe or of home processing of local foods (soaking, germination, malting, fermentation) in order to increase their nutritional content. In conclusion, there is moderate to high quality evidence that both lipid-based nutrient supplements and blended foods are effective in treating children with MAM. Although lipid-based nutrient supplements (LNS) led to a clinically significant benefit in the number of children recovered in comparison with blended foods, LNS did not reduce mortality, the risk of default or progression to SAM. It also induced more vomiting. Blended foods such as CSB++ may be equally effective and cheaper than LNS. Most of the research so far has focused on industrialised foods, and on short-term outcomes of MAM. There are no studies evaluating interventions to improve the quality of the home diet, an approach that should be evaluated in settings where food is available, and nutritional education and habits are the main determinants of malnutrition. There are no studies from Asia, where moderate acute malnutrition is most prevalent.
This updated review includes a total of 25 studies, with outcome data for 11,246 mothers and babies enrolled in 21 studies. We assessed the overall risk of bias of included studies to be low or unclear, mainly because of limited reporting or uncertainty in how randomisation was generated or concealed (which led us to downgrade the quality of most outcomes to moderate), and the impracticability of blinding participants. When compared with routine care, programmes offering additional social support for at-risk pregnant women may slightly reduce the number of babies born with a birthweight less than 2500 g from 127 per 1000 to 120 per 1000 (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.86 to 1.04; 16 studies, n = 11,770; moderate-quality evidence), and the number of babies born with a gestational age less than 37 weeks at birth from 128 per 1000 to 117 per 1000 (RR 0.92, 95% CI 0.84 to 1.01, 14 studies, n = 12,282; moderate-quality evidence), though the confidence intervals for the pooled effect for both of these outcomes just crossed the line of no effect, suggesting any effect is not large. There may be little or no difference between interventions for stillbirth/neonatal death (RR 1.11, 95% CI 0.88 to 1.41; 15 studies, n = 12,091; low-quality evidence). Secondary outcomes of moderate quality suggested that there is probably a reduction in caesarean section (from 215 per 1000 to 194 per 1000; RR 0.90, 95% CI 0.83 to 0.97; 15 studies, n = 9550), a reduction in the number of antenatal hospital admissions per participant (RR 0.78, 95% CI 0.68 to 0.91; 4 studies; n = 787), and a reduction in the mean number of hospitalisation episodes (mean difference −0.05, 95% CI −0.06 to −0.04; 1 study, n = 1525) in the social support group, compared to the controls. Postnatal depression and women's satisfaction were reported in different ways in the studies that considered these outcomes and so we could not include data in a meta-analysis. In one study postnatal depression appeared to be slightly lower in the support group in women who screened positively on the Edinbugh Postnatal Depression Scale at eight to 12 weeks postnatally (RR 0.74, 95% CI 0.55 to 1.01; 1 study, n = 1008; moderate-quality evidence). In another study, again postnatal depression appeared to be slightly lower in the support group and this was a self-report measure assessed at six weeks postnatally (RR 0.85, 95% CI 0.69 to 1.05; 1 study, n = 458; low-quality evidence). A higher proportion of women in one study reported that their prenatal care was very helpful in the supported group (RR 1.17, 95% CI 1.05 to 1.30; 1 study, n = 223; moderate-quality evidence), although in another study results were similar. Another study assessed satisfaction with prenatal care as being "not good" in 51 of 945 in the additional support group, compared with 45 of 942 in the usual care group. No studies considered long-term morbidity for the infant. No single outcome was reported in all studies. Subgroup analysis demonstrated consistency of effect when the support was provided by a healthcare professional or a trained lay worker. The descriptions of the additional social support were generally consistent across all studies and included emotional support, tangible support such as home visits, and informational support. Pregnant women need the support of caring family members, friends, and health professionals. While programmes that offer additional social support during pregnancy are unlikely to have a large impact on the proportion of low birthweight babies or birth before 37 weeks' gestation and no impact on stillbirth or neonatal death, they may be helpful in reducing the likelihood of caesarean birth and antenatal hospital admission.
We included seven randomised controlled trials involving 493 participants. In all studies the participants were adults undergoing septoplasty. These studies were heterogeneous and the quality of the body of evidence ranged from low to very low. Few of the studies provided reliable data for the primary outcome in this review. Local anaesthetic injection versus no treatment/placebo Two studies (142 participants) compared local anaesthetic injection versus placebo but these studies did not report postoperative pain at 12, 24 or 48 hours. It is unclear whether local anaesthetic injection changed the risk of vomiting (odds ratio (OR) 3.10, 95% confidence interval (CI) 0.12 to 79.23; 60 participants; one study) (low-quality evidence). Neither study reported the requirement for additional analgesia, duration of hospitalisation or uncontrollable postoperative bleeding. Local anaesthetic application via nasal packing versus no packing/packing with placebo Four studies (301 participants) used nasal packing postoperatively and compared the addition of local anaesthetic to the pack versus packing with a placebo added. Compared with packing with placebo, the addition of local anaesthetic to nasal packing reduced the pain score on a VAS (ranging from 0 to 100) at 12 hours (mean difference (MD) -16.95, 95% CI -22.27 to -11.62; 151 participants; two studies; I2 = 49%) (low-quality evidence) and at 24 hours postoperatively (MD -7.53, 95% CI -9.76 to -5.29; 268 participants; four studies; I2 = 83%) (very low-quality evidence). These studies did not report postoperative pain at 48 hours. The addition of local anaesthetic to nasal packing decreased the requirement for additional analgesia (OR 0.15, 95% CI 0.07 to 0.34; 151 participants; two studies; I2 = 15%) (moderate-quality evidence). No studies reported duration of hospitalisation, postoperative vomiting or uncontrollable postoperative bleeding. No studies compared the addition of local anaesthetic to nasal packing versus no packing. Sphenopalatine ganglion block versus no treatment/placebo One study (50 participants) compared sphenopalatine ganglion block versus no treatment but this study did not report postoperative pain, requirement for additional analgesia, duration of hospitalisation, vomiting or uncontrollable postoperative bleeding. The addition of local anaesthesia to nasal packs (if these are being used) following septal surgery may reduce postoperative pain within the first 12 hours, compared to nasal packing with a placebo added. The effect is uncertain at 24 hours because the quality of the evidence is very low. Evidence was lacking for other outcomes, including adverse effects. There is a lack of evidence about the effects of local anaesthesia added to nasal packing compared to no nasal packing. There is also a lack of evidence about the effects of local anaesthesia given by injection and the effects of sphenopalatine ganglion block.
For this update, we screened 1645 publications of which 45 met the inclusion criteria (20 additional studies to the previous reviews). In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials and we discuss the reasons for this in the review. There were some sources of potential bias in the included studies, including a lack of description of the methods of blinding and allocation concealment, and the small size of the study populations. We included studies investigating pemoline and modafinil in participants with multiple sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue in meta-analysis. Treatment results pointed to weak and inconclusive evidence for the efficacy of amantadine, pemoline and modafinil in multiple sclerosis and for carnitine and donepezil in cancer-related fatigue. Methylphenidate and pemoline seem to be effective in patients with HIV, but this is based only on one study per intervention, with only a moderate number of participants in each study. Meta-analysis shows an estimated superior effect for methylphenidate in cancer-related fatigue (standardised mean difference (SMD) 0.49, 95% confidence interval (CI) 0.15 to 0.83). Therapeutic effects could not be described for dexamphetamine, paroxetine or testosterone. There were a variety of results for the secondary outcomes in some studies. Most studies had low participant numbers and were heterogeneous. In general, adverse reactions were mild and had little or no impact. Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials.
Three studies that included 410 participants met the inclusion criteria of the review. We did not identify any ongoing trials. Two included studies were at low risk of selection, attrition, and reporting biases, but were at high risk of performance and detection biases due to the inability to blind participants to the intervention. One included study was at high risk of attrition bias. The overall quality of the evidence for each comparison ranged from very low to moderate; the main limitations were risk of bias and imprecision. Initiation rate of contraceptive implants at the first postpartum check-up visit was significantly higher in the immediate insertion group than in the delayed insertion group (RR 1.41, 95% CI 1.28 to 1.55; three studies, 410 participants; moderate quality evidence). There appeared to be little or no difference between the groups in the continuation rate of contraceptive implant used at six months after insertion (RR 1.02, 95% CI 0.93 to 1.11; two studies, 125 participants; low quality evidence) or at 12 months after insertion (RR 1.04; 95% CI 0.81 to 1.34; one study, 64 participants;very low quality evidence) Women who received an immediate postpartum contraceptive implant insertion had a higher mean number of days of abnormal vaginal bleeding within six weeks postpartum (MD 5.80 days, 95% CI 3.79 to 7.81; one study, 215 participants; low quality evidence) and a higher rate of other side effects in the first six weeks after birth (RR 2.06, 95% CI 1.38 to 3.06; one study, 215 participants; low quality evidence) than those who received a delayed postpartum insertion. There appeared to be little or no difference between the groups in heavy, irregular vaginal bleeding or associated severe cramping within 12 months (RR 1.01, 95% CI 0.72 to 1.44, one study, 64 participants;very low quality evidence). It was unclear whether there was any difference between the groups in scores for participant satisfaction on a 0-10 scale (MD -0.40, 95% CI -1.26 to 0.46, low quality evidence), or in rates of unintended pregnancy (RR 1.82, 95% CI 0.38 to 8.71, 1 RCT, 64 women, very low quality evidence) at 12 months, or in rate of breastfeeding rate at six months (RR 2.01, 95% CI 0.72 ro 5.63, 1 RCT, 64 women, very low quality evidence) rate did not differ significantly between the groups. Evidence from this review indicates that the rate of initiation of contraceptive implant at the first postpartum check-up visit was higher with immediate postpartum insertion than with delayed insertion. There appeared to be little or no difference between the groups in the continuation rate of contraceptive implant use at 6 months. It was unclear whether there was any difference between the groups in continuation of contraceptive use at 12 months or in the unintended pregnancy rate at 12 months.
We included seven published trials: six comparing fetal pulse oximetry and CTG with CTG alone (or when fetal pulse oximetry values were blinded) and one comparing fetal pulse oximetry plus CTG with fetal ECG plus CTG. The published trials, with some unpublished data, were at high risk of bias in terms of the impractical nature of blinding participants and clinicians, as well as high risk or unclear risk of bias for outcome assessor for all but one report. Selection bias, attrition bias, reporting bias and other sources of bias were of low or unclear risk. The trials reported on a total of 8013 pregnancies. Differing entry criteria necessitated separate analyses, rather than meta-analysis of all trials. Systematic review of four trials from 34 weeks not requiring fetal blood sampling (FBS) prior to study entry showed no evidence of differences in the overall caesarean section rate between those monitored with fetal oximetry and those not monitored with fetal pulse oximetry or for whom the fetal pulse oximetry results were masked (average risk ratio (RR) 0.99 using random-effects, 95% confidence intervals (CI) 0.86 to 1.13, n = 4008, I² = 45%). There was evidence of a higher risk of caesarean section in the group with fetal oximetry plus CTG than in the group with fetal ECG plus CTG (one study, n = 180, RR 1.56, 95% CI 1.06 to 2.29). Neonatal seizures and neonatal encephalopathy were rare in both groups. No studies reported details of long-term disability. There was evidence of a decrease in caesarean section for nonreassuring fetal status in the fetal pulse oximetry plus CTG group compared to the CTG group, gestation from 34 weeks (average RR (random-effects) 0.65, 95% CI 0.46 to 0.90, n = 4008, I² = 63%). There was no evidence of differences between groups in caesarean section for dystocia, although the overall incidence rates varied between the trials. The addition of fetal pulse oximetry does not reduce overall caesarean section rates. One study found a higher caesarean section rate in the group monitored with fetal pulse oximetry plus CTG, compared with fetal ECG plus CTG. The data provide limited support for the use of fetal pulse oximetry when used in the presence of a nonreassuring CTG, to reduce caesarean section for nonreassuring fetal status. A better method than pulse oximetry is required to enhance the overall evaluation of fetal well-being in labour.
In this review update, we included five new trials, bringing the total number of included studies to eight. The included trials (pertaining to 10 papers), provided data on 1973 participants and assessed the impact of cancer genetic risk assessment on outcomes including perceived risk of inherited cancer, and psychological distress. This review suggests that cancer genetic risk-assessment services help to reduce distress, improve the accuracy of the perceived risk of breast cancer, and increase knowledge about breast cancer and genetics. The health professional delivering the risk assessment does not appear to have a significant impact on these outcomes. This review found favourable outcomes for patients after risk assessment for familial breast cancer. However, there were too few papers to make any significant conclusions about how best to deliver cancer genetic risk-assessment services. Further research is needed assessing the best means of delivering cancer risk assessment, by different health professionals, in different ways and in alternative locations.
Three randomised controlled trials with a total of 63 participants were found comparing SLT with placebo for speech disorders in Parkinson's disease. Data were available from 41 participants in two trials. Vocal loudness for reading a passage increased by 6.3 dB (P = 0.0007) in one trial, and 11.0 dB (P = 0.0002) in another trial. An increase was also seen in both of these trials for monologue speaking of 5.4 dB (P = 0.002) and 11.0 dB (P = 0.0002), respectively. It is likely that these areclinically significant improvements. After six months, patients from the first trial were still showing a statistically significant increase of 4.5 dB (P = 0.0007) for reading and 3.5 dB for monologue speaking. Some measures of speech monotonicity and articulation were investigated; however, all these results were non-significant. Although improvements in speech impairments were noted in these studies, due to the small number of patients examined, methodological flaws, and the possibility of publication bias, there is insufficient evidence to conclusively support or refute the efficacy of SLT for speech problems in Parkinson's disease. A large well designed placebo-controlled RCT is needed to demonstrate SLT's effectiveness in Parkinson's disease. The trial should conform to CONSORT guidelines. Outcome measures with particular relevance to patients with Parkinson’s disease should be chosen and patients followed for at least six months to determine the duration of any improvement.
Eighty-three studies, 36 of which were new to this update, met the inclusion criteria, representing 29,536 participants. Overall, we judged 16 studies to be at low risk of bias and 21 studies to be at high risk of bias. All other studies were judged to be at unclear risk of bias. Results were not sensitive to the exclusion of studies at high risk of bias. We pooled all studies comparing more versus less support in the main analysis. Findings demonstrated a benefit of behavioural support in addition to pharmacotherapy. When all studies of additional behavioural therapy were pooled, there was evidence of a statistically significant benefit from additional support (RR 1.15, 95% CI 1.08 to 1.22, I² = 8%, 65 studies, n = 23,331) for abstinence at longest follow-up, and this effect was not different when we compared subgroups by type of pharmacotherapy or intensity of contact. This effect was similar in the subgroup of eight studies in which the control group received no behavioural support (RR 1.20, 95% CI 1.02 to 1.43, I² = 20%, n = 4,018). Seventeen studies compared interventions matched for contact time but that differed in terms of the behavioural components or approaches employed. Of the 15 comparisons, all had small numbers of participants and events. Only one detected a statistically significant effect, favouring a health education approach (which the authors described as standard counselling containing information and advice) over motivational interviewing approach (RR 0.56, 95% CI 0.33 to 0.94, n = 378). There is high-certainty evidence that providing behavioural support in person or via telephone for people using pharmacotherapy to stop smoking increases quit rates. Increasing the amount of behavioural support is likely to increase the chance of success by about 10% to 20%, based on a pooled estimate from 65 trials. Subgroup analysis suggests that the incremental benefit from more support is similar over a range of levels of baseline support. More research is needed to assess the effectiveness of specific components that comprise behavioural support.
Five studies (n = 333 patients) were included in the review. Three studies were judged to be at low risk of bias. Two studies were judged to be at high risk of bias due to blinding. Intramuscular methotrexate was superior to placebo for maintenance of remission at 40 weeks follow-up. Sixty-five per cent of patients in the intramuscular methotrexate group maintained remission compared to 39% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 76 patients).The number needed to treat to prevent one relapse was four. A GRADE analysis indicated that the overall quality of evidence supporting this outcome was moderate due to sparse data (40 events). There was no statistically significant difference in maintenance of remission at 36 weeks follow-up between oral methotrexate (12.5 mg/week) and placebo. Ninety per cent of patients in the oral methotrexate group maintained remission compared to 67% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 22 patients). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to very sparse data (17 events). A pooled analysis of two small studies (n = 50) showed no statistically significant difference in continued remission between oral methotrexate (12.5 mg to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day) for maintenance of remission. Seventy-seven per cent of methotrexate patients maintained remission compared to 57% of 6-mercaptopurine patients (RR 1.36, 95% CI 0.92 to 2.00). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was very low due to high risk of bias in one study (no blinding) and very sparse data (33 events). One small (13 patients) poor quality study found no difference in continued remission between methotrexate and 5-aminosalicylic acid (RR 2.62, 95% CI 0.23 to 29.79). A pooled analysis of two studies (n = 145) including one high quality trial (n = 126) found no statistically significant difference in maintenance of remission at 36 to 48 weeks between combination therapy (methotrexate and infliximab) and infliximab monotherapy. Fifty-four percent of patients in the combination therapy group maintained remission compared to 53% of monotherapy patients (RR 1.02, 95% CI 0.76 to 1.38, P = 0.95). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to high risk of bias in one study (no blinding) and sparse data (78 events). Adverse events were generally mild in nature and resolved upon discontinuation or with folic acid supplementation. Common adverse events included nausea and vomiting, symptoms of a cold, abdominal pain, headache, joint pain or arthralgia, and fatigue. Moderate quality evidence indicates that intramuscular methotrexate at a dose of 15 mg/week is superior to placebo for maintenance of remission in Crohn's disease. Intramuscular methotrexate appears to be safe. Low dose oral methotrexate (12.5 to 15 mg/week) does not appear to be effective for maintenance of remission in Crohn's disease. Combination therapy (methotrexate and infliximab) does not appear to be any more effective for maintenance of remission than infliximab monotherapy. The results for efficacy outcomes between methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn’s disease may provide stronger evidence for the use of methotrexate in this manner.
We identified four studies (13 reports), with 2818 participants, and one ongoing study. Overall certainty of evidence ranged from high to very low. There is probably little or no difference between TAVI and SAVR for the following short-term outcomes: all-cause mortality (RR 0.69, 95% CI 0.33 to 1.44; SAVR 11 deaths per 1000, TAVI 8 deaths per 1000 (95% CI 4 to 16); 2818 participants; 4 studies; moderate-certainty evidence); stroke (RR 0.73, 95% CI 0.42 to 1.25; SAVR 21 strokes per 1000, TAVI 16 strokes per 1000 (95% CI 9 to 27); 2818 participants; 4 studies; moderate-certainty evidence); MI (RR 0.82, 95% CI 0.42 to 1.58; SAVR 14 MI per 1000, TAVI 11 MI per 1000 (95% CI 6 to 21); 2748 participants; 3 studies; moderate-certainty evidence); and cardiac death (RR 0.71, 95% CI 0.32 to 1.56; SAVR 10 cardiac deaths per 1000, TAVI 7 cardiac deaths per 1000 (95% CI 3 to 16); 2818 participants; 4 studies; moderate-certainty evidence). TAVI may reduce the risk of short-term rehospitalisation, although the confidence interval also includes the possibility of no difference in risk between groups (RR 0.64, 95% CI 0.39 to 1.06; SAVR 30 cases per 1000, TAVI 19 cases per 1000 (95% CI 12 to 32); 2468 participants; 2 studies; low-certainty evidence). TAVI, compared with SAVR, probably increases the risk of PPM implantation (RR 3.65, 95% CI 1.50 to 8.87; SAVR 47 per 1000, TAVI 170 cases per 1000 (95% CI 70 to 413); number needed to treat for an additional harmful outcome (NNTH) = 7; 2683 participants; 3 studies; moderate-certainty evidence). We are uncertain whether TAVI, compared with SAVR, affects the LOS in days, although it appears to be associated with shorter LOS. TAVI, compared with SAVR, reduces the risk of atrial fibrillation (RR 0.21, 95% CI 0.15 to 0.30; 2683 participants; 3 studies), AKI (RR 0.30, 95% CI 0.16 to 0.58; 2753 participants; 4 studies), and bleeding (RR 0.31, 95% CI 0.16 to 0.62; 2753 participants; 4 studies) (all high-certainty evidence). Our meta-analysis indicates that, in the short term, TAVI probably has little or no mortality difference compared to SAVR for severe AS in individuals with low surgical risk. Similarly, there is probably little or no difference in risk of stroke, MI, and cardiac death between the two approaches. TAVI may reduce the risk of rehospitalisation, but we are uncertain about the effects on LOS. TAVI reduces the risk of atrial fibrillation, AKI, and bleeding. However, this benefit is offset by the increased risk of PPM implantation. Long-term follow-up data are needed to further assess and validate these outcomes, especially durability, in the low surgical risk population.
We found 13 trials (1960 patients). Lipid-based amphotericin B was not more effective than conventional amphotericin B on mortality (relative risk (RR) 0.5; 95% confidence interval (CI) 0.64 to 1.14) but decreased invasive fungal infection (RR 0.65; 95% CI 0.44 to 0.97), nephrotoxicity defined as a 100% increase in serum creatinine (RR 0.45; 95% CI 0.37 to 0.54), and number of dropouts (RR 0.78; 95% CI 0.62 to 0.97). For the drug used in most patients, AmBisome (4 trials, 1214 patients), there was no significant difference in mortality (RR 0.77; 95% CI 0.54 to 1.10) whereas it tended to be more effective than conventional amphotericin B on invasive fungal infection (RR 0.63; 95% CI 0.39 to 1.01, P value 0.053). AmBisome, amphotericin B in Intralipid (6 trials, 379 patients), amphotericin B colloidal dispersion (ABCD) (2 trials, 262 patients), and amphotericin B lipid complex (ABLC) (1 trial, 105 patients) all decreased the occurrence of nephrotoxicity, but conventional amphotericin B was rarely administered under optimal circumstances. It is not clear whether there are any advantages of lipid-based formulations if conventional amphotericin B is administered under optimal circumstances, and their high cost prohibits routine use in most settings. There is a need for large trials comparing lipid-based formulations of amphotericin B with conventional amphotericin B given in the same dose, with routine premedication for prevention of infusion-related toxicity, and with supplementation with fluid, potassium, and magnesium for prevention of nephrotoxicity.
Fifteen studies were included in the review. Studies included children with a range of severe neurological impairments in differing settings, for example, home and critical care. Several different treatment modalities were assessed, and a wide range of outcome measures were used. Most studies used a non-randomised design and included small sample groups. Only four randomised controlled trials were identified. Non-randomised design, lack of information about how participants were selected and who completed outcome measures and incomplete reporting led to high or unclear risk of bias in many studies. Results from low-quality studies suggest that use of non-invasive ventilation, mechanically assisted coughing, high-frequency chest wall oscillation (HFCWO), positive expiratory pressure and supportive seating may confer potential benefits. No serious adverse effects were reported for ventilatory support or airway clearance interventions other than one incident in a clinically unstable child following mechanically assisted coughing. Night-time positioning equipment and spinal bracing were shown to have a potentially negative effect for some participants. However, these findings must be considered as tentative and require testing in future randomised trials. This review found no high-quality evidence for any single intervention for the management of respiratory morbidity in children with severe global developmental delay. Our search yielded data on a wide range of interventions of interest. Significant differences in study design and in outcome measures precluded the possibility of meta-analysis. No conclusions on efficacy or safety of interventions for respiratory morbidity in children with severe global developmental delay can be made based upon the findings of this review. A co-ordinated approach to future research is vital to ensure that high-quality evidence becomes available to guide treatment for this vulnerable patient group.
We included in this update 28 studies (4287 women) with sample sizes ranging from 20 to 372. Most studies had low risk of bias for randomisation, attrition, and selective reporting. Less than half of these studies had adequate allocation concealment, and most were unblinded. Using GRADE, we determined that the quality of evidence ranged from moderate to very low. We downgraded evidence for risk of bias, imprecision, and inconsistency. Overall comparison of second-generation versus first-generation (i.e. gold standard hysteroscopic ablative) techniques revealed no evidence of differences in amenorrhoea at 1 year and 2 to 5 years' follow-up (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.78 to 1.27; 12 studies; 2145 women; I² = 77%; and RR 1.16, 95% CI 0.78 to 1.72; 672 women; 4 studies; I² = 80%; very low-quality evidence) and showed subjective improvement at 1 year follow-up based on a Pictorial Blood Assessment Chart (PBAC) (< 75 or acceptable improvement) (RR 1.03, 95% CI 0.98 to 1.09; 5 studies; 1282 women; I² = 0%; and RR 1.12, 95% CI 0.97 to 1.28; 236 women; 1 study; low-quality evidence). Study results showed no difference in patient satisfaction between second- and first-generation techniques at 1 year follow-up (RR 1.01, 95% CI 0.98 to 1.04; 11 studies; 1750 women; I² = 36%; low-quality evidence) nor at 2 to 5 years' follow-up (RR 1.02, 95% CI 0.93 to 1.13; 672 women; 4 studies; I² = 81%). Compared with first-generation techniques, second-generation endometrial ablation techniques were associated with shorter operating times (mean difference (MD) -13.52 minutes, 95% CI -16.90 to -10.13; 9 studies; 1822 women; low-quality evidence) and more often were performed under local rather than general anaesthesia (RR 2.8, 95% CI 1.8 to 4.4; 6 studies; 1434 women; low-quality evidence). We are uncertain whether perforation rates differed between second- and first-generation techniques (RR 0.32, 95% CI 0.10 to 1.01; 1885 women; 8 studies; I² = 0%). Trials reported little or no difference between second- and first-generation techniques in requirement for additional surgery (ablation or hysterectomy) at 1 year follow-up (RR 0.72, 95% CI 0.41 to 1.26; 6 studies: 935 women; low-quality evidence). At 5 years, results showed probably little or no difference between groups in the requirement for hysterectomy (RR 0.85, 95% CI 0.59 to 1.22; 4 studies; 758 women; moderate-quality evidence). Approaches to endometrial ablation have evolved from first-generation techniques to newer second- and third-generation approaches. Current evidence suggests that compared to first-generation techniques (endometrial laser ablation, transcervical resection of the endometrium, rollerball endometrial ablation), second-generation approaches (thermal balloon endometrial ablation, microwave endometrial ablation, hydrothermal ablation, bipolar radiofrequency endometrial ablation, endometrial cryotherapy) are of equivalent efficacy for heavy menstrual bleeding, with comparable rates of amenorrhoea and improvement on the PBAC. Second-generation techniques are associated with shorter operating times and are performed more often under local rather than general anaesthesia. It is uncertain whether perforation rates differed between second- and first-generation techniques. Evidence was insufficient to show which second-generation approaches were superior to others and to reveal the efficacy and safety of third-generation approaches versus first- and second-generation techniques.
We included 18 trials (633 participants) in this update of this review. Treadmill training improved gait speed (MD = 0.09 m/s; 95% confidence interval (CI) 0.03 to 0.14; P = 0.001; I2 = 24%; moderate quality of evidence), stride length (MD = 0.05 metres; 95% CI 0.01 to 0.09; P = 0.01; I2 = 0%; low quality of evidence), but walking distance (MD = 48.9 metres; 95% CI -1.32 to 99.14; P = 0.06; I2 = 91%; very low quality of evidence) and cadence did not improve (MD = 2.16 steps/minute; 95% CI -0.13 to 4.46; P = 0.07; I2 = 28%; low quality of evidence) at the end of study. Treadmill training did not increase the risk of patients dropping out from intervention (RD = -0.02; 95% CI -0.06 to 0.02; P = 0.32; I2 = 13%; moderate quality of evidence). Adverse events were not reported in included studies. This update of our systematic review provides evidence from eighteen trials with moderate to low risk of bias that the use of treadmill training in patients with PD may improve clinically relevant gait parameters such as gait speed and stride length (moderate and low quality of evidence, respectively). This apparent benefit for patients is, however, not supported by all secondary variables (e.g. cadence and walking distance). Comparing physiotherapy and treadmill training against other alternatives in the treatment of gait hypokinesia such as physiotherapy without treadmill training this type of therapy seems to be more beneficial in practice without increased risk. The gain seems small to moderate clinically relevant. However, the results must be interpreted with caution because it is not known how long these improvements may last and some studies used no intervention in the control group and underlie some risk of bias. Additionally the results were heterogenous and we found variations between the trials in patient characteristics, the duration and amount of training, and types of treadmill training applied.
We scanned more than 6800 citations and included six studies with a total of 333 participants in the analysis. There were insufficient data to assess the effect on survival. The use of CSF significantly reduced the number of episodes of febrile neutropenia episodes (Rate Ratio = 0.63; 95% confidence interval (CI) 0.46 to 0.85; P = 0.003, with substantial heterogeneity), the length of hospitalisation (weighted mean difference (WMD) = -1.58; 95% CI -3.00 to -0.15; P = 0.03), and number of infectious disease episodes (Rate Ratio = 0.56; 95% CI 0.39 to 0.80; P = 0.002). Despite these results, CSF did not influence the length of episodes of neutropenia (WMD = -1.11; 95% CI -3.55 to 1.32; P = 0.4) or delays in chemotherapy courses (Rate Ratio = 0.75; 95% CI 0.47 to 1.20; P = 0.23) . Children with ALL treated with CSF benefit from shorter hospitalisation and fewer infections. However, there was no evidence of shortened duration of neutropenia nor fewer treatment delays. There was also no useful information about survival.   The role of CSF in the context of febrile neutropenia episodes is still uncertain. Although current data show statistical benefit with CSF use, substantial heterogeneity between included trials does not allow this conclusion.
Twenty-six studies, randomising 2959 women, were included in this review. Inhaled analgesia versus a different type of inhaled analgesia  Pain relief was measured using a Visual Analogue Scale (VAS) from 0 to 100 mm where 100 corresponds to the most relief. Pain intensity was measured using a VAS from 0 to 100 mm, where 0 corresponds to no pain at all and 100 corresponds to the worst pain. The highest score for pain relief is the most positive in contrast to 'pain intensity' in which the higher score is more negative.   Flurane derivatives were found to offer better pain relief than nitrous oxide in first stage of labour as measured by a lower pain intensity score (average mean difference (MD) 14.39, 95% confidence interval (CI) 4.41 to 24.37, three studies, 70 women), also a higher pain relief score for flurane derivatives compared with nitrous oxide (average MD -16.32, 95% CI -26.85 to -5.79, two studies, 70 women). Substantial heterogeneity was found in the analyses of pain intensity (P = 0.003) and in the analysis of pain relief (P = 0.002).These findings should be considered with caution because of the questionable design of the included cross-over trials. More nausea was found in the nitrous oxide group compared with the flurane derivatives group (risk ratio (RR) 6.60 95% CI 1.85 to 23.52, two studies, 98 women). Inhaled analgesia versus placebo or no treatment  Placebo or no treatment was found to offer less pain relief compared to nitrous oxide (average RR 0.06, 95% CI 0.01 to 0.34, two studies, 310 women; MD -3.50, 95% CI -3.75 to -3.25, one study, 509 women). However, nitrous oxide resulted in more side effects for women such as nausea (RR 43.10, 95% CI 2.63 to 706.74, one study, 509 women), vomiting (RR 9.05, 95% CI 1.18 to 69.32, two studies, 619 women), dizziness (RR 113.98, 95% CI 7.09 to 1833.69, one study, 509 women) and drowsiness (RR 77.59, 95% CI 4.80 to 1254.96, one study, 509 women) when compared with placebo or no treatment. There were no significant differences found for any of the outcomes in the studies comparing one strength versus a different strength of inhaled analgesia, in studies comparing different delivery systems or in the study comparing inhaled analgesia with TENS. Due to lack of data, the following outcomes were not analysed within the review: sense of control; satisfaction with childbirth experience; effect on mother/baby interaction; breastfeeding; admission to special care baby unit; poor infant outcomes at long-term follow-up; or costs. Inhaled analgesia appears to be effective in reducing pain intensity and in giving pain relief in labour. However, substantial heterogeneity was detected for pain intensity. Furthermore, nitrous oxide appears to result in more side effects compared with flurane derivatives. Flurane derivatives result in more drowsiness when compared with nitrous oxide. When inhaled analgesia is compared with no treatment or placebo, nitrous oxide appears to result in even more side effects such as nausea, vomiting, dizziness and drowsiness. There is no evidence for differences for any of the outcomes comparing one strength verus a different strength of inhaled analgesia, comparing different delivery systems or comparing inhaled analgesia with TENS.
Eighteen studies (7446 participants) compared cinacalcet in addition to standard therapy with no treatment or placebo plus standard therapy. In adults with GFR category G5 (GFR below 15 mL/min/1.73 m²) treated with dialysis, routine cinacalcet treatment had little or no effect on all-cause mortality (RR 0.97, 95% CI 0.89 to 1.05), imprecise effects on cardiovascular mortality (RR 0.67, 95% CI 0.16 to 2.87), and prevented surgical parathyroidectomy (RR 0.49, 95% CI 0.40 to 0.59) and hypercalcaemia (RR 0.23, 95% CI 0.05 to 0.97), but increased hypocalcaemia (RR 6.98, 95% CI 5.10 to 9.53), nausea (RR 2.02, 95% CI 1.45 to 2.81) and vomiting (RR 1.97, 95% CI 95% CI 1.73 to 2.24). Cinacalcet decreased serum PTH (MD -281.39 pg/mL, 95% CI -325.84 to -234.94) and calcium (MD -0.87 mg/dL, 95% CI -0.96 to -0.77) levels, but had little or no effect on serum phosphorous levels (MD -0.23 mg/dL, 95% CI -0.58 to 0.12). Data were sparse for adults with GFR categories G3a to G4 (GFR 15 to 60 mL/min/1.73 m²) and kidney transplant recipients. Overall, based on GRADE criteria, evidence for cinacalcet in adults with GFR category G5 treated with dialysis (mortality, parathyroidectomy, hypocalcaemia, and nausea) is of high or moderate quality. High quality evidence suggests "further research is very unlikely to change our confidence in the estimate of treatment effect" and moderate quality evidence is "further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate". Information for adults with less severe CKD GFR category G3a to G4 is of low or very low quality. This means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Routine cinacalcet therapy reduced the need for parathyroidectomy in adults treated with dialysis and elevated PTH levels but does not improve all-cause or cardiovascular mortality. Cinacalcet increases risks of nausea, vomiting and hypocalcaemia, suggesting harms may outweigh benefits in this population.
We included four studies with a total of 272 participants (6 to 18 years of age) who had either chronic neuropathic pain, complex regional pain syndrome type 1, irritable bowel syndrome, functional abdominal pain, or functional dyspepsia. All of the studies were small. One study investigated amitriptyline versus gabapentin (34 participants), two studies investigated amitriptyline versus placebo (123 participants), and one study investigated citalopram versus placebo (115 participants). Due to a lack of available data we were unable to complete any quantitative analysis. Risk of bias for the four included studies varied, due to issues with randomisation and allocation concealment (low to unclear risk); blinding of participants, personnel, and outcome assessors (low to unclear risk); reporting of results (low to unclear risk); and size of the study populations (high risk). We judged the remaining domains, attrition and other potential sources of bias, as low risk of bias. Primary outcomes No studies reported our primary outcomes of participant-reported pain relief of 30% or greater or 50% or greater, or Patient Global Impression of Change. Secondary outcomes All studies measured adverse events, with very few reported (11 out of 272 participants). All but one adverse event occurred in the active treatment groups (amitriptyline, citalopram, and gabapentin). Adverse events in all studies, across active treatment and comparator groups, were considered to be a mild reaction, such as nausea, dizziness, drowsiness, tiredness, and abdominal discomfort (very low-quality evidence). There were also very few withdrawals due to adverse events, again all but one from the active treatment groups (very low-quality evidence). No serious adverse events were reported across any of the studies (very low-quality evidence). There were few or no data for our remaining secondary outcomes. Quality of evidence For the outcomes with available data, we downgraded the quality of the evidence by three levels to very low-quality due to too few data and the fact that the number of events was too small to be meaningful. We identified only a small number of studies with small numbers of participants and insufficient data for analysis. As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of antidepressants to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life. We know from adult randomised controlled trials that some antidepressants, such as amitriptyline, can provide some pain relief in certain chronic non-cancer pain conditions.
Sixty-one studies (37,250 participants) compared oral sumatriptan with placebo or an active comparator. Most of the data were for the 50 mg and 100 mg doses. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 50 mg versus placebo the NNTs were 6.1, 7.5, and 4.0 for pain-free at two hours and headache relief at one and two hours, respectively. NNTs for sustained pain-free and sustained headache relief during the 24 hours postdose were 9.5 and 6.0, respectively. For sumatriptan 100 mg versus placebo the NNTs were 4.7, 6.8, 3.5, 6.5, and 5.2, respectively, for the same outcomes. Results for the 25 mg dose were similar to the 50 mg dose, while sumatriptan 100 mg was significantly better than 50 mg for pain-free and headache relief at two hours, and for sustained pain-free during 24 hours. Treating early, during the mild pain phase, gave significantly better NNTs for pain-free at two hours and sustained pain-free during 24 hours than did treating established attacks with moderate or severe pain intensity. Relief of associated symptoms, including nausea, photophobia, and phonophobia, was greater with sumatriptan than with placebo, and use of rescue medication was lower with sumatriptan than with placebo. For the most part, adverse events were transient and mild and were more common with the sumatriptan than with placebo, with a clear dose response relationship (25 mg to 100 mg). Sumatriptan was compared directly with a number of active treatments, including other triptans, paracetamol (acetaminophen), acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), and ergotamine combinations. Oral sumatriptan is effective as an abortive treatment for migraine attacks, relieving pain, nausea, photophobia, phonophobia, and functional disability, but is associated with increased adverse events.
We identified two eligible studies: one of CPAP and one of CNEP (published as an abstract). Both were unblinded studies with mainly unclear risk of bias due to lack of adequate information to assess this. The CPAP study enrolled 37 children to oxygen mask and CPAP and reported improvement in respiratory rate and oxygen saturation in both arms after 30 minutes of application. The CNEP study was published as an abstract and included 33 infants with bronchiolitis. In the CNEP study there was a reduction in the fraction of inspired oxygen (FiO2) (less than 30% within one hour of initiation of therapy) in four participants in the CNEP group compared to none in the control group (RR 10.7, 95% CI 0.6 to 183.9). One infant required CPAP and mechanical ventilation in the control group while all infants in the CNEP group were managed without intubation (RR for both outcomes 0.40, 95% CI 0.02 to 9.06). None of the trials reported on mortality. No adverse events were reported in ether of the included trials. There is a lack of well-designed, controlled trials of non-invasive modes of respiratory support in children with AHRF. Studies assessing the outcomes mortality, avoidance of intubation and its associated complications, hospital stay and patient comfort are needed.
Thirteen relevant trials with 1770 participants were included. All of them were of low quality. Fifty-two studies still need to be assessed because the original authors could not be interviewed. None of these trials analysed mortality, health related quality of life, economic outcomes or compliance. Compared to antithyroid drugs alone the results showed that Chinese herbal medicines combined with antithyroid drugs may offer benefits in lowering relapse rates, reducing the incidence of adverse effects, relieving symptoms, improving thyroid antibody status and thyroid function. Two trials investigated Chinese herbal medicine versus radioiodine and reported improvements in anxiety, tachycardia and heat intolerance. However, thyroid function - with the exception of restored thyroid stimulating hormone (TSH) - was not significantly altered. The results suggest that traditional Chinese herbal medicines added to other routine treatment have a therapeutic potential for people with hyperthyroidism. However, due to methodological limitations, we could not identify a well-designed trial to provide strong evidence for Chinese traditional herbal medicine in the treatment of hyperthyroidism. Thus, we currently cannot recommend any single preparation or formulation for clinical use.
Thirty-eight studies, involving some 12,400 participants, were included. The majority were descriptive studies, or randomisation processes did not relate to the data extracted, and most studies were judged to be at high risk of bias. Studies consistently show that oral substitution treatment for opioid-dependent injecting drug users with methadone or buprenorphine is associated with statistically significant reductions in illicit opioid use, injecting use and sharing of injecting equipment. It is also associated with reductions in the proportion of injecting drug users reporting multiple sex partners or exchanges of sex for drugs or money, but has little effect on condom use. It appears that the reductions in risk behaviours related to drug use do translate into reductions in cases of HIV infection. However, because of the high risk of bias and variability in several aspects of the studies, combined totals were not calculated. Oral substitution treatment for injecting opioid users reduces drug-related behaviours with a high risk of HIV transmission, but has less effect on sex-related risk behaviours. The lack of data from randomised controlled studies limits the strength of the evidence presented in this review.
Of 1041 publications obtained from the search strategy, we examined nine studies. Four studies were excluded, and five studies with 211 participants were eligible for inclusion. There was no difference in the immediate success rate of IAL when compared with IVAS in the closed manual reduction of acute anterior shoulder dislocation (RR 0.95; 95% CI 0.83 to 1.10). There were significantly fewer adverse effects associated with IAL compared with IVAS (RR 0.16; 95% CI 0.06 to 0.43). The mean time spent in the emergency department was significantly less with IAL compared with IVAS (MD 109.46 minutes; 95% CI 84.60 to 134.32). One trial reported significantly less time for reduction with IVAS (105 seconds; 95% CI 84.0 to 126.1) compared with IAL (284.6 seconds; 95% CI 185.3 to 383.9). One trial reported no joint infection associated with intra-articular lignocaine injection and no mortality associated with either IAL or IVAS. We observed no significant difference between IAL and IVAS with regard to the immediate success rate of reduction, pain during reduction, post-reduction pain relief and reduction failure. Compared to IVAS, IAL may be less expensive and may be associated with fewer adverse effects and a shorter recovery time.
Seven trials, totaling 542 participants, met the eligibility criteria. Studies varied widely on risk of bias, interventions used and outcome measures reported. From these studies, there was no evidence to suggest that psychosocial intervention promotes global quality of life for patients with head and neck cancer at end of intervention (MD 1.23, 95% CI -5.82 to 8.27) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). This quality of life tool includes five functional scales, namely cognitive, physical, emotional, social and role. There was no evidence to demonstrate that psychosocial intervention provides an immediate or medium-term improvement on any of these five functional scales. From the data available, there was no significant change in levels of anxiety (SMD -0.09, 95% CI -0.40 to 0.23) or depression following intervention (SMD -0.03, 95% CI -0.24 to 0.19). At present, there is insufficient evidence to refute or support the effectiveness of psychosocial intervention for patients with head and neck cancer. The evidence for psychosocial intervention is limited by the small number of studies, methodological shortcomings such as lack of power, difficulties with comparability between types of interventions and a wide divergence in outcome measures used. Future research should be targeted at patients who screen positive for distress and use validated outcome measures, such as the EORTC scale, as a measure of quality of life. These studies should implement interventions that are theoretically derived. Other shortcomings should be addressed in future studies, including using power calculations that may encourage multi-centred collaboration to ensure adequate sample sizes are recruited.
No studies were included in this review. Although it is generally recognised that CFA may be episodic and resolve spontaneously, treatment with analgesics and anti-inflammatory agents may be needed. While this approach may be sufficient to manage symptoms, it is disappointing that no randomised controlled trials to rigorously evaluate these agents were found, nor could the authors identify any quasi-randomised. This systematic review has identified the need for a well-designed adequately-powered randomised controlled trial to assess the efficacy and safety of pharmacological agents for the symptomatic management of cystic fibrosis-related arthritis (CFA and HPO) in adults and children with cystic fibrosis. Studies should also better define the two conditions. A study has recently been conducted in CFA and may help fill this gap when analysed and published. There are no trials included in the review up to January 2016. We will continue to run searches to identify any potentially relevant studies; however, we do not plan to update other sections of the review until new studies are published.
We included three RCTs (four reports) of 246 children aged under 16 years undergoing tonsillectomy. Children were given weight-appropriate doses of the study medication, either PRN or ATC, by a parent or carer at home for up to four days following surgery. We did not identify any studies assessing the management of postoperative pain in children in any other setting (i.e. as an inpatient). All studies included in this review were based on the use of paracetamol, and an opioid was added to paracetamol in two studies. Analgesics were administered either orally (tablet or elixir) or rectally (suppository). Reporting quality was poor and there were fewer than 50 children in each arm. Mean pain intensity scores decreased over time, as did medication use. However, children were still reporting pain at the final assessment, suggesting that no administration schedule provided adequate analgesia. There were no significant differences in pain intensity scores at any time point. The studies reported adverse events that may have been related to the study medication, such as nausea and vomiting, and constipation, but no statistically significant differences were noted between the groups. There were too few data from only three small studies and meta-analysis was not possible. One study reported that a higher amount of analgesics was consumed in the ATC group compared with the PRN group: it would have been helpful to show that the higher volume in the ATC group led to better analgesia but we were not able to demonstrate this. There was limited evidence available to draw any conclusions about the efficacy of PRN versus ATC analgesic administration for the management of postoperative pain in children.
Eleven RCTs, all at high risk of bias, and four economic evaluations were included. Apart from one study, the times to fracture healing were comparable between the BMP and control groups. There was some evidence for increased healing rates, without requiring a secondary procedure, of BMP compared with usual care control in acute, mainly open, tibial fractures (risk ratio (RR) 1.19, 95% CI 0.99 to 1.43). The pooled RR for achieving union for nonunited fractures was 1.02 (95% CI 0.90 to 1.15). One study found no difference in union for patients who had corrective osteotomy for radial malunions. Data from three RCTs indicated that fewer secondary procedures were required for acute fracture patients treated with BMP versus controls (RR 0.65, 95% CI 0.50 to 0.83). Adverse events experienced were infection, hardware failure, pain, donor site morbidity, heterotopic bone formation and immunogenic reactions. The evidence on costs for BMP-2 for acute open tibia fractures is from one large RCT. This indicates that the direct medical costs associated with BMP would generally be higher than treatment with standard care, but this cost difference may decrease as fracture severity increases. Limited evidence suggests that the direct medical costs associated with BMP could be offset by faster healing and reduced time off work for patients with the most severe open tibia fractures. This review highlights a paucity of data on the use of BMP in fracture healing as well as considerable industry involvement in currently available evidence. There is limited evidence to suggest that BMP may be more effective than controls for acute tibial fracture healing, however, the use of BMP for treating nonunion remains unclear. The limited available economic evidence indicates that BMP treatment for acute open tibial fractures may be more favourable economically when used in patients with the most severe fractures.
We included two RCTs (116 adult participants). One compared large-volume (150 ml) hypertonic (2%) saline irrigation with usual treatment over a six-month period; the other compared 5 ml nebulised saline twice a day with intranasal corticosteroids, treating participants for three months and evaluating them on completion of treatment and three months later. Large-volume, hypertonic nasal saline versus usual care One trial included 76 adult participants (52 intervention, 24 control) with or without polyps.Disease-specific HRQL  was reported using the Rhinosinusitis Disability Index (RSDI; 0 to 100, 100 = best quality of life). At the end of three months of treatment, patients in the saline group were better than those in the placebo group (mean difference (MD) 6.3 points, 95% confidence interval (CI) 0.89 to 11.71) and at six months there was a greater effect (MD 13.5 points, 95% CI 9.63 to 17.37). We assessed the evidence to be of low quality for the three months follow-up and very low quality for the six months follow-up. Patient-reported disease severity  was evaluated using a "single-item sinus symptom severity assessment" but the range of scores is not stated, making it impossible for us to determine the meaning of the data presented. No adverse effects  data were collected in the control group but 23% of participants in the saline group experienced side effects including epistaxis. General HRQL  was measured using SF-12 (0 to 100, 100 = best quality of life). No difference was found after three months of treatment (low quality evidence) but at six months there was a small difference favouring the saline group, which may not be of clinical significance and has high uncertainty (MD 10.5 points, 95% CI 0.66 to 20.34) (very low quality evidence). Low-volume, nebulised saline versus intranasal corticosteroids One trial included 40 adult participants with polyps. Our primary outcome of disease-specific HRQL  was not reported. At the end of treatment (three months) the patients who had intranasal corticosteroids had less severe symptoms  (MD -13.50, 95% CI -14.44 to -12.56); this corresponds to a large effect size. We assessed the evidence to be of very low quality. The two studies were very different in terms of included populations, interventions and comparisons and so it is therefore difficult to draw conclusions for practice. The evidence suggests that there is no benefit of a low-volume (5 ml) nebulised saline spray over intranasal steroids. There is some benefit of daily, large-volume (150 ml) saline irrigation with a hypertonic solution when compared with placebo, but the quality of the evidence is low for three months and very low for six months of treatment.
Sixty-two trials with 10,187 randomised participants have been included in the review. Maximum duration of intervention was 18 months. Most included trials had poor study quality. The pooled weighted mean difference (WMD) for percentage weight change showed a benefit of supplementation of 2.2% (95% confidence interval (CI) 1.8 to 2.5) from 42 trials. There was no significant reduction in mortality in the supplemented compared with control groups (relative risk (RR) 0.92, CI 0.81 to 1.04) from 42 trials. Mortality results were statistically significant when limited to trials in which participants (N = 2461) were defined as undernourished (RR 0.79, 95% CI 0.64 to 0.97). The risk of complications was reduced in 24 trials (RR 0.86, 95% CI 0.75 to 0.99). Few trials were able to suggest any functional benefit from supplementation. The WMD for length of stay from 12 trials also showed no statistically significant effect (-0.8 days, 95% CI -2.8 to 1.3). Adverse effects included nausea or diarrhoea. Supplementation produces a small but consistent weight gain in older people. Mortality may be reduced in older people who are undernourished. There may also be a beneficial effect on complications which needs to be confirmed. However, this updated review found no evidence of improvement in functional benefit or reduction in length of hospital stay with supplements. Additional data from large-scale multi-centre trials are still required.
We identified 25 RCTs from 27 papers (with 8453 participants) studying the effect of PPIs versus placebo, H2RAs or prokinetics for improvement of global symptoms of dyspepsia and quality of life in people with FD. Low-dose PPIs had similar efficacy as standard-dose PPIs, therefore we combined these subgroups for the analysis. PPI was more effective than placebo at relieving overall dyspepsia symptoms in people with FD (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.82 to 0.94; participants = 6172; studies = 18; number needed to treat for an additional beneficial outcome (NNTB) 11; moderate quality evidence). PPIs may have little or no effect compared with H2RAs (RR 0.88, 95% CI 0.74 to 1.04; participants = 740; studies = 2; low quality evidence), and may be slightly more effective than prokinetics (RR 0.89, 95% CI 0.81 to 0.99; participants = 1033; studies = 5; NNTB 16; low quality evidence) at relieving overall dyspepsia symptoms in people with FD. PPIs plus prokinetics have probably little or no effect compared with PPIs alone at relieving overall dyspepsia symptoms (RR 0.85, 95% CI 0.68 to 1.08; participants = 407; studies = 2; moderate quality evidence). There was no difference when subgrouped by Helicobacter pylori status, country of origin, or presence of reflux or Rome III subtypes. There were no differences in the number of adverse events observed between PPIs and any of the other treatments. There were fewer adverse events in the combination of PPI plus prokinetics compared to prokinetics alone (RR 0.60, 95% CI 0.39 to 0.93; participants = 407; studies = 2; moderate quality evidence). There is evidence that PPIs are effective for the treatment of FD, independent of the dose and duration of treatment compared with placebo. PPIs may be slightly more effective than prokinetics for the treatment of FD; however, the evidence is scarce. The trials evaluating PPIs versus prokinetics are difficult to interpret as they are at risk of bias. Although the effect of these drugs seems to be small, the drugs are well tolerated.
No new RCTs of biopsy or resection for LGG were identified. No additional ineligible non-randomized studies (NRS) were included in this updated review. Twenty other ineligible studies were previously retrieved for further analysis despite not meeting the pre-specified criteria. Ten studies were retrospective or were literature reviews. Three studies were prospective, however they were limited to tumor recurrence and volumetric analysis and extent of resection. One study was a population-based parallel cohort in Norway, but not an RCT. Four studies were RCTs, however patients were randomized with respect to varying radiotherapy regimens to assess timing and dose of radiation. One RCT was on high-grade gliomas (HGGs) and not LGG. Finally, one RCT evaluated diffusion tensor imaging (DTI)-based neuro-navigation for surgical resection. Since the last version of this review, no new studies have been identified for inclusion and currently there are no RCTs or CCTs available on which to base definitive clinical decisions. Therefore, physicians must approach each case individually and weigh the risks and benefits of each intervention until further evidence is available. Some retrospective studies and non-randomized prospective studies do seem to suggest improved OS and seizure control correlating to higher extent of resection. Future research could focus on RCTs to determine outcomes benefits for biopsy versus resection.
Four studies, including 83 participants, are included in this review. Two studies used mantra meditation while the other two used yoga compared with drugs, relaxation training, non-specific exercises and standard treatment control. Design limitations caused high risk of bias across the studies. Only one out of four studies provided data appropriate for analysis. For this study there was no statistically significant difference between the meditation therapy group and the drug therapy group on the teacher rating ADHD scale (MD -2.72, 95% CI -8.49 to 3.05, 15 patients). Likewise, there was no statistically significant difference between the meditation therapy group and the standard therapy group on the teacher rating ADHD scale (MD -0.52, 95% CI -5.88 to 4.84, 17 patients). There was also no statistically significant difference between the meditation therapy group and the standard therapy group in the distraction test (MD -8.34, 95% CI -107.05 to 90.37, 17 patients). As a result of the limited number of included studies, the small sample sizes and the high risk of bias, we are unable to draw any conclusions regarding the effectiveness of meditation therapy for ADHD. The adverse effects of meditation have not been reported. More trials are needed.
We included 11 studies (four CTPA, five lung scintigraphy, two both) with a total of 695 CTPA and 665 lung scintigraphy results. Lung scintigraphy was applied by different techniques. No MRA studies matched our inclusion criteria. Overall, risk of bias and concerns regarding applicability were high in all studies as judged in light of the review research question, as was heterogeneity in study methods. We did not undertake meta-analysis. All studies used clinical follow-up as a reference standard, none in a manner that enabled reliable identification of false positives. Sensitivity and negative predictive value were therefore the only valid test accuracy measures. The median negative predictive value for CTPA was 100% (range 96% to 100%). Median sensitivity was 83% (range 0% to 100%). The median negative predictive value for lung scintigraphy was 100% (range 99% to 100%). Median sensitivity was 100% (range 0% to 100%). The median frequency of inconclusive results was 5.9% (range 0.9% to 36%) for CTPA and 4.0% (range 0% to 23%) for lung scintigraphy. The overall median prevalence of pulmonary embolism was 3.3% (range 0.0% to 8.7%). Both CTPA and lung scintigraphy seem appropriate for exclusion of pulmonary embolism during pregnancy. However, the quality of the evidence mandates cautious adoption of this conclusion. Important limitations included poor reference standards, necessary assumptions in the analysis regarding inconclusive test results and the inherent inability of included studies to identify false positives. It is unclear which test has the highest accuracy. There is a need for direct comparisons between diagnostic methods, including MR, in prospective randomized diagnostic studies.
We included one unpublished RCT, randomising 180 children aged three years at study commencement. The setting was nursery schools in an area with high prevalence of dental caries and a low level of fluoride in drinking water. Data from 166 participants were available for analysis. The study carried a high risk of bias. After three years, there was a reduction of caries in permanent teeth (mean difference (MD) −0.13, 95% confidence interval (CI) −0.24 to −0.02) and in primary teeth (MD −1.14, 95% CI −1.86 to −0.42), as measured by the decayed, missing and filled teeth index (DMFT for permanent teeth and dmft for primary teeth). For primary teeth, this is a substantial reduction, equivalent to a prevented fraction of 31%. For permanent teeth, the disease level was very low in the study, resulting in a small absolute effect size. The included study did not report any other outcomes of interest for this review (adverse events, dental pain, antibiotic use or requirement for general anaesthesia due to dental procedures). There is low-quality evidence to suggest fluoridated milk may be beneficial to schoolchildren, contributing to a substantial reduction in dental caries in primary teeth. Due to the low quality of the evidence, further research is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. There was only one relatively small study, which had important methodological limitations on the data for the effectiveness in reducing caries. Furthermore, there was no information about the potential harms of the intervention. Additional RCTs of high quality are needed before we can draw definitive conclusions about the benefits of milk fluoridation.
Two studies met the inclusion criteria, enrolling 157 participants (37 participants in one study and 120 in the other study), of whom 114 were included in the analyses. The studies compared oral dexamethasone to placebo, followed by an open-label phase in one study. One study lasted seven days, and the duration of the other study was 15 days. We were unable to conduct many of our predetermined analyses due to different agents, dosages, comparators and outcome measures, routes of drug delivery, measurement scales and time points. Subgroup analysis according to type of cancer was not possible. Primary outcomes We included two studies (114 participants) with data at one week in the meta-analysis for change in dyspnoea intensity/dyspnoea relief from baseline. Corticosteroid therapy with dexamethasone resulted in an MD of lower dyspnoea intensity compared to placebo at one week (MD –0.85 lower dyspnoea (scale 0–10; lower score = less breathlessness), 95% CI -1.73 to 0.03; very low-quality evidence), although we were uncertain as to whether corticosteroids had an important effect on dyspnoea as results were imprecise. We downgraded the quality of evidence by three levels from high to very low due to very serious study limitations and imprecision. One study measured affective distress (quality of dyspnoea) and results were similar between groups (29 participants; very low-quality evidence). We downgraded the quality of the evidence three times for imprecision, inconsistency, and serious study limitations. Both studies assessed symptom impact (burden of dyspnoea or impact on function) (113 participants; very low-quality evidence). In one study, it was unclear whether dexamethasone had an effect on dyspnoea as results were imprecise. The second study showed more improvement for physical well-being scores at days eight and 15 in the dexamethasone group compared with the control group, but there was no evidence of a difference for FACIT social/family, emotional or functional scales. We downgraded the quality of the evidence three times for imprecision, inconsistency, and serious study limitations. Secondary outcomes Due to the lack of homogenous outcome measures and inconsistency in reporting, we could not perform quantitative analysis for any secondary outcomes. In both studies, the frequency of adverse events was similar between groups, and corticosteroids were generally well tolerated. The withdrawal rates for the two studies were 15% and 36%. Reasons for withdrawal included lost to follow-up, participant or carer (or both) refusal, and death due to disease progression. We downgraded the quality of evidence for these secondary outcomes by three levels from high to very low due to serious study limitations, inconsistency and imprecision. Neither study examined participant satisfaction with treatment. There are few studies assessing the effects of systemic corticosteroids on cancer-related dyspnoea in adults with cancer. We judged the evidence to be of very low quality that neither supported nor refuted corticosteroid use in this population. Further high-quality studies are needed to determine if corticosteroids are efficacious in this setting.
Seven randomised controlled trials were identified that satisfied the inclusion criteria. In patients with moderate to severe ulcerative colitis whose disease was refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab (three intravenous infusions at 0, 2, and 6 weeks) was more effective than placebo in inducing clinical remission (Relative Risk (RR) 3.22, 95% CI 2.18 to 4.76); inducing endoscopic remission (RR 1.88, 95% CI 1.54 to 2.28); and in inducing clinical response (RR 1.99, 95% CI 1.65 to 2.41) at 8 weeks. A single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.44, 95% CI 0.22 to 0.87). In patients with moderate to severe ulcerative colitis whose disease is refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab is effective in inducing clinical remission, inducing clinical response, promoting mucosal healing, and reducing the need for colectomy at least in the short term. Serious adverse events attributable to infliximab were not common in the included studies but physicians should be aware of and be prepared to deal with potential adverse events such as anaphylactic reactions and infections.
Six RCTs (n = 2324 patients) met the inclusion criteria. A low risk of bias was assigned to all studies. The two briakinumab trials were not pooled due to differences in doses and time points for analysis. In both studies there was no statistically significant difference in remission rates. One study (n = 79) compared doses of 1 mg/kg and 3 mg/kg to placebo. In the briakinumab group 70% (44/63) of patients failed to enter clinical remission at 6 or 9 weeks compared to 81% (13/16) of placebo patients (RR 0.86, 95% CI 0.65 to 1.14). Subgroup analysis revealed no significant differences by dose. The other briakinumab study (n = 230) compared intravenous doses of 200 mg, 400 mg and 700 mg with placebo. Eighty-four per cent (154/184) of briakinumab patients failed to enter clinical remission at six weeks compared to 91% (42/46) of placebo patients (RR 0.92, 95% CI 0.83 to 1.03). Subgroup analysis revealed no significant differences by dose. GRADE analyses of the briakinumab studies rated the overall quality of the evidence for the outcome clinical remission as low. Based on the results of these two studies the manufacturers of briakinumab stopped production of this medication. The ustekinumab studies were pooled despite differences in intravenous doses (i.e. 1mg/kg, 3 mg/kg, 4.5 mg/kg, and 6 mg/kg), however the subcutaneous dose group was not included in the analysis, as it was unclear if subcutaneous was equivalent to intravenous dosing. There was a statistically significant difference in remission rates. At week six, 84% (764/914) of ustekinumab patients failed to enter remission compared to 90% (367/406) of placebo patients (RR 0.92, 95% CI 0.88 to 0.96; 3 studies; high-quality evidence). Subgroup analysis showed a statistically significant difference for the 6.0 mg/kg dose group (moderate-quality evidence). There were statistically significant differences in clinical improvement between ustekinumab and placebo-treated patients. In the ustekinumab group, 55% (502/914) of patients failed to improve clinically (i.e. 70-point decline in CDAI score), compared to 71% (287/406) of placebo patients (RR 0.78, 95% CI 0.71 to 0.85; 3 studies). Subgroup analysis revealed significant differences compared to placebo for the 1 mg/kg, 4.5 mg/kg and 6 mg/kg dosage subgroups. Similarly for a 100-point decline in CDAI, 64% (588/914) of patients in the ustekinumab group failed to improve clinically compared to 78% (318/406) of placebo patients (RR 0.82, 95% CI 0.77 to 0.88; 3 studies; high-quality evidence). Subgroup analysis showed a significant difference compared to placebo for the 4.5 mg/kg and 6.0 mg/kg (high-quality evidence) dose groups. There were no statistically significant differences in the incidence of adverse events, serious adverse events or withdrawal due to adverse events. Sixty-two per cent (860/1386) of ustekinumab patients developed at least one adverse event compared to 64% (407/637) of placebo patients (RR 0.97, 95% CI 0.90 to 1.04; 4 studies; high-quality evidence). Five per cent (75/1386) of ustekinumab patients had a serious adverse event compared to 6% (41/637) of placebo patients (RR 0.83, 95% CI 0.58 to 1.20; 4 studies; moderate-quality evidence). The most common adverse events in briakinumab patients were injection site reactions and infections. Infections were the most common adverse event in ustekinumab patients. Worsening of Crohn's disease and serious infections were the most common serious adverse events. High quality evidence suggests that ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's disease. Moderate to high quality evidence suggests that the optimal dosage of ustekinumab is 6 mg/kg. Briakinumab and ustekinumab appear to be safe. Moderate quality evidence suggests no increased risk of serious adverse events. Future studies are required to determine the long-term efficacy and safety of ustekinumab in patients with moderate to severe Crohn's disease.
We found five reports of two single-centre, placebo-controlled, double-blinded studies (130 participants). Participants in both studies were a mix of adults with either intermittent or persistent allergic rhinitis. Both studies had a low risk of bias. One study, with 12 weeks’ follow-up, used a single percutaneous application of 10 Necator americanus (i.e. human hookworm) larvae. The other study, with 24 weeks’ follow-up, used three-weekly oral dosing with 2500 Trichuris suis (i.e. pig whipworm) eggs in aqueous suspension. Of 17 outcomes evaluated in this review, eight were positive (i.e. favoured helminths). Participants taking helminths had no reduction in allergic rhinitis symptoms, percentage of well days (i.e. days with minimal symptoms and no use of medication for allergic rhinitis), lung function measures and quality of life scores. Total use of medication for allergic rhinitis (eye drops, nasal sprays, tablets) did not change; however, in the helminth group there was a statistically significant reduction in the percentage of days during the grass pollen season when participants needed to take tablets as rescue medication for their allergic rhinitis symptoms (MD –14.0%, 95% CI –26.6 to –1.40); in a typical 60-day pollen season this 14% reduction translates into 19 days when tablets would be needed in the helminth group versus 27 days when tablets would be needed in the placebo group. Participants taking helminths percutaneously (i.e. as hookworm larvae) had local skin itching and redness in the first few days after administration. Participants taking helminths were more likely to report any gastrointestinal adverse event (RR 1.79, 95% CI 1.31 to 2.45), moderate or severe abdominal pain (RR 7.67, 95% CI 1.87 to 31.57), moderate or severe flatulence (RR 2.01, 95% CI 1.06 to 3.81) and moderate or severe diarrhoea (RR 1.99, 95% CI 1.18 to 3.37). There was no difference between the helminth and placebo groups in the incidence of serious adverse events, and in study withdrawals. There is currently insufficient evidence on the efficacy, tolerability and likely costs of helminth therapy to support its use in the routine management of allergic rhinitis. Administered to humans in carefully measured doses, helminths appear to be safe. More preclinical studies should be performed, before larger and extended duration trials of helminths for allergic rhinitis are carried out. Future studies should collect and report comparative data on the costs of helminth therapy versus conventional pharmacotherapy.
We included four randomised controlled trials (all conducted in Italy) reporting on 567 women who were less than 11 weeks' to 24 weeks' pregnant at the start of the trials. The trials had small sample sizes and one trial only reported an interim analysis. Two trials were open-label. The overall risk of bias was unclear. For the mother, supplementation with myo-inositol was associated with a reduction in the incidence of gestational diabetes compared with control (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.29 to 0.64; three trials; n = 502 women). Using GRADE methods this evidence was assessed as low with downgrading due to unclear risk of bias for allocation concealment in two of the included trials and lack of generalisability of findings. For women who received myo-inositol supplementation, the incidence of GDM ranged from 8% to 18%; for women in the control group, the incidence of GDM was 28%, using International Association of Diabetes and Pregnancy Study Groups Consensus Panel 2010 criteria to diagnose GDM. Two trials reported on hypertensive disorders of pregnancy, a primary maternal outcome of this review. There was no clear difference in risk of hypertensive disorders of pregnancy between the myo-inositol and control groups (average RR 0.43, 95% CI 0.02 to 8.41; two trials; n = 398 women; Tau2 = 3.23; I2 = 69%). Using GRADE methods, this evidence was assessed as very low, with downgrading due to wide confidence intervals with very low event rates, a small sample size, and lack of blinding and unclear allocation concealment methods, and a lack of generalisability. For women who received myo-inositol the risk of hypertensive disorders of pregnancy ranged from 0% to 33%; for women in the control group the risk was 4%. For the infant, none of the included trials reported on the primary neonatal outcomes of this systematic review (large-for-gestational age, perinatal mortality, mortality or morbidity composite). In terms of this review's secondary outcomes, there was no clear difference in the risk of caesarean section between the myo-inositol and control groups (RR 0.95, 95% CI 0.76 to 1.19; two trials; n = 398 women). Using GRADE methods, this evidence was assessed as low, with downgrading due to unclear risk of bias in one trial and lack of generalisability. For women who received myo-inositol supplementation, the risk of having a caesarean section ranged from 34% to 54%; for women in the control group the was 45%. There were no maternal adverse effects of therapy in the two trials that reported on this outcome (the other two trials did not report this outcome). Two trials found no clear difference in the risk of macrosomia between infants whose mothers received myo-inositol supplementation compared with controls (average RR 0.35, 95% CI 0.02 to 6.37; two trials; n = 398 infants;Tau2 = 3.33; I2 = 73%). Similarly, there was no clear difference between groups in terms of neonatal hypoglycaemia (RR 0.36, 95% CI 0.01 to 8.66) or shoulder dystocia (average RR 2.33, 95% CI 0.12 to 44.30, Tau2 = 3.24; I2 = 72%). There was a lack of data available for a large number of maternal and neonatal secondary outcomes, and no data for any of the long-term childhood or adulthood outcomes, or for health service cost outcomes. Evidence from four trials of antenatal dietary supplementation with myo-inositol during pregnancy shows a potential benefit for reducing the incidence of gestational diabetes. No data were reported for any of this review's primary neonatal outcomes. There were very little outcome data for the majority of this review's secondary outcomes. There is no clear evidence of a difference for macrosomia when compared with control. The current evidence is based on small trials that are not powered to detect differences in outcomes including perinatal mortality and serious infant morbidity. All of the included studies were conducted in Italy which raises concerns about the lack of generalisability of the evidence to other settings. There is evidence of inconsistency and indirectness and as a result, many of the judgements on the quality of the evidence were downgraded to low or very low quality (GRADEpro Guideline Development Tool). Further trials for this promising antenatal intervention for preventing gestational diabetes are encouraged and should include pregnant women of different ethnicities and varying risk factors and use of myo-inositol (different doses, frequency and timing of administration) in comparison with placebo, diet and exercise or pharmacological interventions. Outcomes should include potential harms including adverse effects.
We included nine reviews with 152 included studies and 13,524 participants, but because some studies appeared in more than one review the number of unique studies and participants was smaller than this. Most participants had moderate or severe pain associated with a range of different types of cancer. Studies in the reviews typically compared one type of opioid or formulation with either a different formulation of the same opioid, or a different opioid; few included a placebo control. Typically the reviews titrated dose to effect, a balance between pain relief and adverse events. Various routes of administration of opioids were considered in the reviews; oral with most opioids, but transdermal administration with fentanyl, and buprenorphine. No review included studies of subcutaneous opioid administration. Pain outcomes reported were varied and inconsistent. The average size of included studies varied considerably between reviews: studies of older opioids, such as codeine, morphine, and methadone, had low average study sizes while those involving newer drugs tended to have larger study sizes. Six reviews reported a GRADE assessment (buprenorphine, codeine, hydromorphone, methadone, oxycodone, and tramadol), but not necessarily for all comparisons or outcomes. No comparative analyses were possible because there was no consistent placebo or active control. Cohort outcomes for opioids are therefore reported, as absolute numbers or percentages, or both. Reviews on buprenorphine, codeine with or without paracetamol, hydromorphone, methadone, tramadol with or without paracetamol, tapentadol, and oxycodone did not have information about the primary outcome of mild or no pain at 14 days, although that on oxycodone indicated that average pain scores were within that range. Two reviews, on oral morphine and transdermal fentanyl, reported that 96% of 850 participants achieved that goal. Adverse event withdrawal was reported by five reviews, at rates of between 6% and 19%. Participants with at least one adverse event were reported by three reviews, at rates of between 11% and 77%. Our GRADE assessment of evidence quality was very low for all outcomes, because many studies in the reviews were at high risk of bias from several sources, including small study size. The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low, although the evidence we have indicates that around 19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days. This accords with the clinical experience in treating many people with cancer pain, but overstates to some extent the effectiveness found for the WHO pain ladder. Most people will experience adverse events, and help may be needed to manage the more common undesirable adverse effects such as constipation and nausea. Perhaps between 1 in 10 and 2 in 10 people treated with opioids will find these adverse events intolerable, leading to a change in treatment.
We included three trials, all in women with type 1 diabetes (223 women and babies). All three trials were at high risk of bias due to lack of blinding, unclear methods of randomisation and selective reporting of outcomes. Two trials compared very tight (3.33 to 5.0 mmol/L fasting blood glucose (FBG)) with tight-moderate (4.45 to 6.38 mmol/L) glycaemic control targets, with one trial of 22 babies reporting no perinatal deaths orserious perinatal morbidity (evidence graded low for both outcomes). In the same trial, there were two congenital anomalies in the very tight, and none in the tight-moderate group, with no significant differences in caesarean section between groups (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.49 to 1.73; evidence graded very low). In these two trials, glycaemic control was not significantly different between the very tight and tight-moderate groups by the third trimester, although one trial of 22 women found significantly less maternal hypoglycaemia in the tight-moderate group. In a trial of 60 women and babies comparing tight (≤ 5.6 mmol/L FBG); moderate (5.6 to 6.7 mmol/L); and loose (6.7 to 8.9 mmol/L) glycaemic control targets, there were two neonatal deaths in the loose and none in the tight or moderate groups (evidence graded very low). There were significantly fewer women with pre-eclampsia (evidence graded low), fewer caesarean sections (evidence graded low) and fewer babies with birthweights greater than 90th centile (evidence graded low) in the combined tight-moderate compared with the loose group. The quality of the evidence was graded low or very low for important outcomes, because of design limitations to the studies, the small numbers of women included, and wide confidence intervals crossing the line of no effect. Many of the important outcomes were not reported in these studies. In a very limited body of evidence, few differences in outcomes were seen between very tight and tight-moderate glycaemic control targets in pregnant women with pre-existing type 1 diabetes, including actual glycaemic control achieved. There is evidence of harm (increased pre-eclampsia, caesareans and birthweights greater than 90th centile) for 'loose' control (FBG above 7 mmol/L). Future trials comparing interventions, rather than glycaemic control targets, may be more feasible. Trials in pregnant women with pre-existing type 2 diabetes are required.
We included three randomised controlled trials (351 participants) investigating immediate versus delayed chemotherapy in people diagnosed with asymptomatic, metastatic, incurable colorectal cancer. Giving immediate versus delayed chemotherapy may make little or no difference to overall survival (hazard ratio (HR) 1.17, 95% confidence interval (CI) 0.93 to 1.46; 3 studies, 351 persons; low-quality evidence). For toxicity, giving immediate versus delayed chemotherapy may make little or no difference to the risk of grade 3 or 4 nausea and vomiting (risk ratio (RR) 0.84, 95% CI 0.31 to 2.25; 2 studies, 140 persons; very low-quality evidence), stomatitis (RR 1.10, 95% CI 0.47 to 2.55; 2 studies, 140 persons; very low-quality evidence), or diarrhoea (RR 0.69, 95% CI 0.34 to 1.40; 2 studies, 140 persons, very low-quality evidence). We are uncertain whether delayed chemotherapy made a difference to quality of life (very low-quality evidence), progression-free survival (low-quality evidence), or compliance with chemotherapy (low-quality evidence), as we had insufficient data to pool for these outcomes. Based on a limited number of trials, very sparse data, and uncertainty of the evidence, this review was unable to establish whether there was a difference in overall survival or other clinically relevant outcomes, between immediate or delayed chemotherapy in persons with metastatic, incurable, colorectal cancer. The results should be interpreted with caution.
Of 2029 screened records, we included seven studies in the review and six in the meta-analysis. Risk of bias varied: the randomisation and allocation process was often not clearly described, five of seven studies were double-blind and there was almost no missing data. The quality of the evidence for mortality was high. Risk ratios for overall mortality for adjunctive corticosteroids were 0.56 (95% confidence interval (CI) 0.32 to 0.98) at one month and 0.59 (95% CI 0.41 to 0.85) at three to four months of follow-up. In adults, to prevent one death, numbers needed to treat are nine patients in a setting without highly active antiretroviral therapy (HAART) available, and 23 patients with HAART available. The three largest trials provided moderate quality data on the need for mechanical ventilation, with a risk ratio of 0.38 (95% CI 0.20 to 0.73) in favour of adjunctive corticosteroids. One study was conducted in infants, suggesting a risk ratio for death in hospital of 0.81 (95% CI 0.51 to 1.29; moderate quality evidence). The number and size of trials investigating adjunctive corticosteroids for HIV-infected patients with PCP is small, but the evidence from this review suggests a beneficial effect for adult patients with substantial hypoxaemia. There is insufficient evidence on the effect of adjunctive corticosteroids on survival in infants.
The searches identified 104 trial reports which represented 51 trials, of which three cross-over trials (providing data on 77 participants) met our inclusion criteria. We present three comparisons: inhalation before versus during airway clearance techniques; inhalation before versus after airway clearance techniques; and inhalation during versus after airway clearance techniques. One trial (50 participants), given its three-arm design, was eligible for all three comparisons. No trials compared morning versus evening inhalation of hypertonic saline. The evidence from the three trials was judged to be of low quality downgraded for limitations (high risk of bias due to blinding) and indirectness (all participants are adults, and therefore not applicable to children). Intervention periods ranged from one treatment to three treatments in one day. There were no clinically important differences between the timing regimens of inhaling hypertonic saline before, during or after airway clearance techniques in the mean amount of improvement in lung function or symptom scores (77 participants), with the between-group comparisons being non-significant (low-certainty evidence). While there may be little or no difference in the rating of satisfaction when hypertonic saline was inhaled before versus during the airway clearance techniques (64 participants) (with the 95% confidence interval including the possibility of both a higher and lower rating of satisfaction), satisfaction may be lower on a 100-mm scale when inhaled after the airway clearance techniques compared to before: mean difference (MD) 20.38 mm (95% confidence interval (CI) 12.10 to 28.66) and when compared to during the techniques, MD 14.80 mm (95% CI 5.70 to 23.90). Perceived effectiveness showed similar results: little or no difference for inhalation before versus during airway clearance techniques (64 participants); may be lower when inhaled after the airway clearance techniques compared to before, MD 10.62 (95% CI 2.54 to 18.70); and also when compared to during the techniques, MD 15.60 (95% CI 7.55 to 23.65). There were no quality of life or adverse events reported in any of the trials. Timing of hypertonic saline inhalation makes little or no difference to lung function (low-certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long-term efficacy of hypertonic saline has only been established for twice-daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available. The identified trials were all of very short intervention periods, so longer-term research could be conducted to establish the effects arising from regular use, which would incorporate the influence of changes in adherence with long-term use, as well as generating data on any adverse effects that occur with long-term use.
We included seven trials with a total of 435 participants. Three trials focused on Physalia (Bluebottle) jellyfish, one trial on Carukia jellyfish and three on Carybdea alata (Hawaiian box) jellyfish. Two ongoing trials were identified. Six of the seven trials were judged as having high risk of bias. Blinding was not feasible in four of the included trials because of the nature of the interventions. A wide range of interventions were assessed across trials, and a wide range of outcomes were measured. We reported results from the two trials for which data were available and reported the effects of interventions according to our definition of primary or secondary outcomes. Hot water immersion was superior to ice packs in achieving clinically significant (at least 50%) pain relief at 10 minutes (one trial, 96 participants, risk ratio (RR) 1.66, 95% confidence interval (CI) 1.01 to 2.72; low-quality evidence) and 20 minutes (one trial, 88 participants, RR 2.66, 95% CI 1.71 to 4.15; low-quality evidence). No statistically significant differences between hot water immersion and ice packs were demonstrated for dermatological outcomes. Treatment with vinegar or Adolph's meat tenderizer compared with hot water made skin appear worse (one trial, 25 participants, RR 0.31, 95% CI 0.14 to 0.72; low-quality evidence). Adverse events due to treatment were not reported in any trial. This review located a small number of trials that assessed a variety of different interventions applied in different ways and in different settings. Although heat appears to be an effective treatment for Physalia (Bluebottle) stings, this evidence is based on a single trial of low-quality evidence. It is still unclear what type of application, temperature, duration of treatment and type of water (salt or fresh) constitute the most effective treatment. In addition, these results may not apply to other species of jellyfish with different envenomation characteristics. Future research should further assess the most effective interventions using standardised research methodology.
We included 51 RCTs with 2793 participants; of these 45 RCTs (2491 participants: peripheral nerve block = 1288; comparators = 1203) were included in meta-analyses. There are 11 ongoing studies and three awaiting classification. Compared to systemic analgesia alone, peripheral nerve blocks reduced: pain at rest on arrival in the postoperative care unit (SMD -1.12, 95% CI -1.67 to -0.56; 9 trials, 429 participants; equivalent to 3.2 on 0 to 10 scale; moderate-quality evidence); risk of acute confusional status: risk ratio (RR) 0.10 95% CI 0.02 to 0.54; 1 trial, 225 participants; number needed to treat for additional benefit (NNTB) 12, 95% CI 11 to 22; very low-quality evidence); pruritus (RR 0.16, 95% CI 0.04 to 0.70; 2 trials, 259 participants for continuous peripheral nerve blocks; NNTB 4 (95% CI 4 to 8); very low-quality evidence); hospital length of stay (SMD -0.75, 95% CI -1.02 to -0.48; very low-quality evidence; 2 trials, 249 participants; equivalent to 0.75 day). Participant satisfaction increased (SMD 0.67, 95% CI 0.45 to 0.89; low-quality evidence; 5 trials, 363 participants; equivalent to 2.4 on 0 to 10 scale). We did not find a difference for the number of participants walking on postoperative day one (very low-quality evidence). Two nerve block-related complications were reported: one local haematoma and one delayed persistent paresis. Compared to neuraxial blocks, peripheral nerve blocks reduced the risk of pruritus (RR 0.33, 95% CI 0.19 to 0.58; 6 trials, 299 participants; moderate-quality evidence; NNTB 6 (95% CI 5 to 9). We did not find a difference for pain at rest on arrival in the postoperative care unit (moderate-quality evidence); number of nerve block-related complications (low-quality evidence); acute confusional status (very low-quality evidence); hospital length of stay (low quality-evidence); time to first walk (low-quality evidence); or participant satisfaction (high-quality evidence). We found that peripheral nerve blocks provide better pain control compared to systemic analgesia with no major differences between peripheral nerve blocks and neuraxial blocks. We also found that peripheral nerve blocks may be associated with reduced risk of postoperative acute confusional state and a modest reduction in hospital length of stay that could be meaningful in terms of cost reduction considering the increasing numbers of procedures performed annually. Compared to systemic analgesia alone, there is moderate-quality evidence that peripheral nerve blocks reduce postoperative pain, low-quality evidence that patient satisfaction is increased and very low-quality evidence for reductions in acute confusional status, pruritus and hospital length of stay . We found moderate-quality evidence that peripheral nerve blocks reduce pruritus compared with neuraxial blocks. The 11 ongoing studies, once completed, and the three studies awaiting classification may alter the conclusions of the review once assessed
We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically-treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatment The three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatment The three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight-bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight-bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time. There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials.
We included 17 RCTs with a total of 1496 participants. Apart from two trials, the trial participants were women identified as 'poor responders' to standard IVF protocols. The included trials compared either testosterone or DHEA treatment with placebo or no treatment. When DHEA was compared with placebo or no treatment, pre-treatment with DHEA was associated with higher rates of live birth or ongoing pregnancy (OR 1.88, 95% CI 1.30 to 2.71; eight RCTs, N = 878, I² statistic = 27%, moderate quality evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 15% and 26%. However, in a sensitivity analysis removing trials at high risk of performance bias, the effect size was reduced and no longer reached significance (OR 1.50, 95% CI 0.88 to 2.56; five RCTs, N = 306, I² statistic = 43%). There was no evidence of a difference in miscarriage rates (OR 0.58, 95% CI 0.29 to 1.17; eight RCTs, N = 950, I² statistic = 0%, moderate quality evidence). Multiple pregnancy data were available for five trials, with one multiple pregnancy in the DHEA group of one trial (OR 3.23, 95% CI 0.13 to 81.01; five RCTs, N = 267, very low quality evidence). When testosterone was compared with placebo or no treatment we found that pre-treatment with testosterone was associated with higher live birth rates (OR 2.60, 95% CI 1.30 to 5.20; four RCTs, N = 345, I² statistic = 0%, moderate evidence). This suggests that in women with an 8% chance of live birth with placebo or no treatment, the live birth rate in women using testosterone will be between 10% and 32%. On removal of studies at high risk of performance bias in a sensitivity analysis, the remaining study showed no evidence of a difference between the groups (OR 2.00, 95% CI 0.17 to 23.49; one RCT, N = 53). There was no evidence of a difference in miscarriage rates (OR 2.04, 95% CI 0.58 to 7.13; four RCTs, N = 345, I² = 0%, low quality evidence). Multiple pregnancy data were available for three trials, with four events in the testosterone group and one in the placebo/no treatment group (OR 3.09, 95% CI 0.48 to 19.98; three RCTs, N = 292, very low quality evidence). One study compared testosterone with estradiol and reported no evidence of a difference in live birth rates (OR 2.06, 95% CI 0.43 to 9.87; one RCT, N = 46, very low quality evidence) or miscarriage rates (OR 0.70, 95% CI 0.11 to 4.64; one RCT, N = 46, very low quality evidence). The quality of the evidence was moderate, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in some trials. In women identified as poor responders undergoing ART, pre-treatment with DHEA or testosterone may be associated with improved live birth rates. The overall quality of the evidence is moderate. There is insufficient evidence to draw any conclusions about the safety of either androgen. Definitive conclusions regarding the clinical role of either androgen awaits evidence from further well-designed studies.
We included four trials involving 543 women and their babies (but only data from 521 women and their babies is included in our analyses). Three of the four included studies had moderate to high risk of bias and one study was at low to moderate risk of bias. Babies born to women receiving management for borderline GDM (generally dietary counselling and metabolic monitoring) were less likely to be macrosomic (birthweight greater than 4000 g) (three trials, 438 infants, risk ratio (RR) 0.38, 95% confidence interval (CI) 0.19 to 0.74) or large-for-gestational (LGA) age (three trials, 438 infants, RR 0.37, 95% CI 0.20 to 0.66) when compared with those born to women in the routine care group. There were no significant differences in rates of caesarean section (three trials, 509 women, RR 0.93, 95% CI 0.68 to 1.27) and operative vaginal birth (one trial, 83 women, RR 1.37, 95% CI 0.20 to 9.27) between the two groups. This review found interventions including providing dietary advice and blood glucose level monitoring for women with pregnancy hyperglycaemia not meeting GDM and T2DM diagnostic criteria helped reduce the number of macrosomic and LGA babies without increasing caesarean section and operative vaginal birth rates. It is important to notice that the results of this review were based on four small randomised trials with moderate to high risk of bias without follow-up outcomes for both women and their babies.
We included nine studies with 994 participants in this update. Occupational therapy targeted towards activities of daily living after stroke increased performance scores (standardised mean difference (SMD) 0.17, 95% confidence interval (CI) 0.03 to 0.31, P = 0.02; 7 studies; 749 participants; low-quality evidence) and reduced the risk of poor outcome (death, deterioration or dependency in personal activities of daily living) (odds ratio (OR) 0.71, 95% CI 0.52 to 0.96; P = 0.03; 5 studies; 771 participants; low-quality evidence). We also found that those who received occupational therapy were more independent in extended activities of daily living (OR 0.22 (95% CI 0.07 to 0.37); P = 0.005; 5 studies; 665 participants; low-quality evidence). Occupational therapy did not influence mortality (OR: 1.02 (95% CI 0.65 to 1.61); P = 0.93; 8 studies; 950 participants), or reduce the combined odds of death and institutionalisation (OR 0.89 (95% CI 0.60 to 1.32); P = 0.55; 4 studies; 671 participants), or death and dependency (OR 0.89 (95% CI 0.64 to 1.23); P = 0.47; 4 trials; 659 participants). Occupational therapy did not improve mood or distress scores (OR 0.08 (95% CI -0.09 to 0.26); P = 0.35; 4 studies; 519 participants; low-quality evidence). There were insufficient data to determine the effects of occupational therapy on health-related quality of life. We found no studies of consenting carers prior to study participation and therefore there were no carer-related outcomes in our review. There were insufficient data to determine participants' and carers' satisfaction with services. Using GRADE, the quality of evidence was low. The major limitation was the number of studies at unclear risk of selection bias and an inevitable high risk of performance and detection bias, as both participants and occupational therapists could not be blinded to the intervention. In addition, there was a sparseness of data for our outcomes of interest and we downgraded the quality of our evidence for these reasons. We found low-quality evidence that occupational therapy targeted towards activities of daily living after stroke can improve performance in activities of daily living and reduce the risk of deterioration in these abilities. Because the included studies had methodological flaws, this research does not provide a reliable indication of the likely effect of occupational therapy for adults with stroke.
Thirty-six trials involving 1718 people met the inclusion criteria. Study quality was mixed. Compared with control, CPAP showed significant improvements in certain objective and subjective sleepiness, measures of quality of life and cognitive function (parallel-group studies: Epworth sleepiness scale (ESS) -3.83 units, 95% CI -4.57 to -3.09; crossover studies: ESS -1.84 units, 95% CI -2.57 to -1.11). Twenty-four hour systolic and diastolic blood pressures were lower with CPAP compared with control (parallel-group trials). Compared with oral appliances, CPAP significantly reduced the apnoea and hypopnoea index (crossover studies: -7.97 events/hr, 95% CI -9.56 to -6.38) and improved sleep efficiency (crossover studies: 2.31%, 95% CI 0.02 to 4.6) and minimum oxygen saturation (4.14%, 95% CI 3.25 to 5.03). Responders to both treatments expressed a strong preference for the oral appliance. However, participants were more likely to withdraw on OA than on CPAP therapy. CPAP is effective in reducing symptoms of sleepiness and improving quality of life measures in people with moderate and severe obstructive sleep apnoea (OSA). It is more effective than oral appliances in reducing respiratory disturbances in these people but subjective outcomes are more equivocal. Certain people tend to prefer oral appliances to CPAP where both are effective. This could be because they offer a more convenient way of controlling OSA. Short-term data indicate that CPAP leads to lower blood pressure than control. Long-term data are required for all outcomes in order to determine whether the initial benefits seen in short-term clinical trials persist.
Five trials randomised 201 participants (110 participants to subcutaneous rapid-acting insulin analogues and 91 to intravenous regular insulin). The criteria for DKA were consistent with the American Diabetes Association criteria for mild or moderate DKA. The underlying cause of DKA was mostly poor compliance with diabetes therapy. Most trials did not report on type of diabetes. Younger diabetic participants and children were underrepresented in our included trials (one trial only). Four trials evaluated the effects of the rapid-acting insulin analogue lispro, and one the effects of the rapid-acting insulin analogue aspart. The mean follow-up period as measured by mean hospital stay ranged between two and seven days. Overall, risk of bias of the evaluated trials was unclear in many domains and high for performance bias for the outcome measure time to resolution of DKA. No deaths were reported in the included trials (186 participants; 3 trials; moderate- (insulin lispro) to low-quality evidence (insulin aspart)). There was very low-quality evidence to evaluate the effects of subcutaneous insulin lispro versus intravenous regular insulin on the time to resolution of DKA: mean difference (MD) 0.2 h (95% CI -1.7 to 2.1); P = 0.81; 90 participants; 2 trials. In one trial involving children with DKA, the time to reach a glucose level of 250 mg/dL was similar between insulin lispro and intravenous regular insulin. There was very low-quality evidence to evaluate the effects of subcutaneous insulin aspart versus intravenous regular insulin on the time to resolution of DKA: MD -1 h (95% CI -3.2 to 1.2); P = 0.36; 30 participants; 1 trial. There was low-quality evidence to evaluate the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin on hypoglycaemic episodes: 6 of 80 insulin lispro-treated participants compared with 9 of 76 regular insulin-treated participants reported hypoglycaemic events; risk ratio (RR) 0.59 (95% CI 0.23 to 1.52); P = 0.28; 156 participants; 4 trials. For insulin aspart compared with regular insulin, RR for hypoglycaemic episodes was 1.00 (95% CI 0.07 to 14.55); P = 1.0; 30 participants; 1 trial; low-quality evidence. Socioeconomic effects as measured by length of mean hospital stay for insulin lispro compared with regular insulin showed a MD of -0.4 days (95% CI -1 to 0.2); P = 0.22; 90 participants; 2 trials; low-quality evidence and for insulin aspart compared with regular insulin 1.1 days (95% CI -3.3 to 1.1); P = 0.32; low-quality evidence. Data on morbidity were limited, but no specific events were reported for the comparison of insulin lispro with regular insulin. No trial reported on adverse events other than hypoglycaemic episodes, and no trial investigated patient satisfaction. Our review, which provided mainly data on adults, suggests on the basis of mostly low- to very low-quality evidence that there are neither advantages nor disadvantages when comparing the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin for treating mild or moderate DKA.
Eleven studies with a total of 404 participants (337 pemphigus vulgaris, 27 pemphigus foliaceus and 40 not specified ) were identified. The quality of included studies was not high, the majority of studies did not report allocation concealment, and power was limited by very small sample sizes. Interventions assessed included prednisolone dose regimen, pulsed dexamethasone, azathioprine, cyclophosphamide, cyclosporine, dapsone, mycophenolate, plasma exchange, topical epidermal growth factor and traditional Chinese medicine. Ten studies included participants with newly diagnosed or newly active recurrent disease, and one trial included participants in maintenance phase. There was sufficient data for 4 meta-analyses, each pooling results of two studies only. For the majority of interventions, results were inconclusive. We found some interventions to be superior for certain outcomes, although we were unable to conclude which treatments are superior overall. Mycophenolate was more effective in achieving disease control than azathioprine (1 study; n=40; RR 0.72; 95% CI 0.52 to 0.99, NNT 3.7). There was evidence of a steroid-sparing benefit of azathioprine (1 study; n=57; MWD -3919 mg prednisolone; 95% CI -6712 to -1126) and cyclophosphamide (1 study; n=54; MWD -3355 mg prednisolone; 95% CI -6144 to -566) compared to glucocorticoids alone. Topical epidermal growth factor decreased time to control (1 study; n=20; HR 2.35; 95% CI 1.62 to 3.41). There is inadequate information available at present to ascertain the optimal therapy for pemphigus vulgaris or pemphigus foliaceus. Further research is required, especially to assess the optimal glucocorticoid dose, the role of adjuvant immunosuppressive medications, and long-term adverse events to improve harm:benefit analyses.
Fourteen eligible trials, which recruited patients between 1974 and 2005, were identified, eight of which compared 'more' with 'less' chemotherapy. Results from these eight trials, including 1519 patients, showed that treatment consisting of 'more' chemotherapy was associated with longer overall survival (OS) (hazard ratio (HR) 0.86; 95% confidence intervals (CI) 0.77 to 0.96; P = 0.005) and with longer progression-free survival (PFS) (n = 1526; HR 0.82; 95% CI 0.74 to 0.90; P < 0.0001). However, serious acute toxicities were more common in women randomised to the more-intense chemotherapy regimens. There was no evidence to suggest that any particular doublet chemotherapy was better (or worse) than any other, or that any single-agent chemotherapy was better (or worse) than another; however, data for these two comparisons were limited. There were no comparative trials of chemotherapy with endocrine therapy or best supportive care alone. This review suggests that more-intense chemotherapy regimens may improve both OS and PFS for women with advanced or recurrent endometrial cancer. However, owing to inconsistencies between cytotoxic drug combinations that have been assessed in randomised trials to date, the optimum regimen has still to be defined. Future trials should aim to include measures of quality of life (QoL) and symptom control in addition to survival and progression outcomes.
Five trials involving 213 women were included.   Behavioural intervention vs control: One trial of pain management training reported reduction in pain and symptoms compared to a control. Three trials of relaxation compared to control reported varied results, two trials showed no difference in symptom severity scores however one trial reported relaxation was effective for reducing symptoms in menstrual sufferers with spasmodic symptoms. Two trials reported less restriction in daily activities following treatment with either relaxation of pain management training compared to a control. One trial also reported less time absent from school following treatment wit pain management training compared to a control. Behavioural intervention vs other behavioural interventions: Three trials showed no difference between behavioural interventions for the outcome of improvement in symptoms. One trial showed that relaxation resulted in a decrease in the need for resting time compared to the relaxation and imagery. There is some evidence from five RCTs that behavioural interventions may be effective for dysmenorrhoea. However results should be viewed with caution as they varied greatly between trials due to inconsistency in the reporting of data, small trial size, poor methodological quality and age of the trials.
Five trials were included in this review, representing 924 randomised children with epilepsy, all under 16 years of age at randomisation, with a median follow-up of 5.6 years. No eligible trial evaluated adults or assessed mortality or status epilepticus as outcomes. The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI 1.13 to 1.59, P = 0.0007). Conforming to this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 8 (95% CI 5 to 20). Early discontinuation was associated with greater relapse rates in people with partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07). Absence type epilepsy showed a lower risk of relapse. Variables associated with higher risk of seizure relapse were abnormal EEG findings (pooled RR 1.44, 95% CI 1.13 to 1.83, P = 0.003), especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P < 0.0001); epilepsy onset before 2 years or after 10 years of age; history of status epilepticus; intellectual disability (IQ < 70); and high seizure frequency before and during treatment. Gender and family history did not show any significant influence over seizure relapse. Overall, the included trials were classified as low or unclear risk of bias where methodological information was not reported and could not be provided by original study authors. There is evidence to support waiting for at least two seizure-free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG or partial seizures, or both. There is insufficient evidence to establish when to withdraw AEDs in children with generalised seizures. There is no evidence to guide the timing of withdrawal of AEDs in seizure-free adults. Further high-quality randomised controlled trials are needed, particularly recruiting adults and recruiting those with generalised seizure types, to identify the optimal timing of AED withdrawal and risk factors predictive of relapse.
Our search did not yield any trial investigating treatment of VVC in HIV positive women. Two trials dealing with prophylaxis were eligible for inclusion.One trial (n= 323) favoured the use of weekly Fluconazole as compared to placebo (RR 0.68; 95% CI 0.47 to 0.97). The second trial with three arms of comparison; Clotrimazole, Lactobacillus and Placebo gave no definitive results in preventing an episode of VVC. Clotrimazole against placebo (RR 0.49; 95% CI 0.22 to 1.09), Clotrimazole against lactobacillus (RR 1.11; 95% CI 0.45 to 2.76) and lactobacillus against placebo (RR 0.54 ;95% CI 0.26 to 1.13). Implications for practice No trials were found addressing treatment of VVC in HIV positive women.In comparison to placebo,Fluconazole was found to be an effective preventative intervention. However, the potential for resistant Candida organisms to develop might impact the feasibility of implementation. Direction of findings suggests that Clotrimazole and Lactobacillus improved the prophylactic outcomes when compared to placebo. Implications for research  There is a need to evaluate drugs and drug regimens for VVC treatment and prophylaxis in HIV positive women through randomised clinical trials. Development of resistance to azoles remains under-studied and more work must be done in this area, so as to determine whether routine prophylaxis for VVC is at all needed or whether adequate ART would be sufficient to prevent recurrent VVC. The viral load in vaginal secretions with or without treatment or prophylaxis has not been studied, this is very relevant to the spread of HIV.
We included 15 studies with a total of 1326 women. All included studies compared a vasodilator versus placebo or no treatment. We judged most of these studies as having unclear risk of bias. Overall, the quality of evidence was low to moderate for most outcomes. The main limitations were imprecision due to low numbers of events and participants and risk of bias due to unclear methods of randomisation. Vasodilators probably make little or no difference in rates of live birth compared with placebo or no treatment (RR 1.18, 95% confidence interval (CI) 0.83 to 1.69; three RCTs; N = 350; I² = 0%; moderate-quality evidence) but probably increase overall rates of side effects including headache and tachycardia (RR 2.35, 95% CI 1.51 to 3.66; four RCTs; N = 418; I² = 0%; moderate-quality evidence). Evidence suggests that if 236 per 1000 women achieve live birth with placebo or no treatment, then between 196 and 398 per 1000 will do so with the use of vasodilators. Compared with placebo or no treatment, vasodilators may slightly improve clinical pregnancy rates (RR 1.45, 95% CI 1.19 to 1.77; 11 RCTs; N = 1054; I² = 6%; low-quality evidence). Vasodilators probably make little or no difference in rates of multiple gestation (RR 1.15, 95% CI 0.55 to 2.42; three RCTs; N = 370; I² = 0%; low-quality evidence), miscarriage (RR 0.83, 95% CI 0.37 to 1.86; three RCTs; N = 350; I² = 0%; low-quality evidence), or ectopic pregnancy (RR 1.48, 95% CI 0.25 to 8.69; two RCTs; N = 250; I² = 5%; low-quality evidence). All studies found benefit for endometrial thickening, but reported effects varied (I² = 92%) and ranged from a mean difference of 0.80 higher (95% CI 0.18 to 1.42) to 3.57 higher (95% CI 3.01 to 4.13) with very low-quality evidence, so we are uncertain how to interpret these results. Evidence was insufficient to show whether vasodilators increase the live birth rate in women undergoing fertility treatment. However, low-quality evidence suggests that vasodilators may slightly increase clinical pregnancy rates. Moderate-quality evidence shows that vasodilators increase overall side effects in comparison with placebo or no treatment. Adequately powered studies are needed so that each treatment can be evaluated more accurately.
We found three RCTs involving 1815 men. Adjuvant RT following prostatectomy did not affect overall survival at 5 years (RD (risk difference) 0.00; 95% CI -0.03 to 0.03), but improved survival at 10 years (RD -0.11; 95% CI -0.20 to -0.02). Adjuvant RT did not improve prostate cancer-specific mortality at 5 years (RD -0.01; 95% CI -0.03 to 0.00). Adjuvant RT did not reduce metastatic disease at 5 years (RD -0.00; 95% CI -0.04 to 0.03), but reduced it at 10 years (RD -0.11; 95% CI -0.20 to -0.01). It improved local control at 5 and 10 years (RD -0.10; 95% CI -0.13 to -0.06 and RD -0.14; 95% CI -0.21 to -0.07, respectively), and biochemical progression-free survival at 5 years and 10 years (RD -0.16; 95% CI -0.21 to -0.11 and RD -0.29; 95% CI -0.39 to -0.19, respectively). There were no data for clinical disease-free survival. Adjuvant RT increased acute and late gastrointestinal toxicity [do you have the rd for this?], urinary stricture (RD 0.05; 95% CI 0.01 to 0.09) and incontinence (RD 0.04; 95% CI 0.01 to 0.08). It did not increase erectile dysfunction or degrade quality of life (RD 0.01; 95% CI -0.06 to -0.26), but with limited data. Adjuvant RT after RP improves overall survival and reduces the rate of distant metastases, but these effects are only evident with longer follow up. At 5 and 10 years it improves local control and reduces the risk of biochemical failure, although the latter is not a clinical endpoint. Moderate or severe acute and late toxicity is minimal. There is an increased risk of urinary stricture and incontinence, but no detriment to quality of life, based on limited data. Given that the majority of men who have undergone a RP have a longer life expectancy, radiotherapy should be considered for those with high-risk features following radical prostatectomy. The optimal timing is unclear.
We included 43 studies with 6617 participants that evaluated the impact of an eHealth intervention in people with CKD. Included studies were heterogeneous in terms of eHealth modalities employed, type of intervention, CKD population studied and outcomes assessed. The majority of studies (39 studies) were conducted in an adult population, with 16 studies (37%) conducted in those on dialysis, 11 studies (26%) in the pre-dialysis population, 15 studies (35%) in transplant recipients and 1 studies (2%) in transplant candidates We identified six different eHealth modalities including: Telehealth; mobile or tablet application; text or email messages; electronic monitors; internet/websites; and video or DVD. Three studies used a combination of eHealth interventions. Interventions were categorised into six types: educational; reminder systems; self-monitoring; behavioural counselling; clinical decision-aid; and mixed intervention types. We identified 98 outcomes, which were categorised into nine domains: blood pressure (9 studies); biochemical parameters (6 studies); clinical end-points (16 studies); dietary intake (3 studies); quality of life (9 studies); medication adherence (10 studies); behaviour (7 studies); physical activity (1 study); and cost-effectiveness (7 studies). Only three outcomes could be meta-analysed as there was substantial heterogeneity with respect to study population and eHealth modalities utilised. There was found to be a reduction in interdialytic weight gain of 0.13kg (4 studies, 335 participants: MD -0.13, 95% CI -0.28 to 0.01; I2 = 0%) and a reduction in dietary sodium intake of 197 mg/day (2 studies, 181 participants: MD -197, 95% CI -540.7 to 146.8; I2 = 0%). Both dietary sodium and fluid management outcomes were graded as being of low evidence due to high or unclear risk of bias and indirectness (interdialytic weight gain) and high or unclear risk of bias and imprecision (dietary sodium intake). Three studies reported death (2799 participants, 146 events), with 45 deaths/1000 cases compared to standard care of 61 deaths/1000 cases (RR 0.74, CI 0.53 to 1.03; P = 0.08). We are uncertain whether using eHealth interventions, in addition to usual care, impact on the number of deaths as the certainty of this evidence was graded as low due to high or unclear risk of bias, indirectness and imprecision. eHealth interventions may improve the management of dietary sodium intake and fluid management. However, overall these data suggest that current evidence for the use of eHealth interventions in the CKD population is of low quality, with uncertain effects due to methodological limitations and heterogeneity of eHealth modalities and intervention types. Our review has highlighted the need for robust, high quality research that reports a core (minimum) data set to enable meaningful evaluation of the literature.
We identified 11 trials investigating a total of 742 children in treatment arms relevant to our study question. Risks of bias in the studies were mainly low or unclear, but two studies had aspects of their methodology that had a high risk of bias. Overall, the quality of the evidence from pooled studies was low or had unclear risk of bias. Four trials compared clonidine with a placebo or no treatment, six trials compared clonidine with midazolam, and one trial compared clonidine with fentanyl. There was substantial methodological heterogeneity between trials; the dose and route of clonidine administration varied as did the patient populations, the types of surgery and the outcomes measured. It was therefore difficult to combine the outcomes of some trials for meta-analysis. When clonidine was compared to placebo, pooling studies of low or unclear risk of bias, the need for additional analgesia was reduced when clonidine premedication was given orally at 4 µg/kg (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.11 to 0.51). Only one small trial (15 patients per arm) compared clonidine to midazolam for the same outcome; this also found a reduction in the need for additional postoperative analgesia (RR 0.25, 95% CI 0.09 to 0.71) when clonidine premedication was given orally at 2 or 4 µg/kg compared to oral midazolam at 0.5 mg/kg. A trial comparing oral clonidine at 4 µg/kg with intravenous fentanyl at 3 µg/kg found no statistically significant difference in the need for rescue analgesia (RR 0.89, 95% CI 0.56 to 1.42). When clonidine 4 µg/kg was compared to clonidine 2 µg/kg, there was a statistically significant difference in the number of patients requiring additional analgesia, in favour of the higher dose, as reported by a single, higher-quality trial (RR 0.38, 95% CI 0.23 to 0.65). The effect of clonidine on pain scores was hard to interpret due to differences in study methodology, the doses and route of drug administration, and the pain scale used. However, when given at a dose of 4 µg/kg, clonidine may have reduced analgesia requirements after surgery. There were no significant side effects of clonidine that were reported such as severe hypotension, bradycardia, or excessive sedation requiring intervention. However, several studies used atropine prophylactically with the aim of preventing such adverse effects. There were only 11 relevant trials studying 742 children having surgery where premedication with clonidine was compared to placebo or other drug treatment. Despite heterogeneity between trials, clonidine premedication in an adequate dosage (4 µg/kg) was likely to have a beneficial effect on postoperative pain in children. Side effects were minimal, but some of the studies used atropine prophylactically with the intention of preventing bradycardia and hypotension. Further research is required to determine under what conditions clonidine premedication is most effective in providing postoperative pain relief in children.
Two trials of moderate quality in children (n = 134) with no evidence of airflow restriction did not find any benefits from oral beta2-agonists. Five trials in adults (n = 418) had mixed results but overall summary statistics did not reveal any significant benefits from oral (three trials) nor from inhaled (two trials) beta2-agonists. Three studies with low-quality evidence demonstrated no significant differences in daily cough scores, nor in the percentage of adults still coughing after seven days (control group 71%; risk ratio (RR) 0.86, 95% confidence interval (CI) 0.63 to 1.18; 220 participants). In one trial, subgroups with evidence of airflow limitation had lower symptom scores if given beta2-agonists. The trials that noted quicker resolution of cough with beta2-agonists were those with a higher proportion of people wheezing at baseline. Low-quality evidence suggests that adults given beta2-agonists were more likely to report tremor, shakiness or nervousness (RR 7.94, 95% CI 1.17 to 53.94; 211 participants; number needed to treat for an additional harmful outcome (NNTH) 2). There is no evidence to support the use of beta2-agonists in children with acute cough who do not have evidence of airflow restriction. There is also little evidence that the routine use of beta2-agonists is helpful for adults with acute cough. These agents may reduce symptoms, including cough, in people with evidence of airflow restriction. However, this potential benefit is not well supported by the available data and must be weighed against the adverse effects associated with their use.
We included seven studies (662 participants). Five were planned as RCTs and two as prospective controlled trials. One RCT failed completely, another was continued as an observational study, reporting also the results of the participants that had been randomized. There was very low quality evidence from one small RCT (111 participants) that quality of life (QoL) during treatment did not differ significantly between rigid bracing and observation (mean difference (MD) -2.10, 95% confidence interval (CI) -7.69 to 3.49). There was very low quality evidence from a subgroup of 77 adolescents from one prospective cohort study showing that QoL, back pain, psychological, and cosmetic issues did not differ significantly between rigid bracing and observation in the long term (16 years). Results of the secondary outcomes showed that there was low quality evidence that rigid bracing compared with observation significantly increased the success rate in 20° to 40° curves at two years' follow-up (one RCT, 116 participants; risk ratio (RR) 1.79, 95% CI 1.29 to 2.50). There was low quality evidence that elastic bracing increased the success rate in 15° to 30° curves at three years' follow-up (one RCT, 47 participants; RR 1.88, 95% CI 1.11 to 3.20). There is very low quality evidence from two prospective cohort studies with a control group that rigid bracing increases the success rate (curves not evolving to 50° or above) at two years' follow-up (one study, 242 participants; RR 1.50, 95% CI 1.19 to 1.89) and at three years' follow-up (one study, 240 participants; RR 1.75, 95% CI 1.42 to 2.16). There was very low quality evidence from a prospective cohort study (57 participants) that very rigid bracing increased the success rate (no progression of 5° or more, fusion, or waiting list for fusion) in adolescents with high degree curves (above 45°) (one study, 57 adolescents; RR 1.79, 95% CI 1.04 to 3.07 in the intention-to-treat (ITT) analysis). There was low quality evidence from one RCT that a rigid brace was more successful than an elastic brace at curbing curve progression when measured in Cobb degrees in low degree curves (20° to 30°), with no significant differences between the two groups in the subjective perception of daily difficulties associated with wearing the brace (43 girls; risk of success at four years' follow-up: RR 1.40, 1.03 to 1.89). Finally, there was very low quality evidence from one RCT (12 participants) that a rigid brace with a pad pressure control system is no better than a standard brace in reducing the risk of progression. Only one prospective cohort study (236 participants) assessed adverse events: neither the percentage of adolescents with any adverse event (RR 1.27, 95% CI 0.96 to 1.67) nor the percentage of adolescents reporting back pain, the most common adverse event, were different between the groups (RR 0.72, 95% CI 0.47 to 1.10). Due to the important clinical differences among the studies, it was not possible to perform a meta-analysis. Two studies showed that bracing did not change QoL during treatment (low quality), and QoL, back pain, and psychological and cosmetic issues in the long term (16 years) (very low quality). All included papers consistently showed that bracing prevented curve progression (secondary outcome). However, due to the strength of evidence (from low to very low quality), further research is very likely to have an impact on our confidence in the estimate of effect. The high rate of failure of RCTs demonstrates the huge difficulties in performing RCTs in a field where parents reject randomization of their children. This challenge may prevent us from seeing increases in the quality of the evidence over time. Other designs need to be implemented and included in future reviews, including 'expertise-based' trials, prospective controlled cohort studies, prospective studies conducted according to pre-defined criteria such as the Scoliosis Research Society (SRS) and the international Society on Scoliosis Orthopedic and Rehabilitation Treatment (SOSORT) criteria. Future studies should increase their focus on participant outcomes, adverse effects, methods to increase compliance, and usefulness of physiotherapeutic scoliosis specific exercises added to bracing.
We included eight RCTs (n = 1243 children) that were at relatively high risk of bias. We found high levels of clinical heterogeneity in the participants, interventions and outcome measures across studies. Nevertheless, in order to quantify pooled effects of supplementary feeding, we decided to combine studies according to prespecified characteristics. These were the children's age (younger or older than 24 months), their nutritional status at baseline (stunted or wasted, or not stunted or wasted) and the duration of the intervention (less or more than 12 months). A statistically significant difference of effect was only found for length during the intervention in children aged less than 12 months (two studies; 795 children; mean difference 0.19 cm; 95% confidence interval (CI) 0.07 to 0.31). Based on the summary statistic calculated for each study, the mean difference (MD) between intervention and control groups ranged from 0.48 cm (95% CI 0.07 to 0.89) to 1.3 cm (95% CI 0.03 to 2.57) after 3 and 12 months of intervention, respectively. Data on potential adverse effects were lacking. The scarcity of available studies and their heterogeneity makes it difficult to reach any firm conclusions. The review findings suggest supplementary feeding has a negligible impact on child growth; however, the pooled results should be interpreted with great caution because the studies included in the review are clinically diverse. Future studies should address issues of research design, including sample size calculation, to detect meaningful clinical effects and adequate intervention allocation concealment. In the meantime, families and children in need should be provided appropriate feeding, health care and sanitation without waiting for new RCTs to establish a research basis for feeding children.
We included 28 studies. We found no clear-cut evidence of effect of the well-researched practice of reviewer and/or author concealment on the outcome of the quality assessment process (9 studies). Checklists and other standardisation media have some evidence to support their use (2 studies). There is no evidence that referees' training has any effect on the quality of the outcome (1 study). Different methods of communicating with reviewers and means of dissemination do not appear to have an effect on quality (3 studies). On the basis of one study, little can be said about the ability of the peer-review process to detect bias against unconventional drugs. Validity of peer review was tested by only one small study in a specialist area. Editorial peer review appears to make papers more readable and improve the general quality of reporting (2 studies), but the evidence for this has very limited generalisability. At present, little empirical evidence is available to support the use of editorial peer review as a mechanism to ensure quality of biomedical research. However, the methodological problems in studying peer review are many and complex. At present, the absence of evidence on efficacy and effectiveness cannot be interpreted as evidence of their absence. A large, well-funded programme of research on the effects of editorial peer review should be urgently launched.
An initial search yielded 2808 citations. After excluding studies failing to meet the inclusion criteria, 19 were deemed eligible for inclusion. Of these studies, two presented duplicate data and were removed. The remaining 17 studies were included in the qualitative synthesis and 8 studies were meta-analyzed.  Twelve studies offered  clinic-based VCT, 3 were employment-based, 1 involved mobile VCT, and 1 provided home-based VCT.  In meta-analysis, the odds of reporting increased number of sexual partners were reduced when comparing participants who received VCT to those who did not, unadjusted random effects pooled OR= 0.69 (95% CI: 0.53-0.90, p=0.007). When stratified by serostatus, these results only remained significant for those who tested HIV-positive. There was an insignificant increase in the odds of condom use/protected sex among participants who received VCT compared to those who did not, unadjusted random effects pooled OR=1.39 (95% CI: 0.97-1.99, p=0.076). When stratified by HIV status, this effect became significant among HIV-positive participants, random effects pooled OR= 3.24 (95% CI: 2.29-4.58, p<0.001). These findings add to growing evidence that VCT can change HIV-related sexual risk behaviors thereby reducing HIV-related risk, and confirming its importance as an HIV prevention strategy. To maximize the effectiveness of VCT, more studies should be conducted to understand which modalities and counseling strategies produce significant reductions in risky behaviors and lead to the greatest uptake of VCT.
We pooled mortality data from eight studies and found a non-significant reduction in mortality at 12 months (OR 0.72, 95% CI 0.45 to, 1.15). We pooled four studies that assessed disease-specific heath-related quality of life (HRQL) and found a statistically significant improvement in HRQL (mean difference -2.61, 95% CI -4.82 to -0.40). Hospitalisations were reported in five studies. Although there was no statistically significant difference in the number of hospitalisations (OR 1.01, 95% CI 0.71 to 1.44), there was significant heterogeneity. Although this heterogeneity appeared to be caused by one outlying study with a statistically significant decrease in hospitalisations in patients receiving home care, whereas the other studies showed a non-significant increase in hospitalisations, we could not draw firm conclusions about why this heterogeneity exists. Data on GP visits and emergency department presentations were available, however no consistent effect in these was observed with the intervention. The intervention also incurred higher health care costs than standard care as reported in a single study. Very few studies provided data on lung function or exercise performance, so there was insufficient evidence to assess impact on these outcomes. Outreach nursing programmes for COPD improved disease-specific HRQL. However the effect on hospitalisations was heterogeneous, reducing admissions in one study, but increasing them in others, therefore we could not draw firm conclusions for this outcome.
Seven trials were identified. Two of them were at low risk of bias (the HALT-C and EPIC3 trials) and included 1676 patients. Both of these trials addressed the role of long-term low-dose pegylated interferon therapy in patients with severe fibrosis (demonstrated on liver biopsy) and were designed to assess the clinical outcomes. The remaining five trials included 300 patients and were at high risk of bias. Based on all trials reporting the outcomes, no significant difference was observed in either all-cause mortality (78/843 (9.3%) versus 62/867 (7.2%); risk ratio (RR) 1.30, 95% confidence interval (CI) 0.95 to 1.79; 3 trials) or hepatic mortality (41/532 (7.7%) versus 40/552 (7.2%); RR 1.07, 95% CI 0.70 to 1.63; 2 trials); however, when only the two trials at low risk of bias were combined, all-cause mortality was significantly higher in the recipients of the pegylated interferon (78/828 (9.4%) versus 57/848 (6.7%); RR 1.41, 95% CI 1.02 to 1.96) although trial sequential analysis could not exclude the possibility of random error. There was less variceal bleeding in the recipients of the interferon (4/843 (0.5%) versus 18/867 (2.1%); RR 0.24, 95% CI 0.09 to 0.67; 3 trials), although again trial sequential analysis could not exclude the presence of a type I error and the effect could not be confirmed in a random-effects model meta-analysis. No significant differences were seen with regard to the development of ascites, encephalopathy, hepatocellular carcinoma, or the need for liver transplantation. One trial reported quality of life data; the pain score was significantly worse in the recipients of the pegylated interferon. Adverse effects tended to be more common in the interferon recipients; the ones that were significantly more common included hematologic complications, infections, flu-like symptoms, and rash. The recipients of interferon had significantly more sustained viral responses (20/557 (3.6%) versus 1/579 (0.2%); RR 15.38, 95% CI 2.93 to 80.71; 4 trials) and a type I error was excluded by trial sequential analysis. The METAVIR activity score also improved (36/55 (65%) versus 20/46 (43.5%); RR 1.49, 95% CI 1.02 to 2.18; 2 trials). No significant differences were seen with regard to histologic fibrosis assessments. The clinical data were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon. In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events. On the other hand, the treatment did result in improvement in some surrogate outcomes, namely sustained viral responses and histologic evidence of inflammation. Interferon monotherapy retreatment cannot be recommended for these patients. No clinical data are available for patients with less severe fibrosis. The sustained viral response cannot be used as a surrogate marker for hepatitis C treatment in this clinical setting with low sustained viral response rates and needs to be validated in others in which higher sustained viral response rates are reported.
We included six studies that compared early oropharyngeal colostrum versus water, saline, placebo, or donor, or versus no intervention, enrolling 335 preterm infants with gestational ages ranging from 25 to 32 weeks' gestation and birth weights of 410 to 2500 grams. Researchers found no significant differences between OPC and control for primary outcomes - incidence of NEC (typical risk ratio (RR) 1.42, 95% confidence interval (CI) 0.50 to 4.02; six studies, 335 infants; P = 0.51; I² = 0%; very low-quality evidence), incidence of late-onset infection (typical RR 0.86, 95% CI 0.56 to 1.33; six studies, 335 infants; P = 0.50; I² = 0%; very low-quality evidence), and death before hospital discharge (typical RR 0.76, 95% CI 0.34 to 1.71; six studies, 335 infants; P = 0.51; I² = 0%; very low-quality evidence). Similarly, meta-analysis showed no difference in length of hospital stay between OPC and control groups (mean difference (MD) 0.81, 95% CI -5.87 to 7.5; four studies, 293 infants; P = 0.65; I² = 49%). Days to full enteral feeds were reduced in the OPC group with MD of -2.58 days (95% CI -4.01 to -1.14; six studies, 335 infants; P = 0.0004; I² = 28%; very low-quality evidence). The effect of OPC was uncertain because of small sample sizes and imprecision in study results (very low-quality evidence). No adverse effects were associated with OPC; however, data on adverse effects were insufficient, and no numerical data were available from the included studies. Overall the quality of included studies was low to very low across all outcomes. We downgraded GRADE outcomes because of concerns about allocation concealment and blinding, reporting bias, small sample sizes with few events, and wide confidence intervals. Large, well-designed trials would be required to evaluate more precisely and reliably the effects of oropharyngeal colostrum on important outcomes for preterm infants.
This review includes a total of 1897 children and 729 adults in 39 trials. Thirty-three trials were conducted in the emergency room and equivalent community settings, and six trials were on inpatients with acute asthma (207 children and 28 adults). The method of delivery of beta₂-agonist did not show a significant difference in hospital admission rates. In adults, the risk ratio (RR) of admission for spacer versus nebuliser was 0.94 (95% CI 0.61 to 1.43). The risk ratio for children was 0.71 (95% CI 0.47 to 1.08, moderate quality evidence). In children, length of stay in the emergency department was significantly shorter when the spacer was used. The mean duration in the emergency department for children given nebulised treatment was 103 minutes, and for children given treatment via spacers 33 minutes less (95% CI -43 to -24 minutes, moderate quality evidence). Length of stay in the emergency department for adults was similar for the two delivery methods. Peak flow and forced expiratory volume were also similar for the two delivery methods. Pulse rate was lower for spacer in children, mean difference -5% baseline (95% CI -8% to -2%, moderate quality evidence), as was the risk of developing tremor (RR 0.64; 95% CI 0.44 to 0.95, moderate quality evidence). Nebuliser delivery produced outcomes that were not significantly better than metered-dose inhalers delivered by spacer in adults or children, in trials where treatments were repeated and titrated to the response of the participant. Spacers may have some advantages compared to nebulisers for children with acute asthma. The studies excluded people with life-threatening asthma; therefore, the results of this meta-analysis should not be extrapolated to this patient population.
We identified eight RCTs with a total of 1183 participants. The duration of the interventions ranged from 12 to 26 weeks; in five trials, the duration of intervention was 12 or 13 weeks. The included studies had moderate risk of bias, and the overall quality of evidence was low or very low for all outcomes. We compared CCT first against active control interventions, such as watching educational videos. Negative SMDs favour CCT over control. Trial results suggest slight improvement in global cognitive function at the end of the intervention period (12 weeks) (standardised mean difference (SMD) -0.31, 95% confidence interval (CI) -0.57 to -0.05; 232 participants; 2 studies; low-quality evidence). One of these trials also assessed global cognitive function 12 months after the end of the intervention; this trial provided no clear evidence of a persistent effect (SMD -0.21, 95% CI -0.66 to 0.24; 77 participants; 1 study; low-quality evidence). CCT may result in little or no difference at the end of the intervention period in episodic memory (12 to 17 weeks) (SMD 0.06, 95% CI -0.14 to 0.26; 439 participants; 4 studies; low-quality evidence) or working memory (12 to 16 weeks) (SMD -0.17, 95% CI -0.36 to 0.02; 392 participants; 3 studies; low-quality evidence). Because of the very low quality of the evidence, we are very uncertain about the effects of CCT on speed of processing and executive function. We also compared CCT to inactive control (no interventions). We found no data on our primary outcome of global cognitive function. At the end of the intervention, CCT may lead to slight improvement in episodic memory (6 months) (mean difference (MD) in Rivermead Behavioural Memory Test (RBMT) -0.90 points, 95% confidence interval (CI) -1.73 to -0.07; 150 participants; 1 study; low-quality evidence) but can have little or no effect on executive function (12 weeks to 6 months) (SMD -0.08, 95% CI -0.31 to 0.15; 292 participants; 2 studies; low-quality evidence), working memory (16 weeks) (MD -0.08, 95% CI -0.43 to 0.27; 60 participants; 1 study; low-quality evidence), or verbal fluency (6 months) (MD -0.11, 95% CI -1.58 to 1.36; 150 participants; 1 study; low-quality evidence). We could not determine any effects on speed of processing because the evidence was of very low quality. We found no evidence on quality of life, activities of daily living, or adverse effects in either comparison. We found low-quality evidence suggesting that immediately after completion of the intervention, small benefits of CCT may be seen for global cognitive function when compared with active controls, and for episodic memory when compared with an inactive control. These benefits are of uncertain clinical importance. We found no evidence that the effect on global cognitive function persisted 12 months later. Our confidence in the results was low, reflecting the overall quality of the evidence. In five of the eight trials, the duration of the intervention was just three months. The possibility that more extensive training could yield larger benefit remains to be more fully explored. We found substantial literature on cognitive training, and collating all available scientific information posed problems. Duration of treatment may not be the best way to categorise interventions for inclusion. As the primary interest of older people and of guideline writers and policymakers involves sustained cognitive benefit, an alternative would be to categorise by length of follow-up after selecting studies that assess longer-term effects.
We included 50 studies with a total of 3704 participants. Forty studies (81%) were at high risk of bias, nine (18%) were at unclear risk of bias, with just one assessed as at low risk of bias. There were 34 different sedatives used with or without inhalational nitrous oxide. Dosages, mode of administration and time of administration varied widely. Studies were grouped into placebo-controlled, dosage and head-to-head comparisons. Meta-analysis of the available data for the primary outcome (behaviour) was possible for studies investigating oral midazolam versus placebo only. There is moderate-certainty evidence from six small clinically heterogeneous studies at high or unclear risk of bias, that the use of oral midazolam in doses between 0.25 mg/kg to 1 mg/kg is associated with more co-operative behaviour compared to placebo; standardized mean difference (SMD) favoured midazolam (SMD 1.96, 95% confidence interval (CI) 1.59 to 2.33, P < 0.0001, I2 = 90%; 6 studies; 202 participants). It was not possible to draw conclusions regarding the secondary outcomes due to inconsistent or inadequate reporting or both. There is some moderate-certainty evidence that oral midazolam is an effective sedative agent for children undergoing dental treatment. There is a need for further well-designed and well-reported clinical trials to evaluate other potential sedation agents. Further recommendations for future research are described and it is suggested that future trials evaluate experimental regimens in comparison with oral midazolam or inhaled nitrous oxide.
We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I2 = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I2 = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I2 = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I2 = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I2 = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.
We identified 1549 records; 85 items from electronic databases, 45 from study registries, and 1419 from congress proceedings. The revised search strategy did not identify any additional RCTs. In the previous version of the review, we identified one RCT comparing HDCT followed by autologous HSCT versus standard-dose chemotherapy (SDCT). The trial randomized 87 participants who were considerably heterogeneous with respect to 19 different tumor entities. The data from 83 participants were available for analysis. In the single included trial, overall survival at three years was 32.7% in the HDCT arm versus 49.4% in the SDCT arm and there was no difference between the treatment groups (hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.70 to 2.29, P = 0.44; 1 study, 83 participants; high quality evidence). In a subgroup of participants who had a complete response before HDCT, overall survival was higher in both treatment groups and overall survival at three years was 42.8% in the HDCT arm versus 83.9% in the SDCT arm and favored the SDCT group (HR 2.92, 95% CI 1.1 to 7.6, P = 0.028; 1 study, 39 participants). In the single included trial, the authors reported one treatment-related leukemia death two years after HDCT. They also evaluated severe adverse events WHO grade 3 to 4 in 22 participants in the HDCT arm and in 51 participants in the SDCT arm. The authors reported 11 events concerning digestive-, infection-, pain-, or asthenia-related toxicity in the HDCT arm and one event in the SDCT arm (moderate quality evidence). The development of secondary neoplasia was not addressed. We judged the study to have an overall unclear risk of bias as three of seven items had unclear and four items had low risk of bias. For GRADE, we judged three items as high quality and three items were not reported. The limited data of a single RCT with an unclear risk of bias and moderate to high quality evidence showed no survival advantage for HDCT. If this treatment is offered it should only be given after careful consideration on an individual person basis and possibly only as part of a well-designed RCT.
We found no trials comparing one type of support versus another. We included seven RCTs (including one cluster-RCT) involving 831 women. The number of women in each trial ranged from 36 to 226. The trials were conducted in high-income countries: USA (5 trials); Denmark (1 trial) and Australia (1 trial), between 2006 and 2015. Three trials only included women who were obese prior to pregnancy and four trials included both women who were overweight and women who were obese. We judged risk of bias in the included trials to be mixed; only one trial was judged to be low risk of bias for random sequence generation, allocation concealment and attrition bias. Physical breastfeeding support (manual or electric breast pump) versus usual care (no breast pump) Very low-certainty evidence from one small trial (39 women) looking at a physical support intervention (manual or electric breast pump) versus usual care (no pump) means it is unclear whether physical support improves exclusive breastfeeding at four to six weeks (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.20 to 1.51) or any breastfeeding at four to six weeks (RR 0.65, 95% CI 0.41 to 1.03). The trial did not report other important outcomes of interest in this review: non-initiation of breastfeeding, exclusive or any breastfeeding at six months postpartum. Multiple methods of breastfeeding support versus usual care Six trials (involving 792 women) used multiple methods of support including education and social support through telephone or face-to-face contact. One of these trials also provided physical support through providing a breast pump and a baby sling and one trial provided a small gift to the women at each trial visit. Support in the trials was provided by a professional (four trials) or a peer (two trials). One trial provided group support, with the other five trials supporting women individually. One trial (174 women) did not report on any of our main outcomes of interest. We are unclear about the effects of the intervention because we identified very low-certainty evidence for all of the important outcomes in this review: rate of non-initiation of breastfeeding (average RR 1.03, 95% CI 0.07 to 16.11; 3 trials, 380 women); exclusive breastfeeding at four to six weeks (average RR 1.21, 95% CI 0.83 to 1.77; 4 trials, 445 women); any breastfeeding at four to six weeks (average RR 1.04, 95% CI 0.57 to 1.89; 2 trials, 103 women); rate of exclusive breastfeeding at six months postpartum (RR 7.23, 95% CI 0.38 to 137.08; 1 trial, 120 women); and any breastfeeding at six months postpartum (average RR 1.42, 95% CI 1.08 to 1.87; 2 trials, 223 women). The included trials under the above comparisons also reported on some of this review's secondary outcomes but very low-certainty evidence means that we are unclear about the effects of the intervention on those outcomes. There is insufficient evidence to assess the effectiveness of physical interventions, or multiple methods of support (social, educational or physical) for supporting the initiation or continuation of breastfeeding in women who are overweight or obese. We found no RCTs comparing one type of support to another type of support. All of our GRADE assessments resulted in very low-certainty evidence, with downgrading decisions based on limitations in trial design (e.g. risk of attrition bias), imprecision, inconsistency. The available trials were mostly of variable quality with small numbers of participants, confounded by poor adherence within both the intervention and control groups. Well designed, adequately powered research is needed to answer questions about the social, educational, physical support, or any combination of these interventions that could potentially help mothers who are overweight or obese to achieve optimal breastfeeding outcomes. We need trials that examine interventions designed specifically for women who are overweight or obese, delivered by people with training about how to overcome some of the challenges these women face when establishing and maintaining breastfeeding. Particular attention could be given to the assessment of antenatal interventions aimed at improving breastfeeding initiation in women with a raised BMI, and not just focusing on recruiting women who have an intention to breastfeed. Given that the majority of current trials were undertaken in the USA, further trials in a diverse range of countries and settings are required. Future trials need to give consideration to the theoretical basis of the intervention using established frameworks to enable replicability by others and to better determine the components of effective interventions.
We included two trials involving 189 participants. One study, with 35 participants, compared methadone with levo-alpha-acetylmethadol (LAAM) for maintenance treatment lasting 16 weeks, after which patients were detoxified. The other study, with 154 participants, compared maintenance treatment with buprenorphine-naloxone and detoxification with buprenorphine. We did not perform meta-analysis because the two studies assessed different comparisons. In the study comparing methadone and LAAM, the authors declared that there was no difference in the use of a substance of abuse or social functioning (data not shown). The quality of the evidence was very low. No side effects, such as nausea, vomiting, constipation, weakness or fatigue, were reported by study participants. In the comparison between buprenorphine maintenance and buprenorphine detoxification, maintenance treatment appeared to be more efficacious in retaining patients in treatment (drop-out risk ratio (RR) 0.37; 95% confidence interval (CI) 0.26 to 0.54), but not in reducing the number of patients with a positive urine test at the end of the study (RR 0.97; 95% CI 0.78 to 1.22). Self reported opioid use at one-year follow-up was significantly lower in the maintenance group, even though both groups reported a high level of opioid use (RR 0.73; 95% CI 0.57 to 0.95). More patients in the maintenance group were enrolled in other addiction treatment programmes at 12-month follow-up (RR 1.33; 95% CI 0.94 to 1.88). The quality of the evidence was low. No serious side effects attributable to buprenorphine-naloxone were reported by study participants and no patients were removed from the study due to side effects. The most common side effect was headache, which was reported by 16% to 21% of patients in both groups It is difficult to draft conclusions on the basis of only two trials. One of the possible reasons for the lack of evidence could be the difficulty of conducting trials with young people for practical and ethical reasons. There is an urgent need for further randomised controlled trials comparing maintenance treatment with detoxification treatment or psychosocial treatment alone before carrying out studies that compare different pharmacological maintenance treatments. These studies should have long follow-up and measure relapse rates after the end of treatment and social functioning (integration at school or at work, family relationships).
At this update six trials and a new comparison (Mechanical bowel preparation versus enema) were added. Altogether eighteen trials were analysed, with 5805 participants; 2906 allocated to MBP (Group A), and 2899 to no preparation (Group B), before elective colorectal surgery. For the comparison Mechanical Bowel Preparation Versus No Mechanical Bowel Preparation results were: 1. Anastomotic leakage for low anterior resection: 8.8% (38/431) of Group A, compared with 10.3% (43/415) of Group B; Peto OR 0.88 [0.55, 1.40]. 2. Anastomotic leakage for colonic surgery: 3.0% (47/1559) of Group A, compared with 3.5% (56/1588) of Group B; Peto OR 0.85 [0.58, 1.26]. 3. Overall anastomotic leakage: 4.4% (101/2275) of Group A, compared with 4.5% (103/2258) of Group B; Peto OR 0.99 [0.74, 1.31]. 4. Wound infection: 9.6% (223/2305) of Group A, compared with 8.5% (196/2290) of Group B; Peto OR 1.16 [0.95, 1.42]. Sensitivity analyses did not produce any differences in overall results. For the comparison Mechanical Bowel Preparation (A) Versus Rectal Enema (B) results were: 1. Anastomotic leakage after rectal surgery: 7.4% (8/107) of Group A, compared with 7.9% (7/88) of Group B; Peto OR 0.93 [0.34, 2.52]. 2. Anastomotic leakage after colonic surgery: 4.0% (11/269) of Group A, compared with 2.0% (6/299) of Group B; Peto OR 2.15 [0.79, 5.84]. 3. Overall anastomotic leakage: 4.4% (27/601) of Group A, compared with 3.4% (21/609) of Group B; Peto OR 1.32 [0.74, 2.36]. 4. Wound infection: 9.9% (60/601) of Group A, compared with 8.0% (49/609) of Group B; Peto OR 1.26 [0.85, 1.88]. Despite the inclusion of more studies with a total of 5805 participants, there is no statistically significant evidence that patients benefit from mechanical bowel preparation, nor the use of rectal enemas. In colonic surgery the bowel cleansing can be safely omitted and induces no lower complication rate. The few studies focused in rectal surgery suggested that mechanical bowel preparation could be used selectively, even though no significant effect was found. Further research on patients submitted for elective rectal surgery, below the peritoneal verge, in whom bowel continuity is restored, and studies with patients submitted to laparoscopic surgeries are still warranted.
We included six RCTs that involved a total of 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data. We found no change in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; moderate-quality evidence). Similarly, we found no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; low-quality evidence). Studies reported more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low-quality evidence). Blood pressures were lower in the lower target group by 8.9/4.5 mmHg. More drugs were needed in the lower target group, but blood pressure targets were achieved more frequently in the standard target group. We found no evidence of a difference in total mortality, serious adverse events, or total cardiovascular events between people with hypertension and cardiovascular disease treated to a lower or to a standard blood pressure target. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on adverse events, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (≤ 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to examine this topic.
No trials were included in the review. There are no published or ongoing randomised controlled clinical trials relevant to this review question. Therefore, in the absence of any high level evidence, clinicians should base their decisions on clinical experience and in conjunction with preferences of the individual where appropriate. This does not mean that carnitine is ineffective or should not be used in any inborn error of metabolism. However, given the lack of evidence both on the effectiveness and safety of carnitine and on the necessary dose and frequency to be prescribed, the current prescribing practice should continue to be observed and monitored with care until further evidence is available. Methodologically sound trials, reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement, are required. It should be considered whether placebo-controlled trials in potentially lethal diseases, e.g. carnitine transporter disorder or glutaric aciduria type I, are ethical.
Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed. During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence). This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.
Ten studies were identified of which 4 met the inclusion criteria. The included studies either differed in the type of TNF-a blocking agent used or in the way outcomes were assessed to such an extent that we considered it inappropriate to combine the data statistically. There is evidence from one randomised controlled trial that suggests that a single intravenous infusion of the monoclonal antibody cA2, infliximab, may be effective for induction of remission in Crohn's disease. There was no difference in response rates among infliximab doses of 5, 10 or 20 mg/kg. The results of two other trials suggested that CDP571, the genetically engineered human TNF monoclonal antibody, may also be effective in reducing disease activity index at 2 weeks after an infusion. We did not find any evidence to support the use of etanercept in Crohn's disease. Evidence from one randomized controlled trial suggests that a single infusion of infliximab may be effective for induction of remission in Crohn's disease. Based on this study, we can recommend a dose of 5 mg/kg. There is also some evidence that CDP571 may be effective in inducing remission in Crohn's disease. We did not find any evidence that supports the use of etanercept in Crohn's disease. The period of follow up for the patients in these studies was probably too short to allow adequate assessment of recently reported serious adverse effects such as tuberculosis and lymphoma.
Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC. 1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence). With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens. We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.
In this updated review, one new eligible study was identified and included, yielding a total of two eligible studies (including a combined total of 401 participants). Of those 401 participants, 170 received 'high'-dose partial liquid ventilation (i.e. a mean dose of at least 20 mL/kg), 99 received 'low-dose' partial liquid ventilation (i.e. a dose of 10 mL/kg) and 132 received conventional mechanical ventilation (CMV). Pooled estimates of effect were calculated for all those who received 'high'-dose PLV versus conventional ventilation. No evidence indicated that 'high'-dose PLV either reduced mortality at 28 d (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.79 to 1.85, P = 0.37) or increased the number of days free of CMV at 28 d (mean difference (MD) -2.24, 95% CI -4.71 to 0.23, P = 0.08). The pooled estimate of effect for bradycardia in those who received PLV was significantly greater than in those who received CMV (RR 2.51, 95% CI 1.31 to 4.81, P = 0.005). Pooled estimates of effect for the following adverse events－hypoxia, pneumothorax, hypotension and cardiac arrest－all showed a nonsignificant trend towards a higher occurrence of these events in those treated with PLV. Because neither eligible study addressed morbidity or mortality beyond 28 d, it was not possible to determine the effect of PLV on these outcomes. No evidence supports the use of PLV in ALI or ARDS; some evidence suggests an increased risk of adverse events associated with its use.
We detected four eligible trials. Two trials compared lower versus higher rates of glucose infusion in the early postnatal period. These trials were too small to assess effects on mortality or major morbidities. Two trials, one a moderately large multicentre trial (NIRTURE, Beardsall 2008), compared insulin infusion with standard care. Insulin infusion reduced hyperglycemia but increased death before 28 days and hypoglycemia. Reduction in hyperglycemia was not accompanied by significant effects on major morbidities; effects on neurodevelopment are awaited. Glucose infusion rate: There is insufficient evidence from trials comparing lower with higher glucose infusion rates to inform clinical practice. Large randomized trials are needed, powered on clinical outcomes including death, major morbidities and adverse neurodevelopment. Insulin infusion: The evidence reviewed does not support the routine use of insulin infusions to prevent hyperglycemia in VLBW neonates. Further randomized trials of insulin infusion may be justified. They should enrol extremely low birth weight neonates at very high risk for hyperglycemia and neonatal death. They might use real time glucose monitors if these are validated for clinical use. Refinement of algorithms to guide insulin infusion is needed to enable tight control of glucose concentrations within the target range.
Nine randomized placebo-controlled trials involving 499 individuals with HIV infection and AIDS met the inclusion criteria. Methodological quality of trials was assessed as adequate in five full publications and unclear in other trials. Eight different herbal medicines were tested. A compound of Chinese herbs (IGM-1) showed significantly better effect than placebo in improvement of health-related quality of life in 30 symptomatic HIV-infected patients (WMD 0.66, 95% CI 0.05 to 1.27). IGM-1 appeared not to affect overall health perception, symptom severity, CD4 count, anxiety or depression (Burack 1996a). An herbal formulation of 35 Chinese herbs did not affect CD4 cell counts, viral load, AIDS events, symptoms, psychosocial measure, or quality of life (Weber 1999). There was no statistical difference between SPV30 and placebo in new AIDS-defining events, CD4 cell counts, or viral load (Durant 1998) although an earlier pilot trial showed positive effect of SPV30 on CD4 cell count (Durant 1997). Combined treatment of Chinese herbal compound SH and antiretroviral agents showed increased antiviral benefit compared with antiretrovirals alone (Sangkitporn 2004). SP-303 appeared to reduce stool weight (p = 0.008) and abnormal stool frequency (p = 0.04) in 51 patients with AIDS and diarrhoea (Holodniy 1999). Qiankunning appeared not to affect HIV-1 RNA levels (Shi 2003), Curcumin ineffective in reducing viral load or improving CD4 cell counts (Hellinger 1996), and Capsaicin ineffective in relieving pain associated with HIV-related peripheral neuropathy (Paice 2000). The occurrence of adverse effects was higher in the 35 Chinese herbs preparation (19/24) than in placebo (11/29) (79% versus 38%, p = 0.003) (Weber 1999). Qiankunning was associated with stomach discomfort and diarrhoea (Shi 2003). There is insufficient evidence to support the use of herbal medicines in HIV-infected individuals and AIDS patients. Potential beneficial effects need to be confirmed in large, rigorous trials.
Four trials (2300 women) are included. The interventions ranged from brief advice through to education on health and lifestyle over several sessions. For most outcomes, data were only available from individual studies. Only one study followed up through pregnancy and there was no strong evidence of a difference between groups for preterm birth, congenital anomalies or weight for gestational age; only one finding (mean birthweight) reached statistical significance (mean difference -97.00, 95% confidence interval (CI) -168.05 to -25.95). This finding needs to be interpreted with caution as pregnancy outcome data were available for only half of the women randomised. There was some evidence that health promotion interventions were associated with positive maternal behavioural change including lower rates of binge drinking (risk ratio 1.24, 95% CI 1.06 to 1.44). Overall, there has been little research in this area and there is a lack of evidence on the effects of pre-pregnancy health promotion on pregnancy outcomes. There is little evidence on the effects of pre-pregnancy health promotion and much more research is needed in this area. There is currently insufficient evidence to recommend the widespread implementation of routine pre-pregnancy health promotion for women of childbearing age, either in the general population or between pregnancies.
We found two completed studies involving a total of 1136 participants that ultimately met our inclusion criteria. We also found one ongoing study and one planned study. We noted significant heterogeneity in the characteristics of interventions and outcomes measured or reported across these studies, thus we could not pool study results. One completed study considered the dispatch of police and fire service CFRs equipped with automatic external defibrillators (AEDs) in an EMS system in Amsterdam and surrounding areas. This study was an RCT with allocation made by cluster according to non-overlapping geographical regions. It was conducted between 5 January 2000 and 5 January 2002. All participants were 18 years of age or older and had experienced witnessed OHCA. The study found no difference in survival at hospital discharge (odds ratio (OR) 1.3, 95% confidence interval (CI) 0.8 to 2.2; 1 RCT; 469 participants; low-certainty evidence), despite the observation that all 72 incidences of defibrillation performed before EMS arrival occurred in the intervention group (OR and 95% CI - not applicable; 1 RCT; 469 participants; moderate-certainty evidence). This study reported increased survival to hospital admission in the intervention group (OR 1.5, 95% CI 1.1 to 2.0; 1 RCT; 469 participants; moderate-certainty evidence). The second completed study considered the dispatch of nearby lay volunteers in Stockholm, Sweden, who were trained to perform cardiopulmonary resuscitation (CPR). This represented a supplementary CFR intervention in an EMS system where police and fire services were already routinely dispatched to OHCA in addition to EMS ambulances. This study, an RCT, included both witnessed and unwitnessed OHCA and was conducted between 1 April 2012 and 1 December 2013. Participants included adults and children eight years of age and older. Researchers found no difference in 30-day survival (OR 1.34, 95% CI 0.79 to 2.29; 1 RCT; 612 participants; low-certainty evidence), despite a significant increase in CPR performed before EMS arrival (OR 1.49, 95% CI 1.09 to 2.03; 1 RCT; 665 participants; moderate-certainty evidence). Neither of the included completed studies considered neurological function at hospital discharge or at 30 days, measured by cerebral performance category or by any other means. Neither of the included completed studies considered health-related quality of life. The overall certainty of evidence for the outcomes of included studies was low to moderate. Moderate-certainty evidence shows that context-specific CFR interventions result in increased rates of CPR or defibrillation performed before EMS arrival. It remains uncertain whether this can translate to significantly increased rates of overall patient survival. When possible, further high-quality RCTs that are adequately powered to measure changes in survival should be conducted. The included studies did not consider survival with good neurological function. This outcome is likely to be important to patients and should be included routinely wherever survival is measured. We identified one ongoing study and one planned trial whose results once available may change the results of this review. As this review was limited to randomized and quasi-randomized trials, we may have missed some important data from other study types.
We found six trials of five different interventions eligible for inclusion in this review. The trials were conducted in hospitals in Canada, China, Germany, Japan and the UK, and included 151 participants in total. All trials randomised participants aged 16 years and older (mean or median age in the trials ranged from 36 to 57 years in the intervention groups and 34 to 60 years in the control groups) with severe GBS, defined by the inability to walk unaided. One trial also randomised patients with mild GBS who were still able to walk unaided. We identified two new trials at this update.The primary outcome measure for this review was improvement in disability grade four weeks after randomisation. Four of six trials had a high risk of bias in at least one respect. We assessed all evidence for the outcome mean improvement in disability grade as very low certainty, which means that we were unable to draw any conclusions from the data. One RCT with 19 participants compared interferon beta-1a (IFNb-1a) and placebo. It is uncertain whether IFNb-1a improves disability after four weeks (mean difference (MD) -0.1; 95% CI −1.58 to 1.38; very low-certainty evidence). A trial with 10 participants compared brain-derived neurotrophic factor (BNDF) and placebo. It is uncertain whether BDNF improves disability after four weeks (MD 0.75; 95% CI −1.14 to 2.64; very low-certainty evidence). A trial with 37 participants compared cerebrospinal fluid (CSF) filtration and plasma exchange. It is uncertain whether CSF filtration improves disability after four weeks (MD 0.02; 95% CI −0.62 to 0.66; very low-certainty evidence). One trial that compared the Chinese herbal medicine tripterygium polyglycoside with corticosteroids with 43 participants did not report the risk ratio (RR) for an improvement by one or more disability grade after four weeks, but did report improvement after eight weeks. It is uncertain whether tripterygium polyglycoside improves disability after eight weeks (RR 1.47; 95% CI 1.02 to 2.11; very low-certainty evidence). We performed a meta-analysis of two trials comparing eculizumab and placebo with 41 participants. It is uncertain whether eculizumab improves disability after four weeks (MD -0.23; 95% CI −1.79 to 1.34; very low-certainty evidence). Serious adverse events were uncommon in each of the trials and evidence was graded as either low or very low. It is uncertain whether serious adverse events were more common with IFNb-1a versus placebo (RR 0.92, 95% CI 0.23 to 3.72; 19 participants), BNDF versus placebo (RR 1.00, 95% CI 0.28 to 3.54; 10 participants) or CSF filtration versus plasma exchange (RR 0.13, 95% CI 0.01 to 2.25; 37 participants). The trial of tripterygium polyglycoside did not report serious adverse events. There may be no clear difference in the number of serious adverse events after eculizumab compared to placebo (RR 1.90, 0.34 to 10.50; 41 participants). We found no clinically important differences in any of the outcome measures selected for this review in any of the six trials. However, sample sizes were small and therefore clinically important benefit or harm cannot be excluded. All six RCTs were too small to exclude clinically important benefit or harm from the assessed interventions. The certainty of the evidence was low or very low for all interventions and outcomes.
We included two studies (212 participants) comparing antibiotics versus no treatment, and identified three on-going studies. Overall, incidence of symptomatic UTI varied between 19% and 31% in the groups not treated for asymptomatic bacteriuria. Antibiotic treatment had uncertain effects on preventing symptomatic UTI (2 studies, 200 participants: RR 0.86, 95% CI 0.51 to 1.45). Risk for selecting multidrug-resistant organisms was uncertain with antibiotic treatment (1 study, 112 participants: RR 1.21, 95% CI 0.60 to 2.41). Persistence of asymptomatic bacteriuria was high regardless of treatment. Antibiotics also have uncertain effects on other important patient and graft outcomes, for instance on all-cause mortality (1 study, 112 participants: RR 2.23, 95% CI 0.21 to 23.86), graft loss (1 study, 112 participants: RR 1.11, 95% CI 0.07 to 17.36), acute rejection (1 study, 112 participants: RR 0.93, 95% CI 0.44 to 1.97), hospitalisation for UTI (1 study, 112 participants: RR 0.74, 95% CI 0.13 to 4.27), graft function (2 studies, 200 participants, MD in serum creatinine concentration -0.06 mg/dL, 95% CI -0.19 to 0.08) and adverse reactions (1 study, 112 participants: no severe adverse event attributable to the antibiotic treatment). Evidence quality was low for all outcomes. Currently, there is insufficient evidence to support routinely treating kidney transplant recipients with antibiotics in case of asymptomatic bacteriuria after transplantation, but data are scarce. Further studies assessing routine antibiotic treatment would inform practice and we await the results of three ongoing randomised studies, which may help resolve existing uncertainties.
The search identified three RCTs with 138 participants. All three trials included only children with viral encephalitis, one of these included only children with Japanese encephalitis, a specific form of viral encephalitis. Only the trial of Japanese encephalitis (22 children) contributed to the primary outcome of this review and follow-up in that study was for three to six months after hospital discharge. There was no follow-up of participants in the other two studies. We identified one ongoing trial. For the primary outcomes, the results showed no significant difference between IVIG and placebo when used in the treatment of children with Japanese encephalitis: significant disability (RR 0.75, 95% CI 0.22 to 2.60; P = 0.65) and serious adverse events (RR 1.00, 95% CI 0.07 to 14.05; P = 1.00). For the secondary outcomes, the study of Japanese encephalitis showed no significant difference between IVIG and placebo when assessing significant disability at hospital discharge (RR 1.00, 95% CI 0.60 to 1.67). There was no significant difference (P = 0.53) in Glasgow Coma Score at discharge between IVIG (median score 14; range 3 to 15) and placebo (median 14 score; range 7 to 15) in the Japanese encephalitis study. The median length of hospital stay in the Japanese encephalitis study was similar for IVIG-treated (median 13 days; range 9 to 21) and placebo-treated (median 12 days; range 6 to 18) children (P = 0.59). Pooled analysis of the results of the other two studies resulted in a significantly lower mean length of hospital stay (MD -4.54 days, 95% CI -7.47 to -1.61; P = 0.002), time to resolution of fever (MD -0.97 days, 95% CI -1.25 to -0.69; P < 0.00001), time to stop spasms (MD -1.49 days, 95% CI -1.97 to -1.01; P < 0.00001), time to regain consciousness (MD -1.10 days, 95% CI -1.48 to -0.72; P < 0.00001), and time to resolution of neuropathic symptoms (MD -3.20 days, 95% CI -3.34 to -3.06; P < 0.00001) in favour of IVIG when compared with standard care. None of the included studies reported other outcomes of interest in this review including need for invasive ventilation, duration of invasive ventilation, cognitive impairment, poor adaptive functioning, quality of life, number of seizures, and new diagnosis of epilepsy. The quality of evidence was very low for all outcomes of this review. The findings suggest a clinical benefit of adjunctive IVIG treatment for children with viral encephalitis for some clinical measures (i.e. mean length of hospital stay, time (days) to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever. For children with Japanese encephalitis, IVIG had a similar effect to placebo when assessing significant disability and serious adverse events. Despite these findings, the risk of bias in the included studies and quality of the evidence make it impossible to reach any firm conclusions on the efficacy and safety of IVIG as add-on treatment for children with encephalitis. Furthermore, the included studies involved only children with viral encephalitis, therefore findings of this review cannot be generalised to all forms of encephalitis. Future well-designed RCTs are needed to assess the efficacy and safety of IVIG in the management of children with all forms of encephalitis. There is a need for internationally agreed core outcome measures for clinical trials in childhood encephalitis.
We included eight RCTs that evaluated the effects of chlorhexidine varnishes (1%, 10% or 40% concentration) and chlorhexidine gel (0.12%) on the primary or permanent teeth, or both, of children from birth to 15 years of age at the start of the study. The studies randomised a total of 2876 participants, of whom 2276 (79%) were evaluated. We assessed six studies as being at high risk of bias overall and two studies as being at unclear risk of bias overall. Follow-up assessment ranged from 6 to 36 months. Six trials compared chlorhexidine varnish with placebo or no treatment. It was possible to pool the data from two trials in the permanent dentition (one study using 10% chlorhexidine and the other, 40%). This led to an increase in the DMFS increment in the varnish group of 0.53 (95% confidence interval (CI) -0.47 to 1.53; two trials, 690 participants; very low quality evidence). Only one trial (10% concentration chlorhexidine varnish) provided usable data for elevated mutans streptococci levels > 4 with RR 0.93 (95% CI 0.80 to 1.07, 496 participants; very low quality evidence). One trial measured adverse effects (for example, ulcers or tooth staining) and reported that there were none; another trial reported that no side effects of the treatment were noted. No trials reported on pain, quality of life, patient satisfaction or costs. Two trials compared chlorhexidine gel (0.12% concentration) with no treatment in the primary dentition. The presence of new caries gave rise to a 95% confidence interval that was compatible with either an increase or a decrease in caries incidence (RR 1.00, 95% CI 0.36 to 2.77; 487 participants; very low quality evidence). Similarly, data for the effects of chlorhexidine gel on the prevalence of mutans streptococci were inconclusive (RR 1.26, 95% CI 0.95 to 1.66; two trials, 490 participants; very low quality evidence). Both trials measured adverse effects and did not observe any. Neither of these trials reported on the other secondary outcomes such as measures of pain, quality of life, patient satisfaction or direct and indirect costs of interventions. We found little evidence from the eight trials on varnishes and gels included in this review to either support or refute the assertion that chlorhexidine is more effective than placebo or no treatment in the prevention of caries or the reduction of mutans streptococci levels in children and adolescents. There were no trials on other products containing chlorhexidine such as sprays, toothpastes, chewing gums or mouthrinses. Further high quality research is required, in particular evaluating the effects on both the primary and permanent dentition and using other chlorhexidine-containing oral products.
We added nine studies to this review to bring the total number of included studies to 32 comparing an intervention tailored to address identified determinants of practice to no intervention or an intervention(s) not tailored to the determinants. The outcome was implementation of recommended practice, e.g. clinical practice guideline recommendations. Fifteen studies provided enough data to be included in the quantitative analysis. The pooled odds ratio was 1.56 (95% confidence interval (CI) 1.27 to 1.93, P value < 0.001). The 17 studies not included in the meta-analysis had findings showing variable effectiveness consistent with the findings of the meta-regression. Despite the increase in the number of new studies identified, our overall finding is similar to that of the previous review. Tailored implementation can be effective, but the effect is variable and tends to be small to moderate. The number of studies remains small and more research is needed, including trials comparing tailored interventions to no or other interventions, but also studies to develop and investigate the components of tailoring (identification of the most important determinants, selecting interventions to address the determinants). Currently available studies have used different methods to identify determinants of practice and different approaches to selecting interventions to address the determinants. It is not yet clear how best to tailor interventions and therefore not clear what the effect of an optimally tailored intervention would be.
The updated search resulted in the identification of one ongoing trial comparing surgery versus conservative treatment. Four trials, involving a total of 237 participants, were included. All four trials were methodologically flawed and potentially biased. Three trials tested conservative treatment interventions. One trial, which compared short arm (below elbow) pre-fabricated functional braces with long arm (elbow included) plaster casts, found there was no significant difference in the time it took for fracture union. Patient satisfaction and return to work during treatment were significantly better in the brace group. The other two trials, both quasi-randomised, had three treatment groups. One trial compared Ace Wrap elastic bandage versus short arm plaster cast versus long arm plaster cast. The large loss to follow-up in this trial makes any data analysis tentative. However, the need for replacement of the Ace wrap by other methods due to pain indicates the potential for a serious problem with this intervention. The other trial, which compared immediate mobilisation versus short arm plaster cast versus long arm plaster cast for minimally displaced fractures, found no significant differences in outcome between these three interventions. The fourth trial, which compared two types of plates for surgical fixation, found no significant differences in functional or anatomical outcomes nor complications between the two groups. There is insufficient evidence from randomised trials to determine which method of treatment is the most appropriate for isolated fractures of the ulnar shaft in adults. Well designed and reported randomised trials of current forms of conservative treatment are recommended.
The search retrieved 1585 records; from those five studies were eligible, including 351 women (intervention = 166; control = 185). All studies were judged to be at high risk of bias. All reported per-woman rather than per-cycle data. When use of low-dose hCG to replace FSH was compared with conventional COH for the outcome of live birth, confidence intervals were very wide and findings were compatible with appreciable benefit, no effect or appreciable harm for the intervention (RR 1.56, 95% CI 0.75 to 3.25, 2 studies, 130 women, I² = 0%, very-low-quality evidence). This suggests that for women with a 14% chance of achieving live birth using conventional COH, the chance of achieving live birth using low-dose hCG would be between 10% and 45%. Similarly confidence intervals were very wide for the outcome of OHSS and findings were compatible with benefit, no effect or harm for the intervention (OR 0.30, 95% CI 0.06 to 1.59, 5 studies, 351 women, I² = 59%, very-low-quality evidence). This suggests that for women with a 3% risk of OHSS using conventional COH, the risk using low-dose hCG would be between 0% and 4%. The confidence intervals were wide for the outcome of ongoing pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.14, 95% CI 0.81 to 1.60, 3 studies, 252 women, I² = 0%, low-quality evidence). This suggests that for women with a 32% chance of achieving ongoing pregnancy using conventional COH, the chance using low-dose hCG would be between 27% and 53%. The confidence intervals were wide for the outcome of clinical pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.19, 95% CI 0.92 to 1.55, 5 studies, 351 women, I² = 0%, low-quality evidence). This suggests that for women with a 35% chance of achieving clinical pregnancy using conventional COH, the chance using low-dose hCG would be between 32% and 54%. The confidence intervals were very wide for the outcome of miscarriage and findings were compatible with benefit, no effect or harm for the intervention (RR 1.08, 95% CI 0.50 to 2.31, 3 studies, 127 pregnant women, I² = 0%, very-low-quality evidence). This suggests that for pregnant women with a 16% risk of miscarriage using conventional COH, the risk using low-dose hCG would be between 8% and 36%. The findings for the outcome of FSH consumption were compatible with benefit for the intervention (MD -639 IU, 95% CI -893 to -385, 5 studies, 333 women, I² = 88%, moderate-quality evidence). The findings for the outcome of number of oocytes retrieved were compatible with no effect for the intervention (MD -0.12 oocytes, 95% CI -1.0 to 0.8 oocytes, 5 studies, 351 women, I² = 0%, moderate-quality evidence). We are very uncertain of the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH. The current evidence suggests that this intervention does not reduce the chance of ongoing and clinical pregnancy; and that it is likely to result in an equivalent number of oocytes retrieved expending less FSH. More studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.
There are 77 studies included in this updated review. We retained 12 studies from the original review and identified 65 new studies. Evidence from 21 countries is provided in this update, an increase of eight countries from the original review. The nature of the intervention precludes randomized controlled trials. Thirty-six studies used an interrupted time series study design, 23 studies use a controlled before-and-after design and 18 studies are before-and-after studies with no control group; six of these studies use a cohort design. Seventy-two studies reported health outcomes, including cardiovascular (44), respiratory (21), and perinatal outcomes (7). Eleven studies reported national mortality rates for smoking-related diseases. A number of the studies report multiple health outcomes. There is consistent evidence of a positive impact of national smoking bans on improving cardiovascular health outcomes, and reducing mortality for associated smoking-related illnesses. Effects on respiratory and perinatal health were less consistent. We found 24 studies evaluating the impact of national smoke-free legislation on smoking behaviour. Evidence of an impact of legislative bans on smoking prevalence and tobacco consumption is inconsistent, with some studies not detecting additional long-term change in existing trends in prevalence. Since the first version of this review was published, the current evidence provides more robust support for the previous conclusions that the introduction of a legislative smoking ban does lead to improved health outcomes through reduction in SHS for countries and their populations. The clearest evidence is observed in reduced admissions for acute coronary syndrome. There is evidence of reduced mortality from smoking-related illnesses at a national level. There is inconsistent evidence of an impact on respiratory and perinatal health outcomes, and on smoking prevalence and tobacco consumption.
We included a total of 18 studies involving 2366 participants (976 participants with common bile duct stones and 1390 participants without common bile duct stones). Eleven studies evaluated EUS alone, and five studies evaluated MRCP alone. Two studies evaluated both tests. Most studies included patients who were suspected of having common bile duct stones based on abnormal liver function tests; abnormal transabdominal ultrasound; symptoms such as obstructive jaundice, cholangitis, or pancreatitis; or a combination of the above. The proportion of participants who had undergone cholecystectomy varied across studies. Not one of the studies was of high methodological quality. For EUS, the sensitivities ranged between 0.75 and 1.00 and the specificities ranged between 0.85 and 1.00. The summary sensitivity (95% confidence interval (CI)) and specificity (95% CI) of the 13 studies that evaluated EUS (1537 participants; 686 cases and 851 participants without common bile duct stones) were 0.95 (95% CI 0.91 to 0.97) and 0.97 (95% CI 0.94 to 0.99). For MRCP, the sensitivities ranged between 0.77 and 1.00 and the specificities ranged between 0.73 and 0.99. The summary sensitivity and specificity of the seven studies that evaluated MRCP (996 participants; 361 cases and 635 participants without common bile duct stones) were 0.93 (95% CI 0.87 to 0.96) and 0.96 (95% CI 0.90 to 0.98). There was no evidence of a difference in sensitivity or specificity between EUS and MRCP (P value = 0.5). From the included studies, at the median pre-test probability of common bile duct stones of 41% the post-test probabilities (with 95% CI) associated with positive and negative EUS test results were 0.96 (95% CI 0.92 to 0.98) and 0.03 (95% CI 0.02 to 0.06). At the same pre-test probability, the post-test probabilities associated with positive and negative MRCP test results were 0.94 (95% CI 0.87 to 0.97) and 0.05 (95% CI 0.03 to 0.09). Both EUS and MRCP have high diagnostic accuracy for detection of common bile duct stones. People with positive EUS or MRCP should undergo endoscopic or surgical extraction of common bile duct stones and those with negative EUS or MRCP do not need further invasive tests. However, if the symptoms persist, further investigations will be indicated. The two tests are similar in terms of diagnostic accuracy and the choice of which test to use will be informed by availability and contra-indications to each test. However, it should be noted that the results are based on studies of poor methodological quality and so the results should be interpreted with caution. Further studies that are of high methodological quality are necessary to determine the diagnostic accuracy of EUS and MRCP for the diagnosis of common bile duct stones.
We found five relevant trials (total n=537), but no usable data on service outcomes, general functioning, behaviour, engagement with services, satisfaction with treatment or economic outcomes. Overall, reporting of data was poor. Those data we were able to use suggested that equal proportions of people allocated lamotrigine or placebo had no global response (n=208, 1 RCT, RR 1.06 CI 0.73 to 1.54). There was no significant difference between groups in the proportions of people whose mental state did not improve (n=297, 3 RCT, RR 1.26 CI 0.81 to 1.97). There was, however, a significant reduction in the PANSS total scores (n=67, 2 RCT, WMD -16.88 CI -8.57 to -25.18, p=0.0001), positive symptom sub-scale scores (n=65, 2 RCTs, WMD -5.10 CI -8.86 to -1.34) and negative symptom sub-scale scores (n=67, 2 RCTs, WMD -5.25, CI -7.07 to -3.43). Most cognitive measures showed no differences (n=329, 2 RCTs, RR not attaining BACS composite score of 0.5 1.10 CI 0.59 to 2.04). The proportion of participants leaving studies was about 25% at 12 weeks (n=537, 5 RCTs, RR 0.96 CI 0.71 to 1.29). The lamotrigine group did experience the outcome of any adverse effects significantly more frequent than people allocated placebo (n=429, 2 RCTs, RR 1.19 CI 1.02 to 1.38, NNH 10 CI 5 to 90). Among the many effects listed, only nausea was found to be significantly more (9%) in the lamotrigine group compared with placebo (n=465, 3 RCTs, RR 2.26 CI 1.05 to 4.88). Evidence for use of lamotrigine as an adjuvant for people with schizophrenia is not robust and large well-designed, conducted and reported real-world randomised trials are needed to determine its place in everyday clinical practice.
Primary outcomes Stenting may slightly reduce the number of unplanned return visits (16 trials with 1970 participants; very low CoE), but we are very uncertain of this finding. Pain on the day of surgery as measured on a visual analogue scale (scale 0 to 10; higher values reflect more pain) is probably similar (mean difference (MD) 0.32 higher, 95% confidence interval (CI) 0.13 lower to 0.78 higher; 4 trials with 346 participants; moderate CoE). Pain on postoperative days 1 to 3 may show little to no difference (standardised mean difference (SMD) 0.25 higher, 95% CI 0.32 lower to 0.82 higher; 8 trials with 683 participants; low CoE). On postoperative days 4 to 30, stented participants may experience more pain (8 trials with 903 participants; very low CoE), but we are very uncertain of this finding. Stenting may result in little to no difference in the need for secondary interventions (risk ratio (RR) 1.15, 95% CI 0.39 to 3.33; 10 studies with 1435 participants; low CoE); this corresponds to three more interventions per 1000 participants (95% CI 13 fewer to 48 more). Secondary outcomes Stenting may reduce the need for narcotics (7 trials with 830 participants; very low CoE), but we are very uncertain of this finding. Rates of urinary tract infection (UTI) up to 90 days are probably not substantially different (RR 0.94, 95% CI 0.59 to 1.51; 10 trials with 1207 participants; moderate CoE); this corresponds to three fewer infections per 1000 participants (95% CI 23 fewer to 29 more). Ureteral stricture rates up to 90 days may be slightly reduced (14 trials with 1625 participants; very low CoE), but we are very uncertain of this finding. Rates of hospital admission may be slightly reduced (RR 0.70, 95% CI 0.32 to 1.55; 13 studies with 1647 participants; low CoE). This corresponds to 15 fewer admissions per 1000 participants (95% CI 33 fewer to 27 more). Findings of this review illustrate the trade-offs of risks and benefits faced by urologists and their patients when it comes to decision-making about stent placement after uncomplicated ureteroscopy for stone disease. We noted that both desirable and undesirable effects were small in absolute terms, with findings based mostly on low and very low CoE. The main issues reducing our confidence in research findings were study limitations (mostly risk of performance and detection bias) and imprecision. We were unable to conduct any of the preplanned subgroup analyses, in particular those based on stone size, stone location, and use of ureteral dilation, which may be important effect modifiers. Given the importance of this question, higher-quality and sufficiently large trials are needed to better inform decision-making.
Four trials compared the short-term effects of ipratropium bromide versus a beta2-agonist. Short-term changes in FEV1 (up to 90 minutes) showed no significant difference between beta2-agonist and ipratropium bromide treated patients. The differences were similar among the studies and when combined: Weighted Mean Difference (WMD) 0.0 liters (95% Confidence Interval (95% CI) -0.19 to 0.19). There was no significant additional increase in change in FEV1 on adding ipratropium to beta2-agonist: WMD 0.02 liter (95% CI -0.08 to 0.12). Long-term effects (24 hours) of the ipratropium bromide and beta2-agonist treatment combination were similar: WMD 0.05 liters (95% CI -0.14 to 0.05). Neither of two studies found significant changes in PaO2, either short- or long-term, with ipratropium versus beta-agonist, although one showed an increase in PaO2 in subjects receiving ipratropium bromide at 60 minutes. Adverse drug reactions included dry mouth and tremor. There was no evidence that the degree of bronchodilation achieved with ipratropium bromide was greater than that using a short-acting beta2-agonist. The combination of a beta2-agonist and ipratropium did not appear to increase the effect on FEV1 more than either used alone.
Forty-five trials, studying 69 exercise interventions, were eligible for this review, including 2250 people with MS. The prescribed exercise interventions were categorised as endurance training (23 interventions), muscle power training (nine interventions), task-oriented training (five interventions), mixed training (15 interventions), or 'other' (e.g. yoga; 17 interventions). Thirty-six included trials (1603 participants) provided sufficient data on the outcome of fatigue for meta-analysis. In general, exercise interventions were studied in mostly participants with the relapsing-remitting MS phenotype, and with an Expanded Disability Status Scale less than 6.0. Based on 26 trials that used a non-exercise control, we found a significant effect on fatigue in favour of exercise therapy (standardized mean difference (SMD) -0.53, 95% confidence interval (CI) -0.73 to -0.33; P value < 0.01). However, there was significant heterogeneity between trials (I2 > 58%). The mean methodological quality, as well as the combined body of evidence, was moderate. When considering the different types of exercise therapy, we found a significant effect on fatigue in favour of exercise therapy compared to no exercise for endurance training (SMDfixed effect -0.43, 95% CI -0.69 to -0.17; P value < 0.01), mixed training (SMDrandom effect -0.73, 95% CI -1.23 to -0.23; P value < 0.01), and 'other' training (SMDfixed effect -0.54, 95% CI -0.79 to -0.29; P value < 0.01). Across all studies, one fall was reported. Given the number of MS relapses reported for the exercise condition (N = 25) and non-exercise control condition (N = 26), exercise does not seem to be associated with a significant risk of a MS relapse. However, in general, MS relapses were defined and reported poorly. Exercise therapy can be prescribed in people with MS without harm. Exercise therapy, and particularly endurance, mixed, or 'other' training, may reduce self reported fatigue. However, there are still some important methodological issues to overcome. Unfortunately, most trials did not explicitly include people who experienced fatigue, did not target the therapy on fatigue specifically, and did not use a validated measure of fatigue as the primary measurement of outcome.
The search identified a total of 824 citations; one study was identified for inclusion and two studies are awaiting classification. The 214 participants involved in the included study were adults with AECOPD, receiving treatment by paramedics en route to hospital. The mean age of participants was 68 years. A reduction in pre/in-hospital mortality was observed in favour of the titrated oxygen group (two deaths in the titrated oxygen group compared to 11 deaths in the high-flow control arm; risk ratio (RR) 0.22, 95% confidence interval (CI) 0.05 to 0.97; 214 participants). This translates to an absolute effect of 94 per 1000 (high-flow oxygen) compared to 21 per 1000 (titrated oxygen), and a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 12 to 355) with titrated oxygen therapy. Other than mortality, no other adverse events were reported in the included study. Wide confidence intervals were observed between groups for arterial blood gas (though this may be confounded by protocol infidelity in the included study for this outcome measure), treatment failure requiring invasive or non-invasive ventilation or hospital utilisation. No data were reported for quality of life, lung function or dyspnoea. Risk of bias within the included study was largely unclear, though there was high risk of bias in domains relating to performance and attrition bias. We judged the evidence to be of low certainty, according to GRADE criteria. The one included study found a reduction in pre/in-hospital mortality for the titrated oxygen arm compared to the high-flow control arm. However, the paucity of evidence somewhat limits the reliability of these findings and generalisability to other settings. There is a need for robust, well-designed RCTs to further investigate the effect of oxygen therapies in the pre-hospital setting for people with AECOPD.
We included 14 trials involving 1014 women. The trials were small and not of high methodologic quality. Of the nine trials reporting on physical fitness, six reported significant improvement in physical fitness in the exercise group, although inconsistencies in summary statistics and measures used to assess fitness prevented quantitative pooling of results. Eleven trials reported on pregnancy outcomes. A pooled increased risk of preterm birth (risk ratio 1.82, 95% confidence interval (CI) 0.35 to 9.57) with exercise, albeit statistically non-significant, does not cohere with the absence of effect on mean gestational age (mean difference +0.10, 95% CI -0.11 to +0.30 weeks), while the results bearing on growth of the fetus are inconsistent. One small trial reported that physically fit women who increased the duration of exercise bouts in early pregnancy and then reduced that duration in later pregnancy gave birth to larger infants with larger placentas. Regular aerobic exercise during pregnancy appears to improve (or maintain) physical fitness. Available data are insufficient to infer important risks or benefits for the mother or infant. Larger and better trials are needed before confident recommendations can be made about the benefits and risk of aerobic exercise in pregnancy.
For this updated review, we added 24 new studies meeting the eligibility criteria to the 11 studies from prior updates. We have therefore included 35 studies, randomising 925,171 participants. Seven studies including 11,204 individuals compared adherence rates of those in an intensification of a patient care intervention (e.g. electronic reminders, pharmacist-led interventions, healthcare professional education of patients) versus usual care over the short term (six months or less), and were pooled in a meta-analysis. Participants in the intervention group had better adherence than those receiving usual care (odds ratio (OR) 1.93, 95% confidence interval (CI) 1.29 to 2.88; 7 studies; 11,204 participants; moderate-quality evidence). A separate analysis also showed improvements in long-term adherence rates (more than six months) using intensification of care (OR 2.87, 95% CI 1.91 to 4.29; 3 studies; 663 participants; high-quality evidence). Analyses of the effect on total cholesterol and LDL-cholesterol levels also showed a positive effect of intensified interventions over both short- and long-term follow-up. Over the short term, total cholesterol decreased by a mean of 17.15 mg/dL (95% CI 1.17 to 33.14; 4 studies; 430 participants; low-quality evidence) and LDL-cholesterol decreased by a mean of 19.51 mg/dL (95% CI 8.51 to 30.51; 3 studies; 333 participants; moderate-quality evidence). Over the long term (more than six months) total cholesterol decreased by a mean of 17.57 mg/dL (95% CI 14.95 to 20.19; 2 studies; 127 participants; high-quality evidence). Included studies did not report usable data for health outcome indications, adverse effects or costs/resource use, so we could not pool these outcomes. We assessed each included study for bias using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. In general, the risk of bias assessment revealed a low risk of selection bias, attrition bias, and reporting bias. There was unclear risk of bias relating to blinding for most studies. The evidence in our review demonstrates that intensification of patient care interventions improves short- and long-term medication adherence, as well as total cholesterol and LDL-cholesterol levels. Healthcare systems which can implement team-based intensification of patient care interventions may be successful in improving patient adherence rates to lipid-lowering medicines.
There are sixteen included trials, all of which included participants with mild-moderate dementia or cognitive decline. All trials assessed the cognitive effects of ALC and in addition most considered severity of dementia, functional ability and clinical global impression.  When considering clinical global impression (CGI-I) as a dichotomous variable (numbers improved versus numbers unchanged or worse) there were statistically significant treatment effects in favour of ALC at 12 and 24 weeks, (Peto odds ratio (OR) 1.90, 95% Confidence Interval (CI) 1.31 to 2.76) and (OR 2.33, 95% CI 1.31 to 4.14) but not at 52 weeks (OR 0.91, 95% CI 0.58 to 1.43). There was also a statistically significant treatment effect on MMSE at 24 weeks (Weighted Mean Difference (WMD) 0.69, 95% CI 0.09 to 1.29, P = 0.02), but not at 12 or 52 weeks. There was no evidence of benefit of ALC in the areas of severity of dementia, functional ability or Clinical Global Impression as a continuous measure.  Various adverse events were reported, but from the meta-analyses there were no statistically significant differences between treated and placebo groups. There is evidence for benefit of ALC on clinical global impression as a categorical measure and on MMSE at 24 weeks, but there is no evidence using objective assessments in any other area of outcome. Given the large number of comparisons made, the statistically significant results may be due to chance. At present there is no evidence to recommend its routine use in clinical practice. Many of the trials used rather vague descriptions of dementia and trials using more strictly defined groups may be informative. Individual patient data may add to the findings, as would trials including other outcomes (e.g. mood and caregiver quality of life). However, the evidence does not suggest that ALC is likely to prove an important therapeutic agent. More work on the pharmacokinetics of ALC in humans is also required.
High-standard 14-day course versus standard 14-day course Two RCTs compared the high-standard 14-day regimen with the standard 14-day regimen. People with G6PD deficiency and pregnant or lactating women were excluded. We do not know if there is any difference in P vivax recurrences at 6 months with 0.5 mg/kg/day primaquine therapy for 14 days compared to 0.25 mg/kg/day primaquine therapy for 14 days (with chloroquine: RR 0.82, 95% CI 0.47 to 1.43, 639 participants, very low-certainty evidence; with chloroquine or an ACT: RR 1.11, 95% CI 0.17 to 7.09, 38 participants, very low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events with the higher dosage (very low-certainty evidence). 0.5 mg/kg/day primaquine for 7 days versus standard 14-day course Five RCTs compared 0.5 mg/kg/day primaquine for 7 days with the standard 14-day course. There may be little or no difference in P vivax recurrences at 6 to 7 months when using the same total dose (0.5 mg/kg/day to 210 mg) over 7 days as compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 1211 participants; low-certainty evidence). No serious adverse events were reported. There may be little or no difference in the number of adverse events known to occur with primaquine between the primaquine shorter regimen as compared to the longer regimen (RR 1.06, 95% CI 0.64 to 1.76; 1154 participants; low-certainty evidence). We do not know whether there is any difference in the frequency of anaemia or discontinuation of treatment between groups (very low-certainty evidence). Three trials excluded people with G6PD deficiency, and two did not provide this information. Pregnant and lactating women were either excluded or no details were provided regarding their inclusion or exclusion. 0.75 mg/kg primaquine/week for 8 weeks versus high-standard course One RCT compared weekly primaquine with the high-standard 14-day course. G6PD-deficient patients were not randomized but were included in the weekly primaquine group. Only one G6PD-deficient participant was detected during the trial. We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to the 14-day regimen at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.6; 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. Three other RCTs evaluated different alternative regimens and doses of primaquine, but one of these RCTs did not have results available, and two used regimens that have not been widely used and the evidence was of very low certainty. Although limited data were available, the analysis did not detect a difference in recurrence between the 7-day regimen and the standard 14-day regimen of 0.5 mg/kg/day primaquine, and no serious adverse events were reported in G6PD-normal participants taking 0.5 mg/kg/day of primaquine. This shorter regimen may be useful in G6PD-normal patients if there are treatment adherence concerns. Further large high-quality RCTs are needed, such as the IMPROV trial, with more standardised comparison regimens and longer follow-up to help resolve uncertainties.
Two studies met the inclusion criteria. 1. Randomised comparison between operative hysteroscopy versus control for unexplained subfertility associated with suspected major uterine cavity abnormalities. In women with otherwise unexplained subfertility and submucous fibroids, we were uncertain whether hysteroscopic myomectomy improved the clinical pregnancy rate compared to expectant management (odds ratio (OR) 2.44, 95% confidence interval (CI) 0.97 to 6.17; P = 0.06, 94 women; very low-quality evidence). We are uncertain whether hysteroscopic myomectomy improves the miscarriage rate compared to expectant management (OR 1.54, 95% CI 0.47 to 5.00; P = 0.47, 94 women; very low-quality evidence). We found no data on live birth or hysteroscopy complication rates. We found no studies in women with endometrial polyps, intrauterine adhesions or uterine septum for this randomised comparison. 2. Randomised comparison between operative hysteroscopy versus control for suspected major uterine cavity abnormalities prior to medically assisted reproduction. The hysteroscopic removal of polyps prior to IUI may have improved the clinical pregnancy rate compared to diagnostic hysteroscopy only: if 28% of women achieved a clinical pregnancy without polyp removal, the evidence suggested that 63% of women (95% CI 45% to 89%) achieved a clinical pregnancy after the hysteroscopic removal of the endometrial polyps (OR 4.41, 95% CI 2.45 to 7.96; P < 0.00001, 204 women; low-quality evidence). We found no data on live birth, hysteroscopy complication or miscarriage rates in women with endometrial polyps prior to IUI. We found no studies in women with submucous fibroids, intrauterine adhesions or uterine septum prior to IUI or in women with all types of suspected uterine cavity abnormalities prior to IVF/ICSI. Uncertainty remains concerning an important benefit with the hysteroscopic removal of submucous fibroids for improving the clinical pregnancy rates in women with otherwise unexplained subfertility. The available low-quality evidence suggests that the hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI may improve the clinical pregnancy rate compared to simple diagnostic hysteroscopy. More research is needed to measure the effectiveness of the hysteroscopic treatment of suspected major uterine cavity abnormalities in women with unexplained subfertility or prior to IUI, IVF or ICSI.
Three trials with 146 participants met the inclusion criteria of this review. Two parallel group trials with 100 participants provided information on one or more outcomes. The remaining trial was a cross-over trial, with no usable data for analysis. All the trials were at high risk of bias. Overall, all the evidence was of very low quality. All three trials compared erythrocytapheresis (removal of red cells only, instead of whole blood) versus phlebotomy. Two of the trials shared the same first author. The mean or median age in the three trials ranged from 42 to 55 years. None of the trials reported whether the included participants were symptomatic or asymptomatic or a mixture of both. Two trials were conducted in people who were haemochromatosis treatment-naive. The trial that provided most data for this review excluded people with malignancy, heart failure, and serious cardiac arrhythmias. We found no trials assessing iron-chelating agents. Only one of the trials with 38 participants reported no short-term mortality and no serious adverse events at the end of the short-term follow-up (eight months). Two trials reported the proportion of people with adverse events: 10/49 (20.4%) in the erythrocytapheresis group versus 11/51 (21.6%) in the phlebotomy group. One of these two trials provided data on adverse event rates (42.1 events per 100 participants with erythrocytapheresis versus 52.6 events per 100 participants with phlebotomy). There was no evidence of differences in the proportion of people with adverse events and the number of adverse events (serious and non-serious) between the groups (proportion of people with adverse events: OR 0.93, 95% CI 0.36 to 2.43; participants = 100; trials = 2; number of adverse events: rate ratio 0.80, 95% CI 0.32 to 2.03; participants = 38; trial = 1). There was no difference between the groups regarding short-term health-related quality of life (mean difference (MD) 1.00, 95% CI -10.80 to 12.80; participants = 38; trials = 1). This outcome was measured using EQ-VAS (range: 0 to 100 where a higher score indicates better health-related quality of life). None of the trials reported mortality beyond one year, health-related quality of life beyond one year, liver transplantation, decompensated liver disease, cirrhosis, hepatocellular carcinoma, diabetes, or cardiovascular complications during the long-term follow-up. The two trials that provided data for this review were funded by parties with no vested interest in the results; the source of funding of the third trial was not reported. There is currently insufficient evidence to determine whether erythrocytapheresis is beneficial or harmful compared with phlebotomy. Phlebotomy has less equipment requirements and remains the treatment of choice in people with hereditary haemochromatosis who require blood letting in some form. However, it should be noted that there is no evidence from randomised clinical trials that blood letting in any form is beneficial in people with hereditary haemochromatosis. Having said this, a trial including no treatment is unlikely to be conducted. Future trials should compare different frequencies of phlebotomy and erythrocytapheresis versus phlebotomy with and without different iron-chelating agents compared with each other, and with placebo. Such trials should include long-term follow-up of participants (e.g. using national record linkage databases) to determine whether treatments are beneficial or harmful in terms of clinical outcomes such as deaths, health-related quality of life, liver damage and its consequences, heart damage and its consequences, and other outcomes that are of importance to people with hereditary haemochromatosis.
We identified no RCTs or quasi-RCTs that fulfilled the inclusion criteria. Our searches retrieved eight potentially relevant studies, but after assessment of the full-text reports we excluded all of them due to the absence of randomisation or because the patients did not have Frey's syndrome. We excluded one randomised controlled trial that compared two different doses of botulinum toxin in patients with Frey's syndrome because the comparator was not an alternative treatment. We are unable to establish the efficacy and safety of the different methods used for the treatment of Frey's syndrome. RCTs are urgently needed to assess the effectiveness of interventions for the treatment of Frey's syndrome. Future RCTs should include patients with Frey's syndrome of different ranges of severity and report these patients separately. Studies should investigate all possibly effective treatments (such as anticholinergics, antiperspirants and botulinum toxin) compared to control groups using different treatments or placebo. Subjective assessment of Frey's syndrome should be considered as one of the outcome measures.
We included seven new studies with 663 participants in the 2017 update; five RCTs and two CCTs. These were added to the nine previously included studies (six RCTs and three CCTs with a total of 373 participants) for a total of 16 included studies and 1036 participants in this updated review. The mean age and range data for all participants were not reported for all studies. We identified two registered trials that met the inclusion criteria for this review; however there are no results for these studies yet. Overall, the GRADE assessment of evidence quality ranged from moderate to very low. The method of randomization in 11 of the 12 included RCTs was explicitly stated and adequate. Incomplete or methodologically diverse reporting of data affected the completeness of the analysis. Data on additional aromatherapies were added in the 2017 update (blended aromatherapy products, and peppermint products). Heterogeneity of outcome measures and time points between studies affected the completeness of the analysis. In the summary of the findings of six studies, we did not find aromatherapy to be effective in reducing nausea severity in comparison to placebo (SMD -0.22, 95% CI -0.63 to 0.18, P value = 0.28, 241 participants, level of evidence: low). Those participants receiving aromatherapy were no more likely to be free of nausea at the end of the treatment period than those receiving placebo (RR 3.25, 95% CI 0.31 to 34.33, P value = 0.33, 4 trials, 193 participants, evidence level: very low), however they were less likely to require rescue antiemetics (RR 0.60, 95% CI 0.37 to 0.97, P value = 0.04, 7 trials, 609 participants, evidence level: low). There were no data reported on adverse events or patient satisfaction for this comparison. A specific comparison of peppermint aromatherapy to placebo did not show evidence of an effect on nausea severity at five minutes post-treatment in the pooled results (SMD -0.18, 95% CI -0.86 to 0.49, P value = 0.59, 4 trials, 115 participants, evidence level: low). There were no data reported on nausea duration, use of rescue antiemetics, adverse events or patient satisfaction for this comparison. When we pooled studies comparing isopropyl alcohol to standard antiemetic treatment in a GRADE summary of findings, in terms of nausea duration, there was a significant effect on the time in minutes to a 50% reduction in nausea scores (SMD -1.10, 95% CI -1.43 to -0.78, P value < 0.00001, 3 trials, 176 participants, evidence level: moderate). Fewer participants who received isopropyl alcohol required rescue antiemetics (RR 0.67, 95% CI 0.46 to 0.98, P value = 0.04, 215 participants, 4 trials, evidence level: moderate). Two studies with 172 participants measured patient satisfaction; there were high levels of satisfaction across both aromatherapy and standard treatment groups and no differences found (evidence level: low). There were no data reported on nausea severity or adverse events for this comparison. There was no difference in effectiveness between isopropyl alcohol vapour inhalation and placebo for reducing the proportion of participants requiring rescue antiemetics (RR 0.39, 95% CI 0.12 to 1.24, P value = 0.11, 291 participants, 4 trials, evidence level: very low). There were no data reported on nausea severity, nausea duration, adverse events or patient satisfaction for this comparison. Overall, for nausea severity at the end of treatment, aromatherapy may have similar effectiveness to placebo and similar numbers of participants were nausea-free. However, this finding is based on low-quality evidence and therefore very uncertain. Low-quality evidence also suggests that participants who received aromatherapy may need fewer antiemetic medications, but again, this is uncertain. Participants receiving either aromatherapy or antiemetic medications may report similar levels of satisfaction with their treatment, according to low-quality evidence.
Nine studies involving 1359 participants met the inclusion criteria. Six studies compared individual education to usual care and three compared individual education to group education (361 participants). There were no long-term studies and overall the quality of the studies was not high. In the six studies comparing individual face-to-face education to usual care, individual education did not significantly improve glycaemic control (weighted mean difference (WMD) in HbA1c -0.1% (95% confidence interval (CI) -0.3 to 0.1, P = 0.33) over a 12 to 18 month period. However, there did appear to be a significant benefit of individual education on glycaemic control in a subgroup analysis of three studies involving participants with a higher mean baseline HbA1c greater than 8% (WMD -0.3% (95% CI -0.5 to -0.1, P = 0.007). In the two studies comparing individual to group education, there was no significant difference in glycaemic control between individual or group education at 12 to 18 months with a WMD in HbA1c of 0.03% (95% CI -0.02 to 0.1, P = 0.22). There was no significant difference in the impact of individual versus usual care or group education on body mass index systolic or diastolic blood pressure. There were too few studies to perform a meta-analysis on the effect of individual education on dietary self management, diabetes knowledge, psychosocial outcomes and smoking habits. No data were available on the other main outcome measures of diabetes complications or health service utilization and cost analysis in these studies. This systematic review suggests a benefit of individual education on glycaemic control when compared with usual care in a subgroup of those with a baseline HbA1c greater than 8%. However, overall there did not appear to be a significant difference between individual education and usual care. In the small number of studies comparing group and individual education, there was an equal impact on HbA1c at 12 to 18 months. Additional studies are needed to delineate these findings further.
Ten trials including 657 patients compared different methods of vascular occlusion. All trials were of high risk of bias. Only one or two trials were included under each comparison. There was no statistically significant differences in mortality, liver failure, or other morbidity between any of the comparisons. Hepatic vascular occlusion does not decrease the blood transfusion requirements. It decreases the cardiac output and increases the systemic vascular resistance. In the comparison between continuous portal triad clamping and intermittent portal triad clamping, four of the five liver failures occurred in patients with chronic liver diseases undergoing the liver resections using continuous portal triad clamping. In the comparison between selective inflow occlusion and portal triad clamping, all four patients with liver failure occurred in the selective inflow occlusion group. There was no difference in any of the other important outcomes in any of the comparisons. In elective liver resection, hepatic vascular occlusion cannot be recommended over portal triad clamping. Intermittent portal triad clamping seems to be better than continuous portal triad clamping at least in patients with chronic liver disease. There is no evidence to support selective inflow occlusion over portal triad clamping. The optimal method of intermittent portal triad clamping is not clear. There is no evidence for any difference between the ischaemic preconditioning followed by vascular occlusion and intermittent vascular occlusion for liver resection in patients with non-cirrhotic livers. Further randomised trials of low risk of bias are needed to determine the optimal technique of vascular occlusion.
A total of 50 trials were potentially eligible for inclusion, of which 42 trials were excluded. We included eight RCTs with a total of 233 extraction sites in 184 participants. One trial was judged to be at unclear risk of bias and the remaining trials were at high risk of bias. From two trials comparing xenograft with extraction alone (70 participants, moderate quality evidence), there was some evidence of a reduction in loss of alveolar ridge height (MD -2.60 mm; 95% CI -3.43 to -1.76) and width (MD -1.97 mm; 95% CI -2.48 to -1.46). This was also found in one trial comparing allograft with extraction (24 participants, low quality evidence): ridge height (MD -2.20 mm; 95% CI -0.75 to -3.65) and width (MD - 1.40 mm; 95% CI 0.00 to -2.80) and height. From two RCTs comparing alloplast versus xenograft no evidence was found that either ridge preservation technique caused a smaller reduction in loss of ridge height (MD -0.35 mm; 95% CI -0.86 to 0.16) or width (MD -0.44 mm; 95% CI -0.90 to 0.02; two trials (55 participants); moderate quality evidence). There was insufficient evidence to determine whether there are clinically significant differences between different ARP techniques and extraction based on the need for additional augmentation prior to implant placement, complications, implant failure, or changes in peri-implant marginal bone levels and probing depths of neighbouring teeth. We found no trials which evaluated parameters relating to clinical attachment levels, specific aesthetic or prosthodontic outcomes. There is limited evidence that ARP techniques may minimise the overall changes in residual ridge height and width six months after extraction. There is also lack of evidence of any differences in implant failure, aesthetic outcomes or any other clinical parameters due to the lack of information or long-term data. There is no convincing evidence of any clinically significant difference between different grafting materials and barriers used for ARP. Further long term RCTs that follow CONSORT guidelines (www.consort-statement.org) are necessary.
We did not include any new trials in this update. One randomised controlled trial of 32 patients is included. Concerning risk of bias, generation of the allocation sequence was at low risk; however, allocation concealment, blinding and selective reporting were at high risk. Treatment response, defined as 20% improvement from basal conditions by clinical, serological and specific neurological measures, was found in 94.7% (18/19) of patients using cyclophosphamide compared with 46.2% (6/13) in the methylprednisolone group at 24 months (RR 2.05, 95% CI 1.13 to 3.73). This was statistically significant and the number needed to treat for an additional beneficial outcome (NNTB) of treatment response is three. We found no statistically significant differences between the groups in damage index measurements (Systemic Lupus International Collaborating Clinics (SLICC)). The median SLE Disease Activity Index (SLEDAI) rating favoured the cyclophosphamide group. Cyclophosphamide use was associated with a reduction in prednisone requirements. All the patients in the cyclophosphamide group had electroencephalographic improvement but there was no statistically significant difference in decrease between groups in the number of monthly seizures. No statistically significant differences in adverse effects, including mortality, were reported between the groups. This systematic review found one randomised controlled trial with a small number of patients in the different clinical subgroups of neurological manifestation. There is very low-quality evidence that cyclophosphamide is more effective in reducing symptoms of neuropsychiatric involvement in SLE compared with methylprednisolone. However, properly designed randomised controlled trials that involve large numbers of individuals, with explicit clinical and laboratory diagnostic criteria, sufficient duration of follow-up and description of all relevant outcome measures, are necessary to guide practice. As we did not find any new trials to include in this review at update, the conclusions of the review did not change.
We included two trials enrolling 624 women in the review. It is uncertain whether breast surgery improves overall survival as the quality of the evidence has been assessed as very low (HR 0.83, 95% CI 0.53 to 1.31; 2 studies; 624 women). The two studies did not report quality of life. Breast surgery may improve local progression-free survival (HR 0.22, 95% CI 0.08 to 0.57; 2 studies; 607 women; low-quality evidence), while it probably worsened distant progression-free survival (HR 1.42, 95% CI 1.08 to 1.86; 1 study; 350 women; moderate-quality evidence). The two included studies did not measure breast cancer-specific survival. Toxicity from local therapy was reported by 30-day mortality and did not appear to differ between the two groups (RR 0.99, 95% CI 0.14 to 6.90; 1 study; 274 women; low-quality evidence). Based on existing evidence from two randomised clinical trials, it is not possible to make definitive conclusions on the benefits and risks of breast surgery associated with systemic treatment for women diagnosed with metastatic breast cancer. Until the ongoing clinical trials are finalised, the decision to perform breast surgery in these women should be individualised and shared between the physician and the patient considering the potential risks, benefits, and costs of each intervention.
We included eight trials, involving 952 participants, of which 64% were women. Included trials were generally of adequate quality, with six trials at low risk of bias, and two trials at high risk of bias. Three trials with 518 participants compared five different drugs with placebo; all reported the primary outcome as mean change in visual analogue scale (VAS) (0 to 100) for nausea severity from baseline to 30 minutes. Trials did not routinely report other primary outcomes of the change in nausea VAS at 60 minutes or number of vomiting episodes. Differences in mean VAS change from baseline to 30 minutes between placebo and the drugs evaluated were: metoclopramide (three trials, 301 participants; mean difference (MD) -5.27, 95% confidence interval (CI) -11.33 to 0.80), ondansetron (two trials, 250 participants; MD -4.32, 95% CI -11.20 to 2.56), prochlorperazine (one trial, 50 participants; MD -1.80, 95% CI -14.40 to 10.80), promethazine (one trial, 82 participants; MD -8.47, 95% CI -19.79 to 2.85) and droperidol (one trial, 48 participants; MD -15.8, 95% CI -26.98 to -4.62). The only statistically significant change in baseline VAS to 30 minutes was for droperidol, in a single trial of 48 participants. No other drug was statistically significantly superior to placebo. Other included trials evaluated a drug compared to "active controls" (alternative antiemetic). There was no convincing evidence of superiority of any particular drug compared to active control. All trials included in this review reported adverse events, but they were variably reported precluding meaningful pooling of results. Adverse events were generally mild, there were no reported serious adverse events. Overall, the quality of the evidence was low, mainly because there were not enough data. In an ED population, there is no definite evidence to support the superiority of any one drug over any other drug, or the superiority of any drug over placebo. Participants receiving placebo often reported clinically significant improvement in nausea, implying general supportive treatment such as intravenous fluids may be sufficient for the majority of people. If a drug is considered necessary, choice of drug may be dictated by other considerations such as a person's preference, adverse-effect profile and cost. The review was limited by the paucity of clinical trials in this setting. Future research should include the use of placebo and consider focusing on specific diagnostic groups and controlling for factors such as intravenous fluid administered.
Two randomized controlled trials were included, with a total of 115 participants. One study compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (published as abstract) compared clonazepam to ethosuximide as monotherapy for children with absence seizures. Based on the available data and the details on methodology provided, we judged both studies as being at unclear or high risk of bias for the domains assessed. In the study comparing clonazepam to carbamazepine, no difference was found between the groups regarding the proportion of participants who were seizure-free at one month after randomization (risk ratio (RR) 1.97, 95% confidence interval (CI) 0.99 to 3.94; 30 participants; very low-certainty evidence), three months after randomization (RR 1.19, 95% CI 0.62 to 2.29; 26 participants; very low-certainty evidence), and six months after randomization (RR 0.50, 95% CI 0.09 to 2.73; 9 participants; very low-certainty evidence). No statistical difference was found between clonazepam and carbamazepine in terms of proportion of participants with TEAEs leading to discontinuation (RR 2.61, 95% CI 0.80 to 8.52; 36 participants; very low-certainty evidence) and in terms of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (RR 1.56, 95% CI 0.61 to 4.02; 36 participants; very low certainty evidence). The study did not provide any information on our other prespecified outcomes of interest. The study comparing clonazepam to ethosuximide did not provide any data on efficacy. The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low-certainty evidence). No information on other outcomes of interest was provided in this study. There is only limited and very low-certainty evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial of children with absence seizures, however no comparative data on efficacy were provided. There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.
Four small randomised controlled trials involving 728 allocated/224 analysed participants met our inclusion criteria. These trials had a high risk of bias. Drug companies sponsored two of the trials. We were unable to pool the data due to the heterogeneity in outcome definitions and the different antibiotics used. The included trials compared the following antibiotic schedules. The first trial compared quinolone (levofloxacin) plus standard treatment (anti-staphylococcal penicillin (cloxacillin or dicloxacillin), aminoglycoside (tobramycin or netilmicin) and rifampicin) versus standard treatment alone reporting uncertain effects on all-cause mortality (8/31 (26%) with levofloxacin plus standard treatment versus 9/39 (23%) with standard treatment alone; RR 1.12, 95% CI 0.49 to 2.56, very low quality evidence). The second trial compared daptomycin versus low-dose gentamicin plus an anti-staphylococcal penicillin (nafcillin, oxacillin or flucloxacillin) or vancomycin. This showed uncertain effects in terms of cure rates (9/28 (32.1%) with daptomycin versus 9/25 (36%) with low-dose gentamicin plus anti-staphylococcal penicillin or vancomycin, RR 0.89 95% CI 0.42 to 1.89; very low quality evidence). The third trial compared cloxacillin plus gentamicin with a glycopeptide (vancomycin or teicoplanin) plus gentamicin. In participants receiving gentamycin plus glycopeptide only 13/23 (56%) were cured versus 11/11 (100%) receiving cloxacillin plus gentamicin (RR 0.59, 95% CI 0.40 to 0.85; very low quality evidence). The fourth trial compared ceftriaxone plus gentamicin versus ceftriaxone alone and found no conclusive differences in terms of cure (15/34 (44%) with ceftriaxone plus gentamicin versus 21/33 (64%) with ceftriaxone alone, RR 0.69, 95% CI 0.44 to 1.10; very low quality evidence). The trials reported adverse events, need for cardiac surgical interventions, uncontrolled infection and relapse of endocarditis and found no conclusive differences between comparison groups (very low quality evidence). No trials assessed septic emboli or quality of life. Limited and very low quality evidence suggested that there were no conclusive differences between antibiotic regimens in terms of cure rates or other relevant clinical outcomes. However, because of the very low quality evidence, this needs confirmation. The conclusion of this Cochrane review was based on randomised controlled trials with high risk of bias. Accordingly, current evidence does not support or reject any regimen of antibiotic therapy for treatment of infective endocarditis.
We included 14 trials (n = 565), 13 (n = 525) of which compared intravenous administration of amino acids to a control (usually saline solution or Ringer's lactate). The remaining trial (n = 40) compared intravenous administration of fructose versus a control. We noted much variation in these trials, which used different types of surgery, variable durations of surgery, and different types of participants. Most trials were at high or unclear risk of bias owing to inappropriate or unclear randomization methods, and to unclear participant and assessor blinding. This may have influenced results, but it is unclear how results might have been influenced. No trials reported any of our prespecified primary outcomes, which were risk of hypothermia and major cardiovascular events. Therefore, we decided to analyse data related to core body temperature instead as a primary outcome. It was not possible to conduct meta-analysis of data related to amino acid infusion for the 60-minute and 120-minute time points, as we observed significant statistical heterogeneity in the results. Some trials showed that higher temperatures were associated with amino acids, but not all trials reported statistically significant results, and some trials reported the opposite result, where the amino acid group had a lower core temperature than the control group. It was possible to conduct meta-analysis for six studies (n = 249) that provided data relating to the end of surgery. Amino acids led to a statistically significant increase in core temperature in comparison to those receiving control (MD = 0.46°C 95% CI 0.33 to 0.59; I2 0.0%; random-effects; moderate quality evidence). Three trials (n = 155) reported shivering as an outcome. Meta-analysis did not show a clear effect, and so it is uncertain whether amino acids reduce the risk of shivering (RR 0.36, 95% CI 0.13 to 1.00; I2 = 93%; random-effects model; very low-quality evidence). Intravenous amino acids may keep participants up to a half-degree C warmer than the control. This difference was statistically significant at the end of surgery, but not at other time points. However, the clinical importance of this finding remains unclear. It is also unclear whether amino acids have any effect on the risk of shivering and if intravenous nutrients confer any other benefits or harms, as high-quality data about these outcomes are lacking.
Ten studies (786 patients) were included. Mupirocin ointment reduced the risk of catheter-related bacteraemia (RR 0.17, 95%CI 0.07 to 0.43) and had a significant effect on catheter-related infections caused by S. aureus. The risk of catheter-related bacteraemia was reduced by polysporin (RR 0.40, 95%CI 0.19 to 0.86) and povidone-iodine ointment (RR 0.10, 95%CI 0.01 to 0.72). Subgroup analysis suggested mupirocin (RR 0.12, 95%CI 0.01 to 2.13) and povidone-iodine ointment (RR 0.84, 95%CI 0.24 to 2.98) had no effect on all-cause mortality while polysporin ointment showed a significant reduction (RR 0.22, 95%CI 0.07 to 0.74). Mortality related to infection was not reduced by mupirocin, polysporin or povidone-iodine ointment. Topical honey did not reduce the risk of exit site infection (RR 0.45, 95%CI 0.10 to 2.11) or catheter-related bacteraemia (RR 0.80, 95%CI 0.37 to 1.73). Transparent polyurethane dressing compared to dry gauze dressing did not reduce the risk of CVC or exit site infection, or catheter-related bacteraemia. Mupirocin ointment appears effective in reducing the risk of catheter-related bacteraemia. Insufficient reporting on mupirocin resistance was noted and needs to be considered in future studies. A lack of high quality data on the routine use of povidone-iodine ointment, polysporin ointment and topical honey warrant larger RCTs. Insufficient data were available to determine which dressing type (transparent polyurethane or dry gauze dressing) has the lowest risk of catheter-related infections.
We identified one RCT which met our inclusion criteria and was included in this review. Sixty-three participants with primary involutional lower eyelid entropion were randomised to everting sutures alone or everting sutures with a lateral tarsal strip. Eight participants were lost to follow-up. The trial indicates that the combined procedure for horizontal and vertical eyelid tightening in the form of everting sutures and lateral tarsal strip is highly curative for involutional entropion compared to vertical tightening in the form of everting sutures alone. The superiority of the combined approach is also supported by many good quality uncontrolled studies on specific surgical procedures but these were not included in the analysis as they were not part of the inclusion criteria. A single RCT showed that the combination of horizontal and vertical eyelid tightening with everting sutures and lateral tarsal strip is highly efficient for entropion compared to vertical tightening with everting sutures alone. Retrospective case series studies also support the combined surgical repair but details from these studies on specific surgical techniques cannot be included in the analysis. Evidence from a single RCT is unlikely to change clinical practice and thus it is still our view that there is a clear need for more randomised studies comparing two or more surgical techniques for entropion surgery addressing the recurrence and complications rate.
No randomised controlled trials or controlled trials were found that examined the efficacy of non-pharmacological swallowing therapy for the treatment of dysphagia in Parkinson's disease. However there is one large RCT currently recruiting patients that will compare 'chin down' posture with thickened liquids in the treatment of dysphagia. The main outcomes will be the rates of aspiration and pneumonia. There is currently no evidence to support or refute the efficacy of non-pharmacological swallowing therapy for dysphagia in Parkinson's disease. Large well designed placebo-controlled RCTs are required to assess the effectiveness of swallowing therapy for dysphagia in Parkinson's disease and reported according to CONSORT guidelines. Suitable outcome measures should be chosen so that the efficacy and effectiveness of non-pharmacological swallowing therapy can be assessed and an economic analysis performed. Outcomes which have meaning to patients and carers should be used wherever possible since they need to know the value of this therapy in practical terms. The patients should be followed for at least 6 months to determine the duration of any improvement.
The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31). Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
We included 15 trials involving 622 women who received G-CSF and 631 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 15 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate. We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.42, 95% confidence interval (CI) 0.83 to 2.42; 2 RCTs; participants = 263; I² = 0%; very low-quality evidence). For a typical clinic with 14% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 12% and 35%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.55, 95% CI 0.17 to 1.83; 3 RCTs; participants = 391; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART. We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.63, 95% CI 1.32 to 2.01; 14 RCTs; participants = 1253; I² = 13%; very low-quality evidence). For a typical clinic with 17% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 35%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.11, 95% CI 0.77 to 1.60; 3 RCTs; participants = 404; I² = 0%; low-quality evidence). G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.11, 95% CI 1.56 to 2.85; 7 RCTs; participants = 643; I² = 0%; low-quality evidence). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment. In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.
We included four studies with 166 participants. No studies compared the effects of home-based upper limb therapy programmes with placebo or no intervention. Three studies compared the effects of home-based upper limb therapy programmes with usual care. Primary outcomes: we found no statistically significant result for performance of ADL (mean difference (MD) 2.85; 95% confidence interval (CI) -1.43 to 7.14) or functional movement of the upper limb (MD 2.25; 95% CI -0.24 to 4.73)). Secondary outcomes: no statistically significant results for extended ADL (MD 0.83; 95% CI -0.51 to 2.17)) or upper limb motor impairment (MD 1.46; 95% CI -0.58 to 3.51). One study compared the effects of a home-based upper limb programme with the same upper limb programme based in hospital, measuring upper limb motor impairment only; we found no statistically significant difference between groups (MD 0.60; 95% CI -8.94 to 10.14). There is insufficient good quality evidence to make recommendations about the relative effect of home-based therapy programmes compared with placebo, no intervention or usual care.
We identified four cluster-RCTs and one cohort study (n = 12,742) of influenza vaccination for HCWs caring for individuals ≥ 60 years in LTCIs. Four cluster RCTs (5896 residents) provided outcome data that addressed the objectives of our review. The studies were comparable in their study populations, intervention and outcome measures. The studies did not report adverse events. The principal sources of bias in the studies related to attrition, lack of blinding, contamination in the control groups and low rates of vaccination coverage in the intervention arms, leading us to downgrade the quality of evidence for all outcomes due to serious risk of bias. Offering influenza vaccination to HCWs based in long term care homes may have little or no effect on the number of residents who develop laboratory-proven influenza compared with those living in care homes where no vaccination is offered (RD 0 (95% CI -0.03 to 0.03), two studies with samples taken from 752 participants; low quality evidence). HCW vaccination probably leads to a reduction in lower respiratory tract infection in residents from 6% to 4% (RD -0.02 (95% CI -0.04 to 0.01), one study of 3400 people; moderate quality evidence). HCW vaccination programmes may have little or no effect on the number of residents admitted to hospital for respiratory illness (RD 0 (95% CI -0.02 to 0.02, one study of 1059 people; low quality evidence). We decided not to combine data on deaths from lower respiratory tract infection (two studies of 4459 people) or all cause deaths (four studies of 8468 people). The direction and size of difference in risk varied between the studies. We are uncertain as to the effect of vaccination on these outcomes due to the very low quality of evidence. Adjusted analyses, which took into account the cluster design, did not differ substantively from the pooled analysis with unadjusted data. Our review findings have not identified conclusive evidence of benefit of HCW vaccination programmes on specific outcomes of laboratory-proven influenza, its complications (lower respiratory tract infection, hospitalisation or death due to lower respiratory tract illness), or all cause mortality in people over the age of 60 who live in care institutions. This review did not find information on co-interventions with healthcare worker vaccination: hand-washing, face masks, early detection of laboratory-proven influenza, quarantine, avoiding admissions, antivirals and asking healthcare workers with influenza or influenza-like illness (ILI) not to work. This review does not provide reasonable evidence to support the vaccination of healthcare workers to prevent influenza in those aged 60 years or older resident in LTCIs. High quality RCTs are required to avoid the risks of bias in methodology and conduct identified by this review and to test further these interventions in combination.
Thirteen trials involving 269 people were included. All trials compared EMG-BFB plus standard physiotherapy to standard physiotherapy either alone or with sham EMG-BFB. Only one study used a motor strength assessment scale for evaluation of patients, which indicated benefit from EMG-BFB (WMD 1.09, 95% CI 0.48 to 1.70). EMG-BFB did not have a significant benefit in improving range of motion (ROM) through the ankle (SMD 0.05, 95% CI -0.36 to 0.46), knee or wrist joints. However, one trial suggested a benefit in ROM at the shoulder (SMD 0.88, 95% CI 0.07 to 1.70). Change in stride length or gait speed was not improved by EMG-BFB. Two studies used different assessment scores to quantify gait quality. One of these suggested a beneficial effect of EMG-BFB (SMD 0.90, 95% CI 0.01 to 1.78). Most of the studies examining functional outcomes used different assessment scales, which made meta-analysis impossible. Two studies that used the same scale did show a beneficial effect (SMD 0.69, 95% CI 0.15 to 1.23). Despite evidence from a small number of individual studies to suggest that EMG-BFB plus standard physiotherapy produces improvements in motor power, functional recovery and gait quality when compared to standard physiotherapy alone, combination of all the identified studies did not find a treatment benefit. Overall the results are limited because the trials were small, generally poorly designed and utilised varying outcome measures.
In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I2 = 72%, two trials, N = 3929; very low-quality evidence). We found no evidence of publication bias. In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo. There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial. Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative.
We included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data. All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I² = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies. There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I² = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies. Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events. This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results. There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone). There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions. Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling.
We identified 11 trials for inclusion in the review. All trials were small (total participants 665) and had various methodological limitations including uncertainty about methods to ensure allocation concealment and blinding. Most participants were clinically stable preterm infants of less than about 34 weeks' gestational age or with birth weight less than about 1750 g. Fewer participants were extremely preterm, extremely low birth weight, or growth restricted. Most trials found no effects on feed intolerance, assessed variously as mean pre-feed gastric residual volume, incidence of abdominal distension or other gastrointestinal signs of concern, or time taken to achieve full enteral feeds (meta-analysis was limited because studies used different measures). Meta-analysis showed no effect on the risk of necrotising enterocolitis (typical risk ratio 1.10, 95% CI 0.36 to 3.34; risk difference 0.00, 95% CI -0.03 to 0.04; 5 trials, 385 infants) (low-certainty evidence; downgraded for imprecision and design weaknesses). The identified trials provide only low-certainty evidence about the effects of feeding preterm infants protein hydrolysate versus standard formula. Existing data do not support conclusions that feeding protein hydrolysate affects the risk of feed intolerance or necrotising enterocolitis. Additional large, pragmatic trials are needed to provide more reliable and precise estimates of effectiveness and cost-effectiveness.
No new trials were identified for inclusion in this update. We identified 12 trials for inclusion, 10 of which contributed outcomes data. There were a total of 6820 participants. In trials of healthy children living in low-income communities, two trials did not demonstrate a significant difference between the zinc-supplemented and placebo groups in the numbers of participants experiencing an episode of definite otitis media during follow-up (3191 participants); another trial showed a significantly lower incidence rate of otitis media in the zinc group (rate ratio 0.69, 95% confidence interval (CI) 0.61 to 0.79, n = 1621). A small trial of 39 infants undergoing treatment for severe malnutrition suggested a benefit of zinc for the mean number of episodes of otitis media (mean difference (MD) -1.12 episodes, 95% CI -2.21 to -0.03). Zinc supplements did not seem to cause any serious adverse events but a small minority of children were reported to have vomited shortly after ingestion of the supplements. The trial evidence included is generally of good quality, with a low risk of bias. Evidence on whether zinc supplementation can reduce the incidence of otitis media in healthy children under the age of five years living in low- and middle-income countries is mixed. There is some evidence of benefit in children being treated for marasmus (severe malnutrition), but this is based on one small trial and should therefore be treated with caution.
We included eight trials covering 109 surgical trainees with limited laparoscopic experience. Of the eight trials, six compared virtual reality versus no supplementary training. One trial compared virtual reality training versus box-trainer training and versus no supplementary training, and one trial compared virtual reality training versus box-trainer training. There were no trials that compared different forms of virtual reality training. All the trials were at high risk of bias. Operating time and operative performance were the only outcomes reported in the trials. The remaining outcomes such as mortality, morbidity, quality of life (the primary outcomes of this review) and hospital stay (a secondary outcome) were not reported. Virtual reality training versus no supplementary training: The operating time was significantly shorter in the virtual reality group than in the no supplementary training group (3 trials; 49 participants; MD -11.76 minutes; 95% CI -15.23 to -8.30). Two trials that could not be included in the meta-analysis also showed a reduction in operating time (statistically significant in one trial). The numerical values for operating time were not reported in these two trials. The operative performance was significantly better in the virtual reality group than the no supplementary training group using the fixed-effect model (2 trials; 33 participants; SMD 1.65; 95% CI 0.72 to 2.58). The results became non-significant when the random-effects model was used (2 trials; 33 participants; SMD 2.14; 95% CI -1.29 to 5.57). One trial could not be included in the meta-analysis as it did not report the numerical values. The authors stated that the operative performance of virtual reality group was significantly better than the control group. Virtual reality training versus box-trainer training: The only trial that reported operating time did not report the numerical values. In this trial, the operating time in the virtual reality group was significantly shorter than in the box-trainer group. Of the two trials that reported operative performance, only one trial reported the numerical values. The operative performance was significantly better in the virtual reality group than in the box-trainer group (1 trial; 19 participants; SMD 1.46; 95% CI 0.42 to 2.50). In the other trial that did not report the numerical values, the authors stated that the operative performance in the virtual reality group was significantly better than the box-trainer group. Virtual reality training appears to decrease the operating time and improve the operative performance of surgical trainees with limited laparoscopic experience when compared with no training or with box-trainer training. However, the impact of this decreased operating time and improvement in operative performance on patients and healthcare funders in terms of improved outcomes or decreased costs is not known. Further well-designed trials at low risk of bias and random errors are necessary. Such trials should assess the impact of virtual reality training on clinical outcomes.
One study (45 participants) met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in people with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) (low-quality evidence) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance) (low-quality evidence). The levels of urinary glycoaminoglycans were also significantly reduced (low-quality evidence). In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all participants in the treatment group with no apparent clinical effect and titres were reducing by the end of the study (very low-quality evidence). Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation (low-quality evidence). As assessed by questionnaires,changes in a 'Disability Index' after treatment were small and did not differ between groups (low-quality evidence). There were no deaths in either group (low-quality evidence). The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive, with few participants and of low quality. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those individuals diagnosed under 2.5 years of age. We do not anticipate any further trials to be undertaken and therefore do not plan to update this review.
All nine identified trials compared different types of contraceptive implant. Eight, involving 1578 women, compared Implanon with Norplant , and one, involving 1198 women, compared Jadelle with Norplant. There was no difference between Implanon and Norplant for contraceptive effectiveness rates or continuation over 4 years. Both were highly effective methods of contraception with no pregnancies occurring in any of the trials during 26,972 and 28,108 women months of follow up respectively. The most common side-effect with Implanon and Norplant was changes in bleeding pattern. The pattern with Implanon was initially more variable, bleeding with both implants became less frequent with duration of use. After two years use the amenorrhoea rate was significantly higher with Implanon. The trials reported no significant difference in hormonal side-effects or adverse events. Implanon was significantly quicker to insert and remove than Norplant.  There was no difference in contraceptive effectiveness and in continuation rates between Jadelle and Norplant. Jadelle was significantly quicker to remove than Norplant. Implanon, Norplant and Jadelle are highly effective contraceptive methods. No significant differences were found in contraceptive effectiveness or continuation. The most common side-effect with all implants was unpredictable vaginal bleeding. Time taken for removal of Implanon and Jadelle was less than that for Norplant.  Although this systematic review was unable to provide a definitive answer on relative effectiveness, tolerability and acceptability of contraceptive implants in comparison to other contraceptive methods, it has raised issues around the conduct of contraceptive research.
We included four studies (2350 women). The overall risk of bias for the included studies was assessed as acceptable in two studies and good in two studies. No statistically significant differences were observed between women who received group antenatal care and those given standard individual antenatal care for the primary outcome of preterm birth (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.57 to 1.00; three trials; N = 1888). The proportion of low-birthweight (less than 2500 g) babies was similar between groups (RR 0.92, 95% CI 0.68 to 1.23; three trials; N = 1935). No group differences were noted for the primary outcomes small-for-gestational age (RR 0.92, 95% CI 0.68 to 1.24; two trials; N = 1473) and perinatal mortality (RR 0.63, 95% CI 0.32 to 1.25; three trials; N = 1943). Satisfaction was rated marginally higher among women who were allocated to group antenatal care, but this 5 point difference is not clinically meaningful on the scale used (mean difference 4.90, 95% CI 3.10 to 6.70; one study; N = 993). No differences in neonatal intensive care admission, initiation of breastfeeding or spontaneous vaginal birth were observed between groups. Several outcomes related to stress and depression were reported in one trial. No differences between groups were observed for any of these outcomes. No data were available on the effects of group antenatal care on care provider satisfaction. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to assess evidence for seven prespecified outcomes; results ranged from low quality (perinatal mortality) to moderate quality (preterm birth, low birthweight, neonatal intensive care unit admission, breastfeeding initiation) to high quality (satisfaction with antenatal care, spontaneous vaginal birth). Available evidence suggests that group antenatal care is acceptable to women and is associated with no adverse outcomes for them or for their babies. No differences in the rate of preterm birth were reported when women received group antenatal care. This review is limited because of the small numbers of studies and women, and because one study contributed 42% of the women. Most of the analyses are based on a single study. Additional research is required to determine whether group antenatal care is associated with significant benefit in terms of preterm birth or birthweight.
We included five trials, which were published between 1986 and 1992. Overall, they included 67 patients, all male, with ages ranging from one to 54 years. Intellectual disability in participants varied from borderline to severe and some studies included patients with an additional diagnosis of autism or autistic behaviour. Four of the studies were placebo-controlled cross-over trials and one study was a parallel design. The duration of follow-up ranged from two months to 12 months and the period on folic acid or placebo ranged from two to eight months. Doses of folic acid ranged from 10 mg to 250 mg per day, 10 mg per day being the most common. Most of the younger patients involved were also taking part in special education programmes (usually involving language and occupational therapy). We were not able to perform meta-analysis to combine results but none of the individual studies found evidence of clinical benefit with the use of folic acid medication in fragile X syndrome patients on any of the areas of interest, either psychological and learning capabilities or behaviour and social performance, as measured with standardised tools. Separate analysis of evidence for patients of different age groups, i.e. prepubertal children and postpubertal young people, found some statistically significant results, but did not show clear evidence of benefit for either group. Adverse effects of folic acid treatment were rare, not serious and transient. Studies were generally poorly reported and we classified only one study as being at low risk of bias. The quality of available evidence is low and not suitable for drawing conclusions about the effect of folic acid on fragile X syndrome patients. It consists of few studies with small samples of patients, all of them male, with little statistical power to detect anything other than huge effects.
We included 24 trials with 2996 participants in this updated review. The number of participants in each trial varied from 39 to 382. Most of the included studies compared bed rest versus immediate mobilization, and only two assessed the effects of supplementary fluids versus no supplementation. We judged the overall risk of bias of the included studies as low to unclear. The overall quality of evidence was low to moderate, downgraded because of the risk of bias assessment in most cases. The primary outcome in our review was the presence of PDPH. There was low quality evidence for an absence of benefits associated with bed rest compared with immediate mobilization on the incidence of severe PDPH (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.68 to 1.41; participants = 1568; studies = 9) and moderate quality evidence on the incidence of any headache after lumbar puncture (RR 1.16; 95% CI 1.02 to 1.32; participants = 2477; studies = 18). Furthermore, bed rest probably increased PDPH (RR 1.24; 95% CI 1.04 to 1.48; participants = 1519; studies = 12) compared with immediate mobilization. An analysis restricted to the most methodologically rigorous trials (i.e. those with low risk of bias in allocation method, missing data and blinding of outcome assessment) gave similar results. There was low quality evidence for an absence of benefits associated with fluid supplementation on the incidence of severe PDPH (RR 0.67; 95% CI 0.26 to 1.73; participants = 100; studies = 1) and PDPH (RR 1; 95% CI 0.59 to 1.69; participants = 100; studies = 1), and moderate quality evidence on the incidence of any headache after lumbar puncture (RR 0.94; 95% CI 0.66 to 1.34; participants = 200; studies = 2). We did not expect other adverse events and did not assess them in this review. Since the previous version of this review, we found one new study for inclusion, but the conclusion remains unchanged. We considered the quality of the evidence for most of the outcomes assessed in this review to be low to moderate. As identified studies had shortcomings on aspects related to randomization and blinding of outcome assessment, we therefore downgraded the quality of the evidence. In general, there was no evidence suggesting that routine bed rest after dural puncture is beneficial for the prevention of PDPH onset. The role of fluid supplementation in the prevention of PDPH remains unclear.
We retrieved 2398 citations: 30 studies were eligible for further examination of their full text, and we found one registered clinical trial in progress. No studies could be included in the analysis or review. We assigned one study as awaiting classification, as it has not been accepted for publication. This systematic review failed to locate relevant published RCTs to support or refute the assertion that vascular access specialist teams are superior to the generalist model. A vascular access specialist team has advanced knowledge with regard to insertion techniques, clinical care, and management of vascular access devices, whereas a generalist model comprises nurses, doctors, or other designated healthcare professionals in the healthcare facility who may have less advanced insertion techniques and who care for vascular access devices amongst other competing clinical tasks. However, this conclusion may change once the one study awaiting classification and one ongoing study are published. There is a need for good-quality RCTs to evaluate the efficacy of a vascular access specialist team approach for vascular access device insertion and care for the prevention of failure.
A total of 13 studies (4495 participants) were included in this review. Agomelatine was compared to selective serotonin reuptake inhibitors (SSRIs), namely paroxetine, fluoxetine, sertraline, escitalopram, and to the serotonin–norepinephrine reuptake inhibitor (SNRI), venlafaxine. Participants were followed up for six to 12 weeks. Agomelatine did not show any advantage or disadvantage over the other antidepressants for our primary outcome, response to treatment (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.95 to 1.08, P value 0.75 compared to SSRIs, and RR 1.06; 95% CI 0.98 to 1.16, P value 0.16 compared to venlafaxine). Also, agomelatine showed no advantage or disadvantage over other antidepressants for remission (RR 0.83; 95% CI 0.68 to 1.01, P value 0.07 compared to SSRIs, and RR 1.08; 95% CI 0.94 to 1.24, P value 0.73 compared to venlafaxine). Overall, agomelatine appeared to be better tolerated than venlafaxine in terms of lower rates of drop outs (RR 0.40; 95% CI 0.24 to 0.67, P value 0.0005), and showed the same level of tolerability as SSRIs (RR 0.95; 95% CI 0.83 to 1.09, P value 0.44). Agomelatine induced a lower rate of dizziness than venlafaxine (RR 0.19, 95% CI 0.06 to 0.64, P value 0.007). With regard to the quality of the body of evidence, there was a moderate risk of bias for all outcomes, due to the number of included unpublished studies. There was some heterogeneity, particularly between published and unpublished studies. The included studies were conducted in inpatient and outpatient settings, thus limiting the generalisability of the results to primary care settings. With regard to precision, the efficacy outcomes were precise, but the tolerability outcomes were mostly imprecise. Publication bias was variable and depended on the outcome of the trial. Our review included unpublished studies, and we think that this reduced the impact of publication bias. The overall methodological quality of the studies was not very good. Almost all of the studies were sponsored by the pharmaceutical company that manufactures agomelatine (Servier), and some of these were unpublished. Attempts to contact the pharmaceutical company Servier for additional information on all unpublished studies were unsuccessful. Agomelatine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. Agomelatine was better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer participants treated with agomelatine dropped out of the trials due to side effects compared to sertraline and venlafaxine, but data were limited because the number of included studies was small. We found evidence that compared agomelatine with only a small number of other active antidepressive agents, and there were only a few trials for each comparison, which limits the generalisability of the results. Moreover, the overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine.
Ten papers describing 10 unique trials met the inclusion criteria. Analysis of data from two trials (63 participants) showed that sodium valproate reduced headache frequency by approximately four headaches per 28 days as compared to placebo (MD -4.31; 95% confidence interval (CI) -8.32 to -0.30). Data from four trials (542 participants) showed that divalproex sodium (a stable combination of sodium valproate and valproic acid in a 1:1 molar ratio) more than doubled the proportion of responders relative to placebo (RR 2.18; 95% CI 1.28 to 3.72; NNT 4; 95% CI 2 to 11). One study of sodium valproate (34 participants) versus placebo supported the latter findings (RR for responders 2.83; 95% CI 1.27 to 6.31; NNT 3; 95% CI 2 to 9). There was no significant difference in the proportion of responders between sodium valproate versus flunarizine (one trial, 41 participants) or between divalproex sodium versus propranolol (one trial, 32 participants). Pooled analysis of post-treatment mean headache frequencies in two trials (88 participants) demonstrates a slight but significant advantage for topiramate 50 mg over valproate 400 mg (MD -0.90; 95% CI -1.58 to -0.22). For placebo-controlled trials of sodium valproate and divalproex sodium, NNHs for clinically important adverse events ranged from 7 to 14. Valproate is effective in reducing headache frequency and is reasonably well tolerated in adult patients with episodic migraine.
We included 12 studies (508 participants) in comparisons with placebo or an active control. Six studies enrolled participants with moderate or severe postherpetic neuralgia, and the remaining studies enrolled different, or mixed, neuropathic pain conditions, including trigeminal neuralgia and postsurgical or post-traumatic neuralgia. Four different formulations were used: 5% medicated patch, 5% cream, 5% gel, and 8% spray. Most studies used a cross-over design, and two used a parallel-group design. Two studies used enriched enrolment with randomised withdrawal. Seven studies used multiple doses, with one to four-week treatment periods, and five used single applications. We judged all of the studies at high risk of bias because of small size or incomplete outcome assessment, or both. There was no first or second tier evidence, and no pooling of data was possible for efficacy outcomes. Only one multiple-dose study reported our primary outcome of participants with ≥ 50% or ≥ 30% pain intensity reduction. Three single-dose studies reported participants who were pain-free at a particular time point, or had a 2-point (of 10) reduction in pain intensity. The two enriched enrolment, randomised withdrawal studies reported time to loss of efficacy. In all but one study, third tier (very low quality) evidence indicated that lidocaine was better than placebo for some measure of pain relief. Pooling multiple-dose studies across conditions demonstrated no clear evidence of an effect of lidocaine on the incidence of adverse events or withdrawals, but there were few events and the withdrawal phase of enriched enrolment designs is not suitable to assess the true impact of adverse events (very low quality evidence). This review found no evidence from good quality randomised controlled studies to support the use of topical lidocaine to treat neuropathic pain, although individual studies indicated that it was effective for relief of pain. Clinical experience also supports efficacy in some patients. Several large ongoing studies, of adequate duration, with clinically useful outcomes should provide more robust conclusions about both efficacy and harm.
We identified 29 randomised clinical trials, five of which were considered high quality. Only three trials reported inclusion of hepatitis B e-antigen negative mothers. Compared with placebo/no intervention, vaccine reduced hepatitis B occurrence (RR 0.28, 95% confidence interval (CI) 0.20 to 0.40, 4 trials). No significant differences of hepatitis B occurrence were found comparing recombinant vaccine (RV) versus plasma-derived vaccine (PDV) (RR 1.00, 95% CI 0.71 to 1.42, 4 trials) and high-dose versus low-dose vaccine (PDV: RR 0.97, 95% CI 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). Compared with placebo/no intervention, hepatitis B immunoglobulin or the combination of vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (hepatitis B immunoglobulin: RR 0.50, 95% CI 0.41 to 0.60, 1 trial; PDV plus hepatitis B immunoglobulin: RR 0.08, 95% CI 0.03 to 0.17, 3 trials). Compared with vaccine, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (RR 0.54, 95% CI 0.41 to 0.73, 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported on adverse events. Vaccine, hepatitis B immunoglobulin, and vaccine plus hepatitis B immunoglobulin prevent hepatitis B occurrence in newborn infants of HBsAg positive mothers.
Fourteen studies (involving 1879 couples) were included. Three studies reported live birth rate and these did not identify a significant difference after pooling the (preliminary) results (OR 1.21, 95% CI 0.67 to 2.19). With regard to pregnancy rates, there was also no evidence that glucocorticoids improved clinical outcome (13 RCTs; OR 1.16, 95% CI 0.94 to 1.44). However, a subgroup analysis of 650 women undergoing IVF (6 RCTs) revealed a significantly higher pregnancy rate for women using glucocorticoids (OR 1.50, 95% CI 1.05 to 2.13). There were no significant differences in adverse events, but these were poorly and inconsistently reported. Overall, there was no clear evidence that administration of peri-implantation glucocorticoids in ART cycles significantly improved the clinical outcome. The use of glucocorticoids in a subgroup of women undergoing IVF (rather than ICSI) was associated with an improvement in pregnancy rates of borderline statistical significance and should be interpreted with care. These findings were limited to the routine use of glucocorticoids and cannot be extrapolated to women with autoantibodies, unexplained infertility or recurrent implantation failure. Further well designed randomised studies are required to elucidate the possible role of this therapy in well defined patient groups.
Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.
We identified two eligible studies reporting 18 methodological filters. All methodological filters in these two studies were developed using terms from the reference standard records. The first study evaluated six filters for retrieving observational studies of surgical interventions. The study reported on six filters: one Precision Terms Filter (comprising terms with higher precision while maximum sensitivity was maintained) and one Specificity Terms Filter (comprising terms with higher specificity while maximum sensitivity was maintained), both of which were adapted for MEDLINE, for Embase, and for combined MEDLINE/Embase searches. The study reported one reference standard consisting of 217 articles from one systematic review of which 83.9% of the included studies were case series The second study reported on 12 filters for retrieving comparative non-randomised studies (cNRSs) including cohort, case-control, and cross-sectional studies. This study reported on 12 filters using four different approaches: Fixed method A (comprising of a fixed set of controlled vocabulary (CV) words), Fixed method B (comprising a fixed set of CV words and text words (TW)), Progressive method (CV) (a random choice of study design-related CV terms), and Progressive method (CV or TW) (a random choice of study design-related CV terms, and title and abstracts-based TWs). The study reported four reference standards consisting of 89 cNRSs from four systematic reviews. The six methodological filters developed from the first study reported sensitivity of 99.5% to 100% and precision of 16.7% to 21.1%. The Specificity Terms Filter for combined MEDLINE/Embase was preferred because it had higher precision and equal sensitivity to the Precision Terms Filter. The 12 filters from the second study reported lower sensitivity (48% to 100%) and much lower precision (0.09% to 4.47%). The Progressive method (CV or TW) had the highest sensitivity. There were methodological limitations in both included studies. The first study used one surgical intervention-focused systematic review thus limiting the generalizability of findings. The second study used four systematic reviews but with less than 100 studies. The external validation was performed only on Specificity Terms Filter from the first study Both studies were published 10 years ago and labelling and indexing of observational studies has changed since then. We found 18 methodological filters across two eligible studies. Search strategies from the first study had higher sensitivity and precision, underwent external validation and targeted observational studies. Search strategies from the second study had lower sensitivity and precision, focused on cNRSs, and were not validated externally. Given this limited and heterogeneous evidence, and its methodological limitations, further research and better indexation are needed.
After screening 1808 abstracts, and the references of 65 reviews, we found only seven relevant studies (1050 patients) that met our inclusion criteria. None of these were considered, methodologically, a high quality randomized controlled trial. Four of the included RCTs on fibromyalgia were graded low quality and suggest no quantifiable benefits. The three included RCTs on widespread musculoskeletal pain showed that based on limited evidence, overall, no evidence of efficacy was observed. However, behavioral treatment and stress management appear to be important components. Education combined with physical training showed some positive effects in long term follow up. We conclude that there appears to be little scientific evidence for the effectiveness of multidisciplinary rehabilitation for these musculoskeletal disorders. However, multidisciplinary rehabilitation is a commonly used intervention for chronic musculoskeletal disorders, which cause much personal suffering and substantial economic loss to the society. There is a need for high quality trials in this field.
Five RCTs involving 895 sporadic and 52 familial ALS/MND participants were included. There was no statistical evidence for a differential response to treatment in participants with familial ALS/MND compared to those with sporadic ALS/MND. The pooled estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among participants with familial ALS/MND, but the result was not statistically significant. Pooled estimates of the rate of decline on the ALSFRS suggested a slightly better overall response to treatment among those with familial ALS/MND, but the result was not statistically significant. Based on the available data, there is little evidence for a differential response to treatment among people with familial and sporadic ALS/MND. Future randomized controlled trials should document whether people with familial ALS/MND are included and the presence or absence of a mutation in an ALS susceptibility gene amongst those with familial ALS/MND.
Four randomised controlled trials involving 543 women were identified and are included in this review. In the included studies, the active treatment arm was the 20 μg/day levonorgestrel-releasing intrauterine system (LNG-IUS) plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS led to a reduction in the incidence of endometrial polyps over both a 12-month period (Peto OR 0.22, 95% CI 0.08 to 0.64, 2 studies, n = 212, I² = 0%) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39, 4 studies, n = 417, I² = 0%, moderate quality evidence). Also the LNG-IUS led to a reduction in the incidence of endometrial hyperplasia over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67, four studies, n = 417, I² = 0%, moderate quality evidence). However, it should be noted that the number of events of endometrial hyperplasia was low (n = 6). None of the trials were sufficiently powered to detect whether LNG-IUS leads to significant changes in the incidence of endometrial cancer in tamoxifen users. At 12 months of follow-up abnormal vaginal bleeding or spotting was more common in the LNG-IUS treatment group (Peto OR 7.26, 95% CI 3.37 to 15.66, 3 studies, n = 376, I² = 0%, moderate quality evidence). By 24 months of follow-up, abnormal vaginal bleeding or spotting occurred less frequently compared to 12 months of follow-up in the LNG-IUS treatment group but was still more common than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10, 2 studies, n = 233, I² = 0%, moderate quality evidence). By 60 months of follow-up, no cases of abnormal vaginal bleeding or spotting were reported in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). There was no evidence of a difference between the LNG-IUS treatment group and controls for these outcomes. The quality of the evidence was judged as moderate, due to limited sample sizes and low event rates for the outcome comparisons. The LNG-IUS reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS increased abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. There is no clear evidence from the available randomised controlled trials that the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available randomised controlled trials that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.
For the first comparison, five studies met the inclusion criteria. Community-based antibiotic delivery for neonatal PSBI reduced neonatal mortality when compared to hospital referral only (typical risk ratio (RR) 0.82, 95% confidence interval (CI) 0.68 to 0.99; 5 studies, n = 125,134; low-quality evidence). There was, however, a high level of statistical heterogeneity (I² = 87%) likely, due to the heterogenous nature of the study settings as well as the fact that four of the studies provided various co-interventions in conjunction with community-based antibiotics. Community-based antibiotic delivery for neonatal PSBI showed a possible effect on reducing sepsis-specific neonatal mortality (typical RR 0.78, 95% CI 0.60 to 1.00; 2 studies, n = 40,233; low-quality evidence). For the second comparison, five studies met the inclusion criteria. Using a simplified antibiotic approach resulted in similar rates of neonatal mortality when compared to the standard regimen of seven days of injectable procaine benzylpenicillin and injectable procaine benzylpenicillin and injectable gentamicin delivered in community-settings for neonatal PSBI (typical RR 0.81, 95% CI 0.44 to 1.50; 3 studies, n = 3476; moderate-quality evidence). In subgroup analysis, the simplified antibiotic regimen of seven days of oral amoxicillin and injectable gentamicin showed no difference in neonatal mortality (typical RR 0.84, 95% CI 0.47 to 1.51; 3 studies, n = 2001; moderate-quality evidence). Two days of injectable benzylpenicillin and injectable gentamicin followed by five days of oral amoxicillin showed no difference in neonatal mortality (typical RR 0.88, 95% CI 0.29 to 2.65; 3 studies, n = 2036; low-quality evidence). Two days of injectable gentamicin and oral amoxicillin followed by five days of oral amoxicillin showed no difference in neonatal mortality (RR 0.67, 95% CI 0.24 to 1.85; 1 study, n = 893; moderate-quality evidence). For fast breathing alone, seven days of oral amoxicillin resulted in no difference in neonatal mortality (RR 0.99, 95% CI 0.20 to 4.91; 1 study, n = 1406; low-quality evidence). None of the studies in the second comparison reported the effect of a simplified antibiotic regimen on sepsis-specific neonatal mortality. Low-quality data demonstrated that community-based antibiotics reduced neonatal mortality when compared to the standard hospital referral for neonatal PSBI in resource-limited settings. The use of co-interventions, however, prevent disentanglement of the contribution from community-based antibiotics. Moderate-quality evidence showed that simplified, community-based treatment of PSBI using regimens which rely on the combination of oral and injectable antibiotics did not result in increased neonatal mortality when compared to the standard treatment of using only injectable antibiotics. Overall, the evidence suggests that simplified, community-based antibiotics may be efficacious to treat neonatal PSBI when hospitalisation is not feasible. However, implementation research is recommended to study the effectiveness and scale-up of simplified, community-based antibiotics in resource-limited settings.
We identified 22 RCTs and two quasi-RCTs evaluating the effectiveness of group-based parenting programmes in improving the emotional and behavioural adjustment of children aged up to three years and 11 months (maximum mean age three years 11 months). The total number of participants in the studies were 3161 parents and their young children. Eight studies were conducted in the USA, five in the UK, four in Canada, five in Australia, one in Mexico, and one in Peru. All of the included studies were of behavioural, cognitive-behavioural or videotape modelling parenting programmes. We judged 50% (or more) of the included studies to be at low risk for selection bias, detection bias (observer-reported outcomes), attrition bias, selective reporting bias, and other bias. As it is not possible to blind participants and personnel to the type of intervention in these trials, we judged all studies to have high risk of performance bias. Also, there was a high risk of detection bias in the 20 studies that included parent-reported outcomes. The results provide evidence that group-based parenting programmes reduce overall emotional and behavioural problems (SMD -0.81, 95% CI -1.37 to -0.25; 5 studies, 280 participants, low quality evidence) based on total parent-reported data assessed at postintervention. This result was not, however, maintained when two quasi-RCTs were removed as part of a sensitivity analysis (SMD -0.67, 95% CI -1.43 to 0.09; 3 studies, 221 participants). The results of data from subscales show evidence of reduced total externalising problems (SMD -0.23, 95% CI -0.46 to -0.01; 8 studies, 989 participants, moderate quality evidence). Single study results show very low quality evidence of reductions in externalising problems hyperactivity-inattention subscale (SMD -1.34; 95% CI -2.37 to -0.31; 19 participants), low quality evidence of no effect on total internalising problems (SMD 0.34; 95% CI -0.12 to 0.81; 73 participants), and very low quality evidence of an increase in social skills (SMD 3.59; 95% CI 2.42 to 4.76; 32 participants), based on parent-reported data assessed at postintervention. Results for secondary outcomes, which were also measured using subscales, show an impact on parent-child interaction in terms of reduced negative behaviour (SMD -0.22, 95% CI -0.39 to -0.06; 7 studies, 941 participants, moderate quality evidence), and improved positive behaviour (SMD 0.48, 95% CI 0.17 to 0.79; 4 studies, 173 participants, moderate quality evidence) as rated by independent observers postintervention. No further meta-analyses were possible. Results of subgroup analyses show no evidence for treatment duration (seven weeks or less versus more than eight weeks) and inconclusive evidence for prevention versus treatment interventions. The findings of this review, which relate to the broad group of universal and at-risk (targeted) children and parents, provide tentative support for the use of group-based parenting programmes to improve the overall emotional and behavioural adjustment of children with a maximum mean age of three years and 11 months, in the short-term. There is, however, a need for more research regarding the role that these programmes might play in the primary prevention of both emotional and behavioural problems, and their long-term effectiveness.
For this update, four trials with a combined total of 3314 participants fulfilled the inclusion criteria. Two trials compared surveillance with immediate open repair; two trials compared surveillance with immediate endovascular repair. Overall, the risk of bias within the included studies was low and the quality of the evidence high. The four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with surgery) but no significant differences in long-term survival (adjusted HR 0.88, 95% confidence interval (CI) 0.75 to 1.02, mean follow-up 10 years; HR 1.21, 95% CI 0.95 to 1.54, mean follow-up 4.9 years; HR 0.76, 95% CI 0.30 to 1.93, median follow-up 32.4 months; HR 1.01, 95% CI 0.49 to 2.07, mean follow-up 20 months). A pooled analysis of participant-level data from two trials (with a maximum follow-up of seven to eight years) showed no statistically significant difference in survival between immediate open repair and surveillance (propensity score-adjusted HR 0.99; 95% CI 0.83 to 1.18), and that this lack of treatment effect did not vary by AAA diameter (P = 0.39) or participant age (P = 0.61). The meta-analysis of mortality at one year for the endovascular trials likewise showed no significant association (RR at one year 1.15, 95% CI 0.60 to 2.17). Quality-of-life results among trials were conflicting. The results from the four trials to date demonstrate no advantage to immediate repair for small AAA (4.0 cm to 5.5 cm), regardless of whether open or endovascular repair is used and, at least for open repair, regardless of patient age and AAA diameter. Thus, neither immediate open nor immediate endovascular repair of small AAAs is supported by currently available evidence.
Four studies randomly assigning 9130 people with asthma were included; two were six-month double-blind studies, and two were 12-month open-label studies. No trials included children younger than age 12. Trials included more women than men, with mean age ranging from 38 to 45, and mean baseline steroid dose (inhaled beclomethasone (BDP) equivalent) from 636 to 888 μg. Mean baseline forced expiratory volume in one second (FEV1) percentage predicted was between 70% and 73% in three of the trials, and 96% in another. All studies were funded by AstraZeneca and were generally free from methodological biases, although the two open-label studies were rated as having high risk for blinding, and some evidence of selective outcome reporting was found. These possible sources of bias did not lead us to downgrade the quality of the evidence. The quantity of inhaled steroids, including puffs taken for relief from symptoms, was consistently lower for SiT than for the comparison groups. Separate data for exacerbations leading to hospitalisations, to emergency room (ER) visits or to a course of oral steroids could not be obtained. Compared with higher fixed-dose combination inhalers, fewer people using SiT had exacerbations requiring hospitalisation or a visit to the ER (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57 to 0.90; I2 = 0%, P = 0.66), and fewer had exacerbations requiring a course of oral corticosteroids (OR 0.75, 95% CI 0.65 to 0.87; I2 = 0%, P = 0.82). This translates to one less person admitted to hospital or visiting the ER (95% CI 0 to 2 fewer) and two fewer people needing oral steroids (95% CI 1 to 3 fewer) compared with fixed-dose combination treatment with a short-acting beta-agonist (SABA) reliever (per 100 treated over eight months). No statistical heterogeneity was observed in either outcome, and the evidence was rated of high quality. Although issues with blinding were evident in two of the studies, and one study recruited a less severe population, sensitivity analyses did not change the main results, so quality was not downgraded. We could not rule out the possibility that SiT increased rates of serious adverse events (OR 0.92, 95% CI 0.74 to 1.13; I2 = 0%, P = 0.98; moderate-quality evidence, downgraded owing to imprecision). We were unable to say whether SiT improved results for several secondary outcomes (morning and evening peak expiratory flow (PEF), rescue medication use, symptoms scales), and in cases where results were significant, the effect sizes were not considered clinically meaningful (predose FEV1, nocturnal awakenings and quality of life). SiT reduces the number of people having asthma exacerbations requiring oral steroids and the number requiring hospitalisation or an ER visit compared with fixed-dose combination inhalers. Evidence for serious adverse events was unclear. The mean daily dose of inhaled corticosteroids (ICS) in SiT, including the total dose administered with reliever use, was always lower than that of the other combination groups. This suggests that the flexibility in steroid administration that is possible with SiT might be more effective than a standard fixed-dose combination by increasing the dose only when needed and keeping it low during stable stages of the disease. Data for hospitalisations alone could not be obtained, and no studies have yet addressed this question in children younger than age 12.
No RCTs or quasi-RCTs were identified. There were 40 longitudinal cohort studies providing data on 63,887 participants; 43,209 (68%) who were referred early and 20,678 (32%) referred late. Comparative mortality was higher in patients referred to specialist services late versus those referred early. Risk ratios (RR) for mortality reductions in patients referred early were evident at three months (RR 0.61, 95% CI 0.55 to 0.67; I² = 84%) and remained at five years (RR 0.66, 95% CI 0.60 to 0.71; I² = 87%). Initial hospitalisation was 9.12 days shorter with early referral (95% CI -10.92 to -7.32 days; I² = 82%) compared to late referral. Pooled analysis showed patients referred early were more likely than late referrals to initiate RRT with peritoneal dialysis (RR 1.74, 95% CI 1.64 to 1.84; I² = 92%). Patients referred early were less likely to receive temporary vascular access (RR 0.47, 95% CL 0.45 to 0.50; I² = 97%) than those referred late. Patients referred early were more likely to receive permanent vascular access (RR 3.22, 95% CI 2.92 to 3.55; I² = 97%). Systolic blood pressure (BP) was significantly lower in early versus late referrals (MD -3.09 mm Hg, 95% CI -5.23 to -0.95; I² = 85%); diastolic BP was significantly lower in early versus late referrals (MD -1.64 mm Hg, 95% CI -2.77 to -0.51; I² = 82%). EPO use was significantly higher in those referred early (RR 2.92, 95% CI 2.42 to 3.52; I² = 0%). eGFR was higher in early referrals (MD 0.42 mL/min/1.73 m², 95% CI 0.28 to 0.56; I² = 95%). Diabetes prevalence was similar in patients referred early and late (RR 1.05, 95% CI 0.96 to 1.15; I² = 87%) as was ischaemic heart disease (RR 1.05, 95% CI 0.97 to 1.13; I² = 74%), peripheral vascular disease (RR 0.99, 95% CI 0.84 to 1.17; I² = 90%), and congestive heart failure (RR 1.00, 95% CI 0.86 to 1.15; I² = 92%). Inability to walk was less prevalent in early referrals (RR 0.66, 95% CI 0.51 to 0.86). Prevalence of chronic obstructive pulmonary disease was similar in those referred early and late (RR 0.89, 95% CI 0.70 to 1.14; I² = 94%) as was cerebrovascular disease (RR 0.90, 95% CI 0.74 to 1.11; I² = 83%). The quality of the included studies was assessed as being low to moderate based on the Newcastle-Ottawa Scale. Slight differences in the definition of early versus late referral infer some risk of bias. Generally, heterogeneity in most of the analyses was high. Our analysis showed reduced mortality and mortality and hospitalisation, better uptake of peritoneal dialysis and earlier placement of arteriovenous fistulae for patients with chronic kidney disease who were referred early to a nephrologist. Differences in mortality and hospitalisation data between the two groups were not explained by differences in prevalence of comorbid disease or serum phosphate. However, early referral was associated with better preparation and placement of dialysis access.
Nine studies involving 751 participants were included. Two of them produced effect sizes which showed a consistent and statistically significant difference in favour of the active drug. Combining all studies produced a pooled estimate of effect of 0.39 standard deviations (confidence interval, 0.24 to 0.54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0.17 (0.00 to 0.34). The pooled effect for inpatient and outpatient trials was highly sensitive to decisions about which combination of data was included but inpatient trials produced the lowest effects. The more conservative estimates from the present analysis found that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted.
Five trials including 391 children aged three to 18 years met our criteria. Two studies (117 children) compared anaesthetic ear drops versus placebo immediately at diagnosis. All children received some form of oral pain relief. In all five studies it was clear that ear pain diminishes rapidly for most sufferers. Nevertheless there was a statistically significant difference in the proportion of children achieving a 50% reduction in pain in favour of anaesthetic drops 10 minutes after instillation (risk ratio (RR) 2.13, 95% confidence interval (CI) 1.19 to 3.80) and 30 minutes after instillation (RR 1.43, 95% CI 1.12 to 1.81) on the day AOM was diagnosed but not at 20 minutes (RR 1.24, 95% CI 0.88 to 1.74). Three trials (274 children) compared anaesthetic ear drops with naturopathic herbal ear drops. Naturopathic drops were favoured 15 and 30 minutes after instillation, one to three days after diagnosis, but the differences were not statistically significant. Only one trial looked at adverse reactions and found none. Overall the findings of this review are based on trial evidence that is at low or unclear risk of bias. Evidence from five RCTs, only two of which addressed the most relevant question of primary effectiveness, provides limited evidence that ear drops are effective 30 minutes after administration in older children with AOM. Uncertainty exists as to the magnitude of this effect and more high-quality studies are needed.
We included two studies in this review, which were both assessed as being at high risk of bias. The two studies, involving a total of 111 participants, compared the use of Tooth Masseuse and OrthoAccel with conventional treatment mechanics during orthodontic alignment and canine retraction phases, respectively. Both studies included objective assessment of the amount or rate of tooth movement, but we were not able to meta-analyse this data as they used different outcome measurements at different stages of the orthodontic treatment process. One study measured subjective evaluation of pain and discomfort and the other evaluated adverse effects. The studies did not directly report either the duration of orthodontic treatment or the number of visits during active treatment. Using the Tooth Masseuse with 111 Hz at 0.06 Newtons (N) for 20 minutes daily resulted in greater reduction in irregularity in the lower incisor region over 10 weeks, assessed using Little's Irregularity Index (LII) with a mean difference (MD) of 0.6 mm (95% confidence interval (CI) -0.94 to 2.34) when compared to the control group. Pain and discomfort increased at six to eight hours after arch wire placement and after seven days, with minimal difference between the intervention and control groups. No statistical tests were provided for either variable and the differences between the two groups were not clinically important. Using OrthoAccel with 30 Hz at 0.25 N for 20 minutes daily produced a higher rate of maxillary canine distalisation in comparison to the control group (MD 0.37 mm/month; 95% CI -0.07 to 0.81; P = 0.05). Whilst this difference suggested 50% faster tooth movement using the vibrational appliance, the absolute differences were marginal and deemed clinically unimportant. Similar levels of non-serious adverse effects were reported in the intervention and control groups with a risk ratio of 0.96 (95% CI 0.32 to 2.85). Overall, the quality of the evidence was very low and therefore we cannot rely on the findings. There is very little clinical research concerning the effectiveness of non-surgical interventions to accelerate orthodontic treatment. The available evidence is of very low quality and so it is not possible to determine if there is a positive effect of non-surgical adjunctive interventions to accelerate tooth movement. Although there have been claims that there may be a positive effect of light vibrational forces, results of the current studies do not reach either statistical or clinical significance. Further well-designed and rigorous RCTs with longer follow-up periods are required to determine whether non-surgical interventions may result in a clinically important reduction in the duration of orthodontic treatment, without any adverse effects.
No new trials were located in our most recent search in September 2014. Six trials with 665 participants contributed to this review. These trials were small and subject to potential bias. Only two reported randomisation procedures in detail and in only one trial was allocation concealed. While only modest numbers of participants were lost to follow-up, in general there is little information on the longer-term outcome for participants. Patients with acute coronary syndrome allocated to HBOT were associated with a reduction in the risk of death by around 42% (RR: 0.58, (95% CI 0.36 to 0.92), 5 trials, 614 participants; low quality evidence). In general, HBOT was well-tolerated. No patients were reported as suffering neurological oxygen toxicity and only a single patient was reported to have significant barotrauma to the tympanic membrane. One trial suggested a significant incidence of claustrophobia in single occupancy chambers of 15% (RR of claustrophobia with HBOT 31.6, 95% CI 1.92 to 521). For people with ACS, there is some evidence from small trials to suggest that HBOT is associated with a reduction in the risk of death, the volume of damaged muscle, the risk of MACE and time to relief from ischaemic pain. In view of the modest number of patients, methodological shortcomings and poor reporting, this result should be interpreted cautiously, and an appropriately powered trial of high methodological rigour is justified to define those patients (if any) who can be expected to derive most benefit from HBOT. The routine application of HBOT to these patients cannot be justified from this review.
We included 77 studies with 5619 randomised participants. There was potential bias in most studies, with small size being the most common; individual treatment groups had fewer than 50 participants in 60 studies. Participants were relatively young, with mean age in the studies typically between 50 and 70 years. Multiple major problems with adverse event reporting were found, including failing to report adverse events in all participants who received medication, all adverse events experienced, how adverse events were collected, and not defining adverse event terminology or whether a reporting system was used. Direct measures of patient consciousness, patient appetite, or thirst were not apparent. For opioids used to treat cancer pain adverse event incidence rates were 25% for constipation, 23% for somnolence, 21% for nausea, 17% for dry mouth, and 13% for vomiting, anorexia, and dizziness. Asthenia, diarrhoea, insomnia, mood change, hallucinations and dehydration occurred at incidence rates of 5% and below. We found no direct evidence that opioids affected patient consciousness, appetite or thirst when used to treat cancer pain. However, somnolence, dry mouth, and anorexia were common adverse events in people with cancer pain treated with morphine, fentanyl, oxycodone, or codeine. We are aware that there is an important literature concerning the problems that exist with adverse event measurement, reporting, and attribution. Together with the known complications concerning concomitant medication, data collection and reporting, and nomenclature, this means that these adverse events cannot always be attributed unequivocally to the use of opioids, and so they provide only a broad picture of adverse events with opioids in cancer pain. The research agenda includes developing definitions for adverse events that have a spectrum of severity or importance, and the development of appropriate measurement tools for recording such events to aid clinical practice and clinical research.
One RCT and two non-randomised studies that allowed for multivariate analyses met the inclusion criteria and included a total of 141 women. One RCT found that neoadjuvant chemoradiation did not appear to offer longer survival compared to primary surgery in advanced vulval tumours (RR = 1.29, 95% confidence interval (CI) 0.87 to 1.91). There was also no statistically significant difference in survival between primary chemoradiation and primary surgery in a study that included 63 women (pooled adjusted HR= 1.09, 95% CI 0.37 to 3.17) and in another study that only included 12 eligible women and compared the same interventions (HR was non-informative when statistical adjustment was made). Adverse events were extensively reported in only one study, which found no statistically significant difference in risk of adverse events between primary chemoradiation and primary surgery due to the very small numbers in each group. In the RCT there was no observed statistically significant difference between neoadjuvant chemoradiation and primary surgery. Adverse events were not reported in the largest study of 63 women. Quality of life (QoL) was not reported in any of the included studies. All studies were at high risk of bias. Women with advanced vulval tumours showed no significant difference in overall survival or treatment-related adverse events when chemoradiation (primary or neoadjuvant) was compared with primary surgery. The retrospective studies had a high risk of bias as the entry criteria for primary chemoradiation was based on inoperability or tumour requiring exenteration.The radiochemotherapy regimens varied widely. There was no data on QoL. There is no standard terminology for 'operable and inoperable vulval cancer', and for 'primary and neoadjuvant chemoradiation'. Stratification according to unresectability of the primary tumour and/or lymph nodes is needed, for good quality comparison.
We included 18 RCTs (7208 participants), of which 16 recruited adults and adolescents (6872) and two recruited children six to 17 years of age (336) with asthma and significant reversibility to bronchodilator at baseline. Fourteen (79%) trials were of high methodological quality. The risk of exacerbations requiring systemic corticosteroids (primary outcome of the review) was significantly lower with the combination of LABA + ICS compared with LTRA + ICS—from 13% to 11% (eight studies, 5923 adults and 334 children; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 0.99; high-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) with LABA compared with LTRA to prevent one additional exacerbation over four to 102 weeks was 62 (95% CI 34 to 794). The choice of LTRA, the dose of ICS and the participants' age group did not significantly influence the magnitude of effect. Although results were inconclusive, the effect appeared stronger in trials that used a single device rather than two devices to administer ICS and LABA and in trials of less than 12 weeks' duration. The addition of LABA to ICS was associated with a statistically greater improvement from baseline in lung function, as well as in symptoms, rescue medication use and quality of life, although the latter effects were modest. LTRA was superior in the prevention of exercise-induced bronchospasm. More participants were satisfied with the combination of LABA + ICS than LTRA + ICS (three studies, 1625 adults; RR 1.12, 95% CI 1.04 to 1.20; moderate-quality evidence). The overall risk of withdrawal was significantly lower with LABA + ICS than with LTRA + ICS (13 studies, 6652 adults and 308 children; RR 0.84, 95% CI 0.74 to 0.96; moderate-quality evidence). Although the risk of overall adverse events was equivalent between the two groups, the risk of serious adverse events (SAE) approached statistical significance in disfavour of LABA compared with LTRA (nine studies, 5658 adults and 630 children; RR 1.33, 95% CI 0.99 to 1.79; P value 0.06; moderate-quality evidence), with no apparent impact of participants' age group. The following adverse events were reported, but no significant differences were demonstrated between groups: headache (11 studies, N = 6538); cardiovascular events (five studies, N = 5163), osteopenia and osteoporosis (two studies, N = 2963), adverse events (10 studies, N = 5977 adults and 300 children). A significant difference in the risk of oral moniliasis was noted, but this represents a low occurrence rate. In adults with asthma that is inadequately controlled by predominantly low-dose ICS with significant bronchodilator reversibility, the addition of LABA to ICS is modestly superior to the addition of LTRA in reducing oral corticosteroid–treated exacerbations, with an absolute reduction of two percentage points. Differences favouring LABA over LTRA as adjunct therapy were observed in lung function and, to a lesser extend, in rescue medication use, symptoms and quality of life. The lower overall withdrawal rate and the higher proportion of participants satisfied with their therapy indirectly favour the combination of LABA + ICS over LTRA + ICS. Evidence showed a slightly increased risk of SAE with LABA compared with LTRA, with an absolute increase of one percentage point. Our findings modestly support the use of a single inhaler for the delivery of both LABA and low- or medium-dose ICS. Because of the paucity of paediatric trials, we are unable to draw firm conclusions about the best adjunct therapy in children.
We identified and included a single eligible trial comparing SLNB with observation which was published in eight different reports (from 2005 to 2014) with 2001 participants. This trial did not report on our first primary outcome of overall survival (which was also the planned primary outcome of this trial). When contacted for this important data, the trial authors stated "there are numerous additional analyses that have yet to be reported for the trial". We were able however to estimate overall survival from data included in the appendix of the published report and found no evidence of benefit for SLNB for overall survival. The overall survival hazard ratio (HR) using ITT (intention-to-treat) analysis was 0.99 95% confidence interval [CI] 0.82 to 1.19, 1661 participants). The overall survival using ITT for intermediate thickness melanomas was (HR 0.92, 95% CI 0.73 to 1.16) and for thick melanomas it was (HR 1.15, 95% CI 0.82 to 1.61). The study did report on our second primary outcome of rate of treatment complications: short-term surgical morbidity (30 days) in 1735 participants showed no difference between SLNB and observation (risk ratio [RR] 1.11, 955 CI 0.9 to 1.37) for wide excision of the tumour site but favoured observation for complications related to the regional nodal basin (RR 14.36, 95% CI 6.74 to 30.59). Our secondary outcomes of disease-specific and disease-free survival, local recurrence and distant metastases were reported. There were 1347 participants in the intermediate-thickness melanoma group and 314 in the thick melanoma group.The study did not report the actual 10-year melanoma-specific survival rate for all included participants. Instead, melanoma-specific survival rates for each group of participants: intermediate-thickness melanoma (defined as 1.2 to 3.5 mm) and thick melanomas (defined as 3.50 mm or more) was reported. In the intermediate-thickness melanoma group there was no statistically significant difference in disease-specific survival between study groups at 10 years (81.4 ± 1.5% versus 78.3 ± 2.0%, HR 0.84, 95% CI 0.65 to 1.09). In the thick melanoma group, again there was no statistically significant difference in disease-specific survival between study groups at 10 years (58.9.3 ± 4.1% versus 64.4 ± 4.6%, HR 1.12, 95% CI 0.77 to 1.64). Combining these groups there was some heterogeneity (I² = 34%) but the total HR was not statistically significant (HR 0.92, 95% CI 0.74 to 1.14). The summary estimate for disease-free survival at 10 years favoured SLNB over observation in participants with intermediate-thickness and thick melanomas (HR 0.75, 95% CI 0.63 to 0.89). With regard to the rate of local and regional recurrence as the site of first recurrence, a benefit of SLNB uniformly existed in both groups of participants with intermediate-thickness and thick melanomas (RR 0.56, 95% CI 0.45 to 0.69). This is in contrast with a uniformly unfavourable effect of SLNB with regard to the rate of distant metastases as site of first recurrence, in both groups of participants with intermediate-thickness and thick melanomas (HR 1.33, 95% CI 1.03 to 1.72). We found no evidence of improved overall survival or melanoma-specific survival rates for participants with intermediate or thick melanomas who underwent SLNB compared with observation alone. Disease-free survival and rate of local and regional recurrence favoured SLNB in both groups of participants with intermediate-thickness and thick melanomas but short-term surgical morbidity was higher in the SLNB group, especially with regard to complications in the nodal basin. The evidence for the outcomes of interest in this review is of low quality due to the risk of bias and imprecision of the estimated effects. Further research may have an important impact on our estimate of the effectiveness of SLNB in managing primary localised cutaneous melanoma. Currently this evidence is not sufficient to document a benefit of SLNB when compared to observation in individuals with primary localised cutaneous melanoma.
Eighteen trials which randomised 3888 people to rosiglitazone treatment were identified. Longest duration of therapy was four years with a median of 26 weeks. Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised (OR 2.27, 95% confidence interval (CI) 1.83 to 2.81). The single large RCT (ADOPT - A Diabetes Outcomes Progression Trial) indicated increased cardiovascular risk. New data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues. New studies should focus on patient-oriented outcomes to clarify the benefit-risk ratio of rosiglitazone therapy. Safety data and adverse events of all investigations (published and unpublished) should be made available to the public.
We found two studies involving 4993 participants. The methodological quality of the trials was good. Both studies included women at low risk for hypertensive disorders, with Doppler ultrasound of the uterine arteries performed in the second trimester of pregnancy. In both studies, pathological finding of uterine arteries was followed by low-dose aspirin administration. We identified no difference in short-term maternal and fetal clinical outcomes. We identified no randomised studies assessing the utero-placental vessels in the first trimester or in women at high risk for hypertensive disorders. Present evidence failed to show any benefit to either the baby or the mother when utero-placental Doppler ultrasound was used in the second trimester of pregnancy in women at low risk for hypertensive disorders. Nevertheless, this evidence cannot be considered conclusive with only two studies included. There were no randomised studies in the first trimester, or in women at high risk. More research is needed to investigate whether the use of utero-placental Doppler ultrasound may improve pregnancy outcome.
Twelve studies comparing pharmacist-provided services versus usual care were included in this review. Of the 12 studies, seven were from lower middle income countries and five were from upper middle income countries. Eleven studies examined pharmacist-provided services targeted at patients and one study evaluated pharmacist interventions targeted at healthcare professionals. Pharmacist-provided services targeting patients resulted in a small improvement of clinical outcomes such as blood pressure (-25 mm Hg/-6 mm Hg and -4.56 mm Hg/-2.45 mm Hg), blood glucose (-39.84 mg/dl and -16.16 mg/dl), blood cholesterol (-25.7 mg/dl)/ triglyceride levels (-80.1 mg/dl) and asthma outcomes (peak expiratory flow rate 1.76 l/min). Moreover, there was a small improvement in the quality of life, although four studies did not report the effect size explicitly. Health service utilisation, such as rate of hospitalisation and general practice and emergency room visits, was also found to be reduced by the patient targeted pharmacist-provided services. A single study examined the effect of patient targeted pharmacist interventions on medical expenses and the cost was found to be reduced. A single study that examined pharmacist services that targeted healthcare professionals demonstrated a very small impact on asthma symptom scores. No studies assessing the impact of pharmacist-provided non-dispensing services that targeted healthcare professionals reported health service utilisation and cost outcomes. Overall, five studies did not adequately report the numerical data for outcomes but instead reported qualitative statements about results, which prevented an estimation of the effect size. Studies for the comparison of patient targeted services provided by pharmacists versus the same services provided by other healthcare professionals or untrained healthcare workers were not found. Similarly, studies for the comparison of healthcare professional targeted services provided by pharmacists versus the same services provided by other healthcare professionals or untrained healthcare workers were not found. Pharmacist-provided services that target patients may improve clinical outcomes such as management of high glucose levels among diabetic patients, management of blood pressure and cholesterol levels and may improve the quality of life of patients with chronic conditions such as diabetes, hypertension and asthma. Pharmacist services may reduce health service utilisation such as visits to general practitioners and hospitalisation rates. We are uncertain about the effect of educational sessions by pharmacists for healthcare professionals due to the imprecision of a single study included in this review. Similarly, conclusions could not be drawn for health service utilisation and costs due to lack of evidence on interventions delivered by pharmacists to healthcare professionals. These results were heterogenous in the types of outcomes measured, clinical conditions and approaches to measurement of outcomes, and require cautious interpretation. All eligible studies were from middle income countries and the results may not be applicable to low income countries.
A total of four studies (one randomized controlled trial, three non- randomized studies) involving 8488 people living with HIV/AIDS were included. The main findings of this review demonstrated a trend to improved outcomes when treated by a provider with more training/expertise in HIV/AIDS care in the outpatient (clinic) setting. Due to the heterogeneity of the included studies, we could not perform a meta-analysis. We present a descriptive review of the results. The results demonstrate improved medical outcomes when treated by a provider with more training/expertise in HIV/AIDS care in the outpatient (clinic) setting. Since all of these studies were conducted in North America, this does not address any issues regarding the level of training/expertise required by providers working in countries with more limited resources. Practitioners who do not consider themselves 'experts' in HIV/AIDS care and care for few of these patients need to seriously consider this review which demonstrates a trend towards worse patient outcomes when receiving care by those with low caseloads/training in HIV/AIDS care.
We identified nine studies. We excluded eight of these as they did not restrict participation to people with high fatigue. The single eligible trial investigated the use of modafinil compared to placebo. Although this study found a significant improvement over time in the primary outcome of fatigue, the improvement occurred after both modafinil and placebo with no significant difference in response between the two groups. The included trial did not reach its planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. The trial was at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation because the investigators did not analyse the impact of imputation on the results. There was insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue.
We included 12 trials, which recruited 389 participants. No studies assessed the primary outcome tooth loss. Ten trials compared FMS and control; three of these were assessed as being at high risk of bias, three as unclear risk and four as low risk. There was no evidence for a benefit for FMS over the control for change in probing pocket depth (PPD), gain in probing attachment (i.e. clinical attachment level; CAL) or bleeding on probing (BOP). The difference in changes between FMS and control for whole mouth PPD at three to four months was 0.01 mm higher (95% CI -0.17 to 0.19, three trials, 82 participants). There was no evidence of heterogeneity. The difference in changes for CAL was 0.02 mm lower (95% CI -0.26 to 0.22, three trials, 82 participants), and the difference in change in BOP was 2.86 per cent of sites lower (95% CI -7.65 to 1.93, four trials, 120 participants). We included six trials in the meta-analyses comparing FMD and control, with two trials assessed as being at high risk of bias, one as low and three as unclear. The analyses did not indicate a benefit for FMD over the control for PPD, CAL or BOP. The difference in changes for whole-mouth PPD between FMD and control at three to four months was 0.13 mm higher (95% CI -0.09 to 0.34, two trials, 44 participants). There was no evidence of heterogeneity. The difference in changes for CAL was 0.04mm higher (95% CI -0.25 to 0.33, two trials, 44 participants) and the difference in change in BOP being 12.59 higher for FMD (95% CI -8.58 to 33.77, three trials, 68 participants). Three trials were included in the analyses comparing FMS and FMD. The mean difference in PPD change at three to four months was 0.11 mm lower (-0.34 to 0.12, two trials, 45 participants) indicating no evidence of a difference between the two interventions. There was a difference in the gain in CAL at three to four months (-0.25 mm, 95% CI -0.42 to -0.07, two trials, 45 participants), favouring FMD but this was not found at six to eight months. There was no evidence for a difference between FMS and FMD for BOP (-1.59, 95% CI -9.97 to 6.80, two trials, 45 participants). Analyses were conducted for different teeth types (single- or multi-rooted) and for teeth with different levels of probing depth at baseline, for PPD, CAL and BOP. There was insufficient evidence of a benefit for either FMS or FMD. Harms and adverse events were reported in eight studies. The most important harm identified was an increased body temperature after FMS or FMD treatments. We assessed the quality of the evidence for each comparison and outcome as 'low' because of design limitations leading to risk of bias and because of the small number of trials and participants, which led to imprecision in the effect estimates. The inclusion of five additional RCTs in this updated review comparing the clinical effects of conventional mechanical treatment with FMS and FMD approaches for the treatment of chronic periodontitis has not changed the conclusions of the original review. From the twelve included trials there is no clear evidence that FMS or FMD provide additional benefit compared to conventional scaling and root planing. In practice, the decision to select one approach to non-surgical periodontal therapy over another should include patient preference and the convenience of the treatment schedule.
We included 56 studies (2838 participants). Antihypertensive agents were the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or combinations of both, versus other antihypertensives and other agents. The benefits of antihypertensive agents, particularly inhibitors of the renin angiotensin system, appear to potentially outweigh the harms in patients with IgAN. The benefits are largely manifest as a reduction in proteinuria, a surrogate outcome. There is no evidence that treatment with any of the antihypertensive agents evaluated affect major renal and/or cardiovascular endpoints or long-term mortality risk beyond the benefit that arises from controlling hypertension in patients with IgAN. The RCT evidence is insufficiently robust to demonstrate efficacy for any of the other non-immunosuppressive therapies evaluated here. IgAN remains a disease in search of adequately powered RCTs to reliably inform clinical practice. More and better evidence is needed to understand the magnitude of benefit and the possible risks of anti-hypertensive or more specifically of ACEi/ARB therapy alone or in combination and which specific types of patients with the IgAN might have the greatest potential for benefit. For other non-immunosuppressive therapies, where neither benefit nor significant harm has yet to be demonstrated, there remains some justification for further exploration of the potential benefits.
We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I² = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I² = 0%; P < 0.00001). Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs. Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated. For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m² dose of PLD than those receiving less than 50 mg/m² (17% versus 2%, respectively; P value 0.01). In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.
Four studies randomising a total of 202 people with schizophrenia are included. Oral fluphenazine was compared with oral amisulpride, risperidone, quetiapine and olanzapine. Comparing oral fluphenazine with amisulpride, there was no difference between groups for mental state using the Brief Psychiatric Rating Scale (BPRS) (1 RCT, n = 57, MD 5.10 95% CI -2.35 to 12.55, very low-quality evidence), nor was there any difference in numbers leaving the study early for any reason (2 RCTs, n = 98, RR 1.19 95% CI 0.63 to 2.28, very low-quality evidence). More people required concomitant anticholinergic medication in the fluphenazine group compared to amisulpride (1 RCT, n = 36, RR 7.82 95% CI 1.07 to 57.26, very low-quality evidence). No data were reported for important outcomes including relapse, changes in life skills, quality of life or cost-effectiveness. Comparing oral fluphenazine with risperidone, data showed no difference between groups for 'clinically important response' (1 RCT, n = 26, RR 0.67 95% CI 0.13 to 3.35, very low-quality evidence) nor leaving the study early due to inefficacy (1 RCT, n = 25, RR 1.08 95% CI 0.08 to 15.46, very low-quality evidence). No data were reported data for relapse; change in life skills; quality of life; extrapyramidal adverse effects; or cost-effectiveness. Once again there was no difference when oral fluphenazine was compared with quetiapine for clinically important response (1 RCT, n = 25, RR 0.62 95% CI 0.12 to 3.07, very low-quality evidence), nor leaving the study early for any reason (1 RCT, n = 25, RR 0.46 95% CI 0.05 to 4.46, very low-quality evidence). No data were reported for relapse; clinically important change in life skills; quality of life; extrapyramidal adverse effects; or cost-effectiveness. Compared to olanzapine, fluphenazine showed no superiority for clinically important response (1 RCT, n = 60, RR 1.33 95% CI 0.86 to 2.07, very low-quality evidence), in incidence of akathisia (1 RCT, n = 60, RR 3.00 95% CI 0.90 to 10.01, very low-quality evidence) or in people leaving the study early (1 RCT, n = 60, RR 3.00 95% CI 0.33 to 27.23, very low-quality evidence). No data were reported for relapse; change in life skills; quality of life; or cost-effectiveness. Measures of clinical response and mental state do not highlight differences between fluphenazine and amisulpride, risperidone, quetiapine or olanzapine. Largely measures of adverse effects are also unconvincing for substantive differences between fluphenazine and the newer drugs. All included trials carry a substantial risk of bias regarding reporting of adverse effects and this bias would have favoured the newer drugs. The four small short included studies do not provide much clear information about the relative merits or disadvantages of oral fluphenazine compared with newer atypical antipsychotics.
We included 38 studies. Based on three studies, acupuncture was not shown to be more effective than a waiting list control for long-term abstinence, with wide confidence intervals and evidence of heterogeneity (n = 393, risk ratio [RR] 1.79, 95% confidence interval [CI] 0.98 to 3.28, I² = 57%). Compared with sham acupuncture, the RR for the short-term effect of acupuncture was 1.22 (95% CI 1.08 to 1.38), and for the long-term effect was 1.10 (95% CI 0.86 to 1.40). The studies were not judged to be free from bias, and there was evidence of funnel plot asymmetry with larger studies showing smaller effects. The heterogeneity between studies was not explained by the technique used. Acupuncture was less effective than nicotine replacement therapy (NRT). There was no evidence that acupuncture is superior to psychological interventions in the short- or long-term. There is limited evidence that acupressure is superior to sham acupressure for short-term outcomes (3 trials, n = 325, RR 2.54, 95% CI 1.27 to 5.08), but no trials reported long-term effects, The pooled estimate for studies testing an intervention that included continuous auricular stimulation suggested a short-term benefit compared to sham stimulation (14 trials, n = 1155, RR 1.69, 95% CI 1.32 to 2.16); subgroup analysis showed an effect for continuous acupressure (7 studies, n = 496, RR 2.73, 95% CI 1.78 to 4.18) but not acupuncture with indwelling needles (6 studies, n = 659, RR 1.24, 95% CI 0.91 to 1.69). At longer follow-up the CIs did not exclude no effect (5 trials, n = 570, RR 1.47, 95% CI 0.79 to 2.74). The evidence from two trials using laser stimulation was inconsistent and could not be combined. The combined evidence on electrostimulation suggests it is not superior to sham electrostimulation (short-term abstinence: 6 trials, n = 634, RR 1.13, 95% CI 0.87 to 1.46; long-term abstinence: 2 trials, n = 405, RR 0.87, 95% CI 0.61 to 1.23). Although pooled estimates suggest possible short-term effects there is no consistent, bias-free evidence that acupuncture, acupressure, or laser therapy have a sustained benefit on smoking cessation for six months or more. However, lack of evidence and methodological problems mean that no firm conclusions can be drawn. Electrostimulation is not effective for smoking cessation. Well-designed research into acupuncture, acupressure and laser stimulation is justified since these are popular interventions and safe when correctly applied, though these interventions alone are likely to be less effective than evidence-based interventions.
A total of 18 studies (systematic reviews or meta-analyses) met our inclusion criteria. Ten compared random allocation versus non-random allocation and nine compared adequate versus inadequate or unclear concealment of allocation within controlled trials. All studies were at high risk of bias. For the comparison of randomised versus non-randomised studies, four comparisons yielded inconclusive results (differed between outcomes or different modes of analysis); three comparisons showed similar results for random and non-random allocation; two comparisons had larger estimates of effect in non-randomised studies than in randomised trials; and two comparisons had larger estimates of effect in randomised than in non-randomised studies. Five studies found larger estimates of effect in trials with inadequate concealment of allocation than in trials with adequate concealment. The four other studies did not find statistically significant differences. The results of randomised and non-randomised studies sometimes differed. In some instances non-randomised studies yielded larger estimates of effect and in other instances randomised trials yielded larger estimates of effect. The results of controlled trials with adequate and inadequate/unclear concealment of allocation sometimes differed. When differences occurred, most often trials with inadequate or unclear allocation concealment yielded larger estimates of effects relative to controlled trials with adequate allocation concealment. However, it is not generally possible to predict the magnitude, or even the direction, of possible selection biases and consequent distortions of treatment effects from studies with non-random allocation or controlled trials with inadequate or unclear allocation concealment.
We included nine trials with low risk of bias, which assessed paracetamol for the treatment of pain in 728 infants. Painful procedures studied included heel lance, assisted vaginal birth, eye examination for retinopathy of prematurity assessment and postoperative care. Results of individual studies could not be combined in meta-analyses as the painful conditions, the use of paracetamol and comparison interventions and the outcome measures differed. Paracetamol compared with water, cherry elixir or EMLA cream (eutectic mixture of lidocaine and prilocaine) did not significantly reduce pain following heel lance. The Premature Infant Pain Profile score (PIPP) within three minutes following lancing was higher in the paracetamol group than in the oral glucose group (mean difference (MD) 2.21, 95% confidence interval (CI) 0.72 to 3.70; one study, 38 infants). Paracetamol did not reduce "modified facies scores" after assisted vaginal birth (one study, 119 infants). In another study (n = 123), the Échelle de Douleur et d'Inconfort du Nouveau-Né score at two hours of age was significantly higher in the group that received paracetamol suppositories than in the placebo suppositories group (MD 1.00, 95% CI 0.60 to 1.40). In that study, when infants were subjected to a heel lance at two to three days of age, Bernese Pain Scale for Neonates scores were higher in the paracetamol group than in the placebo group, and infants spent a longer time crying (MD 19 seconds, 95% CI 14 to 24). For eye examinations, no significant reduction in PIPP scores in the first or last 45 seconds of eye examination was reported, nor at five minutes after the eye examination. In one study (n = 81), the PIPP score was significantly higher in the paracetamol group than in the 24% sucrose group (MD 3.90, 95% CI 2.92 to 4.88). In one study (n = 114) the PIPP score during eye examination was significantly lower in the paracetamol group than in the water group (MD −2.70, 95% CI −3.55 to 1.85). For postoperative care following major surgery, the total amount of morphine (µg/kg) administered over 48 hours was significantly less among infants assigned to the paracetamol group than to the morphine group (MD −157 µg/kg, 95% CI −27 to −288). No adverse events were noted in any study. The quality of evidence according to GRADE was low. The paucity and low quality of existing data do not provide sufficient evidence to establish the role of paracetamol in reducing the effects of painful procedures in neonates. Paracetamol given after assisted vaginal birth may increase the response to later painful exposures. Paracetamol may reduce the total need for morphine following major surgery, and for this aspect of paracetamol use, further research is needed.
Twelve RCTs (n=545) with eight to 26 weeks follow-up met our inclusion criteria. The results of the individual trials were heterogeneous. Combining all trials, participants receiving magnesium supplements as compared to control did not significantly reduce SBP (mean difference: -1.3 mmHg, 95% CI: -4.0 to 1.5, I2=67%), but did statistically significantly reduce DBP (mean difference: -2.2 mmHg, 95% CI: -3.4 to -0.9, I2=47%). Sensitivity analyses excluding poor quality trials yielded similar results. Sub-group analyses and meta-regression indicated that heterogeneity between trials could not be explained by dose of magnesium, baseline blood pressure or the proportion of males among the participants. In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of magnesium supplementation on blood pressure and cardiovascular outcomes.
Data for the primary outcome (prevention of disease) were lacking. We performed a meta-analysis to pool the results of 20 studies with 5874 participants in an immunogenicity analysis and 5232 participants in the reactogenicity analysis. There were no data on clinical outcomes for the primary outcome (prevention of disease) and all studies used immunogenicity and reactogenicity (adverse events). The number of vaccine doses differed significantly between the studies. Heterogeneous interventions, study location, healthcare environment and combining research across disparate geographical locations, may have lead to bias. The risk of bias was unclear across most of the included studies. Comparisons found little heterogeneity. In two immunological responses the combined vaccine achieved lower responses than the separate vaccines for HIB and tetanus. No significant differences in immunogenicity were found for pertussis, diphtheria, polio and hepatitis B. Serious adverse events were comparable with mainly hospitalisation and acute bronchiolitis cases. Minor adverse events such as pain and redness were more common in children given the combined vaccine. Overall, the direction shown by the results is in favour of the DTPw (diptheria-tetanus-whole cell pertussis)-HBV-HIB vaccine rather than the DTPa (diptheria-tetanus-acellular pertussis)-HBV-HIB vaccine when compared to the separate vaccines (size of effect: risk ratio (RR) 1.43; 95% confidence interval (CI) 0.98 to 2.10, for 5269 participants). We could not conclude that the immune responses elicited by the combined vaccine were different from or equivalent to the separate vaccines. There was significantly less immunological response for HIB and tetanus and more local reactions in the combined injections. However, these differences rely mostly on one study each. Studies did not use an intention-to-treat (ITT) analysis and we were uncertain about the risk of bias in many of the studies. These results are therefore inconclusive. Studies addressing clinical end points whenever possible, using correct methodology and a large enough sample size should be conducted.
Thirteen studies (1053 women) reported the accuracy of 3D SIS for focal uterine abnormalities; 11 of these (846 women) were suitable for meta-analysis, and eight reported accuracy according to the type of focal abnormality. The design of the included studies seems applicable. The main problem involving the quality of included studies is insufficient reporting of study methods, resulting in unclear risk of bias for several of the quality domains assessed. Therefore, we considered the overall quality of the evidence as low. The summary estimate (11 studies reporting absence or presence of abnormality at 3D SIS) for sensitivity was 94.5% (95% confidence interval (CI) 90.6% to 96.9%) and for specificity 99.4% (95% CI 96.2% to 99.9%). Meta-analysis of the eight studies (N = 716) directly comparing 2D SIS versus 3D SIS showed summary sensitivity of 96.9% (95% CI 91.9% to 98.8%) and summary specificity of 99.5% (95% CI 96.1% to 100%) for 3D SIS. For 2D SIS, summary sensitivity was 90.9% (95% CI 81.2% to 95.8%) and summary specificity was 96.3% (95% CI 86.1% to 99.1%). The difference in accuracy between 2D SIS and 3D SIS was non-significant (P values of 0.07 for sensitivity and 0.10 for specificity). Low-quality evidence suggests that 3D SIS may be very accurate in detecting intracavitary abnormalities. Meta-analysis revealed no statistically significant differences between 2D SIS and 3D SIS. Summary sensitivity and summary specificity are higher for 3D SIS, but margins of improvement are limited because 2D SIS is already very accurate. When the technology and appropriate expertise are available, 3D SIS offers an alternative to 2D SIS. Both 2D SIS and 3D SIS should be considered alternatives to diagnostic hysteroscopy when intracavitary pathology is suspected in subfertile women and in those with abnormal uterine bleeding.
Four studies met the inclusion criteria (331 participants), with two studies producing a statistically and clinically significant benefit in favour of the intervention for dyspnoea post exercise.The quality of life domain for all four included studies produced a statistically significant benefit for the subcategories of dyspnoea and fatigue, in favour of the oxygen group (dyspnoea mean difference (MD) 0.28, 95% confidence interval (CI) 0.10 to 0.45; P value 0.002; fatigue MD 0.17, 95% CI 0.04 to 0.31; P value 0.009). No evidence of any effect was reported for survival, and limited benefits were observed for exercise capacity (as measured by step test and distance walk test), with one study showing a statistically significant improvement in the number of steps taken in the oxygen group for group N-of-1 studies only. No other statistically significant benefits were observed for exercise capacity among the other trials or individual N-of-1 studies. In patients with COPD with moderate hypoxia, current evidence on ambulatory oxygen therapy reveals improvements in dyspnoea post exercise and in the dyspnoea and fatigue domain of quality of life. However, evidence for the clinical utility and effectiveness of ambulatory oxygen in improving mortality and exercise capacity was not evident in this review. Methodologically rigorous RCTs with sufficient power to detect a difference are required to investigate the role of ambulatory oxygen in the management of COPD.
We included 34 trials with 2848 participants; 26 studies were parallel-group design (2725 participants) and eight used a cross-over design (123 participants). Only three included studies reported data for infants or children. Two further studies (76 participants) are awaiting classification. There was no overall statistical difference in artificial airway occlusion (RR 1.59, 95% CI 0.60 to 4.19; participants = 2171; studies = 15; I2 = 54%), mortality (RR 1.03, 95% CI 0.89 to 1.20; participants = 1951; studies = 12; I2 = 0%) or pneumonia (RR 0.93, 95% CI 0.73 to 1.19; participants = 2251; studies = 13; I2 = 27%). There was some evidence that hydrophobic HMEs may reduce the risk of pneumonia compared to HHs (RR 0.48, 95% CI 0.28 to 0.82; participants = 469; studies = 3; I2 = 0%).. The overall GRADE quality of evidence was low. Although the overall methodological risk of bias was generally unclear for selection and detection bias and low risk for follow-up, the selection of study participants who were considered suitable for HME and in some studies removing participants from the HME group made the findings of this review difficult to generalize. The available evidence suggests no difference between HMEs and HHs on the primary outcomes of airway blockages, pneumonia and mortality. However, the overall low quality of this evidence makes it difficult to be confident about these findings. Further research is needed to compare HMEs to HHs, particularly in paediatric and neonatal populations, but research is also needed to more effectively compare different types of HME to each other as well as different types of HH.
The review authors identified 14 relevant RCTs. They excluded four trials. The 10 included studies, four of which have been added in this update, included a total of 258 participants. Six studies compared an immunosuppressant or immunomodulator with placebo control, and four studies compared two immunosuppressant regimes with each other. Most of the studies were small (the largest had 62 participants) and many of the reports contained insufficient information to assess risk of bias. Amongst the six studies comparing immunosuppressant with placebo, one study, investigating intravenous immunoglobulin (IVIg), showed statistically significant improvement in scores of muscle strength in the IVIg group over three months. Another study investigating etanercept showed some evidence of a longer median time to relapse in the etanercept group, a secondary outcome in this review, but no improvement in other assessed outcomes. The other four randomised placebo-controlled trials assessed either plasma exchange and leukapheresis, eculizumab, infliximab or azathioprine against placebo and all produced negative results. Three of the four studies comparing two immunosuppressant regimes (azathioprine with methotrexate, ciclosporin with methotrexate, and intramuscular methotrexate with oral methotrexate plus azathioprine) showed no statistically significant difference in efficacy between the treatment regimes. The fourth study comparing pulsed oral dexamethasone with daily oral prednisolone and found that the dexamethasone regime had a shorter median time to relapse but fewer side effects. Immunosuppressants were associated with significant side effects. This systematic review highlights the lack of high quality RCTs that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.
We identified 3745 citations after de-duplication of search results. We excluded 3619 records during title and abstract review. We assessed 126 full-text papers for inclusion in the review, but only one study providing data from 46 people met our eligibility criteria. The included RCT had methodological limitations. We rated it as having high risk of performance and detection bias because of lack of blinding, and as having high risk of attrition bias because study authors did not report reasons for dropouts and did not integrate data from dropouts into the analysis. The included RCT compared preventive use of bright white light (2500 lux via visors), infrared light (0.18 lux via visors) and no light treatment. Overall, white light and infrared light therapy reduced the incidence of SAD numerically compared with no light therapy. In all, 43% (6/14) of participants in the bright light group developed SAD, as well as 33% (5/15) in the infrared light group and 67% (6/9) in the non-treatment group. Bright light therapy reduced the risk of SAD incidence by 36%; however, the 95% confidence interval (CI) was very broad and included both possible effect sizes in favour of bright light therapy and those in favour of no light therapy (risk ratio (RR) 0.64, 95% CI 0.30 to 1.38; 23 participants, very low-quality evidence). Infrared light reduced the risk of SAD by 50% compared with no light therapy, but the CI was also too broad to allow precise estimations of effect size (RR 0.50, 95% CI 0.21 to 1.17; 24 participants, very low-quality evidence). Comparison of both forms of preventive light therapy versus each other yielded similar rates of incidence of depressive episodes in both groups (RR 1.29, 95% CI 0.50 to 3.28; 29 participants, very low-quality evidence). Reasons for downgrading evidence quality included high risk of bias of the included study, imprecision and other limitations, such as self-rating of outcomes, lack of checking of compliance throughout the study duration and insufficient reporting of participant characteristics. Investigators provided no information on adverse events. We could find no studies that compared light therapy versus other interventions of interest such as second-generation antidepressants, psychological therapies, melatonin or agomelatine. Evidence on light therapy as preventive treatment for people with a history of SAD is limited. Methodological limitations and the small sample size of the only available study have precluded review author conclusions on effects of light therapy for SAD. Given that comparative evidence for light therapy versus other preventive options is limited, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences.
We included 38 RCTs (6016 participants). There were four main comparisons: chlorhexidine (CHX) mouthrinse or gel versus placebo/usual care; toothbrushing versus no toothbrushing; powered versus manual toothbrushing; and comparisons of oral care solutions. We assessed the overall risk of bias as low in five trials (13%), high in 26 trials (68%), and unclear in seven trials (18%). We did not consider the risk of bias to be serious when assessing the quality of evidence (GRADE) for VAP incidence, but we downgraded other outcomes for risk of bias. High quality evidence from 18 RCTs (2451 participants, 86% adults) shows that CHX mouthrinse or gel, as part of OHC, reduces the risk of VAP compared to placebo or usual care from 24% to about 18% (RR 0.75, 95% confidence intervals (CI) 0.62 to 0.91, P = 0.004, I2 = 35%). This is equivalent to a number needed to treat for an additional beneficial outcome (NNTB) of 17 (95% CI 9 to 50), which indicates that for every 17 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP would be prevented. There is no evidence of a difference between CHX and placebo/usual care for the outcomes of mortality (RR 1.09, 95% CI 0.96 to 1.23, P = 0.20, I2 = 0%, 14 RCTs, 2014 participants, moderate quality evidence), duration of mechanical ventilation (MD -0.09 days, 95% CI -1.73 to 1.55 days, P = 0.91, I2 = 36%, five RCTs, 800 participants, low quality evidence), or duration of intensive care unit (ICU) stay (MD 0.21 days, 95% CI -1.48 to 1.89 days, P = 0.81, I2 = 9%, six RCTs, 833 participants, moderate quality evidence). There is insufficient evidence to determine the effect of CHX on duration of systemic antibiotics, oral health indices, caregivers' preferences or cost. Only two studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups. We are uncertain as to the effects of toothbrushing (± antiseptics) on the outcomes of VAP (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11, I2 = 64%, five RCTs, 889 participants, very low quality evidence) and mortality (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24, I2 = 0%, five RCTs, 889 participants, low quality evidence) compared to OHC without toothbrushing (± antiseptics). There is insufficient evidence to determine whether toothbrushing affects duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, adverse effects, caregivers' preferences or cost. Only one trial (78 participants) compared use of a powered toothbrush with a manual toothbrush, providing insufficient evidence to determine the effect on any of the outcomes of this review. Fifteen trials compared various other oral care solutions. There is very weak evidence that povidone iodine mouthrinse is more effective than saline/placebo (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, three studies, 356 participants, high risk of bias), and that saline rinse is more effective than saline swab (RR 0.47, 95% CI 0.37 to 0.62, P < 0.001, I2 = 84%, four studies, 488 participants, high risk of bias) in reducing VAP. Due to variation in comparisons and outcomes among trials, there is insufficient evidence concerning the effects of other oral care solutions. OHC including chlorhexidine mouthwash or gel reduces the risk of developing ventilator-associated pneumonia in critically ill patients from 24% to about 18%. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence that OHC including both antiseptics and toothbrushing is different from OHC with antiseptics alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline/placebo, and saline rinse is more effective than saline swab in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. There is also insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects.
We identified 19 studies of which we included five, involving 3130 women. We excluded eight studies, one awaits classification and five are ongoing studies. All the included studies looked at women in active labour and at low risk of potentially requiring a general anaesthetic. One study looked at complete restriction versus giving women the freedom to eat and drink at will; two studies looked at water only versus giving women specific fluids and foods and two studies looked at water only versus giving women carbohydrate drinks. When comparing any restriction of fluids and food versus women given some nutrition in labour, the meta-analysis was dominated by one study undertaken in a highly medicalised environment. There were no statistically significant differences identified in: caesarean section (average risk ratio (RR) 0.89, 95% confidence interval (CI) 0.63 to 1.25, five studies, 3103 women), operative vaginal births (average RR 0.98, 95% CI 0.88 to 1.10, five studies, 3103 women) and Apgar scores less than seven at five minutes (average RR 1.43, 95% CI 0.77 to 2.68, four studies, 2902 infants), nor in any of the other outcomes assessed. Women's views were not assessed. The pooled data were insufficient to assess the incidence of Mendelson's syndrome, an extremely rare outcome. Other comparisons showed similar findings, except one study did report a significant increase in caesarean sections for women taking carbohydrate drinks in labour compared with water only, but these results should be interpreted with caution as the sample size was small. Since the evidence shows no benefits or harms, there is no justification for the restriction of fluids and food in labour for women at low risk of complications. No studies looked specifically at women at increased risk of complications, hence there is no evidence to support restrictions in this group of women. Conflicting evidence on carbohydrate solutions means further studies are needed and it is critical in any future studies to assess women's views.
We included seven studies, of which five studies with 4798 participants provided data for analyses in this review. The mean ages of the participants ranged from 56 to 66 years. All participants had a history of adenomas, which had been removed to achieve a polyp-free colon at baseline. The interventions were wheat bran fibre, ispaghula husk, or a comprehensive dietary intervention with high fibre whole food sources alone or in combination. The comparators were low-fibre (2 to 3 g per day), placebo, or a regular diet. The combined data showed no statistically significant difference between the intervention and control groups for the number of participants with at least one adenoma (5 RCTs, n = 3641, RR 1.04, 95% CI 0.95 to 1.13, low-quality evidence), more than one adenoma (2 RCTs, n = 2542, RR 1.06, 95% CI 0.94 to 1.20, low-quality evidence), or at least one adenoma 1 cm or greater (4 RCTs, n = 3224, RR 0.99, 95% CI 0.82 to 1.20, low-quality evidence) at three to four years. The results on the number of participants diagnosed with colorectal cancer favoured the control group over the dietary fibre group (2 RCTS, n = 2794, RR 2.70, 95% CI 1.07 to 6.85, low-quality evidence). After 8 years of comprehensive dietary intervention, no statistically significant difference was found in the number of participants with at least one recurrent adenoma (1 RCT, n = 1905, RR 0.97, 95% CI 0.78 to 1.20), or with more than one adenoma (1 RCT, n = 1905, RR 0.89, 95% CI 0.64 to 1.24). More participants given ispaghula husk group had at least one recurrent adenoma than the control group (1 RCT, n = 376, RR 1.45, 95% CI 1.01 to 2.08). Other analyses by types of fibre intervention were not statistically significant. The overall dropout rate was over 16% in these trials with no reasons given for these losses. Sensitivity analysis incorporating these missing data shows that none of the results can be considered as robust; when the large numbers of participants lost to follow-up were assumed to have had an event or not, the results changed sufficiently to alter the conclusions that we would draw. Therefore, the reliability of the findings may have been compromised by these missing data (attrition bias) and should be interpreted with caution. There is a lack of evidence from existing RCTs to suggest that increased dietary fibre intake will reduce the recurrence of adenomatous polyps in those with a history of adenomatous polyps within a two to eight year period. However, these results may be unreliable and should be interpreted cautiously, not only because of the high rate of loss to follow-up, but also because adenomatous polyp is a surrogate outcome for the unobserved true endpoint CRC. Longer-term trials with higher dietary fibre levels are needed to enable confident conclusion.
This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI −0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.
This review includes, in total, 19 publications of 18 randomized controlled trials with a total of 1096 participants. We incorporated five of those 19 studies (330 participants) after the June 2016 update. Outcome measures in the included studies were thematically similar, covering perioperative electrolyte status, renal function, and acid-base status; however, we found significant clinical and statistical heterogeneity among the included studies. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Trial authors variably reported outcome data at disparate time points and with heterogeneous patient groups. Consequently, many outcome measures are reported in small group sizes, reducing overall confidence in effect size, despite relatively low inherent bias in the included studies. Several studies reported orphan outcome measures. We did not include in the results of this review one large, ongoing study of saline versus Ringer's solution. We found insufficient evidence on effects of fluid therapies on mortality and postoperative organ dysfunction (defined as renal insufficiency leading to renal replacement therapy); confidence intervals were wide and included both clinically relevant benefit and harm: mortality (Peto OR 1.85, 95% CI 0.37 to 9.33; I² = 0%; 3 trials, 6 deaths, 276 participants; low-quality evidence); renal insufficiency (OR 0.82, 95% CI 0.34 to 1.98; I² = 0%; 4 trials, 22 events, 276 participants; low-quality evidence). We noted several metabolic differences, including a difference in postoperative pH measured at end of surgery of 0.05 units - lower in the non-buffered fluid group (12 studies with a total of 720 participants; 95% CI 0.04 to 0.07; I² = 61%). However, this difference was not maintained on postoperative day one. We rated the quality of evidence for this outcome as moderate. We observed a higher postoperative serum chloride level immediately after operation, with use of non-buffered fluids reported in 10 studies with a total of 530 participants (MD 6.77 mmol/L, 95% CI 3.38 to 10.17), and this difference persisted until day one postoperatively (five studies with a total of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). We rated the quality of evidence for this outcome as moderate. Current evidence is insufficient to show effects of perioperative administration of buffered versus non-buffered crystalloid fluids on mortality and organ system function in adult patients following surgery. Benefits of buffered fluid were measurable in biochemical terms, particularly a significant reduction in postoperative hyperchloraemia and metabolic acidosis. Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Larger studies are needed to assess these relevant clinical outcomes.
Eighteen trials involving 1174 children were identified which included a complex or educational intervention for nocturnal enuresis. The trials were mostly small and some had methodological problems including the use of a quasi-randomised method of concealment of allocation in three trials and baseline differences between the groups in another three. A complex intervention (such as dry bed training (DBT) or full spectrum home training (FSHT)) including an alarm was better than no-treatment control groups (for example the relative risk (RR) for failure or relapse after stopping DBT was 0.25; 95% CI 0.16 to 0.39) but there was not enough evidence about the effects of complex interventions alone if an alarm was not used. A complex intervention on its own was not as good as an alarm on its own or the intervention supplemented by an alarm (e.g. RR for failure or relapse after DBT alone versus DBT plus alarm was 2.81; 95% CI 1.80 to 4.38). On the other hand, a complex intervention supplemented by a bed alarm might reduce the relapse rate compared with the alarm on its own (e.g. RR for failure or relapse after DBT plus alarm versus alarm alone was 0.5; 95% CI 0.31 to 0.80). There was not enough evidence to judge whether providing educational information about enuresis was effective, irrespective of method of delivery. There was some evidence that direct contact between families and therapists enhanced the effect of a complex intervention, and that increased contact and support enhanced a package of simple behavioural interventions, but these were addressed only in single trials and the results would need to be confirmed by further randomised controlled trials, in particular the effect on use of resources. Although DBT and FSHT were better than no treatment when used in combination with an alarm, there was insufficient evidence to support their use without an alarm. An alarm on its own was also better than DBT on its own, but there was some evidence that combining an alarm with DBT was better than an alarm on its own, suggesting that DBT may augment the effect of an alarm. There was also some evidence that direct contact with a therapist might enhance the effects of an intervention.
Thirty-five studies were included (1223 participants received codeine 60 mg, 27 codeine 90 mg, and 1252 placebo). Combining all types of surgery (33 studies, 2411 participants), codeine 60 mg had an NNT of at least 50% pain relief over 4 to 6 hours of 12 (8.4 to 18) compared with placebo. At least 50% pain relief was achieved by 26% on codeine 60 mg and 17% on placebo. Following dental surgery the NNT was 21 (12 to 96) (15 studies, 1146 participants), and following other types of surgery the NNT was 6.8 (4.6 to 13) (18 studies, 1265 participants). The NNT to prevent use of rescue medication within 4 to 6 hours was 11 (6.3 to 50) (11 studies, 765 participants, mostly non-dental); the mean time to its use was 2.7 hours with codeine and 2.0 hours with placebo. More participants experienced adverse events with codeine 60 mg than placebo; the difference was not significant and none were serious. Two adverse event withdrawals occurred with placebo. Single dose codeine 60 mg provides good analgesia to few individuals, and does not compare favourably with commonly used alternatives such as paracetamol, NSAIDs and their combinations with codeine, especially after dental surgery; the large difference between dental and other surgery was unexpected. Higher doses were not evaluated.
We included 17 completed randomised clinical trials, but only 16 studies with 1347 participants provided data for the meta-analyses. Ten of the 16 trials assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids (782 participants) and six trials assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). One additional study assessed complete post-operative glucocorticosteroid avoidance but could only be incorporated into qualitative analysis of the results due to limited data published in an abstract. All trials were at high risk of bias. Only eight trials reported on the type of donor used. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.15, 95% CI 0.90 to 1.46; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; very low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; low-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses. Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.
We included four trials involving 350 patients. Not all trials contributed data to each outcome. The trials tested either intra-arterial urokinase or recombinant pro-urokinase versus an open control. One trial used guidewire-mediated clot disruption in some patients randomised to the intervention group. Most data came from trials that started treatment up to six hours after stroke; one small trial started treatment up to a median of 12.5 hours after stroke. Most data came from trials of middle cerebral artery territory infarction. Compared with non-thrombolytic standard medical treatment, the intervention administered up to six hours after ischaemic stroke significantly increased the proportion of patients with favourable outcome (modified Rankin 0 to 2) three months after stroke (relative risk (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.02). The intervention also significantly increased the risk of symptomatic intracranial haemorrhage within 24 hours of treatment (RR 3.85, 95% CI 0.91 to 16.36). There was no significant heterogeneity between the included trials. Overall, intervention results in a significant increase in the proportion of patients with a favourable outcome, despite a significant increase in intracranial haemorrhage. Further trials are needed to confirm or refute these findings and, given the cost and practical difficulties, to establish whether percutaneous techniques are feasible and cost effective in wider clinical practice.
We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly. Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle. In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results. When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results. Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons. There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome. We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful. It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.
We identified 14 trials in which there were 607 participants; one of the trials was newly included at this 2014 update. The use of different outcome measures prevented pooling of data for meta-analysis even when interventions and participants were comparable. All trials displayed bias in four or more areas. One trial reported on the primary outcome of function, though raw data were not available to be analysed. We were able to analyse data on foot alignment (Pirani score), a secondary outcome, from three trials. Two of the trials involved participants at initial presentation. One reported that the Ponseti technique significantly improved foot alignment compared to the Kite technique. After 10 weeks of serial casting, the average total Pirani score of the Ponseti group was 1.15 (95% confidence interval (CI) 0.98 to 1.32) lower than that of the Kite group. The second trial found the Ponseti technique to be superior to a traditional technique, with average total Pirani scores of the Ponseti participants 1.50 lower (95% CI 0.72 to 2.28) after serial casting and Achilles tenotomy. A trial in which the type of presentation was not reported found no difference between an accelerated Ponseti or standard Ponseti treatment. At the end of serial casting, the average total Pirani scores in the standard group were 0.31 lower (95% CI -0.40 to 1.02) than the accelerated group. Two trials in initial cases found relapse following Ponseti treatment was more likely to be corrected with further serial casting compared to the Kite groups which more often required major surgery (risk difference 25% and 50%). There is a lack of evidence for different plaster casting products, the addition of botulinum toxin A during the Ponseti technique, different types of major foot surgery, continuous passive motion treatment following major foot surgery, or treatment of relapsed or neglected cases of CTEV. Most trials did not report on adverse events. In trials evaluating serial casting techniques, adverse events included cast slippage (needing replacement), plaster sores (pressure areas) and skin irritation. Adverse events following surgical procedures included infection and the need for skin grafting. From the limited evidence available, the Ponseti technique produced significantly better short-term foot alignment compared to the Kite technique and compared to a traditional technique. The quality of this evidence was low to very low. An accelerated Ponseti technique may be as effective as a standard technique, according to moderate quality evidence. Relapse following the Kite technique more often led to major surgery compared to relapse following the Ponseti technique. We could draw no conclusions from other included trials because of the limited use of validated outcome measures and lack of available raw data. Future randomised controlled trials should address these issues.
Five studies met our inclusion criteria. Three demonstrated significantly higher quit rates (8% to 20%) for the quit and win group than for the control group at the 12-month assessment. However, the population impact measure, where available, suggests that the effect of contests on community prevalence of smoking is small, with fewer than one in 500 smokers quitting because of the contest. Levels of deception, where they could be quantified, were high. Although surveys suggest that international quit and win contests may be effective, especially in developing countries, the lack of controlled studies precludes any firm conclusions from this review. Quit and win contests at local and regional level appear to deliver quit rates above baseline community rates, although the population impact of the contests seems to be relatively low. Contests may be subject to levels of deception which could compromise the validity of the intervention. International contests may prove to be an effective mechanism, particularly in developing countries, but a lack of well-designed comparative studies precludes any firm conclusions.
Seven RCTs with a total of 339 participants were included in this review. One study was assessed as at low risk of bias, three studies were at high risk of bias, and in the remaining three studies risk of bias was unclear. Four studies reported on the use of a facemask, two on the chin cup, one on the tandem traction bow appliance, and one on mandibular headgear. One study reported on both the chin cup and mandibular headgear appliances. One study (n = 73, low quality evidence), comparing a facemask to no treatment, reported a mean difference (MD) in overjet of 4.10 mm (95% confidence interval (CI) 3.04 to 5.16; P value < 0.0001) favouring the facemask treatment. Two studies comparing facemasks to untreated control did not report the outcome of overjet. Three studies (n = 155, low quality evidence) reported ANB (an angular measurement relating the positions of the top and bottom jaws) differences immediately after treatment with a facemask when compared to an untreated control. The pooled data showed a statistically significant MD in ANB in favour of the facemask of 3.93 ° (95% CI 3.46 to 4.39; P value < 0.0001). There was significant heterogeneity between these studies (I2 = 82%). This is likely to have been caused by the different populations studied and the different ages at the time of treatment. One study (n = 73, low quality evidence) reported outcomes of the use of the facemask compared to an untreated control at three years follow-up. This study showed that improvements in overjet and ANB were still present three years post-treatment. In this study, adverse effects were reported but due to the low prevalence of temporomandibular (TMJ) signs and symptoms no analysis was undertaken. Two studies (n = 90, low quality evidence) compared the chin cup with an untreated control. Both studies found a statistically significant improvement in ANB, and one study also found an improvement in the Wits appraisal. Data from these two studies were not suitable for pooling. A single study of the tandem traction bow appliance compared to untreated control (n = 30, very low quality evidence) showed a statistically significant difference in both overjet and ANB favouring the intervention group. The remaining two studies did not report the primary outcome of this review. There is some evidence that the use of a facemask to correct prominent lower front teeth in children is effective when compared to no treatment on a short-term basis. However, in view of the general poor quality of the included studies, these results should be viewed with caution. Further randomised controlled trials with long follow-up are required.
We included six studies (492 women) that assessed online support groups for women with breast cancer. Online support groups in these six trials lasted from six to 30 weeks. Women participated in these groups between 1.5 and 2.5 hours per week, and investigators conducted all studies in the USA. Participants were predominantly white and well educated and were moderate to high earners. Four studies compared an online support group versus a control group, and the other two compared a 'moderated' versus a 'peer-led' online support group, and a 'standard' versus an 'enhanced' online support group, respectively. None of the included studies measured 'emotional distress' or uncertainty. One study (78 women) for which data for analysis were missing reported no positive effects of online support on 'distress' and 'cancer-specific distress' versus support provided by a control group. Two studies measured anxiety: One study (72 women) found no difference in anxiety at the end of the intervention between the online support group and the control group (MD -0.40, 95% CI -6.42 to 5.62; low-quality evidence), and the second study (184 women) reported a reduction in anxiety levels at the end of the intervention when comparing the 'standard' support group (run by participants without prompting from health professionals) versus an 'enhanced' online support group (in which participants were specifically asked by the researcher to respond to one another's need for support). Five studies (414 women) measured depression. Three studies compared depression in the online support group with depression in the control group. Pooled data from two studies (120 women) showed a small to moderate reduction in depression in the online support group compared with control groups at the end of the intervention (SMD -0.37, 95% CI -0.75 to 0.00; very low-quality evidence). The third study, a pilot study (30 women), provided no data for analysis but reported no difference in depression between participants in support and control groups at the end of the intervention. Of the remaining two studies that measured depression, one study (60 women) provided no extractable data for comparison but reported no difference in depressive symptoms between a 'moderated' and a 'peer-led' support group; the other study (184 women) reported greater reduction in depression in the 'standard' support group than in the 'enhanced' online support group. Three studies measured quality of life. One pilot study (30 women) provided limited data for analysis but reported no change in quality of life at the end of the intervention. Only two studies (140 women) provided data for pooling and showed no positive effects on quality of life at four months post intervention compared with controls (SMD -0.11, 95% CI -0.47 to 0.24; very low-quality evidence). At 12 months post intervention, one study (78 women) reported that the intervention group did not attain better quality of life scores than the control group (MD -10.89, 95% CI -20.41 to -1.37; low-quality evidence). We found no data for subgroup analyses on stage of disease, treatment modality and types and doses of interventions. No studies measured adverse effects. This review did not find the evidence required to show whether participation in online support groups was beneficial for women with breast cancer, because identified trials were small and of low or very low quality. Large, rigorous trials with ethnically and economically diverse participants are needed to provide robust evidence regarding the psychosocial outcomes selected for this review.
We included 33 studies in the review (2242 participants). Antidepressants were compared to placebo (22 studies), psychotherapy (two studies), other medications (four studies), or other antidepressants (five studies). The mean duration of the trials was 9.9 weeks (range 3 to 26 weeks). Eighteen studies took place in the USA, 12 in Europe, two in Turkey, and one in Australia. The antidepressant included in most of the trials was sertraline; other medications were amitriptyline, citalopram, desipramine, doxepin, escitalopram, fluoxetine, fluvoxamine, imipramine, mianserin, mirtazepine, nefazodone, paroxetine, tianeptine, venlafaxine, and viloxazine. Eighteen studies were conducted in an outpatient setting, nine in an inpatient setting, and six in both settings. Psychosocial treatment was provided in 18 studies. There was high heterogeneity in the selection of outcomes and the rating systems used for diagnosis and outcome assessment. Comparing antidepressants to placebo, low-quality evidence suggested that antidepressants reduced the severity of depression evaluated with interviewer-rated scales at the end of trial (14 studies, 1074 participants, standardized mean difference (SMD) -0.27, 95% confidence interval (CI) -0.49 to -0.04). However, the difference became non-significant after the exclusion of studies with a high risk of bias (SMD -0.17, 95% CI -0.39 to 0.04). In addition, very low-quality evidence supported the efficacy of antidepressants in increasing the response to the treatment (10 studies, 805 participants, risk ratio (RR) 1.40, 95% Cl 1.08 to 1.82). This result became non-significant after the exclusion of studies at high risk of bias (RR 1.27, 95% CI 0.96 to 1.68). There was no difference for other relevant outcomes such as the difference between baseline and final score, evaluated using interviewer-rated scales (5 studies, 447 participants, SMD 0.15, 95% CI -0.12 to 0.42). Moderate-quality evidence found that antidepressants increased the number of participants abstinent from alcohol during the trial (7 studies, 424 participants, RR 1.71, 95% Cl 1.22 to 2.39) and reduced the number of drinks per drinking days (7 studies, 451 participants, mean difference (MD) -1.13 drinks per drinking days, 95% Cl -1.79 to -0.46). After the exclusion of studies with high risk of bias, the number of abstinent remained higher (RR 1.69, 95% CI 1.18 to 2.43) and the number of drinks per drinking days lower (MD -1.21 number of drinks per drinking days, 95% CI -1.91 to -0.51) among participants who received antidepressants compared to those who received placebo. However, other outcomes such as the rate of abstinent days did not differ between antidepressants and placebo (9 studies, 821 participants, MD 1.34, 95% Cl -1.66 to 4.34; low-quality evidence). Low-quality evidence suggested no differences between antidepressants and placebo in the number of dropouts (17 studies, 1159 participants, RR 0.98, 95% Cl 0.79 to 1.22) and adverse events as withdrawal for medical reasons (10 studies, 947 participants, RR 1.15, 95% Cl 0.65 to 2.04). There were few studies comparing one antidepressant versus another antidepressant or antidepressants versus other interventions, and these had a small sample size and were heterogeneous in terms of the types of interventions that were compared, yielding results that were not informative. We found low-quality evidence supporting the clinical use of antidepressants in the treatment of people with co-occurring depression and alcohol dependence. Antidepressants had positive effects on certain relevant outcomes related to depression and alcohol use but not on other relevant outcomes. Moreover, most of these positive effects were no longer significant when studies with high risk of bias were excluded. Results were limited by the large number of studies showing high or unclear risk of bias and the low number of studies comparing one antidepressant to another or antidepressants to other medication. In people with co-occurring depression and alcohol dependence, the risk of developing adverse effects appeared to be minimal, especially for the newer classes of antidepressants (such as selective serotonin reuptake inhibitors). According to these results, in people with co-occurring depression and alcohol dependence, antidepressants may be useful for the treatment of depression, alcohol dependence, or both, although the clinical relevance may be modest.
We included four RCTs, involving 564 participants in this review. We compared the effects of colchicine in addition to a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen, aspirin or indomethacin to the effects of the NSAID alone. Two comparable trials studied the effects of colchicine in 204 participants with recurrent pericarditis and two trials studied 360 people with acute pericarditis. All trials had a moderate quality for the primary outcomes. We identified two on-going trials; one of these trials examines acute pericarditis and the other assesses recurrent pericarditis. There was moderate quality evidence that colchicine reduces episodes of pericarditis in people with recurrent pericarditis over 18 months follow-up (HR 0.37; 95% confidence interval (CI) 0.24 to 0.58). It is expected that at 18 months, the number needed to treat (NNT) is 4. In people with acute pericarditis, there was moderate quality evidence that colchicine reduces recurrence (HR 0.40; 95% CI 0.27 to 0.61) at 18 months follow-up. Colchicine led to a greater chance of symptom relief at 72 hours (risk ratio (RR) 1.4; 95% CI 1.26 to 1.56; low quality evidence). Adverse effects were mainly gastrointestinal and included abdominal pain and diarrhoea. The pooled RR for adverse events was 1.26 (95% CI 0.75 to 2.12). While the number of people experiencing adverse effects was higher in the colchicine than the control groups (9% versus 7%), the quality of evidence was low owing to imprecision, and there was no statistically significant difference between the treatment groups (P = 0.42). There was moderate quality evidence that treatment with colchicine led to more people stopping treatment due to adverse events (RR 1.87; 95% CI 1.02 to 3.41). Colchicine, as adjunctive therapy to NSAIDs, is effective in reducing the number of pericarditis recurrences in patients with recurrent pericarditis or acute pericarditis. However, evidence is based on a limited number of small trials. Patients with multiple resistant recurrences were not represented in any published or on-going trials, and it is these patients that are in the most need for treatment.
We screened 4956 records from the searches, selecting 34 unique studies for full-text scrutiny, of which two met the inclusion criteria: one RCT and one NRS. The included studies assessed 113 female BRCA carriers who had risk-reducing surgery, but there was attrition, and outcome data were not available for all participants at final study assessments. We assessed the RCT as at a high risk of bias whilst the NRS did not have a control group. Our GRADE assessment of the studies was very low-certainty due to the paucity of data and methodological shortcomings of the studies. The primary outcome of quality of life was only measured in the RCT and that was specific to the menopause. Both studies reported on psychological distress and sexual function. Neither study measured body image, perhaps because this is most often associated with risk-reducing mastectomy rather than oophorectomy. The RCT (66 participants recruited with 48 followed to 12 months) assessed the short- and long-term effects of an eight-week mindfulness-based stress reduction (MBSR) training programme on quality of life, sexual functioning, and sexual distress in female BRCA carriers (n = 34) in a specialised family cancer clinic in the Netherlands compared to female BRCA carriers (n = 32) who received usual care. Measurements on the Menopause-Specific Quality of Life Questionnaire (MENQOL) showed some improvement at 3 and 12 months compared to the usual care group. At 3 months the mean MENQOL scores were 3.5 (95% confidence interval (CI) 3.0 to 3.9) and 3.8 (95% CI 3.3 to 4.2) for the MBSR and usual care groups respectively, whilst at 12 months the corresponding values were 3.6 (95% CI 3.1 to 4.0) and 3.9 (95% CI 3.5 to 4.4) (1 study; 48 participants followed up at 12 months). However, these results should be interpreted with caution due to the very low-certainty of the evidence, where a lower score is better. Other outcome measures on the Female Sexual Function Index and the Female Sexual Distress Scale showed no significant differences between the two groups. Our GRADE assessment of the evidence was very low-certainty due to the lack of blinding of participants and personnel, attrition bias and self-selection (as only one-third of eligible women chose to participate in the study) and serious imprecision due to the small sample size and wide 95% CI. The NRS comprised 37 female BRCA carriers selected from three Boston-area hospitals who had undergone a novel sexual health intervention following risk-reducing salpingo-oophorectomy (RRSO) without a history of tubo-ovarian cancer. The intervention consisted of targeted sexual-health education, body awareness and relaxation training, and mindfulness-based cognitive therapy strategies, followed by two sessions of tailored telephone counselling. This was a single-arm study without a control group. Our GRADE assessment of the evidence was very low-certainty, and as there was no comparison group in the included study, we could not estimate a relative effect. The study reported change in psychosexual adjustment from baseline to postintervention (median 2.3 months) using measures of Female Sexual Function Index (n = 34), which yielded change with a mean of 3.91, standard deviation (SD) 9.12, P = 0.018 (1 study, 34 participants; very low-certainty evidence). The Brief Symptom Inventory, Global Severity Index yielded a mean change of 3.92, SD 5.94, P < 0.001. The Sexual Self-Efficacy Scale yielded change with a mean of 12.14, SD 20.56, P < 0.001. The Sexual Knowledge Scale reported mean change of 1.08, SD 1.50, P < 0.001 (n = 36). Participant satisfaction was measured by questionnaire, and 100% participants reported that they enjoyed taking part in the psychoeducation group and felt "certain" or "very certain" that they had learned new skills to help them cope with the sexual side effects of RRSO. The effect of psychosocial interventions on quality of life and emotional well-being in female BRCA carriers who undergo risk-reducing surgery is uncertain given the very low methodological quality in the two studies included in the review. The absence of such interventions highlights the need for partnership between researchers and clinicians in this specific area to take forward the patient-reported outcomes and develop interventions to address the psychosocial issues related to risk-reducing surgery in female BRCA carriers, particularly in this new era of genomics, where testing may become more mainstream and many more women are identified as gene carriers.
We included nine cluster-randomized trials, one individual randomized trial, and seven non-randomized controlled studies. Nine studies were conducted in sub-Saharan Africa (Ethiopia, Nigeria, South Africa, Zambia, and Zimbabwe), six in Asia (Bangladesh, Cambodia, India, Nepal, and Pakistan), and two in South America (Brazil and Colombia); which are all high tuberculosis prevalence areas. Tuberculosis outreach screening, using house-to-house visits, sometimes combined with printed information about going to clinic, may increase tuberculosis case detection (RR 1.24, 95% CI 0.86 to 1.79; 4 trials, 6,458,591 participants in 297 clusters, low-certainty evidence); and probably increases case detection in areas with tuberculosis prevalence of 5% or more (RR 1.52, 95% CI 1.10 to 2.09; 3 trials, 155,918 participants, moderate-certainty evidence; prespecified stratified analysis). These interventions may lower the early default (prior to starting treatment) or default during treatment (RR 0.67, 95% CI 0.47 to 0.96; 3 trials, 849 participants, low-certainty evidence). However, this intervention may have may have little or no effect on treatment success (RR 1.07, 95% CI 1.00 to 1.15; 3 trials, 849 participants, low-certainty evidence), and we do not know if there is an effect on treatment failure or mortality. One study investigated long-term prevalence in the community, but with no clear effect due to imprecision and differences in care between the two groups (RR 1.14, 95% CI 0.65 to 2.00; 1 trial, 556,836 participants, very low-certainty evidence). Four studies examined health promotion activities to encourage people to attend for screening, including mass media strategies and more locally organized activities. There was some increase, but this could have been related to temporal trends, with no corresponding increase in case notifications, and no evidence of an effect on long-term tuberculosis prevalence. Two studies examined the effects of two to six nurse practitioner educational sessions in tuberculosis diagnosis, with no clear effect on tuberculosis cases detected. One trial compared mobile clinics every five days with house-to-house screening every six months, and showed an increase in tuberculosis cases. There was also insufficient evidence to determine if sustained improvements in case detection impact on long-term tuberculosis prevalence; this was evaluated in one study, which indicated little or no effect after four years of either contact tracing, extensive health promotion activities, or both (RR 1.31, 95% CI 0.75 to 2.30; 1 study, 405,788 participants in 12 clusters, very low-certainty evidence). The available evidence demonstrates that when used in appropriate settings, active case-finding approaches may result in increase in tuberculosis case detection in the short term. The effect of active case finding on treatment outcome needs to be further evaluated in sufficiently powered studies.
Sixty studies (2773 patients) were included. No formulation, route, or schedule of administration was associated with altered risks of death, bone pain, or parathyroidectomy. Marked heterogeneity in reporting of outcomes resulted in few data available for formal meta-analysis. Compared with placebo, vitamin D compounds lowered serum PTH at the expense of increasing serum phosphorus. Trends toward increased hypercalcaemia and serum calcium did not reach statistical significance but may be clinically relevant. Newer vitamin D compounds (paricalcitol, maxacalcitol, doxercalciferol) lowered PTH compared with placebo, with increased risks of hypercalcaemia, although inadequate data were available for serum phosphorus. Intravenous vitamin D may lower PTH compared with oral treatment, and be associated with lower serum phosphorus and calcium levels, although limitations in the available studies precludes a conclusive statement of treatment efficacy. Few studies were available for intermittent versus daily and intraperitoneal versus oral administration or directly comparative studies of newer versus established vitamin D compounds. We confirm that vitamin D compounds suppress PTH in people with CKD and requiring dialysis although treatment is associated with clinical elevations in serum phosphorus and calcium. All studies were inadequately powered to assess the effect of vitamin D on clinical outcomes and until such studies are conducted the relative importance of changes in serum PTH, phosphorus and calcium resulting from vitamin D therapy remain unknown. Observational data showing vitamin D compounds may be associated with improved survival in CKD need to be confirmed or refuted in specifically designed RCTs.
Seven studies involving 178 participants were included. Two studies were excluded from the meta-analysis of remission rates on the basis of clinical heterogeneity of the initial endoscopic protocols. There was no significant difference between PD or BTX treatment in remission within four weeks of the initial intervention; with a risk ratio of remission of 1.11 (95% CI 0.97 to 1.27). There was also no significant difference in the mean oesophageal pressures between the treatment groups; with a weighted mean difference for PD of -0.77 (95% CI -2.44 to 0.91, P = 0.37). Data on remission rates following the initial endoscopic treatment were available for three studies at six months and four studies at 12 months. At six months 46 of 57 PD participants were in remission compared to 29 of 56 in the BTX group, giving a risk ratio of 1.57 (95% CI 1.19 to 2.08, P = 0.0015); whilst at 12 months 55 of 75 PD participants were in remission compared to 27 of 72 BTX participants, with a risk ratio of 1.88 (95% CI 1.35 to 2.61, P = 0.0002). No serious adverse outcomes occurred in participants receiving BTX, whilst PD was complicated by perforation in three cases. The results of this meta-analysis suggest that PD is the more effective endoscopic treatment in the long term (greater than six months) for patients with achalasia.
Six open-label studies (257 patients) were identified. One study compared ACEi with other antihypertensive drugs, three compared ARBs with other antihypertensive drugs, and two studies compared an ARB with an ACEi. Long-term use (≥ 12 months) of an ARB showed significantly benefit of preserving residual kidney function in continuous ambulatory PD (CAPD) patients (MD 1.11 mL/min/1.73 m², 95% CI 0.38 to 1.83), although there was no significant benefit when an ARB were used short-term (≤ six months). One study showed that compared with other antihypertensive drugs, long-term use (12 months) of the ACEi ramipril showed a significant reduction in the decline of residual kidney function in patients on CAPD (MD -0.93 mL/min/1.73m², 95% CI -0.75 to -0.11), and delayed the progression to complete anuria (RR 0.64, 95% CI 0.41 to 0.99). There was no significant difference in serum potassium, urinary protein excretion, Kt/V, weekly creatinine clearance and blood pressure for ARBs versus other antihypertensive drugs. Compared with other antihypertensive drugs, ramipril showed no difference in mortality and cardiovascular events. Compared with an ACEi, ARBs did not show any difference in residual kidney function. The selection bias assessment was low in four studies and unclear in two. Five studies were open-label; however the primary outcome (residual kidney function) was obtained objectively from laboratory tests, and were not likely to be influenced by the lack of blinding. Reporting bias was unclear in all six studies. Compared with other antihypertensive drugs, long-term use (≥ 12 months) of ACEis or ARBs showed additional benefits of preserving residual kidney function in CAPD patients. There was no significant difference on residual kidney function preservation between ARBs and ACEis. However, limited by the small number of RCTs enrolling small number of participants, there is currently insufficient evidence to support the use of an ACEi or an ARB as first line antihypertensive therapy in PD patients.
We identified four potential studies, of which three were excluded. The included trial reported clinical pregnancy rates but not live births. There was no evidence of a difference in clinical pregnancy rate between those receiving an amoxycillin and clavulanic acid antibiotic combination (64/178: 36%) and those not (61/172: 35.5%) (OR1.02, 95% CI 0.66 to 1.58). Genital tract colonisation was significantly reduced in women receiving this antibiotic regimen (OR 0.59, 95% CI 0.37 to 0.95). This review suggests that the administration of amoxycillin and clavulanic acid prior to embryo transfer reduced upper genital tract microbial contamination but did not alter clinical pregnancy rates. The effect of this intervention on live birth is unknown. There are no data from randomised controlled trials to support or refute other antibiotic regimens in this setting. Future research is warranted to assess the efficacy of alternative antibiotic regimens. Researchers should assess live birth as the primary outcome and address quantitative microbial colonization as a secondary outcome.
No studies were included in this review. Although it is generally recognised that cystic fibrosis-related arthritis can be episodic and resolve spontaneously, treatment with analgesics and anti-inflammatory agents may be needed. But when episodic symptoms progress to persistent disease, disease-modifying anti-rheumatic drugs may be needed to limit the course of the disease. It is disappointing that no randomised controlled trials to rigorously evaluate these drugs could be found. This systematic review has identified the need for a well-designed adequately powered randomised controlled trial to assess the efficacy and safety of disease-modifying anti-rheumatic drugs for the management of cystic fibrosis-related arthropathy and hypertrophic osteoarthropathy in adults and children with cystic fibrosis. However, given the infrequency of cystic fibrosis-related arthritis and the range of symptoms and severity, randomised controlled trials may not be feasible and well-designed non-randomised observational studies may be more appropriate. Studies should also better define the two conditions.
Four trials involving 527 predominantly male participants were included. The main weakness of the studies was the lack of correct stratification of the arthroscopic intervention. The relative risk (RR) of thrombotic events was 0.16 (95% confidence interval (CI); 0.05 to 0.52) comparing any type of low molecular weight heparin (LMWH) versus placebo. All thrombotic events but one (pulmonary embolism in the LMWH group) were distal venous thrombosis. Adverse events were most common in the intervention group than in the control group, RR 2.04 (95% CI 1.21 to 3.44). There were 66 episodes of adverse events. The number needed to harm was 20 for any adverse events. This meta-analysis suggests that LMWH reduces the incidence of distal DVT diagnosed by sonogram. The clinical benefit of this is uncertain. No strong evidence was found to conclude thromboprophylaxis is effective to prevent thromboembolic events and safe, in people with unknown risk factors for thrombosis, undergoing knee arthroscopy.
We included 47 studies with 5102 women. The evidence for most comparisons was of low or moderate quality. The main limitations were poor reporting and imprecision. Vaginal hysterectomy (VH) versus abdominal hysterectomy (AH) (nine RCTs, 762 women) Return to normal activities was shorter in the VH group (mean difference (MD) -9.5 days, 95% confidence interval (CI) -12.6 to -6.4, three RCTs, 176 women, I2 = 75%, moderate quality evidence). There was no evidence of a difference between the groups for the other primary outcomes. Laparoscopic hysterectomy (LH) versus AH (25 RCTs, 2983 women) Return to normal activities was shorter in the LH group (MD -13.6 days, 95% CI -15.4 to -11.8; six RCTs, 520 women, I2 = 71%, low quality evidence), but there were more urinary tract injuries in the LH group (odds ratio (OR) 2.4, 95% CI 1.2 to 4.8, 13 RCTs, 2140 women, I2 = 0%, low quality evidence). There was no evidence of a difference between the groups for the other primary outcomes. LH versus VH (16 RCTs, 1440 women) There was no evidence of a difference between the groups for any primary outcomes. Robotic-assisted hysterectomy (RH) versus LH (two RCTs, 152 women) There was no evidence of a difference between the groups for any primary outcomes. Neither of the studies reported satisfaction rates or quality of life. Overall, the number of adverse events was low in the included studies. Among women undergoing hysterectomy for benign disease, VH appears to be superior to LH and AH, as it is associated with faster return to normal activities. When technically feasible, VH should be performed in preference to AH because of more rapid recovery and fewer febrile episodes postoperatively. Where VH is not possible, LH has some advantages over AH (including more rapid recovery and fewer febrile episodes and wound or abdominal wall infections), but these are offset by a longer operating time. No advantages of LH over VH could be found; LH had a longer operation time, and total laparoscopic hysterectomy (TLH) had more urinary tract injuries. Of the three subcategories of LH, there are more RCT data for laparoscopic-assisted vaginal hysterectomy and LH than for TLH. Single-port laparoscopic hysterectomy and RH should either be abandoned or further evaluated since there is a lack of evidence of any benefit over conventional LH. Overall, the evidence in this review has to be interpreted with caution as adverse event rates were low, resulting in low power for these comparisons. The surgical approach to hysterectomy should be discussed and decided in the light of the relative benefits and hazards. These benefits and hazards seem to be dependent on surgical expertise and this may influence the decision. In conclusion, when VH is not feasible, LH may avoid the need for AH, but LH is associated with more urinary tract injuries. There is no evidence that RH is of benefit in this population. Preferably, the surgical approach to hysterectomy should be decided by the woman in discussion with her surgeon.
The update of this review found two additional studies, totaling 11 studies that randomised 2159 participants (3580 eyes) and followed them up to two years, of which six studies (1454 participants) included people with one eye randomised to treatment and one to control. Studies were conducted in Australia, Europe and North America. Overall, the risk of bias in the included studies was low, particularly for the larger studies and for the primary outcome development of CNV. Photocoagulation did not reduce the development of CNV at two years' follow-up (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.79 to 1.46, 11 studies, 2159 participants (3580 eyes), high quality evidence). This estimate means that, given an overall occurrence of CNV of 8.3% in the control group, we estimated an absolute risk reduction by no more than 1.4% in the laser group, according to the lower CI limit. Only two studies investigated the effect on the development of geographic atrophy and could not show a difference, but estimates were imprecise (OR 1.30, 95% CI 0.38 to 4.51, two studies, 148 participants (148 eyes), low quality evidence). Among secondary outcomes, photocoagulation led to drusen reduction (OR 9.16, 95% CI 6.28 to 13.4, three studies, 570 participants (944 eyes), high quality evidence) but was not shown to limit loss of 3 or more lines of visual acuity (OR 0.99, 95% CI 0.81 to 1.22, nine studies, 2002 participants (2386 eyes), moderate quality evidence). In a subgroup analysis, no difference could be shown for conventional visible (eight studies) versus subthreshold invisible (four studies) photocoagulation for the primary outcomes (P value = 0.29). The effect in the subthreshold group did not suggest a relevant benefit (OR 1.27, 95% CI 0.82 to 1.98). No study used micropulse subthreshold photocoagulation. No other adverse effects (apart from development of CNV, geographic atrophy or visual loss) were reported. The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, treatment does not result in a reduction in the risk of developing CNV, and was not shown to limit the occurrence of geographic atrophy or visual acuity loss. Ongoing studies are being conducted to assess whether the use of extremely short laser pulses (i.e. nanosecond laser treatment) cannot only lead to drusen regression but also prevent neovascular AMD.
This update included one new study in which a subgroup of participants met our inclusion criteria. As none of the four included studies focused solely on people initiating antihypertensive treatment, we asked investigators for data for this subgroup. One study (PREVER-treatment 2016) used a combination of thiazide-type diuretic/potassium-sparing diuretic; as the former is not indicated in monotherapy, we analysed this study separately. The three original trials in the main comparison (monotherapy: 335 participants; combination therapy: 233 participants) included outpatients, mostly European and white people. Two trials only included people with type 2 diabetes; the remaining trial excluded people treated with diabetes, hypocholesterolaemia, or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. It is very uncertain whether combination therapy versus monotherapy reduces total mortality (RR 1.35, 95% CI 0.08 to 21.72), cardiovascular mortality (zero events reported), cardiovascular events (RR 0.98, 95% CI 0.22 to 4.41), serious adverse events (RR 0.77, 95% CI 0.31 to 1.92), or withdrawals due to adverse effects (RR 0.85, 95% CI 0.53 to 1.35); all outcomes had 568 participants, and the evidence was rated as of very low certainty due to serious imprecision and for using a subgroup that was not defined in advance. The confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. The PREVER-treatment 2016 trial, which used a combination therapy with potassium-sparing diuretic (monotherapy: 84 participants; combination therapy: 116 participants), included outpatients. This trial was conducted in Brazil and had a follow-up of 18 months. The number of events was very low and confidence intervals very wide, with zero events reported for cardiovascular mortality and withdrawals due to adverse events. It is very uncertain if there are differences in clinical outcomes between monotherapy and combination therapy in this trial. The numbers of included participants, and hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the review question and report clinically relevant endpoints.
This update included three new studies, providing a 26% increase in participants in comparisons between diclofenac and placebo. We included 18 studies involving 3714 participants, 1902 treated with diclofenac and 1007 with placebo. This update has also changed the focus of the review, examining the effects of formulation in more detail than previously. This is a result of increased understanding of the importance of speed of onset in determining analgesic efficacy in acute pain. The largest body of information, for diclofenac potassium 50 mg, in seven studies, produced an NNT for at least 50% of maximum pain relief compared with placebo of 2.1 (95% confidence interval (CI) 1.9 to 2.5) (high quality evidence). There was a graded improvement in efficacy as doses rose from 25 mg to 100 mg, both for participants achieving at least 50% maximum pain relief, and for remedication within 6 to 8 hours. Fast-acting formulations (dispersible products, solutions, and softgel formulations) had a similar efficacy for a 50 mg dose, with an NNT of 2.4 (2.0 to 3.0). Diclofenac sodium in a small number of studies produced a lesser effect, with an NNT of 6.6 (4.1 to 17) for the 50 mg dose. Adverse event rates were low in these single dose studies, with no difference between diclofenac and placebo (moderate quality evidence). Diclofenac potassium provides good pain relief at 25 mg, 50 mg, and 100 mg doses. Diclofenac sodium has limited efficacy and should probably not be used in acute pain.
We included 17 randomised trials (3149 participants) conducted in nine different countries. Seven studies (1325 women) recruited exclusively women undergoing elective CS and five studies (833 women) only included women having a primary CS. Ten studies (1731 women) used conventional feeding protocols (nil by mouth until the return of intestinal function). The gum-chewing regimen varied among studies, in relation to its initiation (immediately after CS, up to 12 hours later), duration of each session (from 15 to 60 minutes) and number of sessions per day (three to more than six). All the studies were classified as having a high risk of bias due to the nature of the intervention, women could not be blinded and most of the outcomes were self-reported. Primary outcomes of this review: for the women that chewed gum, the time to passage of first flatus was seven hours shorter than those women in the 'usual care' control group (MD -7.09 hours, 95% CI -9.27 to -4.91 hours; 2399 women; 13 studies; random-effects Tau² = 14.63, I² = 95%, very low-quality evidence). This effect was consistent in all subgroup analyses (primary and repeat CS, time spent chewing gum per day, early and conventional feeding protocols, elective and non-elective CS and time after CS when gum-chewing was initiated). The rate of ileus was on average over 60% lower in the chewing-gum group compared to the control (RR 0.39, 95% CI 0.19 to 0.80; 1139 participants; four studies; I² = 39%, low-quality evidence). Tolerance to gum-chewing appeared to be high. Three women in one study complained about the chewing gum (but no further information was provided) and none of the studies reported adverse effects (eight studies, 925 women, low-quality evidence). Secondary outcomes of this review: the time to passage of faeces occurred on average nine hours earlier in the intervention group (MD -9.22 hours, 95% CI -11.49 to -6.95 hours; 2016 participants; 11 studies; random-effects Tau² = 12.53, I² = 93%, very low-quality evidence). The average duration of hospital stay was shorter in the intervention compared to the control group (MD -0.36 days, 95% CI -0.53 to -0.18 days; 1489 participants; seven studies; random-effects Tau² = 0.04, I² = 92%). The first intestinal sounds were heard earlier in the intervention than in the control group (MD -4.56 hours, 95% CI -6.18 to -2.93 hours; 1729 participants; nine studies; random-effects Tau² = 5.41, I² = 96%). None of the studies assessed women's satisfaction in relation to having to chew gum. The need for analgesia or antiemetic agents did not differ between the intervention and control groups (average RR 0.50, 95% CI 0.12 to 2.13; 726 participants; three studies; random-effects Tau² = 0.79, I² = 69%). This review found 17 randomised controlled trials (involving 3149 women). We downgraded the quality of the evidence for time to first passage of flatus and of faeces and for adverse effects/intolerance to gum chewing because of the high risk of bias of the studies (due to lack of blinding and self-report). For time to first flatus and faeces, we downgraded the quality of the evidence further because of the high heterogeneity in these meta-analyses and the potential for publication bias based on the visual inspection of the funnel plots. The quality of the evidence for adverse effects/tolerance to gum chewing and for ileus was downgraded because of the small number of events. The quality of the evidence for ileus was further downgraded due to the unclear risk of bias for the assessors evaluating this outcome. The available evidence suggests that gum chewing in the immediate postoperative period after a CS is a well tolerated intervention that enhances early recovery of bowel function. However the overall quality of the evidence is very low to low. Further research is necessary to establish the optimal regimen of gum-chewing (initiation, number and duration of sessions per day) to enhance bowel function recovery and to assess potential adverse effects of and women's satisfaction with this intervention. New studies also need to assess the compliance of the participants to the recommended gum-chewing instructions. Future large, well designed and conducted studies, with better methodological and reporting quality, will help to inform future updates of this review and enhance the body of evidence for this intervention.
We identified 18 studies, enrolling a total of 2196 randomized patients. The oral fluoroquinolones ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin and prulifloxacin were compared. There were no significant differences in clinical or microbiological efficacy or in the rate of adverse effects between these fluoroquinolones. In chlamydial prostatitis, (i) azithromycin showed improved eradication rates and clinical cure rates compared to ciprofloxacin, with no significant differences regarding adverse effects; (ii) azithromycin was equivalent to clarithromycin, both microbiologically and clinically; (iii) prulifloxacin appeared to improve clinical symptoms, but not eradication rates, compared to doxycycline. In ureaplasmal prostatitis, the comparisons ofloxacin versus minocycline and azithromycin versus doxycycline showed similar microbiological, clinical and toxicity profiles. The microbiological and clinical efficacy, as well as the adverse effect profile, of different oral fluoroquinolones are comparable. No conclusions can be drawn regarding the optimal treatment duration of fluoroquinolones in the treatment of CBP caused by traditional pathogens. Alternative antimicrobial agents tested for the treatment of CBP caused by traditional pathogens are co-trimoxazole, beta-lactams and tetracyclines, but no conclusive evidence can be drawn regarding the role of non-fluoroquinolone antibiotics in the treatment of CBP caused by traditional pathogens. In patients with CBP caused by obligate intracellular pathogens, macrolides showed higher microbiological and clinical cure rates compared to fluoroquinolones.
We included 26 studies (21,704 participants). Moderate-quality evidence found that adrenaline increased survival to hospital discharge compared to placebo (RR 1.44, 95% CI 1.11 to 1.86; 2 studies, 8538 participants; an increase from 23 to 32 per 1000, 95% CI 25 to 42). We are uncertain about survival to hospital discharge for high-dose compared to standard-dose adrenaline (RR 1.10, 95% CI 0.75 to 1.62; participants = 6274; studies = 10); an increase from 33 to 36 per 1000, 95% CI 24 to 53); standard-dose adrenaline versus vasopressin (RR 1.25, 95% CI 0.84 to 1.85; 6 studies; 2511 participants; an increase from 72 to 90 per 1000, 95% CI 60 to 133); and standard-dose adrenaline versus vasopressin plus adrenaline (RR 0.76, 95% CI 0.47 to 1.22; 3 studies; 3242 participants; a possible decrease from 24 to 18 per 1000, 95% CI 11 to 29), due to very low-quality evidence. Moderate-quality evidence found that adrenaline compared with placebo increased survival to hospital admission (RR 2.51, 95% CI 1.67 to 3.76; 2 studies, 8489 participants; an increase from 83 to 209 per 1000, 95% CI 139 to 313). We are uncertain about survival to hospital admission when comparing standard-dose with high-dose adrenaline, due to very low-quality evidence. Vasopressin may improve survival to hospital admission when compared with standard-dose adrenaline (RR 1.27, 95% CI 1.04 to 1.54; 3 studies, 1953 participants; low-quality evidence; an increase from 260 to 330 per 1000, 95% CI 270 to 400), and may make little or no difference when compared to standard-dose adrenaline plus vasopressin (RR 0.95, 95% CI 0.83 to 1.08; 3 studies; 3249 participants; low-quality evidence; a decrease from 218 to 207 per 1000 (95% CI 181 to 236). There was no evidence that adrenaline (any dose) or vasopressin improved neurological outcomes. The rate of return of spontaneous circulation (ROSC) was higher for standard-dose adrenaline versus placebo (RR 2.86, 95% CI 2.21 to 3.71; participants = 8663; studies = 3); moderate-quality evidence; an increase from 115 to 329 per 1000, 95% CI 254 to 427). We are uncertain about the effect on ROSC for the comparison of standard-dose versus high-dose adrenaline and standard-does adrenaline compared to vasopressin, due to very low-quality evidence. Standard-dose adrenaline may make little or no difference to ROSC when compared to standard-dose adrenaline plus vasopressin (RR 0.97, 95% CI 0.87 to 1.08; 3 studies, 3249 participants; low-quality evidence; a possible decrease from 299 to 290 per 1000, 95% CI 260 to 323). The source of funding was not stated in 11 of the 26 studies. The study drugs were provided by the manufacturer in four of the 26 studies, but neither drug represents a profitable commercial option. The other 11 studies were funded by organisations such as research foundations and government funding bodies. This review provides moderate-quality evidence that standard-dose adrenaline compared to placebo improves return of spontaneous circulation, survival to hospital admission and survival to hospital discharge, but low-quality evidence that it did not affect survival with a favourable neurological outcome. Very low -quality evidence found that high-dose adrenaline compared to standard-dose adrenaline improved return of spontaneous circulation and survival to admission. Vasopressin compared to standard dose adrenaline improved survival to admission but not return of spontaneous circulation, whilst the combination of adrenaline and vasopressin compared with adrenaline alone had no effect on these outcomes. Neither standard dose adrenaline, high-dose adrenaline,vasopressin nor a combination of adrenaline and vasopressin improved survival with a favourable neurological outcome. Many of these studies were conducted more than 20 years ago. Treatment has changed in recent years, so the findings from older studies may not reflect current practice.
Forty-five RCTs were identified and, from these, 26 trials including a total of 1217 participants and 2120 implants were included. Two trials were at low risk of bias, 12 were at high risk of bias and for the remaining 12 the risk of bias was unclear. In nine of the included studies there were no prosthetic failures within the first year, with no implant failures in seven studies and the mean rate of implant failure in all 26 trials was a low 2.5%. From 15 RCTs comparing immediate with conventional loading there was no evidence of a difference in either prosthesis failure (RR 1.90; 95% CI 0.67 to 5.34; 8 trials) or implant failure (RR 1.50; 95% CI 0.60 to 3.77; 10 trials) in the first year, but there is some evidence of a small reduction in bone loss favouring immediate loading (MD -0.10 mm; 95% CI -0.20 to -0.01; P = 0.03; 9 trials), with some heterogeneity (Tau² = 0.01; Chi² = 14.37, df = 8 (P = 0.07); I² = 44%). However, this very small difference may not be clinically important. From three RCTs which compared early loading with conventional loading, there is insufficient evidence to determine whether or not there is a clinically important difference in prosthesis failure, implant failure or bone loss. Six RCTs compared immediate and early loading and found insufficient evidence to determine whether or not there is a clinically important difference in prosthesis failure, implant failure or bone loss. From the two trials which compared occlusal loading with non-occlusal loading there is insufficient evidence to determine whether there is a clinically important difference in the outcomes of prosthesis failure, implant failure or bone loss. We did not identify any trials which evaluated progressive loading of implants. Overall there was no convincing evidence of a clinically important difference in prosthesis failure, implant failure, or bone loss associated with different loading times of implants. The quality of the evidence is assessed as very low due to high and unclear risk of bias of primary studies and there is some evidence of reporting bias so clinicians should treat these findings with caution. A high value of insertion torque (at least 35 Ncm) seems to be one of the prerequisites for a successful immediate/early loading procedure. More well-designed RCTs are needed and should be reported according to the CONSORT guidelines (www.consort-statement.org/), and registered with a trials registry.
Fourty RCTs were included, addressing various agents for pregnancy termination and methods of administration. When used alone, misoprostol was an effective inductive agent, though it appeared to be more effective in combination with mifepristone. However, the evidence from RCTs is limited. Misoprostol was preferably administered vaginally, although among multiparous women sublingual administration appeared equally effective. A range of doses of vaginally administered misoprostol has been used. No randomised trials comparing doses of misoprostol were identified; however low doses of misoprostol appear to be associated with fewer side-effects while moderate doses appear to be more efficient in completing abortion. Four RCTs showed that the induction to abortion interval with 3-hourly vaginal administration of prostaglandins is shorter than 6-hourly administration without an increase in side-effects. Many studies reported the need for surgical evacuation. Indications for surgical evacuation include retained products of the placenta and heavy vaginal bleeding. Fewer women required surgical evacuation when misoprostol was administrated vaginally compared with women receiving intra-amniotical PGF2a. Mild, self-limiting diarrhoea was more common among women who received misoprostol compared to other agents. Medical abortion in the second trimester using the combination of mifepristone and misoprostol appeared to have the highest efficacy and shortest abortion time interval. Where mifepristone is not available, misoprostol alone is a reasonable alternative. The optimal route for administering misoprostol is vaginally, preferably using tablets at 3-hourly intervals. Apart from pain, the side-effects of vaginal misoprostol are usually mild and self limiting. Conclusions from this review are limited by the gestational age ranges and variable medical regimens, including dosing, administrative routes and intervals of medication, of the included trials.
Eleven randomized controlled trials with a total of 833 women were included in this review. However, the results of this review are based on single studies with small numbers of participants.The majority of included studies reported insufficient information on sequence generation, allocation concealment as well as blinding. There were no included studies that assessed PTL or PTB as the primary outcome. The included studies were different in terms of intervention, practice, and time, and there were no clear coherent hypotheses. For women not in PTL, the benefits of relaxation was found in one study for maternal stress (Anxiety Stress Scale) at 26 to 29 weeks gestational age (mean difference (MD) -7.04; 95% confidence interval (CI) -13.91 to -0.17). In addition, there were some beneficial effects of relaxation including baby birthweight (MD 285.00 g; 95% CI 76.94 to 493.06); type of delivery; (vaginal delivery; risk ratio (RR) 1.52; 95% CI 1.13 to 2.04), (cesarean section; RR 0.38; 95% CI 0.19 to 0.78); maternal anxiety (MD -15.79; 95% CI -18.33 to -13.25); and stress (MD -13.08; 95% CI -15.29 to -10.87) when applying relaxation therapy together with standard treatment.   For women in PTL, the results for the main outcome of PTB in the intervention and control groups from a single study were not different (RR 0.95; 95% CI 0.57 to 1.59). The MD of birthweight in grams from the fixed-effect model from two included studies was MD -5.68; (95% CI -174.09 to 162.74). According to the results of this review, there is some evidence that relaxation during pregnancy reduces stress and anxiety. However, there was no effect on PTL/PTB. These results should be interpreted with caution as they were drawn from included studies with limited quality.
We included 90 studies; 88 from field settings in Africa. The median S. haematobium infection prevalence was 41% (range 1% to 89%) and 36% for S. mansoni (range 8% to 95%). Study design and conduct were poorly reported against current standards. Tests for S. haematobium Urine reagent test strips versus microscopy Compared to microscopy, the detection of microhaematuria on test strips had the highest sensitivity and specificity (sensitivity 75%, 95% CI 71% to 79%; specificity 87%, 95% CI 84% to 90%; 74 studies, 102,447 participants). For proteinuria, sensitivity was 61% and specificity was 82% (82,113 participants); and for leukocyturia, sensitivity was 58% and specificity 61% (1532 participants). However, the difference in overall test accuracy between the urine reagent strips for microhaematuria and proteinuria was not found to be different when we compared separate populations (P = 0.25), or when direct comparisons within the same individuals were performed (paired studies; P = 0.21). When tests were evaluated against the higher quality reference standard (when multiple samples were analysed), sensitivity was marginally lower for microhaematuria (71% vs 75%) and for proteinuria (49% vs 61%). The specificity of these tests was comparable. Antigen assay Compared to microscopy, the CCA test showed considerable heterogeneity; meta-analytic sensitivity estimate was 39%, 95% CI 6% to 73%; specificity 78%, 95% CI 55% to 100% (four studies, 901 participants). Tests for S. mansoni Compared to microscopy, the CCA test meta-analytic estimates for detecting S. mansoni at a single threshold of trace positive were: sensitivity 89% (95% CI 86% to 92%); and specificity 55% (95% CI 46% to 65%; 15 studies, 6091 participants) Against a higher quality reference standard, the sensitivity results were comparable (89% vs 88%) but specificity was higher (66% vs 55%). For the CAA test, sensitivity ranged from 47% to 94%, and specificity from 8% to 100% (four studies, 1583 participants). Among the evaluated tests for S. haematobium infection, microhaematuria correctly detected the largest proportions of infections and non-infections identified by microscopy. The CCA POC test for S. mansoni detects a very large proportion of infections identified by microscopy, but it misclassifies a large proportion of microscopy negatives as positives in endemic areas with a moderate to high prevalence of infection, possibly because the test is potentially more sensitive than microscopy.
No studies met the inclusion criteria for this review. We excluded one study and one other study is ongoing. We set out to evaluate the RCT evidence pertaining to the impact of antenatal education on perineal wound healing in postnatal women who have birthed in a hospital setting, and who experienced a break in the skin of the perineum as a result of a tear or episiotomy, or both. However, no studies met the inclusion criteria. There is a lack of evidence concerning whether or not antenatal education relating to perineal wound healing in this cohort of women will change the outcome for these women in relation to wound healing, infection rate, re-attendance or re-admission to hospital, pain, health-related quality of life, maternal bonding, and negative emotional experiences. Further study is warranted in this area given the significant physical, psychological and economic impact of perineal wounds, and the large proportion of childbearing women who have experienced a postnatal wound. The benefits of any future research in this field would be maximised by incorporating women in a range of socio-economic groups, and with a range of healthcare options. This research could take both a qualitative and a quantitative approach and examine the outcomes identified in this review in order to assess fully the potential benefits of a tailored antenatal package, and to make recommendations for future practice. There is currently no evidence to inform practice in this regard.
Five trials were identified by the searches, of which three trials (880 children randomised) met the inclusion criteria. All of the included trials showed a reduced incidence of infection in children with SCD (SS or Sβ0Thal) receiving prophylactic penicillin. In trials which investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-quality evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-quality evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five. Overall, the quality of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias). The evidence examined suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.
Four trials were included in the review. One new trial of botulinum toxin was identified in the updated search. Only one trial of custom-made foot orthoses fully met the inclusion criteria. Three additional studies (botulinum toxin, footwear and off-the-shelf foot orthoses), all assessing secondary outcomes were included. We could not pool data used in the four studies due to heterogeneity of diagnostic groups and outcome measures. The one trial that fully met the inclusion criteria investigated the treatment of pes cavus pain in 154 adults over three months. The trial showed a significant reduction in the level of foot pain with custom-made foot orthoses versus sham orthoses (WMD 10.90; 95% CI 3.21 to 18.59). Furthermore, a significant improvement in self-reported foot function and physical functioning was reported with custom-made foot orthoses. There was no difference in reported adverse events following the allocation of custom-made or sham orthoses. Secondary biomechanical outcomes improved with the use of custom-made foot orthoses and footwear (pedobarography), but not with intramuscular injections of botulinum toxin (radiographic) or off-the-shelf foot orthoses (electromyography). This updated review shows that custom-made foot orthoses are significantly more beneficial than sham orthoses for treating foot pain associated with pes cavus in a variety of clinical populations. We also show that some secondary biomechanical outcomes improve with custom-made foot orthoses and footwear, but not with botulinum toxin or off-the-shelf foot orthoses. There is an absence of evidence for any other type of intervention for the treatment or prevention of pes cavus.
From 6396 citations, we included six studies with a total of 562 participants. Five studies were performed in participants undergoing abdominal surgery (including one study in participants undergoing cytoreductive abdominal surgery with hyperthermic intraperitoneal chemotherapy (HIPEC)), and one study was performed in participants undergoing orthopaedic surgery. In all studies, surgeries were elective. In five studies, crystalloids were used for basal infusion and colloids for boluses, and in one study, colloid was used for both basal infusion and boluses. Five studies reported the ASA (American Society of Anesthesiologists) status of participants. Most participants were ASA II (60.4%), 22.7% were ASA I, and only 16.9% were ASA III. No study participants were ASA IV. For the GDFT group, oesophageal doppler monitoring was used in three studies, uncalibrated invasive arterial pressure analysis systems in two studies, and a non-invasive arterial pressure monitoring system in one study. In all studies, GDFT optimization was conducted only intraoperatively. Only one study was at low risk of bias in all domains. The other five studies were at unclear or high risk of bias in one to three domains. RFT may have no effect on the rate of major complications compared to GDFT, but the evidence is very uncertain (RR 1.61, 95% CI 0.78 to 3.34; 484 participants; 5 studies; very low-certainty evidence). RFT may increase the risk of all-cause mortality compared to GDFT, but the evidence on this is also very uncertain (RD 0.03, 95% CI 0.00 to 0.06; 544 participants; 6 studies; very low-certainty evidence). In a post-hoc analysis using a Peto odds ratio (OR) or a Poisson regression model, the odds of all-cause mortality were 4.81 times greater with the use of RFT compared to GDFT, but the evidence again is very uncertain (Peto OR 4.81, 95% CI 1.38 to 16.84; 544 participants; 6 studies; very low-certainty evidence). Nevertheless, sensitivity analysis shows that exclusion of a study in which the final volume of fluid received intraoperatively was higher in the RFT group than in the GDFT group revealed no differences in mortality. Based on analysis of secondary outcomes, such as length of hospital stay (464 participants; 5 studies; very low-certainty evidence), surgery-related complications (364 participants; 4 studies; very low-certainty evidence), non-surgery-related complications (74 participants; 1 study; very low-certainty evidence), renal failure (410 participants; 4 studies; very low-certainty evidence), and quality of surgical recovery (74 participants; 1 study; very low-certainty evidence), GDFT may have no effect on the risk of these outcomes compared to RFT, but the evidence is very uncertain. Included studies provided no data on administration of vasopressors or inotropes to correct haemodynamic instability nor on cost of treatment. Based on very low-certainty evidence, we are uncertain whether RFT is inferior to GDFT in selected populations of adults undergoing major non-cardiac surgery. The evidence is based mainly on data from studies on abdominal surgery in a low-risk population. The evidence does not address higher-risk populations or other surgery types. Larger, higher-quality RCTs including a wider spectrum of surgery types and a wider spectrum of patient groups, including high-risk populations, are needed to determine effects of the intervention.
We included 33 trials with 36 intervention-control pairs and 1853 participants. The risk of bias present in many studies was unclear due to poor reporting; the evidence has therefore been rated 'moderate' or 'low' when using the GRADE system. There is low-quality evidence that RTT improves arm function (standardised mean difference (SMD) 0.25, 95% confidence interval (CI) 0.01 to 0.49; 11 studies, number of participants analysed = 749), hand function (SMD 0.25, 95% CI 0.00 to 0.51; eight studies, number of participants analysed = 619), and lower limb functional measures (SMD 0.29, 95% CI 0.10 to 0.48; five trials, number of participants analysed = 419). There is moderate-quality evidence that RTT improves walking distance (mean difference (MD) 34.80, 95% CI 18.19 to 51.41; nine studies, number of participants analysed = 610) and functional ambulation (SMD 0.35, 95% CI 0.04 to 0.66; eight studies, number of participants analysed = 525). We found significant differences between groups for both upper-limb (SMD 0.92, 95% CI 0.58 to 1.26; three studies, number of participants analysed = 153) and lower-limb (SMD 0.34, 95% CI 0.16 to 0.52; eight studies, number of participants analysed = 471) outcomes up to six months post treatment but not after six months. Effects were not modified by intervention type, dosage of task practice or time since stroke for upper or lower limb. There was insufficient evidence to be certain about the risk of adverse events. There is low- to moderate-quality evidence that RTT improves upper and lower limb function; improvements were sustained up to six months post treatment. Further research should focus on the type and amount of training, including ways of measuring the number of repetitions actually performed by participants. The definition of RTT will need revisiting prior to further updates of this review in order to ensure it remains clinically meaningful and distinguishable from other interventions.
Thirty RCTs (4704 participants) met the eligibility criteria, including 19 comparisons of iron supplementation and placebo or control; one comparison of oral and parenteral iron supplementation; four comparisons of different doses of iron supplementation; one comparison of different treatment durations of iron supplementation; and 12 comparisons of different iron supplementation preparations. Many studies were of low or uncertain methodological quality and therefore at high or uncertain risk of bias. We therefore rated the quality of the evidence for our outcomes as moderate. There was a statistically significant reduction in deferral due to low haemoglobin in donors who received iron supplementation compared with donors who received no iron supplementation, both at the first donation visit after commencement of iron supplementation (risk ratio (RR) 0.34; 95% confidence interval (CI) 0.21 to 0.55; four studies; 1194 participants; P value < 0.0001) and at subsequent donations (RR 0.25; 95% CI 0.15 to 0.41; three studies; 793 participants; P value < 0.00001). Supplementation also resulted in significantly higher haemoglobin levels (mean difference (MD) 2.36 g/L; 95% CI 0.06 to 4.66; eight studies; 847 participants, P value =0.04), and iron stores, including serum ferritin (MD 13.98 ng/mL; 95% CI 8.92 to 19.03; five studies; 640 participants; P value < 0.00001) and transferrin saturation (MD 3.91%; 95% CI 2.02 to 5.80; four studies; 344 participants; P value < 0.0001) prior to further donation. The differences were maintained after subsequent donation(s). Adverse effects were widely reported and were more frequent in donors who received iron supplementation (RR 1.60; 95% CI 1.23 to 2.07; four studies; 1748 participants; P value = 0.0005). Adverse effects included constipation, diarrhoea, nausea, vomiting and taste disturbances, and some participants stopped treatment due to side effects. There is moderate quality evidence that rates of donor deferral due to low haemoglobin are considerably less in those taking iron supplements compared with those without iron supplementation, both at the first donation visit and at subsequent donation. Iron-supplemented donors also show elevated haemoglobin and iron stores. These beneficial effects are balanced by more frequent adverse events in donors who receive iron supplementation than in those who do not; this is likely to limit acceptability and compliance. The long-term effects of iron supplementation without measurement of iron stores are unknown. These considerations are likely to preclude widespread use of iron supplementation by tablets. Blood services may consider targeted use of supplementation in those at greatest risk of iron deficiency, personalised donation intervals and providing dietary advice.
Thirteen new studies were identified for the update of this review. In total, we included 33 cohort studies including 7876 participants investigating hepatic late adverse effects after antineoplastic treatment (especially chemotherapy and radiotherapy) for different types of childhood cancer, both haematological and solid malignancies. All studies had methodological limitations. The prevalence of hepatic late adverse effects, all defined in a biochemical way, varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well-defined as alanine aminotransferase (ALT) above the upper limit of normal, indicating cellular liver injury, resulted in eight studies. In this subgroup, the prevalence of hepatic late adverse effects ranged from 5.8% to 52.8%, with median follow-up durations varying from three to 23 years since cancer diagnosis in studies that reported the median follow-up duration. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal, resulted in five studies, with a prevalence ranging from 0.9% to 44.8%. One study investigated biliary tract injury, defined as gamma-glutamyltransferase (γGT) above the upper limit of normal and above twice the upper limit of normal and reported a prevalence of 5.3% and 0.9%, respectively. Three studies investigated disturbance in biliary function, defined as bilirubin above the upper limit of normal and reported prevalences ranging from 0% to 8.7%. Two studies showed that treatment with radiotherapy involving the liver (especially after a high percentage of the liver irradiated), higher BMI, and longer follow-up time or older age at evaluation increased the risk of cellular liver injury in multivariable analyses. In addition, there was some suggestion that busulfan, thioguanine, hepatic surgery, chronic viral hepatitis C, metabolic syndrome, use of statins, non-Hispanic white ethnicity, and higher alcohol intake (> 14 units per week) increase the risk of cellular liver injury in multivariable analyses. Chronic viral hepatitis was shown to increase the risk of cellular liver injury in six univariable analyses as well. Moreover, one study showed that treatment with radiotherapy involving the liver, higher BMI, higher alcohol intake (> 14 units per week), longer follow-up time, and older age at cancer diagnosis increased the risk of biliary tract injury in a multivariable analysis. The prevalence of hepatic late adverse effects among studies with an adequate outcome definition varied considerably from 1% to 53%. Evidence suggests that radiotherapy involving the liver, higher BMI, chronic viral hepatitis and longer follow-up time or older age at follow-up increase the risk of hepatic late adverse effects. In addition, there may be a suggestion that busulfan, thioguanine, hepatic surgery, higher alcohol intake (>14 units per week), metabolic syndrome, use of statins, non-Hispanic white ethnicity, and older age at cancer diagnosis increase the risk of hepatic late adverse effects. High-quality studies are needed to evaluate the effects of different therapy doses, time trends, and associated risk factors after antineoplastic treatment for childhood cancer.
We considered 27 studies from the 2007 search. In this update we considered a further 38 studies from the 2013 search, and two in the 2014 search. We identified one RCT of moderate quality with low risk of bias overall which met the inclusion criteria for this update, comparing ABH (Ativan®, Benadryl®, Haldol®) gel, applied to the wrist, with placebo for the relief of nausea in 22 participants. ABH gel includes haloperidol as well as diphenhydramine and lorazepam. The gel was not significantly better than placebo in this small study; however haloperidol is reported not to be absorbed significantly when applied topically, therefore the trial does not address the issue of whether haloperidol is effective or well-tolerated when administered by other routes (e.g. by mouth, subcutaneously or intravenously). We identified one ongoing trial of haloperidol for the management of nausea and vomiting in patients with cancer, with initial results published in a conference abstract suggesting that haloperidol is effective for 65% of patients. The trial had not been fully published at the time of our review. A further trial has opened, comparing oral haloperidol with oral methotrimeprazine (levomepromazine) for patients with cancer and nausea unrelated to their treatment, which we aim to include in the next review update. Since the last version of this review, we found one new study for inclusion but the conclusion remains unchanged. There is incomplete evidence from published RCTs to determine the effectiveness of haloperidol for nausea and vomiting in palliative care. Other than the trial of ABH gel vs placebo, we did not identify any fully published RCTs exploring the effectiveness of haloperidol for nausea and vomiting in palliative care patients for this update, but two trials are underway.
Only one study satisfied our inclusion criteria, comparing percutaneous radiofrequency thermal lumbar sympathectomy with lumbar sympathetic neurolysis using phenol in 20 participants with CRPS. There was no comparison of sympathectomy versus sham or placebo. No dichotomous pain outcomes were reported. Average baseline scores of 8-9/10 on several pain scales fell to about 4/10 initially (1 day) and remained at 3-5/10 over four months. There were no significant differences between groups, except for "unpleasant sensation", which was higher with radiofrequency ablation. One participant in the phenol group experienced post sympathectomy neuralgia, while two in the radiofrequency group and one in the phenol group complained of paraesthesia during needle positioning. All participants had soreness at the injection site. The practice of surgical and chemical sympathectomy for neuropathic pain and CRPS is based on very little high quality evidence. Sympathectomy should be used cautiously in clinical practice, in carefully selected patients, and probably only after failure of other treatment options. In these circumstances, establishing a clinical register of sympathectomy may help to inform treatment options on an individual patient basis.
Nine studies were identified, with a total of 5,168 participants. Follow-up ranged from 1 to 10 years. Quantitative synthesis was limited by the heterogeneity of populations, settings, and interventions and by the small number of studies that examined outcomes other than weight. Overall, in comparisons with usual care, four studies with a follow-up of one year reduced weight by 2.8 kg (95 % confidence interval (CI) 1.0 to 4.7) (3.3% of baseline body weight) and decreased body mass index by 1.3 kg/m2 (95% CI 0.8 to 1.9). Weight loss at two years was 2.6 kg (95% CI 1.9 to 3.3) (three studies). Modest improvements were noted in the few studies that examined glycemic control, blood pressure, or lipid concentrations (P > 0.05). No data on quality of life or mortality were found. The incidence of diabetes was significantly lower in the intervention groups versus the controls in three of five studies examining this outcome at 3 to 6 years follow-up. Overall, weight loss strategies using dietary, physical activity, or behavioral interventions produced significant improvements in weight among persons with prediabetes and a significant decrease in diabetes incidence. Further work is needed on the long-term effects of these interventions on morbidity and mortality and on how to implement these interventions in diverse community settings.
Two studies representing 100 participants with a diagnosis of benign epilepsy of childhood with centrotemporal spikes (BECTS) and one study representing 146 participants with a diagnosis of generalised tonic-clonic seizures (GTCS) were included. STM was given as monotherapy compared with placebo in the BECTS studies and compared with phenytoin in the GTCS study. An English translation of the full text of one of the BECTS studies could not be found, and analysis of this study was based solely on the English translation of the abstract. No data were reported for outcome (1), (2), (3) or (5). Reporting of adverse effects was incomplete. Participants receiving STM were significantly less likely to develop gingival hyperplasia than were participants receiving phenytoin in the GTCS study (risk ratio (RR) 0.03, 95% confidence interval (CI) 0.00 to 0.58). No further statistically significant adverse events were noted when STM was compared with phenytoin or placebo. Two ongoing studies comparing STM monotherapy versus placebo or levetiracetam in BECTS were identified. Small sample size, poor methodological quality and lack of data on important outcome measures prevent any meaningful conclusions regarding the efficacy and safety of sulthiame as monotherapy in epilepsy.
Thirteen studies were included in this review. All studies used a crossover design and were of high quality. Spirometry performed at the end of the study period and after the administration of treatment (post-bronchodilator) showed a slight but significant increase in FEV1 and FVC when compared to placebo (WMD 0.14 L; 95%CI 0.04, 0.25 & WMD 0.30 L; 95%CI 0.02, 0.58, respectively). In addition, both morning and evening PEFR were significantly better during active treatment than during placebo (WMD 29.17 L/min; 95%CI 0.25, 58.09 & WMD 36.75 L/min; 95%CI 2.56, 70.94, respectively). A significant improvement in daily breathlessness score was observed during treatment with beta-2 agonist when compared to placebo (SMD 1.33; 95%CI 1.0, 1.65). The risk of dropping out of the study (treatment failure) when on treatment with placebo was almost twice that of patients on treatment with beta-2 agonists (RR 0.49; 95%CI 0.33, 0.73). Patients preferred beta-2 agonists almost 10 times more frequently to placebo (OR 9.04; 95%CI 4.64, 17.61). One study that used a validated questionnaire for 'quality of life' assessment, found highly significant improvements in the scores for dyspnoea (p=0.003) and fatigue (p=0.0003) during treatment with salbutamol. No studies reported serious side effects during treatment with inhaled beta-agonists. However, none of the studies were of sufficient length or size in order to allow any meaningful information on long-term occurrence of side effects. Use of short-acting beta-2 agonists on a regular basis for at least seven days in stable COPD is associated with improvements in post bronchodilator lung function and a decrease in breathlessness. Patients are far more likely to prefer treatment with beta-2 agonists than placebo, and less likely to drop out from such treatment. None of the studies included in this review reported sufficient data or were of sufficient length or size in order to provide reliable information on adverse effects. Therefore large scale, parallel, longer term studies would be needed to investigate the effect of treatment with regular inhaled beta-2 agonists on mortality, disease progression and side effects. Newer, long acting bronchodilators (including long-acting beta-2 agonists) are currently available and they may be more practical and/or effective in these patients. However, this review indicates that treatment with these older, inexpensive drugs is beneficial in patients with COPD.
We included six trials involving 1438 participants. Three of the six trials had adequate sequence generation while all the trials had unclear allocation concealment There was no evidence of any difference in pain perception during surgery with either retrobulbar or peribulbar anaesthesia. Both were largely effective. There was no evidence of any difference in complete akinesia or the need for further injections of local anaesthetic. Conjunctival chemosis was more common after peribulbar block (relative risk (RR) 2.11, 95% confidence interval (CI) 1.46 to 3.05) and lid haematoma was more common after retrobulbar block (RR 0.36, 95% CI 0.15 to 0.88). Retrobulbar haemorrhage was uncommon and occurred only once, in a patient who had a retrobulbar block. There is little to choose between peribulbar and retrobulbar block in terms of anaesthesia and akinesia during surgery measuring acceptability to patients, need for additional injections and development of severe complications. Severe local or systemic complications were rare for both types of block.
We included 25 RCTs involving 7259 participants including 977 (13.5%) men and 6282 (86.5%) women. Mean age reported ranged from 52.6 to 71 years, and range of age of included participants was 23 to 85 years. The trials reported 27 comparisons and included participants who had survived breast cancer (17 trials), colorectal cancer (2 trials), gynaecological cancer (1 trial), and cancer at mixed sites (5 trials). For overall survival, dietary intervention and control groups showed little or no difference in risk of mortality (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.77 to 1.23; 1 study; 3107 participants; low-certainty evidence). For secondary malignancies, dietary interventions versus control trials reported little or no difference (risk ratio (RR) 0.99, 95% CI 0.84 to 1.15; 1 study; 3107 participants; low-certainty evidence). Co-morbidities were not measured in any included trials. Subsequent outcomes reported after 12 months found that dietary interventions versus control probably make little or no difference in energy intake at 12 months (mean difference (MD) -59.13 kcal, 95% CI -159.05 to 37.79; 5 studies; 3283 participants; moderate-certainty evidence). Dietary interventions versus control probably led to slight increases in fruit and vegetable servings (MD 0.41 servings, 95% CI 0.10 to 0.71; 5 studies; 834 participants; moderate-certainty evidence); mixed results for fibre intake overall (MD 5.12 g, 95% CI 0.66 to 10.9; 2 studies; 3127 participants; very low-certainty evidence); and likely improvement in Diet Quality Index (MD 3.46, 95% CI 1.54 to 5.38; 747 participants; moderate-certainty evidence). For anthropometry, dietary intervention versus control probably led to a slightly decreased body mass index (BMI) (MD -0.79 kg/m², 95% CI -1.50 to -0.07; 4 studies; 777 participants; moderate-certainty evidence). Dietary interventions versus control probably had little or no effect on waist-to-hip ratio (MD -0.01, 95% CI -0.04 to 0.02; 2 studies; 106 participants; low-certainty evidence). For QoL, there were mixed results; several different quality assessment tools were used and evidence was of low to very low-certainty. No adverse events were reported in any of the included studies. Evidence demonstrated little effects of dietary interventions on overall mortality and secondary cancers. For comorbidities, no evidence was identified. For nutritional outcomes, there was probably little or no effect on energy intake, although probably a slight increase in fruit and vegetable intake and Diet Quality Index. Results were mixed for fibre. For anthropometry, there was probably a slight decrease in body mass index (BMI) but probably little or no effect on waist-to-hip ratio. For QoL, results were highly varied. Additional high-quality research is needed to examine the effects of dietary interventions for different cancer sites, and to evaluate important outcomes including comorbidities and body composition. Evidence on new technologies used to deliver dietary interventions was limited.
We included 16 cohort studies (median N = 126, range 71 to 2504) and three case control studies (38 to100 cases). Only one study was carried out in a primary care population. When used in isolation, diagnostic performance of most physical tests (scoliosis, paresis or muscle weakness, muscle wasting, impaired reflexes, sensory deficits) was poor. Some tests (forward flexion, hyper-extension test, and slump test) performed slightly better, but the number of studies was small. In the one primary care study, most tests showed higher specificity and lower sensitivity compared to other settings. Most studies assessed the Straight Leg Raising (SLR) test. In surgical populations, characterized by a high prevalence of disc herniation (58% to 98%), the SLR showed high sensitivity (pooled estimate 0.92, 95% CI: 0.87 to 0.95) with widely varying specificity (0.10 to 1.00, pooled estimate 0.28, 95% CI: 0.18 to 0.40). Results of studies using imaging showed more heterogeneity and poorer sensitivity. The crossed SLR showed high specificity (pooled estimate 0.90, 95% CI: 0.85 to 0.94) with consistently low sensitivity (pooled estimate 0.28, 95% CI: 0.22 to 0.35). Combining positive test results increased the specificity of physical tests, but few studies presented data on test combinations. When used in isolation, current evidence indicates poor diagnostic performance of most physical tests used to identify lumbar disc herniation. However, most findings arise from surgical populations and may not apply to primary care or non-selected populations. Better performance may be obtained when tests are combined.
Seven studies with a total of 225 participants met the inclusion criteria for this review. All seven studies compared the effects of a cognitive training intervention to a control intervention at the end of treatment periods lasting four to eight weeks. Six studies included people with PD living in the community. These six studies recruited people with single-domain (executive) or multiple-domain mild cognitive impairment in PD. Four of these studies identified participants with MCI using established diagnostic criteria, and two included both people with PD-MCI and people with PD who were not cognitively impaired. One study recruited people with a diagnosis of PD dementia who were living in long-term care settings. The cognitive training intervention in three studies targeted a single cognitive domain, whilst in four studies multiple domains of cognitive function were targeted. The comparison groups either received no intervention or took part in recreational activities (sports, music, arts), speech or language exercises, computerised motor therapy, or motor rehabilitation combined with recreational activity. We found no clear evidence that cognitive training improved global cognition. Although cognitive training was associated with higher scores on global cognition at the end of treatment, the result was imprecise and not statistically significant (6 trials, 178 participants, standardised mean difference (SMD) 0.28, 95% confidence interval (CI) −0.03 to 0.59; low-certainty evidence). There was no evidence of a difference at the end of treatment between cognitive training and control interventions on executive function (5 trials, 112 participants; SMD 0.10, 95% CI −0.28 to 0.48; low-certainty evidence) or visual processing (3 trials, 64 participants; SMD 0.30, 95% CI −0.21 to 0.81; low-certainty evidence). The evidence favoured the cognitive training group on attention (5 trials, 160 participants; SMD 0.36, 95% CI 0.03 to 0.68; low-certainty evidence) and verbal memory (5 trials, 160 participants; SMD 0.37, 95% CI 0.04 to 0.69; low-certainty evidence), but these effects were less certain in sensitivity analyses that excluded a study in which only a minority of the sample were cognitively impaired. There was no evidence of differences between treatment and control groups in activities of daily living (3 trials, 67 participants; SMD 0.03, 95% CI −0.47 to 0.53; low-certainty evidence) or quality of life (5 trials, 147 participants; SMD −0.01, 95% CI −0.35 to 0.33; low-certainty evidence). There was very little information on adverse events. We considered the certainty of the evidence for all outcomes to be low due to risk of bias in the included studies and imprecision of the results. We identified six ongoing trials recruiting participants with PD-MCI, but no ongoing trials of cognitive training for people with PDD. This review found no evidence that people with PD-MCI or PDD who receive cognitive training for four to eight weeks experience any important cognitive improvements at the end of training. However, this conclusion was based on a small number of studies with few participants, limitations of study design and execution, and imprecise results. There is a need for more robust, adequately powered studies of cognitive training before conclusions can be drawn about the effectiveness of cognitive training for people with PDD and PD-MCI. Studies should use formal criteria to diagnose cognitive impairments, and there is a particular need for more studies testing the efficacy of cognitive training in people with PDD.
We identified seven randomised controlled trials involving 542 breast cancer patients undergoing or having recently undergone chemotherapy. All studies were conducted and published in China. We did not pool the results because few studies were identified and no more than two used the same intervention. All were of low quality and used CMH plus chemotherapy compared with chemotherapy alone. CMH combined with chemotherapy showed no statistically significant difference for the outcomes of phlebitis and alopecia. Only one study showed an improvement in nausea and vomiting, and in fatigue. Three indicated an improvement in white blood cells in the group receiving CMH. Two showed an increase in percentage changes in T-lymphocyte subsets CD4 and CD8. One study showed a statistically significant difference for CMH in percentage changes in T-lymphocyte subsets CD3, CD4 and CD8. Two herbal compounds may have improved quality of life. One study reported that CMH may have some effect on reducing toxicity in liver and kidney, but differences were not statistically significant. This review provides limited evidence about the effectiveness and safety of Chinese medicinal herbs in alleviating chemotherapy induced short term side effects. Chinese medicinal herbs, when used together with chemotherapy, may offer some benefit to breast cancer patients in terms of bone marrow improvement and quality of life, but the evidence is too limited to make any confident conclusions. Well designed clinical trials are required before any conclusions can be drawn about the effectiveness and safety of CHM in the management of breast cancer patients.
In this 2014 update, we found no new studies. The one small randomised double-blind placebo-controlled cross-over trial found in 2012, which included only 45 participants and compared intravenous lidocaine against placebo as a means of pain relief in people with burns still remains central to this review. We assessed this study as being at a high risk of bias due to its small size (fewer than 50 participants per treatment arm). Subjective pain ratings, as measured by the verbal rating scale, increased during procedures for both treatment arms; however, the increase was less in the lidocaine treatment group. There were no significant clinical or statistical differences regarding the effects of lidocaine and placebo on opioid requests and consumption, anxiety or level of satisfaction during a wound care procedure, but the small included study provided insufficient data to draw any conclusions. As current clinical evidence is based on only one RCT as well as case series and reports, intravenous lidocaine must be considered a pharmacological agent under investigation in burns care, the effectiveness of which is yet to be determined with further well-designed and conducted clinical trials.
Fifteen trials involving 10 different drugs were included. Two trials enrolling 1156 patients compared interferon gamma-1beta with placebo: interferon gamma-1beta did not significantly improve survival (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68). Four trials involving 1155 patients compared pirfenidone with placebo. Three trials, conducted in 1046 patients, provided data on progression-free survival: pirfenidone significantly reduced the risk of disease progression by 30% (HR 0.70, 95% CI 0.56 to 0.88, P = 0.002). Data on the effect of pirfenidone on pulmonary function could only be assessed for two studies analysing 314 patients. Forced vital capacity or vital capacity was significantly improved by pirfenidone (mean difference 0.08 L, 95% CI 0.03 to 0.13, P = 0.0006). Based on available data, partly still unpublished, pirfenidone appears to improve progression-free survival and, to a lesser extent, pulmonary function in patients with idiopathic pulmonary fibrosis. More data are needed on overall survival and quality of life on treatment. From the studies in this review, interferon gamma-1beta has not been shown to affect survival. Other agents evaluated in single studies either failed to provide evidence for a benefit or need to be assessed in larger randomised controlled trials.
Altogether 2156 participants took part in the 45 randomised controlled studies that were discovered through extensive search efforts. Though many studies had a randomised, double-blind design, most studies were of poor methodological quality. Purified porcine and semi-synthetic insulin were most often investigated. No significant differences in metabolic control or hypoglycaemic episodes between various insulin species could be elucidated. Insulin dose and insulin antibodies did not show relevant dissimilarities. A comparison of the effects of human and animal insulin as well as of the adverse reaction profile did not show clinically relevant differences. Many patient-oriented outcomes like health-related quality of life or diabetes complications and mortality were never investigated in high-quality randomised clinical trials. The story of the introduction of human insulin might be repeated by contemporary launching campaigns to introduce pharmaceutical and technological innovations that are not backed up by sufficient proof of their advantages and safety.
Three studies with a combined total of 309 participants were included in the review. One study compared two-stage versus one-stage BKA; one study compared skew flaps BKA versus long posterior flap BKA; and one study compared sagittal flaps BKA versus long posterior flap BKA. Overall the quality of the evidence from these studies was moderate. BKA using skew flaps or sagittal flaps conferred no advantage over the well established long posterior flap technique (primary stump healing was 60% for both skew flaps and long posterior flap (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.71 to 1.42) and primary stump healing was 58% for sagittal flaps and 55% for long posterior flap (Peto odds ratio (OR) 1.04, 95% CI 0.45 to 2.43). For participants with wet gangrene, a two-stage procedure with a guillotine amputation at the ankle followed by a definitive long posterior flap amputation led to better primary stump healing than a one-stage procedure (Peto OR 0.08, 95% CI 0.01 to 0.89). Post-operative infection rate or wound necrosis, reamputation, and mobility with a prosthetic limb were similar in the different comparisons. There is no evidence to show a benefit of one type of incision over another. However, in the presence of wet gangrene a two-stage procedure leads to better primary stump healing compared to a one-stage procedure. The choice of amputation technique can, therefore, be a matter of surgeon preference taking into account factors such as previous experience of a particular technique, the extent of non-viable tissue, and the location of pre-existing surgical scars.
Primary outcome measure: one cross-over trial including 18 participants showed after four weeks, 2 (95% confidence interval (CI) 0.9 to 3.1) points more improvement on an 11-point disability scale with plasma exchange (10 exchanges over four weeks) than with sham exchange. Rapid deterioration after plasma exchange occurred in eight of 12 who had improved. Secondary outcome measures: when we combined the results of this cross-over trial and a trial with 29 participants treated in a parallel-group design, there were 31 points (95% CI 18 to 45) more improvement on an impairment scale (maximum score 280) after plasma exchange (six exchanges over three weeks) than after sham exchange. There were significant improvements in both trials in an electrophysiological measure, the proximally evoked compound muscle action potential, after three or four weeks. Non-randomised evidence indicates that plasma exchange induces adverse events in 3% to 17% of procedures. These events are sometimes serious. Both trials had a low risk of bias. A trial that showed no significant difference in the benefit between plasma exchange and intravenous immunoglobulin is included in the Cochrane review of intravenous immunoglobulin for this condition. Moderate- to high-quality evidence from two small trials shows that plasma exchange provides significant short-term improvement in disability, clinical impairment, and motor nerve conduction velocity in CIDP but rapid deterioration may occur afterwards. Adverse events related to difficulty with venous access, use of citrate, and haemodynamic changes are not uncommon. We need more research to identify agents that will prolong the beneficial action of plasma exchange.
We included three trials with 3851 participants. All three were cluster-RCTs. Two of the trials were of complex, single-component, non-pharmacological interventions and one trial was a feasibility trial of a complex, multicomponent, non-pharmacological intervention. Risk of bias ratings were mixed across the three trials. Due to the heterogeneous nature of the interventions, we did not combine the results statistically, but produced a narrative summary. It was not possible to determine the effect of a hydration-based intervention on delirium incidence (RR 0.85, 95% confidence interval (CI) 0.18 to 4.00; 1 study, 98 participants; very low-certainty evidence downgraded for risk of bias and very serious imprecision). This study did not assess delirium prevalence, severity or mortality. The introduction of a computerised system to identify medications that may contribute to delirium risk and trigger a medication review was probably associated with a reduction in delirium incidence (12-month HR 0.42, CI 0.34 to 0.51; 1 study, 7311 participant-months; moderate-certainty evidence downgraded for risk of bias) but probably had little or no effect on mortality (HR 0.88, CI 0.66 to 1.17; 1 study, 9412 participant-months; moderate-certainty evidence downgraded for imprecision), hospital admissions (HR 0.89, CI 0.72 to 1.10; 1 study, 7599 participant-months; moderate-certainty evidence downgraded for imprecision) or falls (HR 1.03, CI 0.92 to 1.15; 1 study, 2275 participant-months; low-certainty evidence downgraded for imprecision and risk of bias). Delirium prevalence and severity were not assessed. In the enhanced educational intervention study, aimed at changing practice to address key delirium risk factors, it was not possible to determine the effect of the intervention on delirium incidence (RR 0.62, 95% CI 0.16 to 2.39; 1 study, 137 resident months; very low-certainty evidence downgraded for risk of bias and serious imprecision) or delirium prevalence (RR 0.57, 95% CI 0.15 to 2.19; 1 study, 160 participants; very low-certainty evidence downgraded for risk of bias and serious imprecision). There was probably little or no effect on mortality (RR 0.82, CI 0.50 to 1.34; 1 study, 215 participants; moderate-certainty evidence downgraded for imprecision). The intervention was probably associated with a reduction in hospital admissions (RR 0.67, CI 0.57 to 0.79; 1 study, 494 participants; moderate-certainty evidence downgraded due to indirectness). Our review identified limited evidence on interventions for preventing delirium in older people in LTC. A software-based intervention to identify medications that could contribute to delirium risk and trigger a pharmacist-led medication review, probably reduces incidence of delirium in older people in institutional LTC. This is based on one large RCT in the US and may not be practical in other countries or settings which do not have comparable information technology services available in care homes. In the educational intervention aimed at identifying risk factors for delirium and developing bespoke solutions within care homes, it was not possible to determine the effect of the intervention on delirium incidence, prevalence or mortality. This evidence is based on a small feasibility trial. Our review identified three ongoing trials of multicomponent delirium prevention interventions. We identified no trials of pharmacological agents. Future trials of multicomponent non-pharmacological delirium prevention interventions for older people in LTC are needed to help inform the provision of evidence-based care for this vulnerable group.
We identified 15 studies described in 27 articles that met our inclusion criteria. These 15 included studies randomised a total of 3062 participants (PAAP vs no PAAP: 2602 participants; PAAP plus education vs education alone: 460 participants). Ten studies (eight PAAP vs no PAAP; two PAAP plus education vs education alone) provided outcome data that contributed to quantitative analyses. The overall quality of evidence was rated as low or very low. Fourteen studies lasted six months or longer, and the remaining study lasted for 14 weeks. When reported, mean age ranged from 22 to 49 years and asthma severity ranged from mild to severe/high risk. PAAP alone compared with no PAAP Results showed no clear benefit or harm associated with PAAPs in terms of the number of participants requiring an ED visit or hospitalisation for an exacerbation (odds ratio (OR) 0.75, 95% confidence interval (CI) 0.45 to 1.24; 1385 participants; five studies; low-quality evidence), change from baseline in asthma symptoms (mean difference (MD) -0.16, 95% CI -0.25 to - 0.07; 141 participants; one study; low-quality evidence) or the number of serious adverse events, including death (OR 3.26, 95% CI 0.33 to 32.21; 125 participants; one study; very low-quality evidence). Data revealed a statistically significant improvement in quality of life scores for those receiving PAAP compared with no PAAP (MD 0.18, 95% CI 0.05 to 0.30; 441 participants; three studies; low-quality evidence), but this was below the threshold for a minimum clinically important difference (MCID). Results also showed no clear benefit or harm associated with PAAPs on the number of participants reporting at least one exacerbation requiring oral corticosteroids (OR 1.45, 95% CI 0.84 to 2.48; 1136 participants; three studies; very low-quality evidence) nor on respiratory function (change from baseline forced expiratory volume in one second (FEV1): MD -0.04 L, 95% CI -0.25L to 0.17 L; 392 participants; three studies; low-quality evidence). In one study, PAAPs were associated with significantly fewer days lost from work or study (MD -6.20, 95% CI -7.32 to - 5.08; 74 participants; low-quality evidence). PAAP plus education compared with education alone Results showed no clear benefit or harm associated with adding a PAAP to education in terms of the number of participants requiring an ED visit or hospitalisation for an exacerbation (OR 1.08, 95% CI 0.27 to 4.32; 70 participants; one study; very low-quality evidence), change from baseline in asthma symptoms (MD -0.10, 95% CI -0.54 to 0.34; 70 participants; one study; low-quality evidence), change in quality of life scores from baseline (MD 0.13, 95% CI -0.13 to 0.39; 174 participants; one study; low-quality evidence) and number of participants requiring oral corticosteroids for an exacerbation (OR 0.28, 95% CI 0.07 to 1.12; 70 participants; one study; very low-quality evidence). No studies reported serious adverse events, respiratory function or days lost from work or study. Analysis of available studies was limited by variable reporting of primary and secondary outcomes; therefore, it is difficult to draw firm conclusions related to the effectiveness of PAAPs in the management of adult asthma. We found no evidence from randomised controlled trials of additional benefit or harm associated with use of PAAP versus no PAAP, or PAAP plus education versus education alone, but we considered the quality of the evidence to be low or very low, meaning that we cannot be confident in the magnitude or direction of reported treatment effects. In the context of this caveat, we found no observable effect on the primary outcomes of hospital attendance with an asthma exacerbation, asthma symptom scores or adverse events. We recommend further research with a particular focus on key patient-relevant outcomes, including exacerbation frequency and quality of life, in a broad spectrum of adults, including those over 60 years of age.
We included 25 studies (6293 participants) in this review. All included studies specified inguinal hernias, and two studies reported that femoral hernias were included. Mesh repair probably reduces the risk of hernia recurrence compared to non-mesh repair (21 studies, 5575 participants; RR 0.46, 95% CI 0.26 to 0.80, I2 = 44%, moderate-quality evidence). In absolute numbers, one hernia recurrence was prevented for every 46 mesh repairs compared with non-mesh repairs. Twenty-four studies (6293 participants) assessed a wide range of complications with varying follow-up times. Neurovascular and visceral injuries were more common in non-mesh repair groups (RR 0.61, 95% CI 0.49 to 0.76, I2 = 0%, NNTB = 22, high-quality evidence). Wound infection was found slightly more commonly in the mesh group (20 studies, 4540 participants; RR 1.29, 95% CI 0.89 to 1.86, I2 = 0%, NNTB = 200, low-quality evidence). Mesh repair reduced the risk of haematoma compared to non-mesh repair (15 studies, 3773 participants; RR 0.88, 95% CI 0.68 to 1.13, I2 = 0%, NNTB = 143, low-quality evidence). Seromas probably occur more frequently with mesh repair than with non-mesh repair (14 studies, 2640 participants; RR 1.63, 95% CI 1.03 to 2.59, I2 = 0%, NNTB = 72, moderate-quality evidence), as does wound swelling (two studies, 388 participants; RR 4.56, 95% CI 1.02 to 20.48, I2 = 33%, NNTB = 72, moderate-quality evidence). The comparative effect on wound dehiscence is uncertain due to wide confidence intervals (two studies, 329 participants; RR 0.55, 95% CI 0.12 to 2.48, I2 = 37% NNTB = 77, low-quality evidence). Testicular complications showed nearly equivocal results; they probably occurred slightly more often in the mesh group however the confidence interval around the effect was wide (14 studies, 3741 participants; RR 1.06, 95% CI 0.63 to 1.76, I2 = 0%, NNTB = 2000, low-quality evidence). Mesh reduced the risk of postoperative urinary retention compared to non-mesh (eight studies, 1539 participants; RR 0.53, 95% CI 0.38 to 0.73, I2 = 56%, NNTB = 16, moderate-quality evidence). Postoperative and chronic pain could not be compared due to variations in measurement methods and follow-up time (low-quality evidence). No deaths occurred during the follow-up periods reported in the seven studies (2546 participants) reporting this outcome (high-quality evidence). The average operating time was longer for non-mesh repairs by a mean of 4 minutes 22 seconds, despite wide variation across the studies regarding size and direction of effect, thus this result is uncertain (20 studies, 4148 participants; 95% CI -6.85 to -1.60, I2= 97%, very low-quality evidence). Hospital stay may be shorter with mesh repair, by 0.6 days (12 studies, 2966 participants; 95% CI -0.86 to -0.34, I2 = 98%, low-quality evidence), and participants undergoing mesh repairs may return to normal activities of daily living a mean of 2.87 days sooner than those with non-mesh repair (10 studies, 3183 participants; 95% CI -4.42 to -1.32, I2 = 96%, low-quality evidence), although the results of both these outcomes are also limited by wide variation in the size and direction of effect across the studies. Mesh and non-mesh repairs are effective surgical approaches in treating hernias, each demonstrating benefits in different areas. Compared to non-mesh repairs, mesh repairs probably reduce the rate of hernia recurrence, and reduce visceral or neurovascular injuries, making mesh repair a common repair approach. Mesh repairs may result in a reduced length of hospital stay and time to return to activities of daily living, but these results are uncertain due to variation in the results of the studies. Non-mesh repair is less likely to cause seroma formation and has been favoured in low-income countries due to low cost and reduced availability of mesh materials. Risk of bias in the included studies was low to moderate and generally handled well by study authors, with attention to details of allocation, blinding, attrition and reporting.
Six trials were included (five on-pump and one off-pump). This update adds the results of one further trial. Data from a total of 255 patients were included in the meta-analysis of mortality outcomes; all on-pump. Generally, the patients were considered as "high risk" and 132 were treated preoperatively with IABP and 123 served as controls. There were four hospital deaths in the intervention arm and 23 in the non-intervention arm (OR 0.18, 95% CI 0.08 to 0.41; P<0.0001). In a subgroup analysis, low cardiac index (<2.0 L/min/m2) was noted in 21 out of 105 patients in the treatment arm and 59 patients out of 88 in the non-treatment arm (OR 0.14, 95% CI: 0.08 to 0.25; P<0.00001). An off-pump versus on-pump analysis was not possible due to the limited number of off-pump studies. However a single well-conducted RCT suggested favourable effect of the preoperative IABP in off-pump patients. Evidence suggests that preoperative IABP may have a beneficial effect on mortality and morbidity in specific high risk patient groups undergoing coronary artery bypass grafting, however there are many problems with the quality, validity and generalisability of the trials. However, the available evidence is not robust enough to extend the use of IABP to truly elective, high risk patients. Defining more precisely which patient groups may benefit would be the challenge for the future.
The search for the original version of the review identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease. This update between September 2013 and May 2018 identified 35 new studies. None of these met the inclusion criteria. There was only one prospective study of 5% imiquimod in recurrent Paget's disease of the vulva, which although of good quality only included eight women. Since the last version of the review was published there are many more cases in the literature reporting a clinical response to 5% imiquimod cream. There is one prospective study of eight women treated with 5% imiquimod for recurrent Paget's disease of the vulva, and one prospective trial of 20 women was due to be reported. This increasing evidence for the safety and efficacy of 5% imiquimod will be helpful for women and clinicians alike. Ideally, a multicentre RCT of reasonable size is needed, but ongoing publications of high-quality non-randomised prospective studies will enhance the current available literature.
Four studies randomising 163 people could be included in the review. It is not clear if brief family intervention reduces the utilisation of health services by patients, as most results are equivocal at long term and only one study reported data for the primary outcomes of interest of hospital admission (n = 30, 1 RCT, RR 0.50, 95% CI 0.22 to 1.11, very low quality evidence). Data for relapse are also equivocal by medium term (n = 40, 1 RCT, RR 0.50, 95% CI 0.10 to 2.43, low quality evidence). However, data for the family outcome of understanding of family member significantly favoured brief family intervention (n = 70, 1 RCT, MD 14.90, 95% CI 7.20 to 22.60, very low quality evidence). No study reported data for other outcomes of interest including days in hospital; adverse events; medication compliance; quality of life or satisfaction with care; or any economic outcomes. The findings of this review are not outstanding due to the size and quality of studies providing data; the analysed outcomes were also minimal, with no meta-analysis possible. All outcomes in the 'Summary of findings' table were rated low or very low quality evidence. However, the importance of brief family intervention should not be dismissed outright, with the present state of demand and resources available. The designs of such brief interventions could be modified to be more effective with larger studies, which may then have enough power to inform clinical practice.
We included two studies (involving 141 women - with data from 124 women). We considered both studies as being at high risk of bias. Meta-analysis was not possible because the included studies examined different interventions (both in comparison with standard care) and reported on few, but different, outcomes. One study compared cervical adapter (mechanical sealing), and the other study examined an immunological membrane sealant. Neither of the included studies reported on this review's primary outcome of interest - perinatal mortality. Similarly, data were not reported for the majority of this review's secondary infant and maternal outcomes. Cervical adapter (mechanical sealing) versus standard care (one study, data from 35 participants) No data were reported for this review's primary outcome - perinatal mortality. Data were reported for few of this review's infant or maternal secondary outcomes. There was no clear difference between the mechanical sealing group and the standard care control in relation to the incidence of neonatal sepsis (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.28 to 5.09 (very low-quality evidence)) or chorioamnionitis (RR 1.19, 95% CI 0.28 to 5.09 (very low-quality evidence)). Oral immunological membrane sealant versus standard care (one study, data from 94 participants) No data were available for perinatal mortality (this review's primary outcome) or for the majority of this review's infant and maternal secondary outcomes. Compared to standard care, the immunological membrane sealant was associated with a reduction in preterm birth less than 37 weeks (RR 0.48, 95% CI 0.34 to 0.68 (very low-quality evidence)) and a reduction in neonatal death (RR 0.38, 95% CI 0.19 to 0.75 (very low-quality evidence)). However, there was no clear difference between groups in terms of neonatal sepsis (RR 0.64, 95% CI 0.28 to 1.46 (very low-quality evidence)) or respiratory distress syndrome (RR 0.64, 95% CI 0.28 to 1.46 (very low-quality evidence)). There is insufficient evidence to evaluate sealing procedures for PPROM. There were no data relating to this review's primary outcome (perinatal mortality) and the majority of our infant and maternal secondary outcomes were not reported in the two included studies. There was limited evidence to suggest that an immunological membrane sealant was associated with a reduction in preterm birth at less than 37 weeks and neonatal death, but these results should be interpreted with caution as this is based on one small study, with a high risk of bias, and the intervention has not been tested in other studies. Although midtrimester PPROM is not a rare occurrence, there are only a small amount of published data addressing the benefits and risks of sealing procedures. Most of these studies are retrospective and cohort based and could therefore not be included in our data-analysis. This review highlights the paucity of prospective randomised trials in this area. Current evidence provides limited information both on effectiveness and safety for the interventions described. Given the paucity of high-quality data, we recommend that future research efforts focus on the conduct of randomised trials assessing the effect of promising interventions that have been only evaluated to date in cohort studies (e.g. amniopatch). Future trials should address outcomes including perinatal mortality, preterm birth, neonatal death, respiratory distress syndrome, neonatal sepsis and developmental delay. They should also evaluate maternal outcomes including sepsis, mode of delivery, length of hospital stay and emotional well-being.
We included two RCTs (with a total of 789 participants) comparing LMWH with 5-FU infusion and placebo. However, we did not perform a meta-analysis because of significant heterogeneity between these studies. One study found a significant beneficial effect of LMWH with 5-FU in reducing postoperative PVR compared to placebo (RR: 0.48, 95% confidence interval: 0.25 to 0.92), in 174 patients who were viewed at high-risk of developing postoperative PVR. The other study included 615 unselected cases of rhegmatogenous retinal detachment and could not show a difference between LMWH with 5-FU infusion and placebo in reducing PVR rates (RR:1.45, 95% confidence interval: 0.76 to 2.76). Results from this review indicate that there is inconsistent evidence from two studies on patients at different risk of PVR on the effect of LMWH and 5-FU used during vitrectomy to prevent PVR. Future research should be conducted on high risk patients only, until a benefit is confirmed at least in this patient subgroup.
In this updated analysis, we included nine trials (N = 1070 infants) comparing prophylactic ibuprofen (IV or oral) with placebo/no intervention or indomethacin. Ibuprofen (IV or oral) probably decreases the risk of PDA on day 3 or 4 (typical RR 0.39, 95% CI 0.31 to 0.48; typical RD -0.26, 95% CI -0.31 to -0.21; NNTB 4, 95% CI 3 to 5; 9 trials; N = 1029) (moderate-quality evidence). In the control group, the spontaneous closure rate was 58% by day 3 to 4 of age. In addition, ibuprofen probably decreases the need for rescue treatment with cyclo-oxygenase inhibitors (typical RR 0.17, 95% CI 0.11 to 0.26; typical RD -0.27, 95% CI -0.32 to -0.22; NNTB 4; 95% CI 3 to 5),and the need for surgical ductal ligation (typical RR 0.46, 95% CI 0.22 to 0.96; typical RD -0.03, 95% CI -0.05 to -0.00; NNTB 33, 95% CI 20 to infinity; 7 trials; N = 925) (moderate-quality evidence). There was a possible decrease in the risk of grade 3 or 4 intraventricular haemorrhage (IVH) in infants receiving prophylactic ibuprofen (typical RR 0.67, 95% CI 0.45 to 1.00; I² = 34%; typical RD -0.04, 95% CI -0.08 to- 0.00; I² = 60%; 7 trials; N = 925) (moderate-quality evidence). High quality evidence showed increased risk for oliguria (typical RR 1.45, 95% CI 1.04 to 2.02; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 17, 95% CI 9 to 100; 4 trials; N = 747). Low quality results from four studies (N = 202) showed that administering oral ibuprofen may decrease the risk of PDA (typical RR 0.47, 95% CI 0.30 to 0.74) and may increase risk of gastrointestinal bleeding (NNTH 7, 95% CI 4 to 25). No evidence of a difference was identified for mortality, any intraventricular haemorrhage (IVH), or chronic lung disease. This review shows that prophylactic use of ibuprofen, compared to placebo or no intervention, probably decreases the incidence of patent ductus arteriosus, the need for rescue treatment with cyclo-oxygenase inhibitors, and for surgical ductal closure. Adverse effects associated with ibuprofen (IV or oral) included increased risks for oliguria, increase in serum creatinine levels, and increased risk of gastrointestinal haemorrhage. There was a reduced risk for intraventricular haemorrhage (grade III - IV) but no evidence of a difference in mortality, chronic lung disease, necrotising enterocolitis, or time to reach full feeds. In the control group, the patent ductus arteriosus had closed spontaneously by day 3 or 4 in 58% of neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefits. Current evidence does not support the use of ibuprofen for prevention of patent ductus arteriosus. Until long-term follow-up results of the trials included in this review have been published, no further trials of prophylactic ibuprofen are recommended. A new approach to patent ductus arteriosus management is an early targeted treatment based on echocardiographic criteria within the first 72 hours of life, that have a high sensitivity for diagnosing a patent ductus arteriosus that is unlikely to close spontaneously. Such trials are currently ongoing in many parts of the world. Results of such trials will be included in updates of our "Ibuprofen for treatment of PDA" review.
We included eight small trials involving a total of 282 participants with chronic osteomyelitis. Data were available from 248 participants. Most participants were male with post-traumatic osteomyelitis, usually affecting the tibia and femur, where recorded. The antibiotic regimens, duration of treatment and follow-up varied between trials. All trials mentioned surgical debridement before starting on antibiotic therapy as part of treatment, but it was unclear in four trials whether all participants underwent surgical debridement. We found that study quality and reporting were often inadequate. In particular, we judged almost all trials to be at moderate to high risk of bias due to failure to conceal allocation and inadequate follow-up. Four trials compared oral versus parenteral route for administration of antibiotics. There was no statistically significant difference between the two groups in the remission at the end of treatment (70/80 versus 58/70; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.92 to 1.18; four trials, 150 participants). There was no statistically significant difference between the two groups in the remission rate 12 or more months after treatment (49/64 versus 44/54; RR 0.94, 95% CI 0.78 to 1.13; three trials, 118 participants). There was also no significant difference between the two groups in the occurrence of mild adverse events (11/64 versus 8/54; RR 1.08, 95% CI 0.49 to 2.42; three trials, 118 participants) or moderate and severe adverse events (3/49 versus 4/42; RR 0.69, 95% CI 0.19 to 2.57; three trials, 91 participants). Superinfection occurred in participants of both groups (5/66 in the oral group versus 4/58 in the parenteral group; RR 1.08, 95% CI 0.33 to 3.60; three trials, 124 participants). Single trials with few participants found no statistical significant differences for remission or adverse events for the following four comparisons: oral only versus parenteral plus oral administration; parenteral plus oral versus parenteral only administration; two different parenteral antibiotic regimens; and two different oral antibiotic regimens. No trials compared different durations of antibiotic treatment for chronic osteomyelitis, or adjusted the remission rate for bacteria species or severity of disease. Limited and low quality evidence suggests that the route of antibiotic administration (oral versus parenteral) does not affect the rate of disease remission if the bacteria are susceptible to the antibiotic used. However, this and the lack of statistically significant differences in adverse effects need confirmation. No or insufficient evidence exists for other aspects of antibiotic therapy for chronic osteomyelitis. The majority of the included trials were conducted over 20 years ago and currently we are faced with a far higher prevalence of bacteria that are resistant to many of the available antibiotics used for healthcare. This continuously evolving bacterial resistance represents another challenge in the choice of antibiotics for treating chronic osteomyelitis.
Seven studies (581 participants) met our inclusion criteria. Trials had an intervention length of 6 weeks to 12 months and follow-up length of 6 to 12 months. The comparison group in all trials was usual care (without any form of structured exercise training or advice) or a no-exercise comparator. The mean age of participants within the trials ranged from 50 to 66 years, the majority of participants being male (range: 74% to 100%). In terms of risk of bias, the majority of studies were unclear about their generation of the randomisation sequence and concealment processes. One study was at high risk of detection bias as it did not blind its participants or outcome assessors, and two studies had a high risk of attrition bias due to the numbers of participants lost to follow-up. Two trials were at high risk of outcome reporting bias. Given the high risk of bias, small number of trials and participants, and concerns about applicability, we downgraded our assessments of the quality of the evidence using the GRADE tool. Due to the very low-quality of the evidence base, we are uncertain about the effect of exercise-based CR on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.18 to 5.67; 195 participants; 3 studies; very low-quality evidence), acute myocardial infarction (RR 0.33, 95% CI 0.07 to 1.63; 254 participants; 3 studies; very low-quality evidence) and cardiovascular-related hospital admissions (RR 0.14, 95% CI 0.02 to 1.1; 101 participants; 1 study; very low-quality evidence). We found low-quality evidence that exercise-based CR may result in a small improvement in exercise capacity compared to control (standardised mean difference (SMD) 0.45, 95% CI 0.20 to 0.70; 267 participants; 5 studies, low-quality evidence). We were unable to draw conclusions about the impact of exercise-based CR on quality of life (angina frequency and emotional health-related quality-of-life score) and CR-related adverse events (e.g. skeletomuscular injury, cardiac arrhythmia), due to the very low quality of evidence. No data were reported on return to work. Due to the small number of trials and their small size, potential risk of bias and concerns about imprecision and lack of applicability, we are uncertain of the effects of exercise-based CR compared to control on mortality, morbidity, cardiovascular hospital admissions, adverse events, return to work and health-related quality of life in people with stable angina. Low-quality evidence indicates that exercise-based CR may result in a small increase in exercise capacity compared to usual care. High-quality, well-reported randomised trials are needed to assess the benefits and harms of exercise-based CR for adults with stable angina. Such trials need to collect patient-relevant outcomes, including clinical events and health-related quality of life. They should also assess cost-effectiveness, and recruit participants that are reflective of the real-world population of people with angina.
We identified one new study with 100 participants for the pooled analysis. We identified two additional reports of a study using an enriched enrolment randomised withdrawal (EERW) design that included participants from earlier randomised controlled trials and an open-label study. Because this study used the same participants already included in our main analysis, and a different design, we dealt with it separately. The main analysis included six studies (five from the earlier review; 4238 participants in total), all of which were placebo-controlled, and used titration to a target dose of milnacipran 100 or 200 mg, with assessment after 8 to 24 weeks of stable treatment. There were no studies with active comparators. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect. Both doses of milnacipran provided moderate levels of pain relief (at least 30% pain intensity reduction) to about 40% of participants treated, compared to 30% with placebo, giving a number needed to treat for an additional beneficial outcome (NNT) of 6 to 10 (high quality evidence). Using a stricter definition for responder and a more conservative method of analysis gave lower levels of response (while maintaining a 10% difference between milnacipran and placebo) and increased the NNT to 11 (high quality evidence). One EERW study was broadly supportive. Adverse events were common in both milnacipran (86%) and placebo (78%) groups (high quality evidence), but serious adverse events did not differ between groups (less than 2%) (low quality evidence). Nausea, constipation, and headache were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome (NNH) of 5.7 for nausea, 13 for constipation, and 29 for headache) (moderate quality evidence). Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg (NNH 9) than 100 mg (NNH 23), compared with placebo. This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg and 7.0 for 200 mg (high quality evidence). Withdrawals due to lack of efficacy were less common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome (NNTp) of 41) (moderate quality evidence). The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Using stricter criteria for 'responder' and a more conservative method of analysis gave lower response rates (about 26% with milnacipran versus 17% with placebo). Milnacipran was associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose.
We included eleven randomised clinical trials with 1664 participants who were mostly at low anaesthetic risk, low frequency of co-morbidities, low risk of conversion to open surgery, and low risk of infectious complications. None of the trials had low risk of bias. We found no statistically significant differences between antibiotic prophylaxis and no prophylaxis in the proportion of surgical site infections (odds ratio (OR) 0.87, 95% CI 0.49 to 1.54) or extra-abdominal infections (OR 0.77, 95% CI 0.41 to 1.46). Heterogeneity was not statistically significant. This systematic review shows that there is not sufficient evidence to support or refute the use of antibiotic prophylaxis to reduce surgical site infection and global infections in patients with low risk of anaesthetic complications, co-morbidities, conversion to open surgery, and infectious complications, and undergoing elective laparoscopic cholecystectomy. Larger randomised clinical trials with intention-to-treat analysis and patients also at high risk of conversion to open surgery are needed.
Two completed and one ongoing clinical trial met the inclusion criteria. One trial (34 patients randomised) examined the effects of H pylori eradication on levodopa absorption and motor symptoms and found significant improvements in both. The ongoing trial has similar objectives and aims to recruit 100 patients. The other completed trial (20 patients analysed) sought to find a causal link between infection with H pylori and Parkinsonism and was non-contributory. A worsening of symptoms was noted with eradication failure. The prevalence of H pylori in Parkinson's disease was reported in four studies and ranged from 37% to 59% which is similar to that of the general population. There is currently a lack of evidence on the effects of screening and treating H pylori in patients with Parkinson's disease. There is limited evidence to suggest that H Pylori eradication improves the absorption of levodopa and improves motor symptoms. Results from an ongoing trial will inform the evidence base and will be incorporated in an update of this review. There is a need for well-conducted randomised controlled trials with standard outcome measures for motor symptoms and incorporating the costs of screening and treatment.
We included 13 trials in this review. Eight studies reported data on the Bayley Scales of Infant Development (BSID) in 2134 participants. We combined the data in a meta-analysis to assess the effect on development as measured by the Mental Development Index (MDI) and Psychomotor Development Index (PDI). There was no significant effect of zinc supplementation: the mean difference between the zinc supplementation and placebo groups on the MDI was -0.50 (95% confidence interval (CI) -2.06 to 1.06; P = 0.53; I2 = 70%) and the mean difference between the groups for the PDI was 1.54 (95% CI -2.26 to 5.34; P = 0.43; I2 = 93%). Most studies had low or unclear risk of bias but there was significant heterogeneity, which was not adequately explained by our subgroup analyses. The overall quality of evidence was considered 'moderate'. Two trials provided data on motor milestone attainment. There was no significant difference in the time to attainment of milestones between the placebo group and the zinc supplementation group in either of the studies. No study provided data on cognition score or intelligence quotient (IQ) or on adverse effects of zinc supplementation. There is no convincing evidence that zinc supplementation to infants or children results in improved motor or mental development.
This review update added three new studies including 419 participants to the review. In total, we identified eight RCTs, most of which were at low risk of bias, involving 1669 participants with mild to moderate asthma. We included three paediatric (n = 422) and five adult (n = 1247) studies; six were parallel-group trials and two had a cross-over design. All but one study followed participants for six months to one year. Allowed maintenance doses of ICS varied in adult and paediatric studies, as did use of concomitant medications and doses of ICS initiated during exacerbations. Investigators gave participants a study inhaler containing additional ICS or placebo to be started as part of an action plan for treatment of exacerbations. The odds of treatment failure, defined as the need for oral corticosteroids, were not significantly reduced among those randomised to increased ICS compared with those taking their usual stable maintenance dose (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.68 to 1.18; participants = 1520; studies = 7). When we analysed only people who actually took their study inhaler for an exacerbation, we found much variation between study results but the evidence did not show a significant benefit of increasing ICS dose (OR 0.84, 95% CI 0.54 to 1.30; participants = 766; studies = 7). The odds of having an unscheduled physician visit (OR 0.96, 95% CI 0.66 to 1.41; participants = 931; studies = 3) or acute visit (Peto OR 0.98, 95% CI 0.24 to 3.98; participants = 450; studies = 3) were not significantly reduced by an increased versus stable dose of ICS, and evidence was insufficient to permit assessment of impact on the duration of exacerbation; our ability to draw conclusions from these outcomes was limited by the number of studies reporting these events and by the number of events included in the analyses. The odds of serious events (OR 1.69, 95% CI 0.77 to 3.71; participants = 394; studies = 2) and non-serious events, such as oral irritation, headaches and changes in appetite (OR 2.15, 95% CI 0.68 to 6.73; participants = 142; studies = 2), were neither increased nor decreased significantly by increased versus stable doses of ICS during an exacerbation. Too few studies are available to allow firm conclusions on the basis of subgroup analyses conducted to investigate the impact of age, time to treatment initiation, doses used, smoking history and the fold increase of ICS on the magnitude of effect; yet, effect size appears similar in children and adults. Current evidence does not support increasing the dose of ICS as part of a self initiated action plan to treat exacerbations in adults and children with mild to moderate asthma. Increased ICS dose is not associated with a statistically significant reduction in the odds of requiring rescue oral corticosteroids for the exacerbation, or of having adverse events, compared with a stable ICS dose. Wide confidence intervals for several outcomes mean we cannot rule out possible benefits of this approach.
We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta-analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes. In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non-elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed.
Four trials involving 91 infants were included. No difference was detected between intravenous doxapram or methylxanthine in the incidence of failed treatment within 48 hours [typical relative risk 0.91, 95% confidence interval (95% CI) 0.45, 1.85] . Only one trial reported results at 7 days and there was no difference in results. No infants were reported to have been given mechanical ventilation on either treatment. No adverse effects were reported. Intravenous doxapram and intravenous methylxanthine appear to be similar in their short term effects for treating apnea in preterm infants, although these trials are too small to exclude an important difference between the two treatments or to exclude the possibility of less common adverse effects. Long term outcome of infants treated in these trials has not been reported. Further studies would require a large number of infants to clarify whether there might be differences in responses or adverse effects with these two drugs at different ages.
Nineteen studies enrolling approximately 5000 preterm and/or LBW infants met inclusion criteria. No new trials were identified in May 2013. When all studies were combined, a significant reduction in sepsis was noted (typical risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74 to 0.98; typical risk difference (RD) -0.03, 95% CI 0.00 to -0.05; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 20 to infinity), and moderate between-study heterogeneity was reported (I2 54% for RR, 55% for RD). A significant reduction of one or more episodes was found for any serious infection when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.02 to -0.06; NNTB 25, 95% CI 17 to 50), and moderate between-study heterogeneity was observed (I2 50% for RR, 62% for RD). No statistically significant differences in mortality from all causes were noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01), and no heterogeneity for RR (I2 = 21%) or low heterogeneity for RD was documented (I2 = 28%). No statistically significant difference was seen in mortality from infection; in incidence of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) or intraventricular haemorrhage (IVH) or in length of hospital stay. No major adverse effects of IVIG were reported in any of these studies. IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection but is not associated with reductions in other clinically important outcomes, including mortality. Prophylactic use of IVIG is not associated with any short-term serious side effects. The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.
Eight studies are now included in this review. When any dose omega-3 (E-EPA or EPA) is compared with placebo, small short trials suggest that the need for neuroleptics appears to be reduced for people allocated omega-3 supplementation (n=30, 1 RCT, RR 0.73 CI 0.54 to 1.00) and mental state may improve (n=30, 1 RCT, RR not gaining 25% change in PANSS scores 0.54 CI 0.30 to 0.96, NNT 3 CI 2 to 29). There are no differences in the number of people leaving the study early (n=595, 6 RCTs, RR 0.86 CI 0.50 to 1.48). There are few data on the comparison of any dose omega-6 (GLA) with placebo. For movement disorder outcomes, the one small study we found does not show any difference for average short-term endpoint AIMS score (n=16, 1 RCT, WMD 1.30 CI -1.96 to 4.56). When any dose omega-3 (E-EPA or EPA) is compared with any dose omega-3 (DHA) there is no significant difference for mental state outcome of not gaining 25% change in PANSS scores (n=31, 1 RCT, RR 0.66 CI 0.39 to 1.11). When different doses of omega-3 (E-EPA) are compared with placebo there are no differences in measures of global and mental state between the studies. For the outcome of 'experiencing at least one adverse effect' no differences between groups are found for any dose (1 g/day E-EPA vs placebo n=63, 1 RCT, RR 0.97 CI 0.60 to 1.56; 2 g/day E-EPA vs placebo n=63, 1 RCT, RR 0.67 CI 0.37 to 1.20; 4 g/day E-EPA vs placebo n=58, 1 RCT, RR 1.15 CI 0.72 to 1.82). Three updates of this review have resulted in more included studies and more people randomised but still relatively little useful additional data. The results remain inconclusive. The new trials all compare the omega-3 polyunsaturated fatty acids, in particular eicosapentaenoic acid and its ester, ethyl-eicosapentaenoic acid. The use of omega-3 polyunsaturated fatty acids for schizophrenia still remains experimental and this review highlights the need for large, well designed, conducted and reported studies.
We included 16 studies assessing a median of 54 RCTs (range: 2 to 362). Twelve studies compared protocols to published reports and four compared trial registry entries to published reports. In two studies, eligibility criteria differed between the protocol and publication in 19% and 100% RCTs. In one study, 16% (9/58) of the reports included the same sample size calculation as the protocol. In one study, 6% (4/63) of protocol-report pairs gave conflicting information regarding the method of allocation concealment, and 67% (49/73) of blinded studies reported discrepant information on who was blinded. In one study unacknowledged discrepancies were found for methods of handling protocol deviations (44%; 19/43), missing data (80%; 39/49), primary outcome analyses (60%; 25/42) and adjusted analyses (82%; 23/28). One study found that of 13 protocols specifying subgroup analyses, 12 of these 13 trials reported only some, or none, of these. Two studies found that statistically significant outcomes had a higher odds of being fully reported compared to nonsignificant outcomes (range of odds ratios: 2.4 to 4.7). Across the studies, at least one primary outcome was changed, introduced, or omitted in 4-50% of trial reports. Discrepancies between protocols or trial registry entries and trial reports were common, although reasons for these were not discussed in the reports. Full transparency will be possible only when protocols are made publicly available or the quality and extent of information included in trial registries is improved, and trialists explain substantial changes in their reports.
The review includes seven trials; five on aspects of lifestyle changes (eg, diet, physical exercise) and two on treatment with a weight reduction drug 'orlistat'. In total, 373 participants were enrolled, and the duration of the trials ranged from 1 month to 1 year. Only one trial on lifestyle programme was judged to be of low risk of bias. We could not perform meta-analyses for the main outcomes as they were either not reported or there were insufficient number of trials for each outcome to be meta-analysed. We could meta-analyse the available data for body weight and body mass index only. Adverse events were poorly reported. The sparse data and high risk of bias preclude us from drawing any definite conclusion on lifestyle programme or orlistat for treatment of NAFLD. Further randomised clinical trials with low risk of bias are needed to test the beneficial and harmful effects of weight reduction for NAFLD patients. The long-term prognosis of development of fibrosis, mortality, and quality of life should be studied.
We included five randomised clinical trials with 265 participants. All trials were prospective, double-blind, placebo-controlled randomised controlled trials on the effects of positive pressure therapy on vertigo complaints in Ménière's disease. Overall, the risk of bias varied: three out of five studies were at low risk, one was at unclear risk and one was at high risk of bias. Control of vertigo For the primary outcome, control of vertigo, it was not possible to pool data due to heterogeneity in the measurement of the outcome measures. In most studies, no significant difference was found between the positive pressure therapy group and the placebo group in vertigo scores or vertigo days. Only one study, at low risk of bias, showed a significant difference in one measure of vertigo control in favour of positive pressure therapy. In this study, the mean visual analogue scale (VAS) score for vertigo after eight weeks of treatment was 25.5 in the positive pressure therapy group and 46.6 in the placebo group (mean difference (MD) -21.10, 95% CI -35.47 to -6.73; scale not stated - presumed to be 0 to 100). Secondary outcomes For the secondary outcomes, we carried out two pooled analyses. We found statistically significant results for loss or gain of hearing  . Hearing was 7.38 decibels better in the placebo group compared to the positive pressure therapy group (MD) (95% CI 2.51 to 12.25; two studies, 123 participants). The severity of tinnitus  and perception of aural fullness  were either not measured or inadequate data were provided in the included studies. For the secondary outcome functional level  , it was not possible to perform a pooled analysis. One included study showed less functional impairment in the positive pressure group than the placebo group (AAO-HNS criteria, one- to six-point scale: MD -1.10, 95% CI -1.81 to -0.39, 40 participants); another study did not show any significant results. In addition to the predefined secondary outcome measures, we included sick days  as an additional outcome measure, as two studies used this outcome measure and it is a complementary measurement of impairment due to Ménière's disease. We did not find a statistically significant difference in sick days. No complications or adverse effects  were noted by any study. There is no evidence, from five included studies, to show that positive pressure therapy is effective for the symptoms of Ménière's disease. There is some moderate quality evidence, from two studies, that hearing levels are worse in patients who use this therapy. The positive pressure therapy device itself is minimally invasive. However, in order to use it, a tympanostomy tube (grommet) needs to be inserted, with the associated risks. These include the risks of anaesthesia, the general risks of any surgery and the specific risks of otorrhoea and tympanosclerosis associated with the insertion of a tympanostomy tube. Notwithstanding these comments, no complications or adverse effects were noted in any of the included studies.
Eight trials involving 3417 people were included. AA may help patients to accept treatment and keep patients in treatment more than alternative treatments, though the evidence for this is from one small study that combined AA with other interventions and should not be regarded as conclusive. Other studies reported similar retention rates regardless of treatment group. Three studies compared AA combined with other interventions against other treatments and found few differences in the amount of drinks and percentage of drinking days. Severity of addiction and drinking consequence did not seem to be differentially influenced by TSF versus comparison treatment interventions, and no conclusive differences in treatment drop out rates were reported. Included studies did not allow a conclusive assessment of the effect of TSF in promoting complete abstinence. No experimental studies unequivocally demonstrated the effectiveness of AA or TSF approaches for reducing alcohol dependence or problems. One large study focused on the prognostic factors associated with interventions that were assumed to be successful rather than on the effectiveness of interventions themselves, so more efficacy studies are needed.
We identified 12 studies (667 participants) and two new ongoing studies for inclusion. Six RCTs were newly included at this update and important non-randomised cohort studies have also been published. Some important studies remain unpublished and not all published studies provide complete outcome data. Primary outcome measure: one two-year deflazacort RCT (n = 28) used prolongation of ambulation as an outcome measure but data were not adequate for drawing conclusions. Secondary outcome measures: meta-analyses showed that corticosteroids (0.75 mg/kg/day prednisone or prednisolone) improved muscle strength and function versus placebo over six months (moderate quality evidence from up to four RCTs). Evidence from single trials showed 0.75 mg/kg/day superior to 0.3 mg/kg/day on most strength and function measures, with little evidence of further benefit at 1.5 mg/kg/day. Improvements were seen in time taken to rise from the floor (Gowers' time), timed walk, four-stair climbing time, ability to lift weights, leg function grade, and forced vital capacity. One new RCT (n = 66), reported better strength, function and quality of life with daily 0.75 mg/kg/day prednisone at 12 months. One RCT (n = 28) showed that deflazacort stabilised muscle strength versus placebo at two years, but timed function test results were too imprecise for conclusions to be drawn. One double-blind RCT (n = 64), largely at low risk of bias, compared daily prednisone (0.75 mg/kg/day) with weekend-only prednisone (5 mg/kg/weekend day), finding no overall difference in muscle strength and function over 12 months (moderate to low quality evidence). Two small RCTs (n = 52) compared daily prednisone 0.75 mg/kg/day with daily deflazacort 0.9 mg/kg/day, but study methods limited our ability to compare muscle strength or function. Adverse effects: excessive weight gain, behavioural abnormalities, cushingoid appearance, and excessive hair growth were all previously shown to be more common with corticosteroids than placebo; we assessed the quality of evidence (for behavioural changes and weight gain) as moderate. Hair growth and cushingoid features were more frequent at 0.75 mg/kg/day than 0.3 mg/kg/day prednisone. Comparing daily versus weekend-only prednisone, both groups gained weight with no clear difference in body mass index (BMI) or in behavioural changes (low quality evidence for both outcomes, one study); the weekend-only group had a greater linear increase in height. Very low quality evidence suggested less weight gain with deflazacort than with prednisone at 12 months, and no difference in behavioural abnormalities. Data are insufficient to assess the risk of fractures or cataracts for any comparison. Non-randomised studies support RCT evidence in showing improved functional benefit from corticosteroids. These studies suggest sustained benefit for up to 66 months. Adverse effects were common, although generally manageable. According to a large comparative longitudinal study of daily or intermittent (10 days on, 10 days off) corticosteroid for a mean period of four years, a daily regimen prolongs ambulation and improves functional scores over the age of seven, but with a greater frequency of side effects than an intermittent regimen. Moderate quality evidence from RCTs indicates that corticosteroid therapy in DMD improves muscle strength and function in the short term (twelve months), and strength up to two years. On the basis of the evidence available for strength and function outcomes, our confidence in the effect estimate for the efficacy of a 0.75 mg/kg/day dose of prednisone or above is fairly secure. There is no evidence other than from non-randomised trials to establish the effect of corticosteroids on prolongation of walking. In the short term, adverse effects were significantly more common with corticosteroids than placebo, but not clinically severe. A weekend-only prednisone regimen is as effective as daily prednisone in the short term (12 months), according to low to moderate quality evidence from a single trial, with no clear difference in BMI (low quality evidence). Very low quality evidence indicates that deflazacort causes less weight gain than prednisone after a year's treatment. We cannot evaluate long-term benefits and hazards of corticosteroid treatment or intermittent regimens from published RCTs. Non-randomised studies support the conclusions of functional benefits, but also identify clinically significant adverse effects of long-term treatment, and a possible divergence of efficacy in daily and weekend-only regimens in the longer term. These benefits and adverse effects have implications for future research and clinical practice.
We included 28 trials, involving 5855 participants, comparing stroke unit care with an alternative service. More-organised care was consistently associated with improved outcomes. Twenty-one trials (3994 participants) compared stroke unit care with care provided in general wards. Stroke unit care showed reductions in the odds of death recorded at final (median one year) follow-up (odds ratio (OR) 0.81, 95% Confidence Interval (CI) 0.69 to 0.94; P = 0.005), the odds of death or institutionalised care (OR 0.78, 95% CI 0.68 to 0.89; P = 0.0003) and the odds of death or dependency (OR 0.79, 95% CI 0.68 to 0.90; P = 0.0007). Sensitivity analyses indicated that the observed benefits remained when the analysis was restricted to securely randomised trials that used unequivocally blinded outcome assessment with a fixed period of follow-up. Outcomes were independent of patient age, sex, initial stroke severity or stroke type, and appeared to be better in stroke units based in a discrete ward. There was no indication that organised stroke unit care resulted in a longer hospital stay. Stroke patients who receive organised inpatient care in a stroke unit are more likely to be alive, independent, and living at home one year after the stroke. The benefits were most apparent in units based in a discrete ward. We observed no systematic increase in the length of inpatient stay.
Six trials with a total of 556 people were included. These trials were all placebo-controlled and double-blind, but of variable quality. They used different homeopathic treatments which precluded quantitative pooling of results for the primary outcome. Standardised treatments in these trials are unlikely to represent common homeopathic practice, where treatment tends to be individualised. No trial reported a significant difference on validated symptom scales. There were conflicting results in terms of lung function between the studies. There has been only a limited attempt to measure a 'package of care' effect (i.e., the effect of the medication as well as the consultation, which is considered a vital part of individualised homeopathic practice). An update search in August 2005 did not identify any new studies. There is not enough evidence to reliably assess the possible role of homeopathy in asthma. As well as randomised trials, there is a need for observational data to document the different methods of homeopathic prescribing and how patients respond. This will help to establish to what extent people respond to a 'package of care' rather than the homeopathic intervention alone.
Seven studies are now included in this review. For the comparison of physical healthcare advice versus standard care we identified six studies (total n = 964) of limited quality. For measures of quality of life one trial found no difference (n = 54, 1 RCT, MD Lehman scale 0.20, CI -0.47 to 0.87, very low quality of evidence) but another two did for the Quality of Life Medical Outcomes Scale - mental component (n = 487, 2 RCTs, MD 3.70, CI 1.76 to 5.64). There was no difference between groups for the outcome of death (n = 487, 2 RCTs, RR 0.98, CI 0.27 to 3.56, low quality of evidence). For service use two studies presented favourable results for health advice, uptake of ill-health prevention services was significantly greater in the advice group (n = 363, 1 RCT, MD 36.90, CI 33.07 to 40.73) and service use: one or more primary care visit was significantly higher in the advice group (n = 80, 1 RCT, RR 1.77, CI 1.09 to 2.85). Economic data were equivocal. Attrition was large (> 30%) but similar for both groups (n = 964, 6 RCTs, RR 1.11, CI 0.92 to 1.35). Comparisons of one type of physical healthcare advice with another were grossly underpowered and equivocal. General physical health could lead to people with serious mental illness accessing more health services which, in turn, could mean they see longer-term benefits such as reduced mortality or morbidity. On the other hand, it is possible clinicians are expending much effort, time and financial resources on giving ineffective advice. The main results in this review are based on low or very low quality data. There is some limited and poor quality evidence that the provision of general physical healthcare advice can improve health-related quality of life in the mental component but not the physical component, but this evidence is based on data from one study only. This is an important area for good research reporting outcome of interest to carers and people with serious illnesses as well as researchers and fundholders.
Cabergoline has been compared with bromocriptine in five randomised, double-blind, parallel group studies including 1071 patients. Only one of the phase II studies was medium term (36 weeks), the others all being short term (12 -15 weeks). The non-significant difference in off time reduction produced by cabergoline compared with bromocriptine was 0.29 hours/day in favour of the former (weighted mean difference; 95% CI -0.10, 0.68; p = 0.15). Dyskinesia reported as an adverse event was significantly increased with cabergoline compared with bromocriptine (Peto odds ratio 1.57; 95% CI 1.05, 2.35; p = 0.03). Motor impairment and disability were measured in four of the studies using the UPDRS rating scale but the small differences in UPDRS ADL (part II) and motor (part III) scores were not statistically significant in any study. Similarly, no significant difference in Schwab and England score was seen. The number of patients rated as much or very much improved on a clinician's global impression scale was similar with both agonists. Levodopa dose reduction was no different between cabergoline and bromocriptine. There was more confusion with cabergoline (Peto odds ratio 2.02; 95% CI 1.09, 3.76; p = 0.03). Otherwise, dopaminergic adverse events were comparable with these agonists and no significant difference in all cause withdrawal rate was found. Cabergoline produces similar benefits to bromocriptine in off time reduction, motor impairment and disability ratings, and levodopa dose reduction over the first three months of therapy. Dyskinesia and confusion were increased with cabergoline but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two agonists.
Of the 3032 records identified, 10 studies were included in this review. Effect of ITN cost on ownership: Four studies including 4566 households and another study comprising 424 participants evaluated the effect of ITN price on ownership. These studies suggest that providing free ITNs probably increases ITN ownership when compared to subsidized ITNs or ITNs offered at full market price. Effect of ITN Cost on appropriate use of ITNs: Three studies including 9968 households and another study comprising 259 individuals found that there is probably little or no difference in the use of ITNs when they are provided free, compared to providing subsidized ITNs or ITNs offered at full market price. Education: Five studies, including 12,637 households, assessed educational interventions regarding ITN use and concluded that education may increase the number of adults and children using ITNs (sleeping under ITNs) compared to no education. One study, including 519 households, assessed the effects of providing an incentive (an undisclosed prize) to promote ITN ownership and use, and found that incentives probably lead to little or no difference in ownership or use of ITNs, compared to not receiving an incentive. None of the included studies reported on adverse effects. Five studies examined the effect of price on ITN ownership and found moderate-certainty evidence that ownership was highest among the groups who received the ITN free versus those who purchased the ITN at any cost. In economic terms, this means that demand for ITNs is elastic with regard to price. However, once the ITN is supplied, the price paid for the ITN probably has little to no effect on its use; the four studies addressing this outcome failed to confirm the hypothesis that people who purchase nets will use them more than those who receive them at no cost. Educational interventions for promoting ITN use have an additional positive effect. However, the impact of different types or intensities of education is unknown.
Four studies involving 127,891 men and 9342 women were included in this review. Only one study included women. Results for men and women were analysed separately. Three to five years after screening there was no significant difference in all-cause mortality between screened and unscreened groups for men or women (men, odds ratio (OR) 0.95; 95% Confidence interval (CI) 0.85 to 1.07; for women OR 1.06; 95% CI 0.93 to 1.21). There was a significant decrease in mortality from AAA in men (OR 0.60; 95% CI 0.47 to 0.78), but not for women (OR 1.99; 95% CI 0.36 to 10.88). In this analysis mortality includes death from rupture and from emergency or elective surgery for aneurysm repair. There was also a decreased incidence of ruptured aneurysm in men (OR 0.45; 95% CI 0.21 to 0.99) but not in women (OR 1.49; 95% CI 0.25 to 8.94). There was a significant increase in surgery for AAA in men (OR 2.03; 95% CI 1.59 to 2.59). This was not reported in women. There were no data on life expectancy, complications of surgery or subjective quality of life. There is evidence of a significant reduction in mortality from AAA in men aged 65 to 79 years who undergo ultrasound screening. There is insufficient evidence to demonstrate benefit in women. The cost effectiveness may be acceptable, but needs further expert analysis. These findings need careful consideration in judging whether a co-ordinated population-based screening programme should be introduced.
For this update, we identified two additional studies, for a total of five eligible trials that enrolled 166 infants. The methodological quality of these studies ranged from low to high risk of bias. Three studies were performed in resource-limited settings, where iNO and high-frequency ventilation were not available at the time of the study. One study compared sildenafil versus active controls, and another study evaluated sildenafil as adjuvant therapy to iNO. When comparing sildenafil with placebo, investigators noted significant reduction in mortality in the sildenafil alone group (three studies, 77 participants; typical RR 0.20, 95% confidence interval (CI) 0.07 to 0.56; I2 = 0% - none; typical RR -0.36, 95% CI -0.53 to -0.18; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 6; I2 = 39% - low). Trials reported no significant differences in mortality upon comparison of the sildenafil group versus the active control group (one study, 65 participants; typical RR 0.55, 95% CI 0.05 to 5.75), or when iNO was administered to both groups (one study, 24 participants; typical RR 1.27, 95% CI 0.26 to 6.28). Physiological parameters of oxygenation (oxygenation index, partial pressure of oxygen in arterial blood (PaO2)) suggested steady improvement after the first dose of sildenafil. None of the included trials identified any clinically important side effects. We rated the quality of evidence as low to very low owing to imprecision related to small sample size and unclear methodological features. Sildenafil used for treatment of pulmonary hypertension has potential for reducing mortality and improving oxygenation in neonates, especially in resource-limited settings where iNO is not available. However, large-scale randomised trials comparing sildenafil versus active controls (other pulmonary vasodilators) and providing follow-up for survivors are needed to assess the comparative effectiveness and long-term safety of sildenafil versus other pulmonary vasodilators.
We included six studies involving 462 participants with chronic peripheral neuropathic pain (442 completers (251 male), mean ages 52 to 63 years). The included studies recruited 403 participants from China and 59 from the UK. Most studies included a small sample size (fewer than 50 participants per treatment arm) and all studies were at high risk of bias for blinding of participants and personnel. Most studies had unclear risk of bias for sequence generation (four out of six studies), allocation concealment (five out of six) and selective reporting (all included studies). All studies investigated manual acupuncture, and we did not identify any study comparing acupuncture with treatment as usual, nor any study investigating other acupuncture techniques (such as electroacupuncture, warm needling, fire needling). One study compared acupuncture with sham acupuncture. We are uncertain if there is any difference between the two interventions on reducing pain intensity (n = 45; MD -0.4, 95% CI -1.83 to 1.03, very low-quality evidence), and neither group achieved 'no worse than mild pain' (visual analogue scale (VAS, 0-10) average score was 5.8 and 6.2 respectively in the acupuncture and sham acupuncture groups, where 0 = no pain). There was limited data on quality of life, which showed no clear difference between groups. Evidence was not available on pain relief, adverse events or other pre-defined secondary outcomes for this comparison. Three studies compared acupuncture alone versus other therapies (mecobalamin combined with nimodipine, and inositol). Acupuncture may reduce the risk of 'no clinical response' to pain than other therapies (n = 209; RR 0.25, 95% CI 0.12 to 0.51), however, evidence was not available for pain intensity, pain relief, adverse events or any of the other secondary outcomes. Two studies compared acupuncture combined with other active therapies (mecobalamin, and Xiaoke bitong capsule) versus other active therapies used alone. We found that the acupuncture combination group had a lower VAS score for pain intensity (n = 104; MD -1.02, 95% CI -1.09 to -0.95) and improved quality of life (n = 104; MD -2.19, 95% CI -2.39 to -1.99), than those receiving other therapy alone. However, the average VAS score of the acupuncture and control groups was 3.23 and 4.25 respectively, indicating neither group achieved 'no worse than mild pain'. Furthermore, this evidence was from a single study with high risk of bias and a very small sample size. There was no evidence on pain relief and we identified no clear differences between groups on other parameters, including 'no clinical response' to pain and withdrawals. There was no evidence on adverse events. The overall quality of evidence is very low due to study limitations (high risk of performance, detection, and attrition bias, and high risk of bias confounded by small study size) or imprecision. We have limited confidence in the effect estimate and the true effect is likely to be substantially different from the estimated effect. Due to the limited data available, there is insufficient evidence to support or refute the use of acupuncture for neuropathic pain in general, or for any specific neuropathic pain condition when compared with sham acupuncture or other active therapies. Five studies are still ongoing and seven studies are awaiting classification due to the unclear treatment duration, and the results of these studies may influence the current findings.
We included 10 RCTs involving a total of 844 participants. The primary outcome was overall incidence of parastomal herniation. Secondary outcomes were rate of reoperation at 12 months, operative time, postoperative length of hospital stay, stoma-related infections, mesh-related infections, quality of life, and rehospitalisation rate. We judged the risk of bias across all domains to be low in six trials. We judged four trials to have an overall high risk of bias. The overall incidence of parastomal hernia was less in participants receiving a prophylactic mesh compared to those who had a standard ostomy formation (RR 0.53, 95% CI 0.43 to 0.66; 10 studies, 771 participants; I2 = 69%; low-quality evidence). In absolute numbers, the incidence of parastomal hernia was 22 per 100 participants (18 to 27) receiving prophylactic mesh compared to 41 per 100 participants having a standard ostomy formation. There were no differences in the need for reoperation (RR 0.90, 95% CI 0.50 to 1.64; 9 studies, 757 participants; I2 = 0%; low-quality evidence); operative time (MD -6.50 (min), 95% CI -18.24 to 5.24; 6 studies, 671 participants; low-quality evidence); postoperative length of hospital stay (MD -0.95 (days), 95% CI -2.03 to 0.70; 4 studies, 500 participants; moderate-quality evidence); or stoma-related infections (RR 0.89, 95% CI 0.32 to 2.50; 6 studies, 472 participants; I2 = 0%; low-quality evidence) between the two groups. We were unable to analyse mesh-related infections, quality of life, and rehospitalisation rate due to sparse data or because the outcome was not reported in the included studies. This Cochrane Review included 10 RCTs with a total of 844 participants. The review demonstrated a reduction in the incidence of parastomal hernia in people who had a prophylactic synthetic mesh placed at the time of the index operation compared to a standard ostomy formation. However, our confidence in this estimate is low due to the presence of a large degree of clinical heterogeneity, as well as high variability in follow-up duration and technique of parastomal herniation detection. We found the rate of stoma-related infection to be similar in both the intervention and control groups.
Fourteen randomised controlled trials comparing exercise against no exercise in type 2 diabetes were identified involving 377 participants. Trials ranged from eight weeks to twelve months duration. Compared with the control, the exercise intervention significantly improved glycaemic control as indicated by a decrease in glycated haemoglobin levels of 0.6% (-0.6 % HbA1c, 95% confidence interval (CI) -0.9 to -0.3; P < 0.05). This result is both statistically and clinically significant. There was no significant difference between groups in whole body mass, probably due to an increase in fat free mass (muscle) with exercise, as reported in one trial (6.3 kg, 95% CI 0.0 to 12.6). There was a reduction in visceral adipose tissue with exercise (-45.5 cm2, 95% CI -63.8 to -27.3), and subcutaneous adipose tissue also decreased. No study reported adverse effects in the exercise group or diabetic complications. The exercise intervention significantly increased insulin response (131 AUC, 95% CI 20 to 242) (one trial), and decreased plasma triglycerides (-0.25 mmol/L, 95% CI -0.48 to -0.02). No significant difference was found between groups in quality of life (one trial), plasma cholesterol or blood pressure. The meta-analysis shows that exercise significantly improves glycaemic control and reduces visceral adipose tissue and plasma triglycerides, but not plasma cholesterol, in people with type 2 diabetes, even without weight loss.
We included two randomised controlled trials that involved a total of 147 adult outpatients with acute sinusitis confirmed by radiology or nasal endoscopy who were assigned to Cyclamen europaeum nasal spray or placebo study arms for up to 15 days. The risk of selection and detection bias was unclear, as allocation concealment and blinding of outcome assessors were not reported in either study. Attrition was high (60%) in one study, although dropouts were balanced between study arms. Neither study reported our two primary outcomes: proportion of participants whose symptoms resolved or improved at 14 days and 30 days. No serious adverse events or complications related to treatment were reported; however, more mild adverse events such as nasal and throat irritation, mild epistaxis, and sneezing occurred in Cyclamen europaeum group participants (50%) compared to placebo group participants (24%) (risk ratio 2.11, 95% confidence interval 1.35 to 3.29); moderate-quality evidence. The effectiveness of Cyclamen europaeum for people with acute sinusitis is unknown. Although no serious side effects were observed, 50% of participants who received Cyclamen europaeum reported adverse events compared with 24% of those who received placebo.
We included two RCTs involving 3375 women. Tamoxifen after surgery for DCIS reduced recurrence of both ipsilateral (same side) DCIS (HR 0.75; 95% CI 0.61 to 0.92) and contralateral (opposite side) DCIS (RR 0.50; 95% CI 0.28 to 0.87). There was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62 to 1.01) and reduced contralateral invasive cancer (RR 0.57; 95% CI 0.39 to 0.83). The number needed to treat in order for tamoxifen to have a protective effect against all breast events is 15. There was no evidence of a difference detected in all cause mortality (RR 1.11; 95% CI 0.89 to 1.39). Only one study, involving 1799 participants followed-up for 163 months (median) reported on adverse events (i.e. toxicity, mood changes, deep vein thrombosis, pulmonary embolism, endometrial cancer) with no significant difference between tamoxifen and placebo groups, but there was a non-significant trend towards more endometrial cancer in the tamoxifen group. While tamoxifen after local excision for DCIS (with or without adjuvant radiotherapy) reduced the risk of recurrent DCIS (in the ipsi- and contralateral breast), it did not reduce the risk of overall mortality.
Seven studies, involving 632 DME eyes were included. Four examined the effectiveness of intravitreal triamcinolone acetate injection (IVTA), three examined intravitreal steroids implantation (fluocinolone acetonide implant (FAI) or dexamethasone drug delivery system (DDS)). Two trials were at low risk of bias, one was at median risk of bias, two were at high risk of bias and the remaining two were at unclear risk of bias.  The preponderance of data suggest a beneficial effect from IVTA. Comparing IVTA with controls, the mean difference in visual acuity was -0.15 LogMAR (95% CI -0.21 to -0.09) at 3 months (based on three trials), -0.23 LogMAR (95% CI -0.33 to -0.13) at 6 months (two trials), -0.29 LogMAR (95% CI -0.47 to -0.11) at 9 months (one trial), and -0.11 LogMAR (95% CI -0.20 to -0.03) at 24 months (one trial), all in favor of IVTA. The relative risk (RR) for one or more lines improvement in visual acuity was 2.85 (95% CI 1.59 to 5.10) at 3 months (two trials), 1.25 (95% CI 0.66 to 2.38) at 6 months (one trial), and 2.17 (95% CI 1.15 to 4.11) at 24 months (one trial), all in favor of IVTA. We did not find evidence for three or more lines improvement in visual acuity. The mean difference in retinal thickness was -131.97 um (95% CI -169.08 to -94.86) at 3 months (two trials), -135.00 um (95% CI -194.50 to -75.50) at 6 months (one trial), -133.00 um (95% CI -199.86 to -66.14) at 9 months (one trial), and -59.00 um (95% CI -103.50 to -14.50) at 24 months (one trial), all in favor of IVTA. The RR for at least one grade macular edema resolution was 5.15 (95% CI 2.23 to 11.88) at 3 months in favor of IVTA (one trial).  Two trials reported improved clinical outcome when FAI was compared to standard of care. Beneficial effect was also observed in one dexamethasone DDS trial.  Increased intraocular pressure and cataract formation were side effects requiring monitoring and management. RCTs included in this review suggest that steroids placed inside the eye by either intravitreal injection or surgical implantation may improve visual outcomes in eyes with persistent or refractory DME. Since the studies in our report focused on chronic or refractory DME, the question arises whether intravitreal steroids therapy could be of value in other stages of DME, especially the earlier stages either as standalone therapy or in combination with other therapies, such as laser photocoagulation.
The electronic search yielded 8746 records. We included 12 RCTs (3885 participants) comparing usual care with the following interventions: commonly used drugs (four studies); sedation regimens (four studies); physical therapy or cognitive therapy, or both (one study); environmental interventions (two studies); and preventive nursing care (one study). We found 15 ongoing studies and five studies awaiting classification. The participants were 48 to 70 years old; 48% to 74% were male; the mean acute physiology and chronic health evaluation (APACHE II) score was 14 to 28 (range 0 to 71; higher scores correspond to more severe disease and a higher risk of death). With the exception of one study, all participants were mechanically ventilated in medical or surgical ICUs or mixed. The studies were overall at low risk of bias. Six studies were at high risk of detection bias due to lack of blinding of outcome assessors. We report results for the two most commonly explored approaches to delirium prevention: pharmacologic and a non-pharmacologic intervention. Haloperidol versus placebo (two RCTs, 1580 participants) The event rate of ICU delirium was measured in one study including 1439 participants. No difference was identified between groups, (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.87 to 1.17) (moderate-quality evidence). Haloperidol versus placebo neither reduced or increased in-hospital mortality, (RR 0.98, 95% CI 0.80 to 1.22; 2 studies; 1580 participants (moderate-quality evidence)); the number of delirium- and coma-free days, (mean difference (MD) -0.60, 95% CI -1.37 to 0.17; 2 studies, 1580 participants (moderate-quality of evidence)); number of ventilator-free days (mean 23.8 (MD -0.30, 95% CI -0.93 to 0.33) 1 study; 1439 participants, (high-quality evidence)); length of ICU stay, (MD 0.18, 95% CI ­0.60 to 0.97); 2 studies, 1580 participants; high-quality evidence). None of the studies measured cognitive impairment. In one study there were three serious adverse events in the intervention group and five in the placebo group; in the other there were five serious adverse events and three patients died, one in each group. None of the serious adverse events were judged to be related to interventions received (moderate-quality evidence). Physical and cognitive therapy interventions (one study, 65 participants) The study did not measure the event rate of ICU delirium. A physical and cognitive therapy intervention versus standard care neither reduced nor increased in-hospital mortality, (RR 0.94, 95% CI 0.40 to 2.20, I² = 0; 1 study, 65 participants; very low-quality evidence); the number of delirium- and coma-free days, (MD -2.8, 95% CI -10.1 to 4.6, I² = 0; 1 study, 65 participants; very low-quality evidence); the number of ventilator-free days (within the first 28/30 days) was median 27.4 (IQR 0 to 29.2) and 25 (IQR 0 to 28.9); 1 study, 65 participants; very low-quality evidence, length of ICU stay, (MD 1.23, 95% CI -0.68 to 3.14, I² = 0; 1 study, 65 participants; very low-quality evidence); cognitive impairment measured by the MMSE: Mini-Mental State Examination with higher scores indicating better function, (MD 0.97, 95% CI -0.19 to 2.13, I² = 0; 1 study, 30 participants; very low-quality evidence); or measured by the Dysexecutive questionnaire (DEX) with lower scores indicating better function (MD -8.76, 95% CI -19.06 to 1.54, I² = 0; 1 study, 30 participants; very low-quality evidence). One patient experienced acute back pain accompanied by hypotensive urgency during physical therapy. There is probably little or no difference between haloperidol and placebo for preventing ICU delirium but further studies are needed to increase our confidence in the findings. There is insufficient evidence to determine the effects of physical and cognitive intervention on delirium. The effects of other pharmacological interventions, sedation, environmental, and preventive nursing interventions are unclear and warrant further investigation in large multicentre studies. Five studies are awaiting classification and we identified 15 ongoing studies, evaluating pharmacological interventions, sedation regimens, physical and occupational therapy combined or separately, and environmental interventions, that may alter the conclusions of the review in future.
A total of five studies including 868 participants met the inclusion criteria for this review. The five studies included in this review reported the value of drain fluid amylase at different thresholds and different postoperative days. The sensitivities and specificities were variable; the sensitivities ranged between 0.72 and 1.00 while the specificities ranged between 0.73 and 0.99 for different thresholds on different postoperative days. At the median prevalence (pre-test probability) of 15.9%, the post-test probabilities for pancreatic leak ranged between 35.9% and 95.4% for a positive drain fluid amylase test and ranged between 0% and 5.5% for a negative drain fluid amylase test. None of the studies used the reference standard of confirmation by surgery or by a combination of surgery and clinical follow-up, but used the International Study Group on Pancreatic Fistula (ISGPF) grade B and C as the reference standard. The overall methodological quality was unclear or high in all the studies. Because of the paucity of data and methodological deficiencies in the studies, we are uncertain whether drain fluid amylase should be used as a method for testing for pancreatic leak in an unselected population after pancreatic resection; and we judge that the optimal cut-off of drain fluid amylase for making the diagnosis of pancreatic leak is also not clear. Further well-designed diagnostic test accuracy studies with pre-specified index test threshold of drain fluid amylase (at three times more on postoperative day 5 or another suitable pre-specified threshold), appropriate follow-up (for at least six to eight weeks to ensure that there are no pancreatic leaks), and clearly defined reference standards (of surgical, clinical, and radiological confirmation of pancreatic leak) are important to reliably determine the diagnostic accuracy of drain fluid amylase in the diagnosis of pancreatic leak.
We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly-used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants) The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants) Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants) For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality. Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.
Our searches identified six randomised, double-blind studies involving 292 participants in suitably characterised fibromyalgia. The mean age of participants was between 39 and 50 years, and 89% to 100% were women. The initial pain intensity was around 7/10 on a 0 to 10 pain scale, indicating severe pain. NSAIDs tested were etoricoxib 90 mg daily, ibuprofen 2400 mg daily, naproxen 1000 mg daily, and tenoxicam 20 mg daily; 146 participants received NSAID and 146 placebo. The duration of treatment in the double-blind phase varied between three and eight weeks. Not all studies reported all the outcomes of interest. Analyses consistently showed no significant difference between NSAID and placebo: substantial benefit (at least 50% pain intensity reduction) (risk difference (RD) -0.07 (95% confidence interval (CI) -0.18 to 0.04) 2 studies, 146 participants; moderate benefit (at least 30% pain intensity reduction) (RD -0.04 (95% CI -0.16 to 0.08) 3 studies, 192 participants; withdrawals due to adverse events (RD 0.04 (95% CI -0.02 to 0.09) 4 studies, 230 participants; participants experiencing any adverse event (RD 0.08 (95% CI -0.03 to 0.19) 4 studies, 230 participants; all-cause withdrawals (RD 0.03 (95% CI -0.07 to 0.14) 3 studies, 192 participants. There were no serious adverse events or deaths. Although most studies had some measures of health-related quality of life, fibromyalgia impact, or other outcomes, none reported the outcomes beyond saying that there was no or little difference between the treatment groups. We downgraded evidence on all outcomes to very low quality, meaning that this research does not provide a reliable indication of the likely effect. The likelihood that the effect could be substantially different is very high. This is based on the small numbers of studies, participants, and events, as well as other deficiencies of reporting study quality allowing possible risks of bias. There is only a modest amount of very low-quality evidence about the use of NSAIDs in fibromyalgia, and that comes from small, largely inadequate studies with potential risk of bias. That bias would normally be to increase the apparent benefits of NSAIDs, but no such benefits were seen. Consequently, NSAIDs cannot be regarded as useful for treating fibromyalgia.
Six studies were included in this review (3256 children, 4 to 17 years of age). Two studies were published as conference abstracts only. Ciclesonide was compared to budesonide and fluticasone. Ciclesonide compared to budesonide (dose ratio 1:2): asthma symptoms and adverse effect were similar in both groups. Pooled results showed no significant difference in children who experience an exacerbation (risk ratio (RR) 2.20, 95% confidence interval (CI) 0.75 to 6.43). Both studies reported that 24-hour urine cortisol levels showed a statistically significant decrease in the budesonide group compared to the ciclesonide group. Ciclesonide compared to fluticasone (dose ratio 1:1): no significant differences were found for the outcome asthma symptoms. Pooled results showed no significant differences in number of patients with exacerbations (RR 1.37, 95% CI 0.58 to 3.21) and data from a study that could not be pooled in the meta-analysis reported similar numbers of patients with exacerbations in both groups. None of the studies found a difference in adverse effects. No significant difference was found for 24-hour urine cortisol levels between the groups (mean difference 0.54 nmol/mmol, 95% CI -5.92 to 7.00). Ciclesonide versus fluticasone (dose ratio 1:2) was assessed in one study and showed similar results between the two corticosteroids for asthma symptoms. The number of children with exacerbations was significantly higher in the ciclesonide group (RR 3.57, 95% CI 1.35 to 9.47). No significant differences were found in adverse effects (RR 0.98, 95% CI 0.81 to 1.14) and 24-hour urine cortisol levels (mean difference 1.15 nmol/mmol, 95% CI 0.07 to 2.23). The quality of evidence was judged 'low' for the outcomes asthma symptoms and adverse events and 'very low' for the outcome exacerbations for ciclesonide versus budesonide (dose ratio 1:1). The quality of evidence was graded 'moderate' for the outcome asthma symptoms, 'very low' for the outcome exacerbations and 'low' for the outcome adverse events for ciclesonide versus fluticasone (dose ratio 1:1). For ciclesonide versus fluticasone (dose ratio 1:2) the quality was rated 'low' for the outcome asthma symptoms and 'very low' for exacerbations and adverse events (dose ratio 1:2). An improvement in asthma symptoms, exacerbations and side effects of ciclesonide versus budesonide and fluticasone could be neither demonstrated nor refuted and the trade-off between benefits and harms of using ciclesonide instead of budesonide or fluticasone is unclear. The resource use or costs of different ICS should therefore also be considered in final decision making. Longer-term superiority trials are needed to identify the usefulness and safety of ciclesonide compared to other ICS. Additionally these studies should be powered for patient relevant outcomes (exacerbations, asthma symptoms, quality of life and side effects). There is a need for studies comparing ciclesonide once daily with other ICS twice daily to assess the advantages of ciclesonide being a pro-drug that can be administered once daily with possibly increased adherence leading to increased control of asthma and fewer side effects.
Twelve trials met the inclusion criteria. Combination injectable contraceptives include depot medroxyprogesterone acetate (DMPA) 25 mg plus estradiol cypionate (E2C) 5 mg, as well as norethisterone enanthate (NET-EN) 50 mg plus estradiol valerate (E2V) 5 mg. These contraceptives resulted in lower rates of early study discontinuation due to amenorrhea or other bleeding problems than progestin-only contraceptives. However, rates were higher for overall discontinuation and discontinuation due to other medical reasons. Acceptability results favored the CIC in one study and the progestin-only in another. Studies comparing two CICs found that NET-EN 50 mg plus E2V 5 mg resulted in less overall discontinuation and less discontinuation due to amenorrhea or prolonged bleeding than DMPA 25 mg plus E2C 5 mg. However, these differences were not detected in all trials. The NET-EN plus E2V group also had more regular bleeding and fewer prolonged bleeding reference periods than the DMPA plus E2C group. The groups did not differ in their amenorrhea rates. While discontinuation rates can be viewed as a measure of method acceptability, the findings should be interpreted with caution since discontinuation depends on many factors. Future research should be directed toward improving the acceptability of combination injectable contraceptives, such as providing injections in settings more convenient than clinics, methods for women to administer their own injections, and counseling about possible bleeding pattern changes.
We included only one small trial (60 participants randomised) which overall was judged to be at low risk of bias. The study examined two doses of menaquinone (vitamin K2) over 3 months in healthy participants aged 40 to 65 years. The primary focus of the trial was to examine the effects of menaquinone (subtype MK7) on different matrix Gla proteins (MGP - vitamin K dependent proteins in the vessel wall) at different doses, but the authors also reported blood pressure and lipid levels. The trial did not report on our primary outcomes (cardiovascular disease clinical events) as it was small, short term and conducted in healthy participants. In terms of cardiovascular disease risk factors, no effects were seen for vitamin K2 on blood pressure or lipid levels, although the trial was small and findings are limited. The trial did not report any of our other secondary outcomes. The very limited results of this review highlight the lack of evidence currently available to determine the effectiveness of vitamin K supplementation for the primary prevention of cardiovascular disease, and demonstrate the need for further high quality trials in this area.
We included 72 RCTs. The included trials studied the effects of 32 drugs belonging to different pharmacological groups. Only two trials mentioned the primary outcome of morbidity and mortality related to the haemodynamic response to tracheal intubation. Of the secondary outcomes, 40 of the included trials observed arrhythmia only, 11 observed myocardial ischaemia only and 20 observed both arrhythmias and myocardial ischaemia. Arrhythmias were observed in 2932 participants and myocardial ischaemia in 1616 participants. Arrhythmias were observed in 134 out of 993 patients in the control group compared to 80 out of 1939 in the intervention group. The risk of arrhythmias was significantly reduced with pharmacological interventions in the pooled data (Peto odds ratio (OR) 0.19, 95% CI 0.14 to 0.26, P < 0.00001, I2= 47%). Local anaesthetics, calcium channel blockers, beta blockers and narcotics reduced the risk of arrhythmia in the intervention group compared to the control group. Myocardial ischaemia was observed in 21 out of 604 patients in the control group compared to 10 out of 1012 in the treatment group; the result was statistically significant (Peto OR 0.45, 95% CI 0.22 to 0.92, P = 0.03, I2 = 19%). However, in subgroup analysis only local anaesthetics significantly reduced the ECG changes indicating ischaemia, but this evidence came from one study. The majority of the studies had a negative outcome. Hypotension and bradycardia were reported with 40 µg kg-1 intravenous alfentanil, chest rigidity with 75 ug kg-1 alfentanil, and increased bronchomotor tone with sympathetic blockers. There were 17 studies which included high risk patients. Pharmacological treatment in this group resulted in the reduction of arrhythmias when the data from nine trials looking at arrhythmias were pooled (Peto OR 0.18, 95% CI 0.05 to 0.59, P = 0.005, I2 = 80%). The analysis from four studies was not included. Three of these trials looked at the effect of sympathetic blockers but arrhythmias or myocardial ischaemia was observed throughout the perioperative period in two studies and some patients had arrhythmias due to atropine premedication in the third study. In the fourth study the authors mentioned myocardial ischaemia in the objectives section but did not report it in the results. The risk of arrhythmias associated with tracheal intubation was significantly reduced with pre-induction administration of local anaesthetics, calcium channel blockers, beta blockers and narcotics compared to placebo. Pharmacological intervention also reduced the risk of ECG evidence of myocardial ischaemia in the pooled data. Lignocaine pretreatment showed a significant effect but evidence came from one study only. The data suggested that there may be a reduction in ECG evidence of myocardial ischaemia with beta blocker pretreatment but this difference was not statistically significant. There is a need to focus on outcomes rather than haemodynamic measurements alone when studying this response in future trials.
We included five trials that recruited 14,624 women, with data analysed for 14,185 women. All trials had adequate allocation concealment, but none had adequate blinding of participants, staff or outcome assessors. Overall and apart from lack of blinding, the risk of bias for the included trials was considered to be low. Overall, routine fetal and umbilical Doppler ultrasound examination in low-risk or unselected populations did not result in increased antenatal, obstetric and neonatal interventions. There were no group differences noted for the review's primary outcomes of perinatal death and neonatal morbidity. Results for perinatal death were as follows: (average risk ratio (RR) 0.80, 95% confidence interval (CI) 0.35 to 1.83; four studies, 11,183 participants). Only one included trial assessed serious neonatal morbidity and found no evidence of group differences (RR 0.99, 95% CI 0.06 to 15.75; one study, 2016 participants). For the comparison of a single Doppler assessment versus no Doppler, evidence for group differences in perinatal death was detected (RR 0.36, 95% CI 0.13 to 0.99; one study, 3891 participants). However, these results are based on a single trial, and we would recommend caution when interpreting this finding. There was no evidence of group differences for the outcomes of caesarean section, neonatal intensive care admissions or preterm birth less than 37 weeks. When the quality of the evidence for the main comparison of 'All Doppler versus no Doppler' was assessed with GRADE software, the outcomes of perinatal death and serious neonatal morbidity data were graded as of low quality. Evidence for the outcome of stillbirth was graded according to regimen subgroups - with a moderate quality rating for stillbirth (fetal/umbilical vessels only) and a low quality rating for stillbirth (fetal/umbilical vessels + uterine artery vessels). Evidence for admission to neonatal intensive care unit was assessed as of moderate quality, and evidence for the outcomes of caesarean section and preterm birth less than 37 weeks was graded as of high quality. There is no available evidence to assess the effect on substantive long-term outcomes such as childhood neurodevelopment and no data to assess maternal outcomes, particularly maternal satisfaction. Existing evidence does not provide conclusive evidence that the use of routine umbilical artery Doppler ultrasound, or combination of umbilical and uterine artery Doppler ultrasound in low-risk or unselected populations benefits either mother or baby. Future studies should be designed to address small changes in perinatal outcome, and should focus on potentially preventable deaths.
Ten trials, involving 361 participants, satisfied the inclusion criteria. All the trials were randomised; two had a parallel design while the remainder had a cross-over design. Although some individual studies reported a beneficial effect of pancreatic enzyme over placebo in improving pain, incidence of steatorrhoea and analgesic consumption, the results of the studies could not be pooled for these outcomes. With the use of pancreatic enzymes, we observed a non-significant benefit for weight loss (kg) (SMD 0.06; 95% CI -0.23 to 0.34); a significant reduction in faecal fat (g/day) (SMD -1.03; 95% CI -1.60 to -0.46) and non-significant difference in subjects' Clinical Global Impression of Disease Symptom Scale (SMD -0.63; 95% CI -1.41 to 0.14). We found no significant benefit in reducing faecal fat with any particular schedule of enzyme preparation or type of enzyme. Another small study did not show any significant benefit of timing the administration of enzyme preparations in relation to meals on faecal fat. The role of pancreatic enzymes for abdominal pain, weight loss, steatorrhoea, analgesic use and quality of life in patients with chronic pancreatitis remains equivocal. Good quality, adequately powered studies are much warranted.
Thirty two studies were identified, of which four met the inclusion criteria. One of these had been reported in the original Cochrane review. Since then, three other studies have been reported. One large study, comparing atropine, hyoscine hydrobromide and hyoscine butylbromide, showed no difference between the treatment groups. A smaller cross-over study of octreotide and hyoscine hydrobromide also showed no difference whichever treatment was used first. A third study involving 13 participants showed a significant reduction in the sound of noisy breathing when glycopyrronium was given, in comparison to hyoscine hydrobromide, but there was no placebo control. In our original Cochrane review, we concluded that there was no evidence to show that any intervention, be it pharmacological or non-pharmacological, was superior to placebo in the treatment of noisy breathing. This conclusion has not changed. We acknowledge that in the face of heightened emotions when death is imminent, it is difficult for staff not to intervene. It is therefore likely that the current therapeutic options will continue to be used. However, patients need to be closely monitored for lack of therapeutic benefit and adverse effects while relatives need time, explanation and reassurance to relieve their fears and concerns. There remains a need for well-designed multi-centre studies with objective outcome measures which demonstrates the efficacy of intervention against placebo for this condition.
We included 14 studies involving 1469 participants with acute middle third clavicle fractures. All studies included adults, with the overall range from 17 to 70 years. Of the studies that reported gender, men were over-represented. Ten studies compared plate fixation with sling or figure-of-eight bandage, or both, and four studies compared intramedullary fixation with wearing either a sling or a figure-of-eight bandage. Almost all studies had design features that carry a high risk of bias, thus limiting the strength of their findings. Low-quality evidence from 10 studies (838 participants), showed that, compared with conservative treatment, surgical treatment of acute middle third clavicle fractures may not improve upper arm function at follow-up of one year or longer: standardised mean difference (SMD) 0.33, 95% confidence interval (CI) −0.02 to 0.67. We downgraded the quality of the evidence because of risk of bias and high statistical heterogeneity (I2 = 83%). This corresponds to a mean improvement of 2.3 points in favour of surgery (0.14 points worse to 4.69 points better), on the 100-point Constant score; this does not represent a clinically important difference. There may be no difference in pain measured using a visual analogue scale (0 to 100 mm; higher scores mean worse pain) between treatments (mean difference (MD) −0.60 mm, 95% CI −3.51 to 2.31; 277 participants, 3 studies; low-quality evidence reflecting risk of bias and imprecision). Surgery may reduce the risk of treatment failure, that is, number of participants who had non-routine secondary surgical intervention (excluding hardware removal), for symptomatic non-union, malunion or other complication (risk ratio (RR) 0.32, 95% CI 0.20 to 0.50; 1197 participants, 12 studies; low-quality evidence, downgraded for risk of bias and imprecision). The main source of treatment failure was mechanical failure (3.4%) in the surgery group and symptomatic non-union (11.6%) in the conservative-treatment group. We are uncertain whether surgery results in fewer people having one or more cosmetic problems, such as deformities, which were more common after conservative treatment, or hardware prominence or scarring, which only occurred in the surgery group (RR 0.55, 95% CI 0.31 to 0.98; 1130 participants, 11 studies; I2 = 63%; very low-quality evidence downgraded for risk of bias, imprecision and inconsistency). We are uncertain whether there is any difference between surgery and conservative treatment in the risk of incurring an adverse outcome that includes local infection, dehiscence, symptomatic malunion, discomfort leading to implant removal, skin and nerve problems: RR 1.34, 95% CI 0.68 to 2.64; 1317 participants, 14 studies; I2 = 72%; very low-quality evidence, downgraded for risk of bias, imprecision and inconsistency). Hardware removal for discomfort was a common adverse outcome in the surgery group (10.2%) while symptomatic malunion was more common in the conservative-treatment group (11.3% versus 1.2% in the surgery group). Infection occurred only in the surgery group (3.2%). There may be no between-group difference in quality of life at one year (SF-12 or SF-36 physical component scores: 0 to 100 scale, where 100 is the best score): MD 0.30 (95% CI −1.95 to 2.56, 321 participants, 2 studies; low-quality evidence downgraded for risk of bias and imprecision). There is low-quality evidence that surgical treatment has no additional benefits in terms of function, pain and quality of life compared with conservative treatment, but may result in fewer treatment failures overall. Very low-quality evidence means that we are very uncertain of the findings of a slightly better cosmetic result after surgery and of no difference between surgical and conservative treatment in the risk of adverse events. For both composite outcomes, there is a need to consider the balance of risks between the individual outcomes; for example, surgical adverse events, including wound infection or dehiscence and hardware irritation, against risk of adverse events that may be more commonly associated with conservative treatment such as symptomatic malunion and shoulder stiffness. Treatment options must be chosen on an individual patient basis, after careful consideration of the relative benefits and harms of each intervention and of patient preferences.
We identified 10 trials with a total of 1730 participants randomised, and one ongoing trial. Six trials investigated the provision of fruit and vegetables, and four trials examined advice to increase fruit and vegetable consumption.The ongoing trial is examining the provision of an avocado-rich diet.The number and type of intervention components for provision, and the dietary advice provided differed between trials. None of the trials reported clinical events as they were all relatively short term. There was no strong evidence for effects of individual trials of provision of fruit and vegetables on cardiovascular risk factors, but trials were heterogeneous and short term. Furthermore, five of the six trials only provided one fruit or vegetable. Dietary advice showed some favourable effects on blood pressure (systolic blood pressure (SBP): mean difference (MD) -3.0 mmHg (95% confidence interval (CI) -4.92 to -1.09), diastolic blood pressure (DBP): MD -0.90 mmHg (95% CI -2.03 to 0.24)) and low-density lipoprotein (LDL) cholesterol but analyses were based on only two trials. Three of the 10 included trials examined adverse effects, which included increased bowel movements, bad breath and body odour. There are very few studies to date examining provision of, or advice to increase the consumption of, fruit and vegetables in the absence of additional dietary interventions or other lifestyle interventions for the primary prevention of CVD. The limited evidence suggests advice to increase fruit and vegetables as a single intervention has favourable effects on CVD risk factors but more trials are needed to confirm this.
74% of patients had FIGO stage IIIB LACC. Treatment outcome was significantly better for patients receiving the combined treatment (Figures 4 to 6). The pooled data analysis yielded a significantly higher complete response rate (relative risk (RR) 0.56; 95% confidence interval (CI) 0.39 to 0.79; p < 0.001), a significantly reduced local recurrence rate (hazard ratio (HR) 0.48; 95% CI 0.37 to 0.63; p < 0.001) and a significantly better overall survival (OS) following the combined treatment with RHT(HR 0.67; 95% CI 0.45 to 0.99; p = 0.05). No significant difference was observed in treatment related acute (RR 0.99; 95% CI 0.30 to 3.31; p = 0.99) or late grade 3 to 4 toxicity (RR 1.01; CI 95% 0.44 to 2.30; p = 0.96) between both treatments. The limited number of patients available for analysis, methodological flaws and a significant over-representation of patients with FIGO stage IIIB prohibit drawing definite conclusions regarding the impact of adding hyperthermia to standard radiotherapy. However, available data do suggest that the addition of hyperthermia improves local tumour control and overall survival in patients with locally advanced cervix carcinoma without affecting treatment related grade 3 to 4 acute or late toxicity.
We included four trials involving 94 participants in this review. There was a significant improvement in activity of daily living (mean difference (MD) 13.20 points on the 'Capacidad funcional' (functional capacity) subscale of the Brazilian-Portuguese version of the SF-36; 95% confidence interval (CI) 8.36 to 18.04; P < 0.00001) and on muscle strength (MD 1.01 Nm/kg; 95% CI 0.19 to 1.83; P = 0.02) but these results should be interpreted with caution because population numbers were small and the results are based on single studies. There was no significant improvement in ability to walk (MD 0.14 m/s; 95% CI -0.32 to 0.606; P = 0.55), postural balance (MD 3.05 points; 95% CI -3.41 to 9.52; P = 0.35) or fitness (MD 3.6 (VO2max; 95% CI -0.53 to 7.73; P = 0.09) after water-based exercises treatment compared to control. Adverse effects were not reported. The evidence from randomised controlled trials so far does not confirm or refute that water-based exercises after stroke might help to reduce disability after stroke. There is a lack of hard evidence for water-based exercises after stroke. Better and larger studies are therefore required.
Ten randomised trials were included, involving 3944 adults with predominantly SUI, randomised to receive duloxetine or placebo and/ or PFMT. All arms in individual trials were comparable for various baseline characteristics. Treatment duration was between three weeks and 12 weeks. Duloxetine was significantly better than placebo in terms of improving patients' quality of life (weighted mean difference 5.26, 95% confidence interval 3.84 to 6.68. P less than 0.00001) and perception of improvement. Individual studies demonstrated a significant reduction in the Incontinence Episode Frequency (IEF) by approximately 50% during treatment with duloxetine. With regard to objective cure, however, meta-analysis of stress pad test and 24 hour pad weight change failed to demonstrate a benefit for duloxetine over placebo though data were relatively few. Subjective cure favoured duloxetine, albeit with a small effect size (3%). One trial suggested that duloxetine was better than pelvic floor muscle training alone in reducing IEF (P less than 0.05) based on median percentage decrease in IEF per week. Although significant side effects were commonly associated with duloxetine, they were reported as acceptable. The available evidence suggests that duloxetine treatment can significantly improve the quality of life of patients with stress urinary incontinence, but it is unclear whether or not benefits are sustainable. Adverse effects are common but not serious. About one in three participants allocated duloxetine reported adverse effects (most commonly nausea) related to treatment, and about one in eight allocated duloxetine stopped treatment as a consequence.
Eleven studies were eligible for this systematic review, with a total of 1817 people. Three studies included only people who experienced clinically relevant fatigue (Fatigue Severity Scale score ≥ 4 out of 7 or Multidimensional Fatigue Inventory total score > 48 out of 100), whereas all other studies did not select participants on the basis of experienced fatigue. Nine studies investigated the effects of medication (i.e. levodopa-carbidopa, memantine, rasagiline, caffeine, methylphenidate, modafinil or doxepin) on subjective fatigue. All studies were placebo controlled. There was insufficient evidence to determine the effect of doxepin on the impact of fatigue on activities in daily life (ADL) or fatigue severity (one study, N = 12, standardised mean difference (SMD) = -1.50, 95% confidence interval (CI) -2.84 to -0.15; low quality evidence). We found high quality evidence that rasagiline reduced or slowed down the progression of physical aspects of fatigue (one study, N = 1176, SMD = -0.27, 95% CI -0.39 to -0.16, I2 = 0%). None of the other pharmacological interventions affected subjective fatigue in PD. With regard to adverse effects, only levodopa-carbidopa showed an increase for the risk of nausea (one study, N = 361, risk ratio (RR) = 1.85, 95% CI 1.05 to 3.27; high quality evidence). Two studies investigated the effect of exercise on fatigue compared with usual care. We found low quality evidence for the effect of exercise on reducing the impact of fatigue on ADL or fatigue severity (two studies, N = 57, SMD = -0.45, 95% CI -1.21 to 0.32, I2 = 44%). Based on the current evidence, no clear recommendations for the treatment of subjective fatigue in PD can be provided. Doxepin may reduce the impact of fatigue on ADL and fatigue severity; however, this finding has to be confirmed in high quality studies. Rasagiline may be effective in reducing levels of physical fatigue in PD. No evidence was found for the effectiveness of levodopa-carbidopa, memantine, caffeine, methylphenidate, modafinil or exercise. Studies are needed to investigate the effect of exercise intensity on exercise capacity and subjective fatigue. Future studies should focus on interventions that address the maladaptive behavioural or cognitive aspects of fatigue in people with PD. Characteristics, such as severity and nature of perceived fatigue and underlying mood disorders should be considered to identify responders and non-responders when studying interventions for fatigue. The development of a core-set of self-report fatigue questionnaires with established responsiveness and known minimal important difference values will facilitate the interpretation of change in fatigue scores.
Twenty-five studies met the inclusion criteria, but only 23 studies contributed data to the review. These 23 trials recruited 18,587 women, with 17,842 women included in final analyses. There were no statistically significant differences between women who received calcium supplementation and those who did not in terms of reducing preterm births less than 37 weeks' gestation (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.70 to 1.05; 13 studies, 16,139 women; random-effects model) or less than 34 weeks' gestation (RR 1.04, 95% CI 0.80 to 1.36; four trials, 5669). Most studies were of low risk of bias. We conducted sensitivity analysis for the outcome of preterm birth less than 37 weeks by removing two trials with unclear risk of bias for allocation concealment; the results then favoured treatment with calcium supplementation (RR 0.80, 95% CI 0.65 to 0.99; 11 trials, 15,379 women). There was no significant difference in infant low birthweight between the two treatment groups (RR 0.93, 95% CI 0.81 to 1.07; six trials, 14,162 infants; random-effects model). However, when compared to the control group, women in the calcium supplementation group gave birth to slightly heavier birthweight infants (mean difference 56.40, 95% CI 13.55 to 99.25; 21 trials, 9202 women; random-effects model). Three outcomes were chosen for assessment with the GRADE software: preterm birth less than 37 weeks; preterm birth less than 34 weeks; and low birthweight less than 2500 g. Evidence for these outcomes was assessed as of moderate quality. This review indicates that there are no clear additional benefits to calcium supplementation in prevention of preterm birth or low infant birthweight. While there was a statistically significant difference of 56 g identified in mean infant birthweight, there was significant heterogeneity identified, and the clinical significance of this difference is uncertain.
We included 25 studies involving 4121 participants (2511 children and 1517 adults; 93 mixed population). Four studies were of high quality with no risk of bias, 14 of medium quality and seven of low quality, indicating a moderate risk of bias for the total analysis. Nine studies were performed in low-income countries and 16 in high-income countries. There was insufficient evidence that corticosteroids caused a reduction in mortality overall (17.8% versus 19.9%; risk ratio (RR) 0.90, 95% confidence interval (CI) 0.80 to 1.01; P = 0.07), or for adults (RR 0.74, 95% CI 0.53 to 1.05; P = 0.09). However they caused lower rates of severe hearing loss (RR 0.67, 95% CI 0.51 to 0.88), any hearing loss (RR 0.74, 95% CI 0.63 to 0.87) and neurological sequelae (RR 0.83, 95% CI 0.69 to 1.00). Subgroup analyses for causative organisms showed that corticosteroids reduced mortality in Streptococcus pneumoniae (S pneumoniae) meningitis (RR 0.84, 95% CI 0.72 to 0.98), but not in Haemophilus influenzae (H influenzae) orNeisseria meningitidis (N meningitidis) meningitis. Corticosteroids reduced severe hearing loss in children with H influenzae meningitis (RR 0.34, 95% CI 0.20 to 0.59) but not in children with meningitis due to non-Haemophilus species. In high-income countries, corticosteroids reduced severe hearing loss (RR 0.51, 95% CI 0.35 to 0.73), any hearing loss (RR 0.58, 95% CI 0.45 to 0.73) and short-term neurological sequelae (RR 0.64, 95% CI 0.48 to 0.85). There was no beneficial effect of corticosteroid therapy in low-income countries. Subgroup analysis for study quality showed no effect of corticosteroids on severe hearing loss in high-quality studies. Corticosteroid treatment was associated with an increase in recurrent fever (RR 1.27, 95% CI 1.09 to 1.47), but not with other adverse events. Corticosteroids significantly reduced hearing loss and neurological sequelae, but did not reduce overall mortality. Data support the use of corticosteroids in patients with bacterial meningitis in high-income countries. We found no beneficial effect in low-income countries.
The search identified 813 references on MEDLINE, 418 on EMBASE, 22 on CINAHL, 666 on PubMed, 291 on PsycINFO and 145 on CENTRAL. When all references were imported into EndNote and duplications were removed, 1348 references remained. Initial screening of titles and abstracts of these references revealed that 42 references were potentially eligible for this review. After reading the full-text versions, we identified no relevant trials comparing hrHPV and cytology testing versus cytology testing alone for detecting residual or recurrent disease during follow-up to LLETZ treatment of adult women with CIN. We found no evidence on the effects of hrHPV and cytology testing on residual or recurrent CIN2 or higher lesions, anxiety and psychosexual morbidity outcomes in women undergoing colposcopy and treatment for CIN. We found no evidence from RCTs to inform decisions about the best surveillance strategy for women following treatment for CIN. A prognostic systematic review is needed to investigate the risk of developing recurrent cervical intraepithelial neoplasia 2+ (CIN2+) in women with a positive hrHPV test after large loop excision of the transformation zone (LLETZ) treatment.
Ten of 31 studies identified were included (959 patients). Five studies with a low risk of bias examined azithromycin versus placebo and demonstrated consistent improvement in forced expiratory volume in one second over six months (mean difference at six months 3.97% (95% confidence interval 1.74% to 6.19%; n = 549, from four studies)). Patients treated with azithromycin were approximately twice as likely to be free of pulmonary exacerbation at six months, odds ratio 1.96 (95% confidence interval 1.15 to 3.33). With respect to secondary outcomes, there was a significant reduction in need for oral antibiotics and greater weight gain in those taking azithromycin. Adverse events were uncommon and not obviously associated with azithromycin, although a once-weekly high dose regimen was associated with more frequent gastrointestinal adverse events. Treatment with azithromycin was associated with reduced identification of Staphylococcus aureus on respiratory culture, but also a significant increase in macrolide resistance. This review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern. A multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.
Twelve studies (2146 participants) that compared 5-ASA to placebo were included. We did not identify any studies that compared sulphasalazine to placebo. Seven studies were judged to be at low risk of bias. The other studies were judged to have an unclear risk of bias for various items due to insufficient details to allow for a judgement. There was no statistically significant difference in relapse rates at 12 months. Fifty-three per cent (526/998) of 5-ASA patients (dose 1.6 g to 4 g/day) relapsed at 12 months compared to 54% (544/1016) of placebo patients (RR 0.98, 95% CI 0.91 to 1.07; 11 studies; 2014 patients; moderate-quality evidence). Sensitivity analyses based on an available case analysis and a random-effects model had no impact on the results. One study found no difference in relapse rates at 24 months. Fifty-four per cent (31/57) of 5-ASA patients (dose 2 g/day) relapsed at 24 months compared to 58% (36/62) of placebo patients (RR 0.94, 95% CI 0.68 to 1.29, 119 patients; low-quality evidence). One paediatric study found no statistically significant difference in relapse rates at 12 months. Sixty-two per cent (29/47) of paediatric 5-ASA patients (dose 50 mg/kg/day) relapsed at 12 months compared to 64% (35/55) of paediatric placebo patients (RR 0.97, 95% CI 0.72 to 1.31; 102 patients; moderate-quality evidence). There was no statistically significant difference in the proportion of patients who experienced an adverse event, withdrawal due to adverse events or serious adverse events. Thirty-four per cent (307/900) of 5-ASA patients had at least one adverse event compared to 33% (301/914) of placebo patients (RR 1.05, 95% CI 0.95 to 1.17; 10 studies; 1814 patients). Fourteen per cent (127/917) of 5-ASA patients withdrew due to adverse events compared to 13% (119/916) of placebo patients (RR 1.11, 95% CI 0.88 to 1.38; 9 studies; 1833 patients). One per cent (3/293) of 5-ASA patients had a serious adverse event compared to 0.7% (2/283) of placebo patients (RR 1.43, 95% CI 0.24 to 2.83; 3 studies; 576 patients). Common adverse events reported in the studies included diarrhoea, nausea and vomiting, abdominal pain, headache and skin rash. We found no evidence in this review to suggest that oral 5-ASA preparations are superior to placebo for the maintenance of medically-induced remission in patients with Crohn's disease. Additional randomised trials may not be justified.
We identified 33 randomised controlled trials, from 6 countries and in a range of settings. A total of 8244 patients was randomised and entered into studies. The most common interventions were question checklists and patient coaching. Most interventions were delivered immediately before the consultations. Commonly-occurring outcomes were: question asking, patient participation, patient anxiety, knowledge, satisfaction and consultation length. A minority of studies showed positive effects for these outcomes. Meta-analyses, however, showed small and statistically significant increases for question asking (standardised mean difference (SMD) 0.27 (95% confidence interval (CI) 0.19 to 0.36)) and patient satisfaction (SMD 0.09 (95% CI 0.03 to 0.16)). There was a notable but not statistically significant decrease in patient anxiety before consultations (weighted mean difference (WMD) -1.56 (95% CI -7.10 to 3.97)). There were small and not statistically significant changes in patient anxiety after consultations (reduced) (SMD -0.08 (95%CI -0.22 to 0.06)), patient knowledge (reduced) (SMD -0.34 (95% CI -0.94 to 0.25)), and consultation length (increased) (SMD 0.10 (95% CI -0.05 to 0.25)). Further analyses showed that both coaching and written materials produced similar effects on question asking but that coaching produced a smaller increase in consultation length and a larger increase in patient satisfaction. Interventions immediately before consultations led to a small and statistically significant increase in consultation length, whereas those implemented some time before the consultation had no effect. Both interventions immediately before the consultation and those some time before it led to small increases in patient satisfaction, but this was only statistically significant for those immediately before the consultation. There appear to be no clear benefits from clinician training in addition to patient interventions, although the evidence is limited. Interventions before consultations designed to help patients address their information needs within consultations produce limited benefits to patients. Further research could explore whether the quality of questions is increased, whether anxiety before consultations is reduced, the effects on other outcomes and the impact of training and the timing of interventions. More studies need to consider the timing of interventions and possibly the type of training provided to clinicians.
The updated search in June 2011 did not identify any new trials. One study is included in the review. This study assessed the effect of intraventricular gentamicin in a mixed population of neonates (69%) and older infants (31%) with gram-negative meningitis and ventriculitis. Mortality was statistically significantly higher in the group that received intraventricular gentamicin in addition to intravenous antibiotics compared to the group receiving intravenous antibiotics alone (RR 3.43; 95% CI 1.09 to 10.74; RD 0.30; 95% CI 0.08 to 0.53); NNTH 3; 95% CI 2 to 13). Duration of CSF culture positivity did not differ significantly (MD -1.20 days; 95% CI -2.67 to 0.27). In one trial that enrolled infants with gram-negative meningitis and ventriculitis, the use of intraventricular antibiotics in addition to intravenous antibiotics resulted in a three-fold increased RR for mortality compared to standard treatment with intravenous antibiotics alone. Based on this result, intraventricular antibiotics as tested in this trial should be avoided. Further trials comparing these interventions are not justified in this population.
We included 11 studies in our synthesis, involving 267 participants (one study did not report the number of participants). Five more studies are awaiting classification and will be dealt with when we update the review. The quality of the evidence was mixed; of the 35 summary statements, we assessed 17 as ‘low’, 13 as ‘moderate’ and five as ‘high’ confidence. Our synthesis produced nine analytical themes, which report potential barriers and facilitators to the use of protocols. The themes are: the need for continual staff training and development; clinical experience as this promotes felt and perceived competence and confidence to wean; the vulnerability of weaning to disparate interprofessional working; an understanding of protocols as militating against a necessary proactivity in clinical practice; perceived nursing scope of practice and professional risk; ICU structure and processes of care; the ability of protocols to act as a prompt for shared care and consistency in weaning practice; maximizing the use of protocols through visibility and ease of implementation; and the ability of protocols to act as a framework for communication with parents. There is a clear need for weaning protocols to take account of the social and cultural environment in which they are to be implemented. Irrespective of its inherent strengths, a protocol will not be used if it does not accommodate these complexities. In terms of protocol development, comprehensive interprofessional input will help to ensure broad-based understanding and a sense of ‘ownership’. In terms of implementation, all relevant ICU staff will benefit from general weaning as well as protocol-specific training; not only will this help secure a relevant clinical knowledge base and operational understanding, but will also demonstrate to others that this knowledge and understanding is in place. In order to maximize relevance and acceptability, protocols should be designed with the patient profile and requirements of the target ICU in mind. Predictably, an under-resourced ICU will impact adversely on protocol implementation, as staff will prioritize management of acutely deteriorating and critically-ill patients.
There were 18 trials that were eligible for inclusion, five of these were still ongoing.Thirteen completed published trials (2331 participants) were included for analysis in the review. The original review contained nine trials (718 participants). This updated review includes six new trials (1818 participants).Two trials (205 participants) in the original review are now excluded because fewer than 80% of participants had a haematological disorder. The four different types of prophylactic platelet transfusion trial, that were the focus of this review, were included within these thirteen trials. Three trials compared prophylactic platelet transfusions versus therapeutic-only platelet transfusions. There was no statistical difference between the number of participants with clinically significant bleeding in the therapeutic and prophylactic arms but the confidence interval was wide (RR 1.66; 95% CI 0.9 to 3.04).The time taken for a clinically significant bleed to occur was longer in the prophylactic platelet transfusion arm. There was a clear reduction in platelet transfusion usage in the therapeutic arm. There was no statistical difference between the number of participants in the therapeutic and prophylactic arms with platelet refractoriness, the only adverse event reported. Three trials compared different platelet count thresholds to trigger administration of prophylactic platelet transfusions. No statistical difference was seen in the number of participants with clinically significant bleeding (RR 1.35; 95% CI 0.95 to 1.9), however, this type of bleeding occurred on fewer days in the group of patients transfused at a higher platelet count threshold (RR 1.72; 95% CI 1.33 to 2.22).The lack of a difference seen for the number of participants with clinically significant bleeding may be due to the studies, in combination, having insufficient power to demonstrate a difference, or due to masking of the effect by a higher number of protocol violations in the groups of patients with a lower platelet count threshold. Using a lower platelet count threshold led to a significant reduction in the number of platelet transfusions used. There were no statistical differences in the number of adverse events reported between the two groups. Six trials compared different doses of prophylactic platelet transfusions. There was no evidence to suggest that using a lower platelet transfusion dose increased: the number of participants with clinically significant (WHO grade 2 or above) (RR 1.02; 95% CI 0.93 to 1.11), or life-threatening (WHO grade 4) bleeding (RR 1.87; 95% CI 0.86 to 4.08). A higher platelet transfusion dose led to a reduction in the number of platelet transfusion episodes, but an increase in total platelet utilisation. Only one adverse event, wheezing after transfusion, had a significantly higher incidence when standard and high dose transfusions were compared but this difference was not seen when low dose and high dose transfusions were compared. It is therefore likely to be a type I error (false positive). One small trial compared prophylactic platelet transfusions versus platelet-poor plasma. The risk of a significant bleed was decreased in the prophylactic platelet transfusion arm (RR 0.47; 95% CI 0.23 to 0.95) and this was statistically significant. All studies had threats to validity; the majority of these were due to methodology of the studies not being described in adequate detail. Although it was not the main focus of the review, it was interesting to note that in one of the pre-specified sub-group analyses (treatment type) two studies showed that patients receiving an autologous transplant have a lower risk of bleeding than patients receiving intensive chemotherapy or an allogeneic transplant (RR 0.73, 95% CI 0.65 to 0.82). These conclusions refer to the four different types of platelet transfusion trial separately. Firstly, there is no evidence that a prophylactic platelet transfusion policy prevents bleeding. Two large trials comparing a therapeutic versus prophylactic platelet transfusion strategy, that have not yet been published, should provide important new data on this comparison. Secondly, there is no evidence, at the moment, to suggest a change from the current practice of using a platelet count of 10 x 109/L. However, the evidence for a platelet count threshold of 10 x 109/L being equivalent to 20 x 109/L is not as definitive as it would first appear and further research is required. Thirdly, platelet dose does not affect the number of patients with significant bleeding, but whether it affects number of days each patient bleeds for is as yet undetermined. There is no evidence that platelet dose affects the incidence of WHO grade 4 bleeding.Prophylactic platelet transfusions were more effective than platelet-poor plasma at preventing bleeding.
We identified only one study for inclusion in this review. This study was a prospective, double-blind cross-over trial that compared the effect of systemic metronidazole with a placebo on odour in malignant wounds. Nine participants with a fungating wound and for whom the smell was troublesome were recruited and six of these completed both the intervention and control (placebo) stages of the trial. Each stage lasted fourteen days, with a fourteen day gap (washout period) between administration of the metronidazole and the placebo. The study, in comparing metronidazole and placebo, reported on two of this review's pre-specified primary outcomes (malodour and adverse effects of the treatment) and on none of the review's pre-specified secondary outcomes. Malodour The mean malodour (smell) scores for the metronidazole group was 1.17 (standard deviation (SD) 1.60) and the mean for the placebo group was 3.33 (SD 0.82). It is unclear if systemic antibiotics were associated with a difference in malodour (1 study with 6 participants; MD —2.16, 95% CI —3.6 to —0.72) as the quality of the evidence (GRADE) was very low for this outcome. The study was downgraded due to high risk of attrition bias (33% loss to follow-up) and very serious imprecision due to the small sample size. Adverse effects No adverse effects of the treatment were reported in either the intervention or control group by the trial authors. It is uncertain whether systemic metronidazole leads to a reduction in malodour in patients with malignant wounds. This is because we were only able to include a single study at high risk of bias with a very small sample size, which focused only on patients with breast cancer. More research is needed to substantiate these findings and to investigate the effects of systemic metronidazole and other antibiotics on quality of life, pain relief, exudate and tumour containment in patients with malignant wounds.
Thirty-five RCTs were included; 20 were published in English, seven in Japanese, five in Chinese and one each in Norwegian, Polish and German. There were only three trials of acupuncture for acute low-back pain. They did not justify firm conclusions, because of small sample sizes and low methodological quality of the studies. For chronic low-back pain there is evidence of pain relief and functional improvement for acupuncture, compared to no treatment or sham therapy. These effects were only observed immediately after the end of the sessions and at short-term follow-up. There is evidence that acupuncture, added to other conventional therapies, relieves pain and improves function better than the conventional therapies alone. However, effects are only small. Dry-needling appears to be a useful adjunct to other therapies for chronic low-back pain. No clear recommendations could be made about the most effective acupuncture technique. The data do not allow firm conclusions about the effectiveness of acupuncture for acute low-back pain. For chronic low-back pain, acupuncture is more effective for pain relief and functional improvement than no treatment or sham treatment immediately after treatment and in the short-term only. Acupuncture is not more effective than other conventional and "alternative" treatments. The data suggest that acupuncture and dry-needling may be useful adjuncts to other therapies for chronic low-back pain. Because most of the studies were of lower methodological quality, there certainly is a further need for higher quality trials in this area.
Ten studies, reporting data from 354 participants, were included in this review, the majority of which were carried out in a university dental hospital setting. The studies were published between 2005 and 2011 and were conducted in Europe and in Brazil. The age range of participants was from nine to 15 years, with an even distribution of males and females in seven of the studies, and a slight predominance of female patients in three of the studies. The quality of the studies was generally poor; seven studies were at an overall high risk of bias, three studies were at an unclear risk of bias, and we judged no study to be at low risk of bias. We carried out random-effects meta-analyses as appropriate for the primary clinical outcomes of movement of upper first molars (mm), and loss of anterior anchorage, where there were sufficient data reported in the primary studies. Four studies, involving 159 participants, compared a distalising appliance to an untreated control. Meta-analyses were not undertaken for all primary outcomes due to incomplete reporting of all summary statistics, expected outcomes, and differences between the types of appliances. The degree and direction of molar movement and loss of anterior anchorage varied with the type of appliance. Four studies, involving 150 participants, compared a distalising appliance versus headgear. The mean molar movement for intraoral distalising appliances was -2.20 mm and -1.04 mm for headgear. There was a statistically significant difference in mean distal molar movement (mean difference (MD) -1.45 mm; 95% confidence interval (CI) -2.74 to -0.15) favouring intraoral appliances compared to headgear (four studies, high or unclear risk of bias, 150 participants analysed). However, a statistically significant difference in mean mesial upper incisor movement (MD 1.82 mm; 95% CI 1.39 to 2.24) and overjet (fixed-effect: MD 1.64 mm; 95% CI 1.26 to 2.02; two studies, unclear risk of bias, 70 participants analysed) favoured headgear, i.e. there was less loss of anterior anchorage with headgear. We reported direct comparisons of intraoral appliances narratively due to the variation in interventions (three studies, high or unclear risk of bias, 93 participants randomised). All appliances were reported to provide some degree of distal movement, and loss of anterior anchorage varied with the type of appliance. No included studies reported on the incidence of adverse effects (harm, injury), number of attendances or rate of non-compliance. It is suggested that intraoral appliances are more effective than headgear in distalising upper first molars. However, this effect is counteracted by loss of anterior anchorage, which was not found to occur with headgear when compared with intraoral distalising appliance in a small number of studies. The number of trials assessing the effects of orthodontic treatment for distilisation is low, and the current evidence is of low or very low quality.
We included one double-blind, double-dummy RCT comparing a quadriphasic oral contraceptive composed of dienogest and estradiol valerate with a monophasic oral contraceptive composed of levonorgestrel and ethinylestradiol. Contraceptive effectiveness, intracyclic bleeding and discontinuation due to side effects were similar for quadriphasic and monophasic pills. The number of women experiencing withdrawal bleeding was higher in the monophasic group compared to the quadriphasic group. Users of quadriphasic pills reported fewer bleeding/spotting days and fewer bleeding/spotting episodes than users of monophasic pills but the report did not specify whether the bleeding/spotting was scheduled or unscheduled. More women using quadriphasic oral contraceptives reported breast pain compared to women using monophasic oral contraceptives. The available evidence is insufficient to determine whether quadriphasic differ from monophasic oral contraceptives in contraceptive effectiveness, bleeding pattern, minor side effects and acceptability. Studies that compare quadriphasic and monophasic oral contraceptives with an identical progestogen and estrogen type are needed to determine whether the quadriphasic approach differs from the monophasic approach. Studies that compare quadriphasic pills with monophasic pills containing 30 μg ethinylestradiol are indicated to determine whether quadriphasic oral contraceptives have an advantage over the current, first choice oral contraceptive. Until then, we recommend monophasic pills containing 30 μg estrogen as the first choice for women starting oral contraceptive use.
We included 11 RCTs with a total of 428 participants 18 years of age or older with low to moderate myopia. These trials were conducted in the Czech Republic, Brazil, Italy, Iran, China, Korea, Mexico, Turkey, USA, and UK. Investigators of 10 out of 11 trials randomly assigned one eye of each participant to be treated with LASEK and the other with PRK, but did not perform paired-eye (matched) analysis. Because of differences in outcome measures and follow-up times among the included trials, few trials contributed data for many of the outcomes we analyzed for this review. Overall, we judged RCTs to be at unclear risk of bias due to poor reporting; however, because of imprecision, inconsistency, and potential reporting bias, we graded the quality of the evidence from very low to moderate for outcomes assessed in this review. The proportion of eyes with uncorrected visual acuity of 20/20 or better at 12-month follow-up was comparable in LASEK and PRK groups (risk ratio (RR) 0.98, 95% confidence interval (95% CI) 0.92 to 1.05). Although the 95% CI suggests little to no difference in effect between groups, we judged the quality of the evidence to be low because only one trial reported this outcome (102 eyes). At 12 months post treatment, data from two trials suggest no difference or a possibly small effect in favor of PRK over LASEK for the proportion of eyes achieving ± 0.50 D of target refraction (RR 0.93, 95% CI 00.84 to 1.03; 152 eyes; low-quality evidence). At 12 months post treatment, one trial reported that one of 51 eyes in the LASEK group lost one line or more best-spectacle corrected visual acuity compared with none of 51 eyes in the PRK group (RR 3.00, 95% CI 0.13 to 71.96; very low-quality evidence). Three trials reported adverse outcomes at 12 months of follow-up or longer. At 12 months post treatment, three trials reported corneal haze score; however, data were insufficient and were inconsistent among the trials, precluding meta-analysis. One trial reported little or no difference in corneal haze scores between groups; another trial reported that corneal haze scores were lower in the LASEK group than in the PRK group; and one trial did not report analyzable data to estimate a treatment effect. At 24 months post treatment, one trial reported a lower, but clinically unimportant, difference in corneal haze score for LASEK compared with PRK (MD -0.22, 95% CI -0.30 to -0.14; 184 eyes; low-quality evidence). Uncertainty surrounds differences in efficacy, accuracy, safety, and adverse effects between LASEK and PRK for eyes with low to moderate myopia. Future trials comparing LASEK versus PRK should follow reporting standards and follow correct analysis. Trial investigators should expand enrollment criteria to include participants with high myopia and should evaluate visual acuity, refraction, epithelial healing time, pain scores, and adverse events.
Nine studies met the inclusion criteria: three compared supervision with no supervision, five compared enhanced supervision with routine supervision, and one study compared less intensive supervision with routine supervision. Most outcomes were scores relating to providers’ practice, knowledge and provider or user satisfaction. The majority of the outcomes were measured within nine months after the interventions were introduced. In two studies comparing supervision with no supervision, small benefits on provider practice and knowledge were found. For methods of enhancing supervision, we identified five studies, and two studies of frequent supportive supervision demonstrated small benefits on workers performance. The one study examining the impact of less intensive supervision found no evidence that reducing the frequency of visits had any effect on the utilisation of services. The GRADE evidence quality for all comparisons and outcomes was "low" or "very low". It is uncertain whether supervision has a substantive, positive effect on the quality of primary health care in low- and middle-income countries. The long term effectiveness of supervision is unknown.
This second update of the review identified 19 additional eligible trials resulting in a total of 33 studies (2793 participants) that met the inclusion criteria. There was low quality evidence that sutures were significantly better than tissue adhesives for reducing the risk of wound breakdown (dehiscence; RR 3.35; 95% CI 1.53 to 7.33; 10 trials, 736 participants that contributed data to the meta-analysis). The number needed to treat for an additional harmful outcome was calculated as 43. For all other outcomes - infection, patient and operator satisfaction and cost - there was no evidence of a difference for either sutures or tissue adhesives. No evidence of differences was found between tissue adhesives and tapes for minimising dehiscence, infection, patients' assessment of cosmetic appearance, patient satisfaction or surgeon satisfaction. However there was evidence in favour of using tape for surgeons' assessment of cosmetic appearance (mean difference (VAS 0 to 100) 9.56 (95% CI 4.74 to 14.37; 2 trials, 139 participants). One trial compared tissue adhesives with a variety of methods of wound closure and found both patients and clinicians were significantly more satisfied with the alternative closure methods than the adhesives. There appeared to be little difference in outcome for different types of tissue adhesives. One study that compared high viscosity with low viscosity adhesives found that high viscosity adhesives were less time-consuming to use than low viscosity tissue adhesives, but the time difference was small. Sutures are significantly better than tissue adhesives for minimising dehiscence. In some cases tissue adhesives may be quicker to apply than sutures. Although surgeons may consider the use of tissue adhesives as an alternative to other methods of surgical site closure in the operating theatre, they need to be aware that sutures minimise dehiscence. There is a need for more well designed randomised controlled trials comparing tissue adhesives with alternative methods of closure. These trials should include people whose health may interfere with wound healing and surgical sites of high tension.
This review includes 38 studies, of which 34 studies examined survival following transportation by HEMS compared with GEMS for adults with major trauma. Four studies were of inter-facility transfer to a higher level trauma center by HEMS compared with GEMS. All studies were NRS; we found no RCTs. The primary outcome was survival at hospital discharge. We calculated unadjusted mortality using data from 282,258 people from 28 of the 38 studies included in the primary analysis. Overall, there was considerable heterogeneity and we could not determine an accurate estimate of overall effect. Based on the unadjusted mortality data from six trials that focused on traumatic brain injury, there was no decreased risk of death with HEMS. Twenty-one studies used multivariate regression to adjust for confounding. Results varied, some studies found a benefit of HEMS while others did not. Trauma-Related Injury Severity Score (TRISS)-based analysis methods were used in 14 studies; studies showed survival benefits in both the HEMS and GEMS groups as compared with MTOS. We found no studies evaluating the secondary outcome, morbidity, as assessed by quality-adjusted life years (QALYs) and disability-adjusted life years (DALYs). Four studies suggested a small to moderate benefit when HEMS was used to transfer people to higher level trauma centers. Road traffic and helicopter crashes are adverse effects which can occur with either method of transport. Data regarding safety were not available in any of the included studies. Overall, the quality of the included studies was very low as assessed by the GRADE Working Group criteria. Due to the methodological weakness of the available literature, and the considerable heterogeneity of effects and study methodologies, we could not determine an accurate composite estimate of the benefit of HEMS. Although some of the 19 multivariate regression studies indicated improved survival associated with HEMS, others did not. This was also the case for the TRISS-based studies. All were subject to a low quality of evidence as assessed by the GRADE Working Group criteria due to their nonrandomized design. The question of which elements of HEMS may be beneficial has not been fully answered. The results from this review provide motivation for future work in this area. This includes an ongoing need for diligent reporting of research methods, which is imperative for transparency and to maximize the potential utility of results. Large, multicenter studies are warranted as these will help produce more robust estimates of treatment effects. Future work in this area should also examine the costs and safety of HEMS, since multiple contextual determinants must be considered when evaluating the effects of HEMS for adults with major trauma.
Sixteen studies involving 1063 participants were identified. The risk of bias for fifteen studies was high and along with imprecision and possible publication bias, this lowered our confidence in the results. There was low quality evidence that Tong-xi-luo reduced the rates of angiographic restenosis (RR 0.16, 95% CI 0.07 to 0.34), myocardial infarction (RR 0.32, 95% CI 0.16 to 0.66), heart failure (RR 0.26, 95% CI 0.11 to 0.62), and use of revascularisation (RR 0.26, 95% CI 0.15 to 0.45). There was very low quality evidence for the effect of Tong-xin-luo on all-cause mortality (RR 0.38, 95% CI 0.06 to 2.56), angina (RR 0.24, 95% CI 0.17 to 0.34) and death due to any cardiovascular event (RR 0.31, 95% CI 0.08 to 1.12). Adverse events were seldom reported, and included gastrointestinal reactions and nausea. The addition of Tong-xin-luo to conventional Western medicine may possibly prevent restenosis and recurrence of cardiovascular events in patients with CHD after PCI. However, the data are limited by publication bias and high risk of bias for included studies. Further high-quality trials are required to evaluate the potential effects of this intervention.
We included 10 studies (12 trial reports) from which 5041 women contributed data for the primary outcome. The overall risk of bias was low. When comparing prophylactic intravenous (IV) antibiotic administration in women undergoing cesarean delivery, there was a reduction in composite maternal infectious morbidity (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.45 to 0.72, high quality evidence), which was specifically due to the reduction in endometritis (RR 0.54, 95% CI 0.36 to 0.79, high quality evidence) and wound infection (RR 0.59, 95% CI 0.44 to 0.81, high quality evidence) in those that received antibiotics preoperatively as compared to those who received antibiotics after neonatal cord clamping. There were no clear differences in neonatal sepsis (RR 0.76, 95% CI 0.51 to 1.13, moderate quality evidence). There were no clear differences for other maternal outcomes such as urinary tract infection (UTI), cystitis and pyelonephritis (moderate quality evidence), respiratory infection (low quality evidence), or any neonatal outcomes. Maternal side effects were not reported in the included studies. The quality of the evidence using GRADE was high for composite morbidity, endomyometritis, wound infection and neonatal intensive care unit admission, moderate for UTI/cystitis/pyelonephritis and neonatal sepsis, and low for maternal respiratory infection. Based on high quality evidence from studies whose overall risk of bias is low, intravenous prophylactic antibiotics for cesarean administered preoperatively significantly decreases the incidence of composite maternal postpartum infectious morbidity as compared with administration after cord clamp. There were no clear differences in adverse neonatal outcomes reported. Women undergoing cesarean delivery should receive antibiotic prophylaxis preoperatively to reduce maternal infectious morbidities. Further research may be needed to elucidate short- and long-term adverse effects for neonates.
No randomised controlled trials or controlled clinical trials were identified for the original review or this update.  We summarised the results of five observational studies (including one with two reports) in the Discussion section of this review. In the absence of randomised controlled trials or controlled clinical trials, the 'best' evidence to date is based on three ‘low’ and two ‘very low quality’ observational studies. These suggest 'very low quality evidence' for an advantage for mental health domains (only) of quality of life without increasing healthcare costs, and 'low level quality' evidence for reduced hospitalisation for MDC in low-intensity outpatient settings; and 'very low quality' evidence for improved disability in high-intensity settings. The evidence for survival is conflicting. These conclusions are tentative and the gap in current research should not be interpreted as proof that MDC is ineffective. Further research is needed into appropriate study designs; outcome measurement; caregiver needs; and the evaluation of optimal settings, type, intensity or frequency and cost-effectiveness of MDC in the MND population. Future research should focus on observational designs to assess care and outcomes in 'real-life' settings. The interface between neurology, rehabilitation and palliative care should be explored to provide long-term support for MND.
We identified no placebo-controlled comparisons of beta-2 agonists. Three studies permitted comparison of ipratropium to an inhaled beta-2 agonist. These studies included a total of 103 patients. The beta2-agonists used were: fenoterol and metaproterenol. One study was a parallel group trial of regular therapy for seven days. The other two were cross over studies of single dose treatments, with efficacy measured 90 min post dose. There was no washout period between treatments. Both treatments produced an improvement in forced expiratory volume (FEV1) after 90 min in the range 150-250 ml. The was no difference between treatments, mean difference in FEV1 10 ml; 95% CI -220, 230 ml. In one small crossover study (n=10) there was a significant improvement in arterial PaO2 after 30 minutes with ipratropium (+5.8 mm Hg ± 3.0 (SEM)) compared to metaproterenol (-6.2 ± 1.2 mm Hg), but this was not significant at 90 min. There were no data concerning respiratory symptoms. The crossover studies showed no evidence of an additive effect of the two treatments, although they were not designed specifically to test this. An update search conducted in February 2002 yielded one further excluded study. There are few controlled trial data concerning the use of inhaled beta2-agonist agents in acute exacerbations of COPD and none that have compared these agents directly with placebo. None of the studies used the more modern beta2-agonists used most widely in this setting (salbutamol and terbutaline). Beta2-agonists and ipratropium both produce small improvements in FEV1, but beta2-agonists may worsen PaO2 for a period. We could not draw conclusions concerning possible additive effects.
Seventeen RCTs (1806 participants) were included. Five RCTs compared acupuncture versus sham acupuncture. The risk of bias in these studies was low. We found no evidence of an improvement with acupuncture relative to sham (placebo) acupuncture for symptom severity (SMD -0.11, 95% CI -0.35 to 0.13; 4 RCTs; 281 patients) or quality of life (SMD = -0.03, 95% CI -0.27 to 0.22; 3 RCTs; 253 patients). Sensitivity analyses based on study quality did not change the results. A GRADE analysis indicated that the overall quality of the evidence for the primary outcomes in the sham controlled trials was moderate due to sparse data. The risk of bias in the four Chinese language comparative effectiveness trials that compared acupuncture with drug treatment was high due to lack of blinding. The risk of bias in the other studies that did not use a sham control was high due to lack of blinding or inadequate methods used for randomization and allocation concealment or both. Acupuncture was significantly more effective than pharmacological therapy and no specific treatment. Eighty-four per cent of patients in the acupuncture group had improvement in symptom severity compared to 63% of patients in the pharmacological treatment group (RR 1.28, 95% CI 1.12 to 1.45; 5 studies, 449 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to a high risk of bias (no blinding) and sparse data. Sixty-three per cent of patients in the acupuncture group had improvement in symptom severity compared to 34% of patients in the no specific therapy group (RR 2.11, 95% CI 1.18 to 3.79; 2 studies, 181 patients). There was no statistically significant difference between acupuncture and Bifidobacterium (RR 1.07, 95% CI 0.90 to 1.27; 2 studies; 181 patients) or between acupuncture and psychotherapy (RR 1.05, 95% CI 0.87 to 1.26; 1 study; 100 patients). Acupuncture as an adjuvant to another Chinese medicine treatment was significantly better than the other treatment alone. Ninety-three per cent of patients in the adjuvant acupuncture group improved compared to 79% of patients who received Chinese medicine alone (RR 1.17, 95% CI 1.02 to 1.33; 4 studies; 466 patients). There was one adverse event (i.e. acupuncture syncope) associated with acupuncture in the 9 trials that reported this outcome, although relatively small sample sizes limit the usefulness of these safety data. Sham-controlled RCTs have found no benefits of acupuncture relative to a credible sham acupuncture control for IBS symptom severity or IBS-related quality of life. In comparative effectiveness Chinese trials, patients reported greater benefits from acupuncture than from two antispasmodic drugs (pinaverium bromide and trimebutine maleate), both of which have been shown to provide a modest benefit for IBS. Future trials may help clarify whether or not these reportedly greater benefits of acupuncture relative to pharmacological therapies are due entirely to patients’ preferences for acupuncture or greater expectations of improvement on acupuncture relative to drug therapy.
Twelve trials were included. They were of variable quality. Limited asthma education did not reduce hospitalisation for asthma (weighted mean difference -0.03 average hospitalisations per person per year, 95% confidence interval -0.09 to 0.03). There was no significant effect on doctor visits, lung function and medication use. The effects on asthma symptoms were variable. There was no reduction in days lost from normal activity, but in two studies, perceived asthma symptoms did improve after limited asthma education (odds ratio 0.44, 95% confidence interval 0.26 to 0.74). In one study, limited asthma education was associated with reduced emergency department visits (reduction of -2.76 average visits per person per year, 95% confidence interval -4.34 to 1.18). Use of limited asthma education as it has been practiced does not appear to improve health outcomes in adults with asthma although perceived symptoms may improve. Provision of information in the emergency department may be effective, but this needs to be confirmed.
We identified 12 randomised controlled trials that meet the criteria for the review. Six were ongoing trials, four had been completed and two had been terminated early. Six studies with a total of 9849 participants provided data for this review. The trials evaluated the following: daily oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms: TDF, TDF-FTC and placebo arm. The studies were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, serodiscordant couples and other high risk men and women. Overall results from the four trials that compared TDF-FTC versus placebo showed a reduction in the risk of acquiring HIV infection (RR 0.49; 95% CI 0.28 to 0.85; 8918 participants). Similarly, the overall results of the studies that compared TDF only versus placebo showed a significant reduction in the risk of acquiring HIV infection (RR 0.33; 95% CI 0.20 to 0.55, 4027 participants). There were no significant differences in the risk of adverse events across all the studies that reported on adverse events. Also, adherence and sexual behaviours were similar in both the intervention and control groups. Finding from this review suggests that pre-exposure prophylaxis with TDF alone or TDF-FTC reduces the risk of acquiring HIV in high-risk individuals including people in serodiscordant relationships, men who have sex with men and other high risk men and women.
Ten trials, involving 6533 women, were included in this review, five trials were rated high quality. For the majority of trials, the antioxidant assessed was combined vitamin C and E therapy. There was no significant difference between antioxidant and control groups for the relative risk (RR) of pre-eclampsia (RR 0.73, 95% confidence intervals (CI) 0.51 to 1.06; nine trials, 5446 women) or any other primary outcome: severe pre-eclampsia (RR 1.25, 95% CI 0.89 to 1.76; two trials, 2495 women), preterm birth (before 37 weeks) (RR 1.10, 95% CI 0.99 to 1.22; five trials, 5198 women), small-for-gestational-age infants (RR 0.83, 95% CI 0.62 to 1.11; five trials, 5271 babies) or any baby death (RR 1.12, 95% CI 0.81 to 1.53; four trials, 5144 babies). Women allocated antioxidants were more likely to self-report abdominal pain late in pregnancy (RR 1.61, 95% CI 1.11 to 2.34; one trial, 1745 women), require antihypertensive therapy (RR 1.77, 95% CI 1.22 to 2.57; two trials, 4272 women) and require an antenatal hospital admission for hypertension (RR 1.54, 95% CI 1.00 to 2.39; one trial, 1877 women). However, for the latter two outcomes, this was not clearly reflected in an increase in any other hypertensive complications. Evidence from this review does not support routine antioxidant supplementation during pregnancy to reduce the risk of pre-eclampsia and other serious complications in pregnancy.
We included eight reviews in this overview: five Cochrane Reviews (33 included trials) and three non-Cochrane reviews (11 included trials). Three reviews (all Cochrane Reviews) scored low risk across all the ROBIS domains in Phase 2 and low risk of bias overall. The remaining five reviews scored high risk on Domain 4 of Phase 2 because the 'Risk of bias' assessment had not been specifically considered and discussed in the review Results and Conclusions. The trials included in the reviews varied in both size and risk of bias. Interventions were compared to usual care. Moderate-quality evidence indicated that C-reactive protein (CRP) point-of-care testing (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92, 3284 participants, 6 trials), shared decision making (odds ratio (OR) 0.44, 95% CI 0.26 to 0.75, 3274 participants, 3 trials; RR 0.64, 95% CI 0.49 to 0.84, 4623 participants, 2 trials; risk difference -18.44, 95% CI -27.24 to -9.65, 481,807 participants, 4 trials), and procalcitonin-guided management (adjusted OR 0.10, 95% CI 0.07 to 0.14, 1008 participants, 2 trials) probably reduce antibiotic prescribing in general practice. We found moderate-quality evidence that procalcitonin-guided management probably reduces antibiotic prescribing in emergency departments (adjusted OR 0.34, 95% CI 0.28 to 0.43, 2605 participants, 7 trials). The overall effect of these interventions was small (few achieving greater than 50% reduction in antibiotic prescribing, most about a quarter or less), but likely to be clinically important. Compared to usual care, shared decision making probably makes little or no difference to reconsultation for the same illness (RR 0.87, 95% CI 0.74 to 1.03, 1860 participants, 4 trials, moderate-quality evidence), and may make little or no difference to patient satisfaction (RR 0.86, 95% CI 0.57 to 1.30, 1110 participants, 2 trials, low-quality evidence). Similarly, CRP testing probably has little or no effect on patient satisfaction (RR 0.79, 95% CI 0.57 to 1.08, 689 participants, 2 trials, moderate-quality evidence) or reconsultation (RR 1.08, 95% CI 0.93 to 1.27, 5132 participants, 4 trials, moderate-quality evidence). Procalcitonin-guided management probably results in little or no difference in treatment failure in general practice compared to normal care (adjusted OR 0.95, 95% CI 0.73 to 1.24, 1008 participants, 2 trials, moderate-quality evidence), however it probably reduces treatment failure in the emergency department compared to usual care (adjusted OR 0.76, 95% CI 0.61 to 0.95, 2605 participants, 7 trials, moderate-quality evidence). The quality of evidence for interventions focused on clinician educational materials and decision support in reducing antibiotic prescribing in general practice was either low or very low (no pooled result reported) and trial results were highly heterogeneous, therefore we were unable draw conclusions about the effects of these interventions. The use of rapid viral diagnostics in emergency departments may have little or no effect on antibiotic prescribing (RR 0.86, 95% CI 0.61 to 1.22, 891 participants, 3 trials, low-quality evidence) and may result in little to no difference in reconsultation (RR 0.86, 95% CI 0.59 to 1.25, 200 participants, 1 trial, low-quality evidence). None of the trials in the included reviews reported on management costs for the treatment of an ARI or any associated complications. We found evidence that CRP testing, shared decision making, and procalcitonin-guided management reduce antibiotic prescribing for patients with ARIs in primary care. These interventions may therefore reduce overall antibiotic consumption and consequently antibiotic resistance. There do not appear to be negative effects of these interventions on the outcomes of patient satisfaction and reconsultation, although there was limited measurement of these outcomes in the trials. This should be rectified in future trials. We could gather no information about the costs of management, and this along with the paucity of measurements meant that it was difficult to weigh the benefits and costs of implementing these interventions in practice. Most of this research was undertaken in high-income countries, and it may not generalise to other settings. The quality of evidence for the interventions of educational materials and tools for patients and clinicians was either low or very low, which prevented us from drawing any conclusions. High-quality trials are needed to further investigate these interventions.
The search identified 20 studies (1615 infants). Most were small, single-centre, prospective cohort studies conducted in neonatal units in high- or middle-income countries since the late 1990s. Risk of bias in the included studies was generally low with independent assessment of index and reference tests. Most studies used a prespecified serum CRP threshold level as the definition of a 'positive' index test (typical cut-off level between 5 mg/L and 10 mg/L) and the culture of a pathogenic micro-organism from blood as the reference standard. At median specificity (0.74), sensitivity was 0.62 (95% CI 0.50 to 0.73). Heterogeneity was evident in the forest plots but it was not possible to conduct subgroup or meta-regression analyses by gestational ages, types of infection, or types of infecting micro-organism. Covariates for whether studies used a predefined threshold or not, and whether studies used a standard threshold of between 5 mg/L and 10 mg/L, were not statistically significant. The serum CRP level at initial evaluation of an infant with suspected late-onset infection is unlikely to be considered sufficiently accurate to aid early diagnosis or select infants to undergo further investigation or treatment with antimicrobial therapy or other interventions.
We included one RCT (a total of 50 participants, 25 in both the intervention and comparator group). The intervention focused on laparoscopic adjustable gastric banding surgery, which was compared to a control group receiving a multi component lifestyle programme. The participating population consisted of Australian adolescents (a higher proportion of girls than boys) aged 14 to 18 years, with a mean age of 16.5 and 16.6 years in the gastric banding and lifestyle group, respectively which was conducted in a private hospital, receiving funding from the gastric banding manufacturer. The study authors were unable to blind participants, personnel and outcome assessors which may have resulted in a high risk of performance and detection bias. Attrition bias was noted as well. The study authors reported a mean reduction in weight of 34.6 kg (95% confidence interval (CI) 30.2 to 39.0) at two years, representing a change in body mass index (BMI) of 12.7 (95% CI 11.3 to 14.2) for the surgery intervention; and a mean reduction in weight of 3.0 kg (95% CI 2.1 to 8.1) representing a change in BMI of 1.3 (95% CI 0.4 to 2.9) for the lifestyle intervention. The differences between groups were statistically significant for all weight measures at 24 months (P < 0.001). The overall quality of the evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was low. Adverse events were reported in 12/25 (48%) participants in the intervention group compared to 11/25 (44%) in the control group (low quality evidence). A total of 28% of the adolescents undergoing gastric banding required revisional surgery. No data were reported for all-cause mortality, behaviour change, participants views of the intervention and socioeconomic effects. At two years, the gastric banding group performed better than the lifestyle group in two of eight health-related quality of life concepts (very low quality evidence) as measured by the Child Health Questionnaire (physical functioning score (94 versus 78, community norm 95) and change in health score (4.4 versus 3.6, community norm 3.5)). Laparoscopic gastric banding led to greater body weight loss compared to a multi component lifestyle program in one small study with 50 patients. These results do not provide enough data to assess efficacy across populations from different countries, socioeconomic and ethnic backgrounds, who may respond differently. This systematic review highlights the lack of RCTs in this field. Future studies should assess the impact of the surgical procedure and post operative care to minimise adverse events, including the need for post operative adjustments and revisional surgery. Long-term follow-up is also critical to comprehensively assess the impact of surgery as participants enter adulthood.
A total of 31 trials, involving 12,587 participants, across a range of clinical specialities (e.g. surgery, critical care) met the eligibility criteria. The trial interventions were split fairly equally with regard to the haemoglobin concentration used to define the restrictive transfusion group. About half of them used a 7 g/dL threshold, and the other half used a restrictive transfusion threshold of 8 g/dL to 9 g/dL. The trials were generally at low risk of bias .Some items of methodological quality were unclear, including definitions and blinding for secondary outcomes. Restrictive transfusion strategies reduced the risk of receiving a RBC transfusion by 43% across a broad range of clinical specialties (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.49 to 0.65; 12,587 participants, 31 trials; high-quality evidence), with a large amount of heterogeneity between trials (I² = 97%). Overall, restrictive transfusion strategies did not increase or decrease the risk of 30-day mortality compared with liberal transfusion strategies (RR 0.97, 95% CI 0.81 to 1.16, I² = 37%; N = 10,537; 23 trials; moderate-quality evidence) or any of the other outcomes assessed (i.e. cardiac events (low-quality evidence), myocardial infarction, stroke, thromboembolism (high-quality evidence)). Liberal transfusion did not affect the risk of infection (pneumonia, wound, or bacteraemia). Transfusing at a restrictive haemoglobin concentration of between 7 g/dL to 8 g/dL decreased the proportion of participants exposed to RBC transfusion by 43% across a broad range of clinical specialities. There was no evidence that a restrictive transfusion strategy impacts 30-day mortality or morbidity (i.e. mortality at other points, cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy. There were insufficient data to inform the safety of transfusion policies in certain clinical subgroups, including acute coronary syndrome, myocardial infarction, neurological injury/traumatic brain injury, acute neurological disorders, stroke, thrombocytopenia, cancer, haematological malignancies, and bone marrow failure. The findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with haemoglobin thresholds above 7 g/dL to 8 g/dL.
Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals. Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 - 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P < 0.0001). One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants' perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants' perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period. We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.
Twenty-four trials involving 4422 participants were reviewed. Most examined symptomatic women only. Only seven trials analysed results by intention to treat; we re-analysed the remainder. Compared with placebo, clindamycin showed a lower rate of treatment failure (relative risk (RR) 0.25, 95% confidence interval (CI) 0.16 to 0.37). Clindamycin and metronidazole showed identical rates of treatment failure, irrespective of regimen type, at two and four-week follow up (RR 1.01, 95% CI 0.69 to 1.46; RR 0.91, 95% CI 0.70 to 1.18, respectively). Clindamycin tended to cause a lower rate of adverse events (RR 0.75, 95% CI 0.56 to 1.02); metallic taste, and nausea and vomiting were more common in the metronidazole group (RR 0.08, 95% CI 0.1 to 0.59; RR 0.23, 95% CI 0.10 to 0.51, respectively). Given intravaginally as gelatin tablets, lactobacillus was more effective than oral metronidazole  (RR 0.20, 95% CI 0.05 to 0.08). Similarly, oral lactobacillus combined with metronidazole was more effective than metronidazole alone (RR 0.33, 95% CI 0.14 to 0.77). Clindamycin showed a lower rate of clinical failure than triple sulfonamide cream (RR 0.46, 95% CI 0.29 to 0.72). Hydrogen peroxide douche showed a higher rate of clinical failure (RR 1.75, 95% CI 1.02 to 3.00) and adverse events (RR 2.33, 95% CI 1.21 to 4.52) than a single 2 g dose of metronidazole. Clindamycin preparations, oral metronidazole, and oral and intravaginal tablets of lactobacillus were effective for bacterial vaginosis. Hydrogen peroxide douche and triple sulphonamide cream were ineffective. Metronidazole caused metallic taste, nausea and vomiting. We need better-designed trials with larger sample sizes to test the effectiveness of promising drugs.
We included one RCT of 100 participants with ocular burns that were randomised to treatment with AMT and medical therapy or medical therapy alone. A subset of patients (n = 68) who were treated within the first seven days of the injury met the inclusion criteria and were included in the analysis. The remaining 32 eyes were excluded. The included subset consisted of 36 moderate (Dua classification II-III) and 32 severe (Dua classification IV-VI) ocular burns from alkali, acid and thermal injuries. In the moderate category, 13/20 control eyes and 14/16 treatment eyes had complete epithelialisation by 21 days. The RR of failure of epithelialisation by day 21 was 0.18 in the treatment group (95% confidence interval (CI) 0.02 to 1.31; P = 0.09). Mean LogMAR final visual acuities were 0.06 (standard deviation (SD) 0.10) in the treatment group and 0.38 (SD 0.52) in the control group, representing a MD of -0.32 (95% CI -0.05 to -0.59). In the severe category, 1/17 treatment and 1/15 control eyes were epithelialised by day 21. The RR of failure of epithelialisation in the treatment group was 1.01 (95% CI 0.84 to 1.21; P = 0.93). Final visual acuity was 1.77 (SD 1.31) in the treated eyes and 1.64 (SD 1.48) in the control group (MD 0.13; 95% CI -0.88 to 1.14). The risks of performance and detection biases were high, because treating personnel and outcome assessors could not be masked to treatment. There was also a high risk of bias in the visual outcomes of the moderate category, since mean visual acuity was significantly worse at presentation in the control eyes. This reduced confidence in the study findings. Conclusive evidence supporting the treatment of acute ocular surface burns with AMT is lacking. Heterogeneity of disease presentation, variations in treatment, undefined criteria for treatment success and failure, and non-uniform outcome measures are some of the factors complicating the search for clear evidence regarding this treatment.
Nine trials were included in the review, involving 1384 randomised participants. Studies varied in risk of bias, although two studies were identified as being at high risk of selection bias because of problems with concealment of allocation. All studies were from primary care in the United Kingdom and thus comparability was high. The analysis found significantly greater clinical effectiveness in the counselling group compared with usual care in terms of mental health outcomes in the short-term (standardised mean difference -0.28, 95% CI -0.43 to -0.13, n = 772, 6 trials) but not in the long-term (standardised mean difference -0.09, 95% CI -0.27 to 0.10, n = 475, 4 trials), nor on measures of social function (standardised mean difference -0.09, 95% CI -0.29 to 0.11, n = 386, 3 trials). Levels of satisfaction with counselling were high. There was some evidence that the overall costs of counselling and usual care were similar. There were limited comparisons between counselling and other psychological therapies, medication, or other psychosocial interventions. Counselling is associated with significantly greater clinical effectiveness in short-term mental health outcomes compared to usual care, but provides no additional advantages in the long-term. Participants were satisfied with counselling. Although some types of health care utilisation may be reduced, counselling does not seem to reduce overall healthcare costs. The generalisability of these findings to settings outside the United Kingdom is unclear.
Of 241 records retrieved by the search, 17 trials conducted between 1961 and 2011, involving 2252 participants with follow-up from six weeks to two years, were included. Homogenous data demonstrated that instances of relapse were significantly higher in people receiving any intermittent drug treatment in the long term (n = 436, 7 RCTs, RR 2.46, 95% CI 1.70 to 3.54, moderate quality evidence). Intermittent treatment was shown to be more effective than placebo, however, and demonstrated that significantly less people receiving intermittent antipsychotics experienced full relapse by medium term (n = 290, 2 RCTs, RR 0.37, 95% CI 0.24 to 0.58, very low quality evidence). Hospitalisation rates were higher for people receiving any intermittent drug treatment by long term (n = 626, 5 RCTs, RR 1.65, 95% CI 1.33 to 2.06, moderate quality evidence). Results demonstrated little difference in instances of tardive dyskinesia in groups with any intermittent drug technique versus maintenance therapy, with equivocal results (displaying slight heterogeneity) at long term (n = 165, 4 RCTs, RR 1.15, 95% CI 0.58 to 2.30, low quality evidence). Results of this review support the existing evidence that intermittent antipsychotic treatment is not as effective as continuous, maintained antipsychotic therapy in preventing relapse in people with schizophrenia. More research is needed to assess any potential benefits or harm of intermittent treatment regarding adverse effects typically associated with maintained antipsychotic treatment, as well as any cost-effectiveness of this experimental treatment.
Five studies on 588 adults and children were included concerning nurse-led care versus physician-led care. One study included 154 patients with uncontrolled asthma, while the other four studies including 434 patients with controlled or partly controlled asthma. The studies were of good methodological quality (although it is not possible to blind people giving or receiving the intervention to which group they are in). There was no statistically significant difference in the number of asthma exacerbations and asthma severity after treatment (duration of follow-up from six months to two years). Only one study had healthcare costs as an outcome parameter, no statistical differences were found. Although not a primary outcome, quality of life is a patient-important outcome and in the three trials on 380 subjects that reported on this outcome, there was no statistically significant difference (standardised mean difference (SMD) -0.03; 95% confidence interval (CI) -0.23 to 0.17). We found no significant difference between nurse-led care for patients with asthma compared to physician-led care for the outcomes assessed. Based on the relatively small number of studies in this review, nurse-led care may be appropriate in patients with well-controlled asthma. More studies in varied settings and among people with varying levels of asthma control are needed with data on adverse events and health-care costs.
We identified six RCTs, involving 221 participants. The mean age of participants ranged from 59 to 70 years; the sample size ranged from 20 to 111 participants. Overall, we found that the risk of bias in the included studies was high, and the quality of evidence for all outcomes was low. Pooled data from four studies demonstrated that, on completion of the intervention period, exercise capacity (6MWD) was significantly higher in the intervention group than the control group (mean difference (MD) 63.33 m; 95% confidence interval (CI) 3.70 to 122.96). On completion of the intervention period, disease-specific global HRQoL was significantly better in the intervention group compared to the control group (standardised mean difference (SMD) 0.51; 95% CI 0.08 to 0.93). There was no significant difference between the intervention and control groups in physical functioning HRQoL (SMD 0.11; 95% CI -0.36 to 0.58), dyspnoea (SMD -0.27; 95% CI -0.64 to 0.10), fatigue (SMD 0.03; 95% CI -0.51 to 0.58), feelings of anxiety (MD -1.21 units on Hospital Anxiety and Depression Scale; 95% CI -5.88 to 3.45) and depression (SMD -1.26; 95% CI -4.68 to 2.17), and FEV1 (SMD 0.43; 95% CI -0.11 to 0.97). Exercise training may improve or avoid the decline in exercise capacity and disease-specific global HRQoL for adults with advanced lung cancer. We found no significant effects of exercise training on dyspnoea, fatigue, feelings of anxiety and depression, or lung function. The findings of this review should be viewed with caution because of the heterogeneity between studies, the small sample sizes, and the high risk of bias of included studies. Larger, high-quality RCTs are needed to confirm and expand knowledge on the effects of exercise training in this population.
We identified 19 studies, which enrolled 13,216 participants (we included four new studies in this second update). Sixteen out of the 19 studies were eligible for quantitative synthesis. Although the studies varied in setting (general practitioner (GP)-led, nurse-led, or surgeon-led) and 'intensity' of follow-up, there was very little inconsistency in the results. Overall survival: we found intensive follow-up made little or no difference (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.80 to 1.04: I² = 18%; high-quality evidence). There were 1453 deaths among 12,528 participants in 15 studies. In absolute terms, the average effect of intensive follow-up on overall survival was 24 fewer deaths per 1000 patients, but the true effect could lie between 60 fewer to 9 more per 1000 patients. Colorectal cancer-specific survival: we found intensive follow-up probably made little or no difference (HR 0.93, 95% CI 0.81 to 1.07: I² = 0%; moderate-quality evidence). There were 925 colorectal cancer deaths among 11,771 participants enrolled in 11 studies. In absolute terms, the average effect of intensive follow-up on colorectal cancer-specific survival was 15 fewer colorectal cancer-specific survival deaths per 1000 patients, but the true effect could lie between 47 fewer to 12 more per 1000 patients. Relapse-free survival: we found intensive follow-up made little or no difference (HR 1.05, 95% CI 0.92 to 1.21; I² = 41%; high-quality evidence). There were 2254 relapses among 8047 participants enrolled in 16 studies. The average effect of intensive follow-up on relapse-free survival was 17 more relapses per 1000 patients, but the true effect could lie between 30 fewer and 66 more per 1000 patients. Salvage surgery with curative intent: this was more frequent with intensive follow-up (risk ratio (RR) 1.98, 95% CI 1.53 to 2.56; I² = 31%; high-quality evidence). There were 457 episodes of salvage surgery in 5157 participants enrolled in 13 studies. In absolute terms, the effect of intensive follow-up on salvage surgery was 60 more episodes of salvage surgery per 1000 patients, but the true effect could lie between 33 to 96 more episodes per 1000 patients. Interval (symptomatic) recurrences: these were less frequent with intensive follow-up (RR 0.59, 95% CI 0.41 to 0.86; I² = 66%; moderate-quality evidence). There were 376 interval recurrences reported in 3933 participants enrolled in seven studies. Intensive follow-up was associated with fewer interval recurrences (52 fewer per 1000 patients); the true effect is between 18 and 75 fewer per 1000 patients. Intensive follow-up probably makes little or no difference to quality of life, anxiety, or depression (reported in 7 studies; moderate-quality evidence). The data were not available in a form that allowed analysis. Intensive follow-up may increase the complications (perforation or haemorrhage) from colonoscopies (OR 7.30, 95% CI 0.75 to 70.69; 1 study, 326 participants; very low-quality evidence). Two studies reported seven colonoscopic complications in 2292 colonoscopies, three perforations and four gastrointestinal haemorrhages requiring transfusion. We could not combine the data, as they were not reported by study arm in one study. The limited data on costs suggests that the cost of more intensive follow-up may be increased in comparison with less intense follow-up (low-quality evidence). The data were not available in a form that allowed analysis. The results of our review suggest that there is no overall survival benefit for intensifying the follow-up of patients after curative surgery for colorectal cancer. Although more participants were treated with salvage surgery with curative intent in the intensive follow-up groups, this was not associated with improved survival. Harms related to intensive follow-up and salvage therapy were not well reported.
Eleven trials involving 2487 participants were included. The quality of the nine trials which predated routine computerised tomography (CT) scanning and the use of the International Normalised Ratio to monitor anticoagulation was poor. There was no evidence of an effect of anticoagulant therapy on either the odds of death or dependency (two trials, odds ratio (OR) 0.83, 95% confidence interval (CI) 0.52 to 1.34) or of 'non-fatal stroke, myocardial infarction, or vascular death' (four trials, OR 0.96, 95% CI 0.68 to 1.37). Death from any cause (OR 0.95, 95% CI 0.73 to 1.24) and death from vascular causes (OR 0.86, 95% CI 0.66 to 1.13) were not significantly different between treatment and control. The inclusion of two recently completed trials did not alter these conclusions. There was no evidence of an effect of anticoagulant therapy on the risk of recurrent ischaemic stroke (OR 0.85, 95% CI 0.66 to 1.09). However, anticoagulants increased fatal intracranial haemorrhage (OR 2.54, 95% CI 1.19 to 5.45), and major extracranial haemorrhage (OR 3.43, 95% CI 1.94 to 6.08). This is equivalent to anticoagulant therapy causing about 11 additional fatal intracranial haemorrhages and 25 additional major extracranial haemorrhages per year for every 1000 patients given anticoagulant therapy. Compared with control, there was no evidence of benefit from long-term anticoagulant therapy in people with presumed non-cardioembolic ischaemic stroke or transient ischaemic attack, but there was a significant bleeding risk.
The original version of this Cochrane review included five RCTs involving 1277 women. In this 2015 update, no new studies met the inclusion criteria but we included an additional paper with mature data (10-year follow-up) relating to a previously included study (ICON1). We included four studies in the meta-analyses and considered them to be at a low risk of bias. Most study participants (> 95%) had stage I ovarian cancer. Meta-analysis of five-year data from three studies indicated that women who received adjuvant platinum-based chemotherapy had better overall survival (OS) than those who did not (Hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53 to 0.93; 1008 women; 3 studies; I² statistic = 0%; high quality evidence). Likewise, meta-analysis of five-year data from four studies indicated that women who received adjuvant chemotherapy had better progression-free survival (PFS) than those who did not (HR 0.67, 95% CI 0.53 to 0.84; 1170 women, 4 studies; I² statistic = 0%; high quality evidence). These findings were robust over time, with 10-year HR estimates of 0.72 (95% CI 0.57 to 0.92; 925 women, 2 studies) and 0.67 (95% CI 0.53 to 0.83; 925 women, 2 studies) for OS and PFS, respectively (high quality evidence). The risk of death at 10 years follow-up favoured the adjuvant chemotherapy arm (0.76, 95% CI 0.62 to 0.94; 923 women, 2 studies; I² statistic = 0%), as did the findings for risk of progression at 10 years (RR 0.72, 95% CI 0.60 to 0.87; 925 women, 2 studies; I² statistic = 0%). Low quality evidence suggested that women with high-risk disease may have the most to gain from adjuvant chemotherapy. However, subgroup analyses could neither confirm nor exclude survival benefits in lower risk disease or in optimally staged disease. We found insufficient data to compare adverse events and long term risks between chemotherapy and observation groups. High-quality evidence indicates that adjuvant platinum-based chemotherapy is effective in prolonging survival in women with early stage (FIGO stage I/IIa) epithelial ovarian cancer. It remains uncertain whether women with low- and intermediate-risk early stage disease will benefit as much from adjuvant chemotherapy as women with high-risk disease. Decisions to use adjuvant chemotherapy (AC) in these women should be mindful of this uncertainty, and the uncertainty regarding adverse events. Treatment of women with lower risk disease should be individualised to take into account individual factors.
We included ten RCTs with varying risk of bias. For patients with acute LBP, results from two trials (N = 401) suggest small improvements in pain relief (SMD 0.22 (95% CI: 0.02 to 0.41) and functional status (SMD 0.29 (95% CI: 0.09 to 0.49) in favour of advice to stay active. For patients with sciatica, there is moderate quality evidence of little or no difference in pain relief (SMD -0.03 (95% CI: -0.24 to 0.18)) or functional status (SMD 0.19 (95% CI: -0.02 to 0.41)), between advice to rest in bed or stay active. Low quality evidence (3 RCTs, N = 931) suggests little or no difference between exercises, advice to rest in bed or stay active for patients with acute LBP. Low quality evidence (1 RCT, N = 250) suggests little or no difference between physiotherapy, advice to rest in bed or stay active for patients with sciatica. No trials that compared different ways of delivering advice. Moderate quality evidence shows that patients with acute LBP may experience small benefits in pain relief and functional improvement from advice to stay active compared to advice to rest in bed; patients with sciatica experience little or no difference between the two approaches. Low quality evidence suggests little or no difference between those who received advice to stay active, exercises or physiotherapy. Further research is very likely to have an important impact on the estimate of effect and is likely to change our confidence in it.
We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias. Two studies compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses). The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence). The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study. The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.
25 studies were included: 2 RCTs, 1 cohort study, 6 case-control studies and 16 cross-sectional surveys. Only one RCT was judged to be at low risk of bias. The other RCT and all observational studies were judged to be at moderate to high risk of bias. Studies were included in four intervention/exposure comparisons. A statistically significant reduction in fluorosis was found if brushing of a child's teeth with fluoride toothpaste commenced after the age of 12 months odds ratio 0.70 (random-effects: 95% confidence interval 0.57 to 0.88) (data from observational studies). Inconsistent statistically significant associations were found between starting using fluoride toothpaste/toothbrushing before or after the age of 24 months and fluorosis (data from observational studies). From the RCTs, use of higher level of fluoride was associated with an increased risk of fluorosis. No significant association between the frequency of toothbrushing or the amount of fluoride toothpaste used and fluorosis was found. There should be a balanced consideration between the benefits of topical fluorides in caries prevention and the risk of the development of fluorosis. Most of the available evidence focuses on mild fluorosis. There is weak unreliable evidence that starting the use of fluoride toothpaste in children under 12 months of age may be associated with an increased risk of fluorosis. The evidence for its use between the age of 12 and 24 months is equivocal. If the risk of fluorosis is of concern, the fluoride level of toothpaste for young children (under 6 years of age) is recommended to be lower than 1000 parts per million (ppm). More evidence with low risk of bias is needed. Future trials assessing the effectiveness of different types of topical fluorides (including toothpastes, gels, varnishes and mouthrinses) or different concentrations or both should ensure that they include an adequate follow-up period in order to collect data on potential fluorosis. As it is unethical to propose RCTs to assess fluorosis itself, it is acknowledged that further observational studies will be undertaken in this area. However, attention needs to be given to the choice of study design, bearing in mind that prospective, controlled studies will be less susceptible to bias than retrospective and/or uncontrolled studies.
Seven randomised, controlled trials encompassing 842 patients undergoing SGIA versus DGIA were retrieved from the electronic databases. There were 408 patients in the SGIA group and 432 patients in the DGIA group. All included studies were small, with sample sizes ranging from 60 to 172. There was no heterogeneity among the included trials. Therefore, in the fixed effects model, incidence of anastomotic dehiscence, peri-operative complications and mortality was statistically equivalent between two techniques of GIA. Average hospital stay following SGIA and DGIA was also comparable. However, SGIA was superior in terms of shorter operative time. Sensitivity analysis of relatively good quality and poor quality trials supported same conclusion. SGIA can be performed quicker as compared to double layer GIA. SGIA is comparable to DGIA in terms of anastomotic leak, peri-operative complications, mortality and hospital stay. SGIA may routinely be used for GIA following bowel resection. However, since this conclusion is derived from smaller number of patients recruited in relatively moderate quality trials, further trials should be aimed to reduce the limitations of this review.
Two small randomised controlled trials were located, one with higher dose NaHCO3 and alternating allocation, the other with lower dose NaHCO3 was presented in abstract form only. In the higher dose study, the RR of death in patients receiving NaHCO3 compared to controls was 0.52 (95% CI 0.05 to 5.39) and the WMD for total dose of atropine was -36.1 (95% CI -68.43 to -3.77). No clinical benefits from lower dose NaHCO3 were noted. Six other studies were identified but none satisfied inclusion criteria; three studies were uncontrolled and three were controlled. NaHCO3 was used in each study to induce alkalinisation. Marked heterogeneity between subjects and treatments was noted - for example, varying regimens of NaHCO3. Preliminary studies suggest benefit from blood alkalinisation with NaHCO3 in OP poisoning, but there is insufficient evidence to support its routine clinical use. Further research is required to determine the method of alkalinisation that will optimise outcomes, and the regimen which will produce the target arterial pH of 7.50 (range 7.45 to 7.55). This should be followed by a well-designed randomised controlled trial to determine efficacy.
A total of 21 eligible RCTs were identified and used for meta-analysis purposes. Overall, 16,215 patients with colorectal cancer were enrolled, 9,785 being affected with rectal carcinoma. Considering patients with rectal cancer only, 4,854 cases were randomized to receive potentially curative surgery of the primary tumour plus adjuvant chemotherapy and 4,367 to receive surgery plus observation. The mean number of patients enrolled was 466 (range: 54-1,243 cases). 11 RCTs had been performed in Western countries and 10 in Japan. All trials used fluoropyrimidine-based chemotherapy (no modern drugs - such as oxaliplatin, irinotecan or biological agents - were tested). Overall survival (OS) data were available in 21 RCTs and the data available for meta-analysis regarded 9,221 patients: of these, 4854 patients were randomized to adjuvant chemotherapy (treatment arm) and 4,367 patients did not receive adjuvant chemotherapy (control arm). The meta-analysis of these RCTs showed a significant reduction in the risk of death (17%) among patients undergoing postoperative chemotherapy as compared to those undergoing observation (HR=0.83, CI: 0.76-0.91). Between-study heterogeneity was moderate (I-squared=30%) but significant (P=0.09) at the 10% alpha level. Disease-free survival (DFS) data were reported in 20 RCTs, and the data suitable for meta-analysis included 8,530 patients. Of these, 4,515 patients were randomized to postoperative chemotherapy (treatment arm) and 4,015 patients received no postoperative chemotherapy (control arm). The meta-analysis of these RCTs showed a reduction in the risk of disease recurrence (25%) among patients undergoing adjuvant chemotherapy as compared to those undergoing observation (HR=0.75, CI: 0.68-0.83). Between-study heterogeneity was moderate (I-squared=41%) but significant (P=0.03). While analyzing both OS and DFS data, sensitivity analyses did not find any difference in treatment effect based on trial sample size or geographical region (Western vs Japanese). Available data were insufficient to investigate on the effect of adjuvant chemotherapy separately in different TNM stages in terms of both OS and DFS. No plausible source of heterogeneity was formally identified, although variability in treatment regimens and TNM stages of enrolled patients might have played a significant role in the difference of reported results. The results of this meta-analysis support the use of 5-FU based postoperative adjuvant chemotherapy for patients undergoing apparently radical surgery for non-metastatic rectal carcinoma. Available data do not allow us to define whether the efficacy of this treatment is highest in one specific TNM stage. The implementation of modern anti-cancer agents in the adjuvant setting is warranted to improve the results shown by this meta-analysis. Randomized trials of adjuvant chemotherapy for patients receiving preoperative neoadjuvant therapy are also needed in order to define the role of postoperative chemotherapy in the multimodal treatment of resectable rectal cancer.
In this updated version of the review, we found no new studies that met our inclusion criteria. We included in this review four studies that compared neuraxial anaesthesia with general anaesthesia. The total number of participants was 696, of whom 417 were allocated to neuraxial anaesthesia and 279 to general anaesthesia. Participants allocated to neuraxial anaesthesia had a mean age of 67 years, and 59% were men. Participants allocated to general anaesthesia had a mean age of 67 years, and 66% were men. Four studies had an unclear risk of bias. No difference was observed between participants allocated to neuraxial or general anaesthesia in mortality rate (OR 0.89, 95% CI 0.38 to 2.07; 696 participants; four trials), myocardial infarction (OR 1.23, 95% CI 0.56 to 2.70; 696 participants; four trials), and lower-limb amputation (OR 0.84, 95% CI 0.38 to 1.84; 465 participants; three trials). Pneumonia was less common after neuraxial anaesthesia than after general anaesthesia (OR 0.37, 95% CI 0.15 to 0.89; 201 participants; two trials). Evidence was insufficient for cerebral stroke, duration of hospital stay, postoperative cognitive dysfunction, complications in the anaesthetic recovery room and transfusion requirements. No data described nerve dysfunction, postoperative wound infection, patient satisfaction, postoperative pain score, claudication distance and pain at rest. Available evidence from included trials that compared neuraxial anaesthesia with general anaesthesia was insufficient to rule out clinically important differences for most clinical outcomes. Neuraxial anaesthesia may reduce pneumonia. No conclusions can be drawn with regard to mortality, myocardial infarction and rate of lower-limb amputation, or less common outcomes.
We included only one small pilot study (involving 30 women). The study, which we considered to be at low risk of bias, was conducted in a tertiary referral hospital in Australia, and involved women with cephalic, singleton pregnancies. The primary outcome was operative delivery (instrumental delivery or caesarean section). In the manual rotation group, 13/15 women went on to have an instrumental delivery or caesarean section, whereas in the control group, 12/15 women had an operative delivery. The estimated risk ratio was 1.08 (95% confidence interval 0.79 to 1.49). There were no maternal or fetal mortalities in either group There were no clear differences for any of the secondary maternal or neonatal outcomes reported (e.g. perineal trauma, analgesia use duration of labour). In terms of adverse events, there were no reported cases of umbilical cord prolapse or cervical laceration and a single case of a non-reassuring or pathological cardiotocograph during the procedure. Currently, there is insufficient evidence to determine the efficacy of prophylactic manual rotation early in the second stage of labour for prevention of operative delivery. One additional study is ongoing. Further appropriately designed trials are required to determine the efficacy of manual rotation.
Eleven trials were selected for inclusion in the review, including a total of 776 men. They were generally small; all were of poor quality and all were deemed to have high risk of bias. Performing intermittent self-dilatationversus not performing intermittent self-dilatation The data from six trials were heterogeneous, imprecise and had a high risk of bias, but indicated that recurrent urethral stricture was less likely in men who performed intermittent self-dilatation than men who did not perform intermittent self-dilatation (RR 0.70, 95% CI 0.48 to 1.00; very low quality evidence). Adverse events were generally poorly reported: two trials did not report adverse events and two trials reported adverse events only for the intervention group. Meta-analysis of the remaining two trials found no evidence of a difference between performing intermittent self-dilatation and not performing it (RR 0.60, 95% CI 0.11 to 3.26). No trials formally assessed acceptability, and no trials reported on patient-reported lower urinary tract symptoms, patient-reported health-related quality of life, or cost-effectiveness. One programme of intermittent self-dilatationversus another We identified two trials that compared different durations of intermittent self-dilatation, but data were not combined. One study could not draw robust conclusions owing to cross-over, protocol deviation, administrative error, post-hoc analysis and incomplete outcome reporting. The other study found no evidence of a difference between intermittent self-dilatation for six months versus for 12 months after optical urethrotomy (RR 0.67, 95% CI 0.12 to 3.64), although again the evidence is limited by the small sample size and risk of bias in the included study. Adverse events were reported narratively and were not stratified by group. No trials formally assessed acceptability, and no trials reported on patient-reported lower urinary tract symptoms, patient-reported health-related quality of life, or cost-effectiveness. One device for performing intermittent self-dilatationversus another Three trials compared one device for performing intermittent self-dilatation with another. Results from one trial at a high risk of bias were too uncertain to determine the effects of a low friction hydrophilic catheter and a standard polyvinyl chloride catheter on the risk of recurrent urethral stricture (RR 0.32, 95% CI 0.07 to 1.40). Similarly one study did not find evidence of a difference between one percent triamcinolone gel for lubricating the intermittent self-dilatation catheter versus water-based gel on risk of recurrent urethral stricture (RR 0.68, 95% CI 0.35 to 1.32). Two trials reported adverse events, but one did not provide sufficient detail for analysis. The other small study reported fewer instances of prostatitis, urethral bleeding or bacteriuria with a low friction hydrophilic catheter compared with a standard polyvinyl chloride catheter (RR 0.13, 95% CI 0.02 to 0.98). ‘Happiness with the intervention’ was assessed using a non-validated scale in one study, but no trials formally assessed patient-reported health-related quality of life or acceptability. No trials reported on patient-reported lower urinary tract symptoms or cost-effectiveness. GRADE quality assessment The evidence that intermittent self-dilatation reduces the risk of recurrent urethral stricture after surgical intervention was downgraded to 'very low' on the basis that the studies comprising the meta-analysis were deemed to have high risk of bias, and the data was imprecise and inconsistent. Insufficient evidence No trials provided cost-effectiveness data or used a validated patient-reported outcome measure, and adverse events were not reported rigorously. Acceptability of the intervention to patients has not been assessed quantitatively or qualitatively. Performing intermittent self-dilatation may confer a reduced risk of recurrent urethral stricture after endoscopic treatment. We have very little confidence in the estimate of the effect owing to the very low quality of the evidence. Evidence for other comparisons and outcomes is limited. Further research is required to determine whether the apparent benefit is sufficient to make the intervention worthwhile, and in whom.
We included 38 unique studies with 3290 men with CP/CPPS across 23 comparisons. 1. Acupuncture: (three studies, 204 participants) based on short-term follow-up, acupuncture probably leads to clinically meaningful reduction in prostatitis symptoms compared with sham procedure (mean difference (MD) in total NIH-CPSI score -5.79, 95% confidence interval (CI) -7.32 to -4.26, high QoE). Acupuncture may result in little to no difference in adverse events (low QoE). Acupuncture may not reduce sexual dysfunction when compared with sham procedure (MD in the International Index of Erectile Function (IIEF) Scale -0.50, 95% CI -3.46 to 2.46, low QoE). Acupuncture may also lead to a clinically meaningful reduction in prostatitis symptoms compared with standard medical therapy (MD -6.05, 95% CI -7.87 to -4.24, two studies, 78 participants, low QoE). We found no information regarding quality of life, depression or anxiety. 2. Lifestyle modifications: (one study, 100 participants) based on short-term follow-up, lifestyle modifications may be associated with a reduction in prostatitis symptoms compared with control (risk ratio (RR) for improvement in NIH-CPSI scores 3.90, 95% CI 2.20 to 6.92, very low QoE). We found no information regarding adverse events, sexual dysfunction, quality of life, depression or anxiety. 3. Physical activity: (one study, 85 participants) based on short-term follow-up, a physical activity programme may cause a small reduction in prostatitis symptoms compared with control (NIH-CPSI score MD -2.50, 95% CI -4.69 to -0.31, low QoE). This programme may not reduce anxiety or depression (low QoE). We found no information regarding adverse events, sexual dysfunction or quality of life. 4. Prostatic massage: (two studies, 115 participants) based on short-term follow-up, we are uncertain whether the prostatic massage reduces or increases prostatitis symptoms compared with control (very low QoE). We found no information regarding adverse events, sexual dysfunction, quality of life, depression or anxiety. 5. Extracorporeal shockwave therapy: (three studies, 157 participants) based on short-term follow-up, extracorporeal shockwave therapy reduces prostatitis symptoms compared with control (NIH-CPSI score MD -6.18, 95% CI -7.46 to -4.89, high QoE). These results may not be sustained at medium-term follow-up (low QoE). This treatment may not be associated with a greater incidence of adverse events (low QoE). This treatment probably improves sexual dysfunction (MD in the IIEF Scale MD 3.34, 95% CI 2.68 to 4.00, one study, 60 participants, moderate QoE). We found no information regarding quality of life, depression or anxiety. 6. Transrectal thermotherapy compared to medical therapy: (two studies, 237 participants) based on short-term follow-up, transrectal thermotherapy alone or in combination with medical therapy may decrease prostatitis symptoms slightly when compared with medical therapy alone (NIH-CPSI score MD -2.50, 95% CI -3.82 to -1.18, low QoE). One included study reported that participants may experience transient adverse events. We found no information regarding sexual dysfunction, quality of life, depression or anxiety. 7. Other interventions: there is uncertainty about the effects of most of the other interventions included in this review. We found no information regarding psychological support or prostatic surgery. Based on the findings of moderate quality evidence, this review found that some non-pharmacological interventions such as acupuncture and extracorporeal shockwave therapy are likely to result in a decrease in prostatitis symptoms and may not be associated with a greater incidence of adverse event. The QoE for most other comparisons was predominantly low. Future clinical trials should include a full report of their methods including adequate masking, consistent assessment of all patient-important outcomes including potential treatment-related adverse events and appropriate sample sizes.
The searches identified 7558 titles, and we excluded 7513 during title and abstract searches. We reviewed 45 papers in full, and excluded 39. We identified four studies on handsearching of the references, which, along with the six eligible papers from the database search, led to 10 studies being included. Four studies, three of which were RCTs and one prospective study, investigated the effect of elemental diet on GI symptoms; one RCT investigated the effect of dietary modification and elemental diet; and five RCTs investigated dietary modification. Studies were varied in terms of risk of bias. Data were dichotomised for presence and absence of diarrhoea at the end of radiotherapy for four trials evaluating dietary modification comprising modified fat, lactose, fibre or combinations of these dietary changes. A reduction in diarrhoea was demonstrated with nutritional intervention (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.51 to 0.87, four studies, 413 participants, moderate quality of evidence) with low heterogeneity (Chi2 = 3.50, I2 = 14%). Two trials evaluating dietary modification on weight change (comparing baseline and end of radiotherapy) showed no difference between intervention or control (mean difference (MD) -0.57 kg; 95% CI -1.22 to 0.09) with low heterogeneity (Chi2 = 1.41, I2 = 29%). Generally adverse effects were poorly reported in included studies. Elemental diet in particular was poorly tolerated. GI symptoms or toxicity > 6 months after radiotherapy was not reported in included studies There have been benefits demonstrated with dietary modification during pelvic radiotherapy to reduce diarrhoea. Those diets included single interventions or combinations of modified fat, lactose-restriction, fat-restriction and fibre supplementation. We were unable to meta-analyse elemental diet, as data were not available. We considered some of the studies to be at high risk of bias. There have been recent advances in novel, more targeted radiotherapy techniques, such that the findings of older studies need to be interpreted with caution. In addition, there were problems with compliance and palatability with some of the interventions, particularly elemental diet, which limits its usefulness in clinical practice.
A single study of 21 patients compared SIRT and systemic chemotherapy (fluorouracil and leucovorin) with chemotherapy alone. There was a significant improvement in progression free survival and median survival associated with SIRT, both for the total studied population and for those disease limited to the liver. There was an increase in toxicity with the use of SIRT. A second study of 63 eligible patients compared SIRT and regional chemotherapy (floxuridine) with regional chemotherapy alone. There was no significant difference in progression free survival and median survival seen with SIRT, in either the total patient group or in the 22 patients with disease limited to the liver. There was no significant increase in toxicity with the addition of SIRT to regional chemotherapy. There were no randomised studies comparing SIRT with best supportive care in patients with refractory disease, and no randomised studies assessing the effect of SIRT in patients with resectable liver metastases. There is a need for well designed, adequately powered phase III trials assessing the effect of SIRT when used with modern combination chemotherapy regimens. Further studies are also needed for patients with refractory disease with a particular focus on the impact on quality of life.
We retrieved 24,310 citations after removal of duplicates. We reviewed the full text of 317 full-text articles and finally included 70 records, referring to 48 studies, in our synthesis. We were able to perform meta-analysis on 28 studies in the community setting (44 articles) and on 6 studies in primary care (8 articles), but we could not extract usable 2 x 2 data for the remaining 14 community studies, which we did not include in the meta-analysis. All of the studies in the community were in asymptomatic people, whereas two of the six studies in primary care were conducted in people who had symptoms of possible dementia. We judged two studies to be at high risk of bias in the patient selection domain, three studies to be at high risk of bias in the index test domain and nine studies to be at high risk of bias regarding flow and timing. We assessed most studies as being applicable to the review question though we had concerns about selection of participants in six studies and target condition in one study. The accuracy of the MMSE for diagnosing dementia was reported at 18 cut points in the community (MMSE score 10, 14-30 inclusive) and 10 cut points in primary care (MMSE score 17-26 inclusive). The total number of participants in studies included in the meta-analyses ranged from 37 to 2727, median 314 (interquartile range (IQR) 160 to 647). In the community, the pooled accuracy at a cut point of 24 (15 studies) was sensitivity 0.85 (95% confidence interval (CI) 0.74 to 0.92), specificity 0.90 (95% CI 0.82 to 0.95); at a cut point of 25 (10 studies), sensitivity 0.87 (95% CI 0.78 to 0.93), specificity 0.82 (95% CI 0.65 to 0.92); and in seven studies that adjusted accuracy estimates for level of education, sensitivity 0.97 (95% CI 0.83 to 1.00), specificity 0.70 (95% CI 0.50 to 0.85). There was insufficient data to evaluate the accuracy of the MMSE for diagnosing dementia subtypes.We could not estimate summary diagnostic accuracy in primary care due to insufficient data. The MMSE contributes to a diagnosis of dementia in low prevalence settings, but should not be used in isolation to confirm or exclude disease. We recommend that future work evaluates the diagnostic accuracy of tests in the context of the diagnostic pathway experienced by the patient and that investigators report how undergoing the MMSE changes patient-relevant outcomes.
Thirteen studies met the inclusion criteria with 8586 participants. Most of the studies were conducted in sub-Saharan Africa. The majority of the studies were of a low or unclear risk of bias. Five studies compared different surgical interventions. Most surgical interventions were performed by non-physician technicians. These trials suggest the most effective surgery is full-thickness incision of the tarsal plate and rotation of the terminal tarsal strip. Pooled data from two studies suggested that the bilamellar rotation was more effective than unilamellar rotation (OR 0.29, 95% CI 0.16 to 0.50). Use of a lid clamp reduced lid contour abnormalities (OR 0.65, 95% CI 0.44 to 0.98) and granuloma formation (OR 0.67, 95% CI 0.46 to 0.97). Absorbable sutures gave comparable outcomes to silk sutures (OR 0.90, 95% CI 0.68 to 1.20) and were associated with less frequent granuloma formation (OR 0.63, 95% CI 0.40 to 0.99). Epilation was less effective at preventing eyelashes from touching the globe than surgery for mild trichiasis, but had comparable results for vision and corneal change. Peri-operative azithromycin reduced post-operative trichiasis; however, the estimate of effect was imprecise and compatible with no effect or increased trichiasis (OR 0.85, 95% CI 0.63 to 1.14; 1954 eyes; 3 studies). Community-based surgery when compared to health centres increased uptake with comparable outcomes. Surgery performed by ophthalmologists and integrated eye care workers was comparable. Adverse events were typically infrequent or mild and included rare postoperative infections, eyelid contour abnormalities and conjunctival granulomas. No trials were designed to evaluate whether the interventions for trichiasis prevent blindness as an outcome; however, several found modest improvement in vision following intervention. Certain interventions have been shown to be more effective at eliminating trichiasis. Full-thickness incision of the tarsal plate and rotation of the lash-bearing lid margin was found to be the best technique and is preferably delivered in the community. Surgery may be carried out by an ophthalmologist or a trained ophthalmic assistant. Surgery performed with silk or absorbable sutures gave comparable results. Post-operative azithromycin was found to improve outcomes where overall recurrence was low.
We included five RCTs evaluating the effects of social skills groups in 196 participants with ASD aged 6 to 21 years old. The results show there is some evidence that social skills groups improve overall social competence (ES = 0.47, 95% confidence interval (CI) 0.16 to 0.78, P = 0.003) and friendship quality (ES = 0.41, 95% CI 0.02 to 0.81, P = 0.04) for this population. No differences were found between treatment and control groups in relation to emotional recognition (ES = 0.34, 95% CI -0.20 to 0.88, P = 0.21) assessed in two studies or social communication as related to the understanding of idioms (ES = 0.05, 95% CI -0.63 to 0.72, P = 0.89), which was assessed in only one study. Two additional quality of life outcomes were evaluated, with results of single studies suggesting decreases in loneliness (ES = -0.66, 95% CI -1.15 to -0.17) but no effect on child or parental depression. No adverse events were reported. Given the nature of the intervention and the selected outcome measures, the risk of performance and detection bias are high. There is limited generalizability from the studies as they were all conducted in the US; they focused mainly on children aged 7 to 12, and the participants were all of average or above average intelligence. There is some evidence that social skills groups can improve social competence for some children and adolescents with ASD. More research is needed to draw more robust conclusions, especially with respect to improvements in quality of life.
We included 16 studies involving data from 1884 participants. Nine studies included participants considering real clinical trials, and eight included participants considering hypothetical clinical trials, with one including both. All studies were conducted in high-income countries. There is still much uncertainty about the effect of audio-visual informed consent interventions on a range of patient outcomes. However, when considered across comparisons, we found low to very low quality evidence that such interventions may slightly improve knowledge or understanding of the parent trial, but may make little or no difference to rate of participation or willingness to participate. Audio-visual presentation of informed consent may improve participant satisfaction with the consent information provided. However its effect on satisfaction with other aspects of the process is not clear. There is insufficient evidence to draw conclusions about anxiety arising from audio-visual informed consent. We found conflicting, very low quality evidence about whether audio-visual interventions took more or less time to administer. No study measured researcher satisfaction with the informed consent process, nor ease of use. The evidence from real clinical trials was rated as low quality for most outcomes, and for hypothetical studies, very low. We note, however, that this was in large part due to poor study reporting, the hypothetical nature of some studies and low participant numbers, rather than inconsistent results between studies or confirmed poor trial quality. We do not believe that any studies were funded by organisations with a vested interest in the results. The value of audio-visual interventions as a tool for helping to enhance the informed consent process for people considering participating in clinical trials remains largely unclear, although trends are emerging with regard to improvements in knowledge and satisfaction. Many relevant outcomes have not been evaluated in randomised trials. Triallists should continue to explore innovative methods of providing information to potential trial participants during the informed consent process, mindful of the range of outcomes that the intervention should be designed to achieve, and balancing the resource implications of intervention development and delivery against the purported benefits of any intervention. More trials, adhering to CONSORT standards, and conducted in settings and populations underserved in this review, i.e. low- and middle-income countries and people with low literacy, would strengthen the results of this review and broaden its applicability. Assessing process measures, such as time taken to administer the intervention and researcher satisfaction, would inform the implementation of audio-visual consent materials.
We included 16 randomised controlled trials involving a total of 2125 participants. The trials evaluated PAP therapy consisting of ASV or continuous PAP therapy for 1 to 31 months. Many trials included participants with heart failure with reduced ejection fraction. Only one trial included participants with heart failure with preserved ejection fraction. We are uncertain about the effects of PAP therapy on all-cause mortality (RR 0.81, 95% CI 0.54 to 1.21; participants = 1804; studies = 6; I2 = 47%; very low-quality evidence). We found moderate-quality evidence of no difference between PAP therapy and usual care on cardiac-related mortality (RR 0.97, 95% CI 0.77 to 1.24; participants = 1775; studies = 5; I2 = 11%). We found low-quality evidence of no difference between PAP therapy and usual care on all-cause rehospitalisation (RR 0.95, 95% CI 0.70 to 1.30; participants = 1533; studies = 5; I2 = 40%) and cardiac-related rehospitalisation (RR 0.97, 95% CI 0.70 to 1.35; participants = 1533; studies = 5; I2 = 40%). In contrast, PAP therapy showed some indication of an improvement in quality of life scores assessed by all measurements (SMD −0.32, 95% CI −0.67 to 0.04; participants = 1617; studies = 6; I2 = 76%; low-quality evidence) and by the Minnesota Living with Heart Failure Questionnaire (MD −0.51, 95% CI −0.78 to −0.24; participants = 1458; studies = 4; I2 = 0%; low-quality evidence) compared with usual care. Death due to pneumonia (N = 1, 3% of PAP group); cardiac arrest (N = 18, 3% of PAP group); heart transplantation (N = 8, 1% of PAP group); cardiac worsening (N = 3, 9% of PAP group); deep vein thrombosis/pulmonary embolism (N = 1, 3% of PAP group); and foot ulcer (N = 1, 3% of PAP group) occurred in the PAP therapy group, whereas cardiac arrest (N = 16, 2% of usual care group); heart transplantation (N = 12, 2% of usual care group); cardiac worsening (N = 5, 14% of usual care group); and duodenal ulcer (N = 1, 3% of usual care group) occurred in the usual care group across three trials. The effect of PAP therapy on all-cause mortality was uncertain. In addition, although we found evidence that PAP therapy did not reduce the risk of cardiac-related mortality and rehospitalisation, there was some indication of an improvement in quality of life for heart failure patients with CSA. Furthermore, the evidence was insufficient to determine whether adverse events were more common with PAP than with usual care. These findings were limited by low- or very low-quality evidence. PAP therapy may be worth considering for individuals with heart failure to improve quality of life.
We included 35 studies (1474 participants) in this review. We assessed seven studies at low risk of bias overall, 11 at unclear and the remaining 17 studies at high risk of bias. We present results for our main outcomes, pain and clinical resolution measured at the end of the treatment course (between one week and six months), and adverse effects. The limited evidence available for comparisons between different corticosteroids, and corticosteroids versus alternative or adjunctive treatments is presented in the full review. Corticosteroids versus placebo Three studies evaluated the effectiveness and safety of topical corticosteroids in an adhesive base compared to placebo. We were able to combine two studies in meta-analyses, one evaluating clobetasol propionate and the other flucinonide. We found low-certainty evidence that pain may be more likely to be resolved when using a topical corticosteroid rather than a placebo (RR 1.91, 95% CI 1.08 to 3.36; 2 studies, 72 participants; I² = 0%). The results for clinical effect of treatment and adverse effects were inconclusive (clinical resolution: RR 6.00, 95% CI 0.76 to 47.58; 2 studies, 72 participants; I² = 0%; very low-certainty evidence; adverse effects RR 1.48, 95% 0.48 to 4.56; 3 studies, 88 participants, I² = 0%, very low-certainty evidence). Corticosteroids versus calcineurin inhibitors Three studies compared topical clobetasol propionate versus topical tacrolimus. We found very low-certainty evidence regarding any difference between tacrolimus and clobetasol for the outcomes pain resolution (RR 0.45, 95% CI 0.24 to 0.88; 2 studies, 100 participants; I² = 80%), clinical resolution (RR 0.61, 95% CI 0.38 to 0.99; 2 studies, 52 participants; I² = 95%) and adverse effects (RR 0.05, 95% CI 0.00 to 0.83; 2 studies, 100 participants; very low-certainty evidence) . One study (39 participants) compared topical clobetasol and ciclosporin, and provided only very low-certainty evidence regarding the rate of clinical resolution with clobetasol (RR 3.16, 95% CI 1.00 to 9.93), pain resolution (RR 2.11, 95% CI 0.76 to 5.86) and adverse effects (RR 6.32, 95% CI 0.84 to 47.69). Two studies (60 participants) that compared triamcinolone and tacrolimus found uncertain evidence regarding the rate of clinical resolution (RR 0.86, 95% CI 0.55 to 1.35; very low-certainty evidence) and that there may be a lower rate of adverse effects in the triamcinolone group (RR 0.47, 95% CI 0.22 to 0.99; low-certainty evidence). These studies did not report on pain resolution. Corticosteroids have been first line for the treatment of OLP. This review found that these drugs, delivered topically as adhesive gels or similar preparations, may be more effective than placebo for reducing the pain of symptomatic OLP; however, with the small number of studies and participants, our confidence in the reliability of this finding is low. The results for clinical response were inconclusive, and we are uncertain about adverse effects. Very low-certainty evidence suggests that calcineurin inhibitors, specifically tacrolimus, may be more effective at resolving pain than corticosteroids, although there is some uncertainty about adverse effects and clinical response to tacrolimus showed conflicting results.
We included two randomised trials with a total of 581 women each comparing different regimens of titrated oral misoprostol with intravenous oxytocin. One study compared 20 mcg doses of misoprostol dissolved in water (repeated every hour up to four hours, after which the dose was increased to 40 mcg per hour up to a maximum total dose of 1600 mcg), while the second study gave women 75 mcg doses (repeated after four hours provided there were no adverse effects observed). Neither trial reported maternal death, severe maternal morbidity, or fetal/neonatal mortality outcomes, and only a few fetal/neonatal morbidity outcomes were considered, none of which were significantly different between groups. For several outcomes (such as maternal side-effects, instrumental birth, maternal blood transfusion for hypovolaemia and epidural analgesia), the number of events was generally too low for sufficient statistical power to be achieved. Maternal satisfaction was not reported in either trial. One trial reported a slight reduction in the median duration of labour from the start of augmentation to vaginal delivery in the oxytocin group. Neither trial reported significantly higher rates of caesarean section (CS) in the oral misoprostol group. Rates of vaginal delivery within 12 and 24 hours of commencing augmentation were not significantly different in the trial using a 20 mcg misoprostol dose. Neither trial had significantly higher rates of uterine hyperstimulation with fetal heart rate changes in the titrated oral misoprostol group. However, the rates of this outcome varied so greatly between the two studies as to suggest that other factors were at play. The only significant differences between groups related to uterine hyperstimulation (without fetal heart rate changes), and results were not consistent in the two trials. In the trial examining the higher dose of misoprostol, more women in the misoprostol group experienced hyperstimulation of labour measured over a 10-minute period compared with those receiving oxytocin (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.02 to 1.35, 350 women). In the study examining the lower titrated dose of misoprostol, there was a lower incidence of tachysystole when labour was augmented with titrated oral misoprostol than with oxytocin (RR 0.39, 95% CI 0.17 to 0.91, 231 women) with no occurrences of hypertonus in either group of women. Important uncertainties still exist on the safety and acceptability of titrated oral misoprostol compared with intravenous oxytocin regimens in women with dystocia following spontaneous onset of labour. Although in facilities where electronic oxytocin infusion is not available, low-dose titrated misoprostol may offer a better alternative to an uncontrolled oxytocin infusion to avoid hyperstimulation. Further research is needed in both high- and low-resource settings More trials should be conducted to evaluate the effect of a standard titration oral misoprostol regimen, both following spontaneous labour and labour induction. Comparisons with other augmentation methods are also warranted, as are any effects on women's birth experiences.
We identified 4245 possible studies from the initial search. Of those studies, four studies (256 participants) met the inclusion criteria. One more study is awaiting classification. Studies were, conducted in single-centre surgical and mixed medical-surgical ICUs. BIS monitor was used to assess the level of sedation in the intervention arm in all the studies. In the control arm, the sedation assessment tools for CA included the Sedation-Agitation Scale (SAS), Ramsay Sedation Scale (RSS) or subjective CA utilizing traditional clinical signs (heart rate, blood pressure, conscious level and pupillary size). Only one study was classified as low risk of bias, the other three studies were classified as high risk. There was no evidence of a difference in one study (N = 50) that measured ICU LOS (Median (Interquartile Range IQR) 8 (4 to 14) in the CA group; 12 (6 to 18) in the BIS group; low-quality evidence).There was little or no effect on the duration of mechanical ventilation (MD -0.02 days (95% CI -0.13 to 0.09; 2 studies; N = 155; I2 = 0%; low-quality evidence)). Adverse events were reported in one study (N = 105) and the effects on restlessness after suction, endotracheal tube resistance, pain tolerance during sedation or delirium after extubation were uncertain due to very low-quality evidence. Clinically relevant adverse events such as self-extubation were not reported in any study. Three studies reported the amount of sedative agents used. We could not measure combined difference in the amount of sedative agents used because of different sedation protocols and sedative agents used in the studies. GRADE quality of evidence was very low. No study reported other secondary outcomes of interest for the review. We found insufficient evidence about the effects of BIS monitoring for sedation in critically ill mechanically ventilated adults on clinical outcomes or resource utilization. The findings are uncertain due to the low- and very low-quality evidence derived from a limited number of studies.
We included 17 observational studies in this review. We found no randomized controlled trials. Twelve studies are based in hospitals, three in prisons and two in universities. Three studies used a controlled before-and-after design, with another site used for comparison. The remaining 14 studies used an uncontrolled before-and-after study design. Five studies reported evidence from two participant groups, including staff and either patients or prisoners (depending on specialist setting), with the 12 remaining studies investigating only one participant group. The four studies (two in prisons, two in hospitals) providing health outcomes data reported an effect of reduced secondhand smoke exposure and reduced mortality associated with smoking-related illnesses. No studies included in the review measured cotinine levels to validate secondhand smoke exposure. Eleven studies reporting active smoking rates with 12,485 participants available for pooling, but with substantial evidence of statistical heterogeneity (I² = 72%). Heterogeneity was lower in subgroups defined by setting, and provided evidence for an effect of tobacco bans on reducing active smoking rates. An analysis exploring heterogeneity within hospital settings showed evidence of an effect on reducing active smoking rates in both staff (risk ratio (RR) 0.71, 95% confidence interval ( CI) 0.64 to 0.78) and patients (RR 0.86, 95% CI 0.76 to 0.98), but heterogeneity remained in the staff subgroup (I² = 76%). In prisons, despite evidence of reduced mortality associated with smoking-related illnesses in two studies, there was no evidence of effect on active smoking rates (1 study, RR 0.99, 95% CI 0.84 to 1.16). We judged the quality of the evidence to be low, using the GRADE approach, as the included studies are all observational. We found evidence of an effect of settings-based smoking policies on reducing smoking rates in hospitals and universities. In prisons, reduced mortality rates and reduced exposure to secondhand smoke were reported. However, we rated the evidence base as low quality. We therefore need more robust studies assessing the evidence for smoking bans and policies in these important specialist settings.
Nineteen studies were identified that met the inclusion criteria.  Most patients in the studies had neurogenic OAB, but some included patients with idiopathic OAB.  All studies demonstrated superiority of botulinum toxin to placebo.  Lower doses of botulinum toxin (100 to 150 U) appeared to have beneficial effects, but larger doses (300 U) may have been more effective and longer lasting, but with more side effects.  Suburothelial injection had comparable efficacy to intradetrusor injection. The effect of botulinum toxin may last for a number of months and is dependent upon dose and type of toxin used. Patients receiving repeated doses do not seem to become refractory to botulinum toxin. Botulinum toxin appeared to have beneficial effects in OAB that quantitatively exceeded the effects of intravesical resiniferatoxin. Intravesical botulinum toxin appeared to be reasonably safe; however, one study was halted due to a perceived unacceptable rate of urinary retention. Intravesical botulinum toxin appears to be an effective therapy for refractory OAB symptoms, but as yet little controlled trial data exist on benefits and safety compared with other interventions, or with placebo. Further robust data are required on long term outcomes, safety, and optimal dose of botulinum toxin for OAB.
We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias. We found no effect on all-cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low-quality evidence). No-recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate-quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low-quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low-quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low-quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta-analysed; low-quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD -8.29 μmol/L, 95% CI -13.17 to -3.41; low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. When probiotics were compared with lactulose, the effects on all-cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low-quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low-quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low-quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low-quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low-quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low-quality evidence); quality of life (results not meta-analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD -2.93 μmol/L, 95% CI -9.36 to 3.50; very low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High-quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.
In total, the search identified 2102 records, of which we reviewed 144 in full text. We included eight studies. Four interventions focused on patient–caregiver dyads and four were aimed specifically at the caregiver. Heterogeneity of populations and methodologies precluded meta-analysis. Risk of bias varied, and all studies included only small numbers of neuro-oncology caregivers (13 to 56 participants). There was some evidence for positive effects of caregiver support on psychological distress, mastery, and quality of life (low to very low certainty of evidence). No studies reported significant effects on caregiver burden or quality of patient–caregiver relationship (low to very low certainty of evidence). None of the studies assessed caregiver physical functioning. For secondary outcomes (patient emotional or physical well-being; health economic effects), we found very little to no evidence for the effectiveness of caregiver support. We identified five ongoing trials. The eight small-scale studies included employed different methodologies across different populations, with low certainty of evidence overall. It is not currently possible to draw reliable conclusions regarding the effectiveness of supportive interventions aimed at improving neuro-oncology caregiver well-being. More high-quality research is needed on support for family caregivers of people diagnosed, and living, with a brain or spinal cord tumour.
Only seven studies were included. Major methodological limitations such as small trial size and large confidence intervals decreased the power of the studies to detect differences between treatments, and meta-analysis of data was not possible for the majority of outcomes. Four placebo-controlled trials did not find evidence that antidepressants improved weight gain, eating disorder or associated psychopathology. Isolated findings, favouring amineptine and nortriptyline, emerged from the antidepressant versus antidepressant comparisons, but cannot be conceived as evidence of efficacy of a specific drug or class of antidepressant in light of the findings from the placebo comparisons. Non-completion rates were similar between the compared groups. A lack of quality information precludes us from drawing definite conclusions or recommendations on the use of antidepressants in acute AN. Future studies testing safer and more tolerable antidepressants in larger, well designed trials are needed to provide guidance for clinical practice.
From 71 papers describing IQCODE test accuracy, we included 1 paper, representing data from 230 individuals (n=16 [7%] with dementia). The paper described those patients consulting a primary care service who self-identified as Japanese-American. Dementia diagnosis was made using Benson & Cummings criteria and the IQCODE was recorded as part of a longer interview with the informant. IQCODE accuracy was assessed at various test thresholds, with a "trade-off" between sensitivity and specificity across these cutpoints. At an IQCODE threshold of 3.2 sensitivity: 100%, specificity: 76%; for IQCODE 3.7 sensitivity: 75%, specificity: 98%. Applying the QUADAS-2 assessments, the study was at high risk of bias in all categories. In particular degree of blinding was unclear and not all participants were included in the final analysis. It is not possible to give definitive guidance on the test accuracy of IQCODE for the diagnosis of dementia in a primary care setting based on the single study identified. We are surprised by the lack of research using the IQCODE in primary care as this is, arguably, the most appropriate setting for targeted case finding of those with undiagnosed dementia in order to maximise opportunities to intervene and provide support for the individual and their carers.
We included one randomised controlled trial involving 64 participants with schizophrenia or schizoaffective disorder. The average age of participants was 54 years; participants had been living with type 2 diabetes for on average nine years, and with their psychiatric diagnosis since they were on average 28 years of age. Investigators evaluated the 24-week Diabetes Awareness and Rehabilitation Training (DART) programme in comparison with usual care plus information (UCI). Follow-up after trial completion was six months. Risk of bias was mostly unclear but was high for selective reporting. Trial authors did not report on diabetes-related complications, all-cause mortality, adverse events, health-related quality of life nor socioeconomic effects. Twelve months of data on self care behaviours as measured by total energy expenditure showed a mean of 2148 kcal for DART and 1496 kcal for UCI (52 participants; very low-quality evidence), indicating no substantial improvement. The intervention did not have a substantial effect on glycosylated haemoglobin A1c (HbA1c) at 6 or 12 months of follow-up (12-month HbA1c data 7.9% for DART vs 6.9% for UCI; 52 participants; very low-quality evidence). Researchers noted small improvements in body mass index immediately after the intervention was provided and at six months, along with improved weight post intervention. Diabetes knowledge and self efficacy improved immediately following receipt of the intervention, and knowledge also at six months. The intervention did not improve blood pressure. Evidence is insufficient to show whether type 2 diabetes self management interventions for people with severe mental illness are effective in improving outcomes. Researchers must conduct additional trials to establish efficacy, and to identify the active ingredients in these interventions and the people most likely to benefit from them.
One randomised trial involving 14 preterm infants was included. There was no evidence of a clear difference between the fat-supplemented and unsupplemented groups in in-hospital rates of growth in weight (MD 0.6 g/kg/day, 95% CI −2.4 to 3.6; 1 RCT, n = 14 infants, very low-quality evidence), length (MD 0.1 cm/week, 95% CI −0.08 to 0.3; 1 RCT, n = 14 infants, very low-quality evidence) and head circumference (MD 0.2 cm/week, 95% CI −0.07 to 0.4; 1 RCT n = 14 infants, very low-quality evidence). There was no clear evidence that fat supplementation increased the risk of feeding intolerance (RR 3.0, 95% CI 0.1 to 64.3; 1 RCT, n = 16 infants, very low-quality evidence). No data were available regarding the effects of fat supplementation on long-term growth, body mass index, body composition, neurodevelopmental, or cardio-metabolic outcomes. The one included trial suggests no evidence of an effect of fat supplementation of human milk on short-term growth and feeding intolerance in preterm infants. However, the very low-quality evidence, small sample size, few events, and low precision diminishes our confidence that these results reflect the true effect of fat supplementation of human milk in preterm infants, and no long-term outcomes were reported. Further high-quality research should evaluate the effect on short and long-term growth, neurodevelopmental and cardio-metabolic outcomes in the context of the development of multicomponent fortifiers. Optimal dosage, adverse effects, and delivery practices should also be evaluated.
Four studies were included involving 640 primary care physicians and more than 6400 patients. There was considerable variation in study setting and the range of outcomes measured. FFS resulted in more primary care visits/contacts, visits to specialists and diagnostic and curative services but fewer hospital referrals and repeat prescriptions compared with capitation. Compliance with a recommended number of visits was higher under FFS compared with capitation payment. FFS resulted in more patient visits, greater continuity of care, higher compliance with a recommended number of visits, but patients were less satisfied with access to their physician compared with salaried payment. It is noteworthy that so few studies met the inclusion criteria. There is some evidence to suggest that the method of payment of primary care physicians affects their behaviour, but the findings' generalisability is unknown. More evaluations of the effect of payment systems on PCP behaviour are needed, especially in terms of the relative impact of salary versus capitation payments.
We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In total there were 2871 participants (1645 active, 1226 placebo), each receiving on average 18 injections. Duration of immunotherapy varied from three days to three years. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the immunotherapy group (SMD -0.73 (95% CI -0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials showed an overall reduction in the immunotherapy group (SMD of -0.57 (95% CI -0.82 to -0.33, p<0.00001)). Clinical interpretation of the effect size is difficult. Adrenaline was given in 0.13% (19 of 14085 injections) of those on active treatment and in 0.01% (1 of 8278 injections) of the placebo group for treatment of adverse events. There were no fatalities. This review has shown that specific allergen injection immunotherapy in suitably selected patients with seasonal allergic rhinitis results in a significant reduction in symptom scores and medication use. Injection immunotherapy has a known and relatively low risk of severe adverse events. We found no long-term consequences from adverse events.
We included 11 randomised controlled studies with 735 participants which produced 16 meta-analyses of outcome data. Meta-analysis indicated that the primary outcome of intervention failure, occurred in lower proportion of participants with PEG compared to NGT (RR 0.18, 95% CI 0.05 to 0.59, eight studies, 408 participants, low quality evidence) and this difference was statistically significant. For this outcome, we also subgrouped the studies by endoscopic gastrostomy technique into pull, and push and not reported. We observed a significant difference favouring PEG in the pull subgroup (RR 0.07, 95% CI 0.01 to 0.35, three studies, 90 participants). Thepush subgroup contained only one clinical trial and the result favoured PEG (RR 0.05, 95% CI 0.00 to 0.74, one study, 33 participants) techniques. We found no statistically significant difference in cases where the technique was not reported (RR 0.43, 95% CI 0.13 to 1.44, four studies, 285 participants). There was no statistically significant difference between the groups for meta-analyses of the secondary outcomes of mortality (RR 0.86, 95% CI 0.58 to 1.28, 644 participants, nine studies, very low quality evidence), overall reports of any adverse event at any follow-up time point (ITT analysis, RR 0.83, 95% CI 0.51 to 1.34), 597 participants, 6 studies, moderate quality evidence), specific adverse events including pneumonia (aspiration) (RR 0.70, 95% CI 0.46 to 1.06, 645 participants, seven studies, low quality evidence), or for the meta- analyses of the secondary outcome of nutritional status including weight change from baseline, and mid-arm circumference at endpoint, although there was evidence in favour of PEG for meta-analyses of mid-arm circumference change from baseline (MD 1.16, 95% CI 1.01 to 1.31, 115 participants, two studies), and levels of serum albumin were higher in the PEG group (MD 6.03, 95% CI 2.31 to 9.74, 107 participants). For meta-analyses of the secondary outcomes of time on enteral nutrition, there was no statistically significant difference (MD 14.48, 95% CI -2.74 to 31.71; 119 participants, two studies). For meta-analyses of quality of life measures (EuroQol) outcomes in two studies with 133 participants, for inconvenience (RR 0.03, 95% CI 0.00 to 0.29), discomfort (RR 0.03, 95% CI 0.00 to 0.29), altered body image (RR 0.01, 95% CI 0.00 to 0.18; P = 0.001) and social activities (RR 0.01, 95% CI 0.00 to 0.18) the intervention favoured PEG, that is, fewer participants found the intervention of PEG to be inconvenient, uncomfortable or interfered with social activities. However, there were no significant differences between the groups for pain, ease of learning to use, or the secondary outcome of length of hospital stay (two studies, 381 participants). PEG was associated with a lower probability of intervention failure, suggesting the endoscopic procedure may be more effective and safe compared with NGT. There is no significant difference in mortality rates between comparison groups, or in adverse events, including pneumonia related to aspiration. Future studies should include details of participant demographics including underlying disease, age and gender, and the gastrostomy technique.
We included 12 studies with a total of 1834 participants in this updated review. The methodological quality of the included studies was difficult to assess as it was poorly reported, so the predominant classification of bias was 'unclear'; the studies did not report on compliance with the prescribed therapy. We were able to include data from only 1160 patients in the meta-analysis. Four trials (152 patients) compared the effects of IS with no respiratory treatment. We found no statistically significant difference between the participants receiving IS and those who had no respiratory treatment for clinical complications (relative risk (RR) 0.59, 95% confidence interval (CI) 0.30 to 1.18). Two trials (194 patients) IS compared incentive spirometry with deep breathing exercises (DBE). We found no statistically significant differences between the participants receiving IS and those receiving DBE in the meta-analysis for respiratory failure (RR 0.67, 95% CI 0.04 to 10.50). Two trials (946 patients) compared IS with other chest physiotherapy. We found no statistically significant differences between the participants receiving IS compared to those receiving physiotherapy in the risk of developing a pulmonary condition or the type of complication. There was no evidence that IS is effective in the prevention of pulmonary complications. There is low quality evidence regarding the lack of effectiveness of incentive spirometry for prevention of postoperative pulmonary complications in patients after upper abdominal surgery. This review underlines the urgent need to conduct well-designed trials in this field. There is a case for large RCTs with high methodological rigour in order to define any benefit from the use of incentive spirometry regarding mortality.
We identified no completed or ongoing RCTs, nRCTs, CBAs, or ITSs. No studies included people undergoing an epidural procedure. No studies compared different platelet count thresholds prior to a procedure. In this update we identified three retrospective cohort studies that contained participants who did and did not receive platelet transfusions prior to lumbar puncture procedures. All three studies were carried out in people with cancer, most of whom had a haematological malignancy. Two studies were in children, and one was in adults. The number of participants receiving platelet transfusions prior to the lumbar puncture procedures was not reported in one study. We therefore only summarised in a narrative form the relevant outcomes from two studies (150 participants; 129 children and 21 adults), in which the number of participants who received the transfusion was given. We judged the overall risk of bias for all reported outcomes for both studies as 'serious' based on the ROBINS-I tool. No procedure-related major bleeding occurred in the two studies that reported this outcome (2 studies, 150 participants, no cases, very low-quality evidence). There was no evidence of a difference in the risk of minor bleeding (traumatic tap) in participants who received platelet transfusions before a lumbar puncture and those who did not receive a platelet transfusion before the procedure (2 studies, 150 participants, very low-quality evidence). One of the 14 adults who received a platelet transfusion experienced minor bleeding (traumatic tap; defined as at least 500 x 106/L red blood cells in the cerebrospinal fluid); none of the seven adults who did not receive a platelet transfusion experienced this event. Ten children experienced minor bleeding (traumatic taps; defined as at least 100 x 106/L red blood cells in the cerebrospinal fluid), six out of the 57 children who received a platelet transfusion and four out of the 72 children who did not receive a platelet transfusion. No serious adverse events occurred in the one study that reported this outcome (1 study, 21 participants, very low-quality evidence). We found no studies that evaluated all-cause mortality within 30 days from the lumbar puncture procedure, length of hospital stay, proportion of participants who received platelet transfusions, or quality of life. We found no evidence from RCTs or non-randomised studies on which to base an assessment of the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future study would need to be very large to detect a difference in the risk of bleeding. A study would need to be designed with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000. The use of a central data collection register or routinely collected electronic records (big data) is likely to be the only method to systematically gather data relevant to this population.
A total of 11 studies recruiting 5862 apparently healthy adults met the inclusion criteria. All of the studies took place in high-income countries. The effect of the interventions on cardiovascular fitness at one year (two studies; 444 participants) was positive and moderate with significant heterogeneity of the observed effects (SMD 0.40; 95% CI 0.04 to 0.76; high quality evidence). The effect of the interventions on self-reported PA at one year (nine studies; 4547 participants) was positive and moderate (SMD 0.20; 95% CI 0.11 to 0.28; moderate quality evidence) with heterogeneity (I2 = 37%) in the observed effects. One study reported positive results at two years (SMD 0.20; 95% CI 0.08 to 0.32; moderate quality evidence). When studies were stratified by risk of bias, the studies at low risk of bias (eight studies; 3403 participants) had an increased effect (SMD 0.28; 95% CI 0.16 to 0.40; moderate quality evidence). The most effective interventions applied a tailored approach to the type of PA and used telephone contact to provide feedback and to support changes in PA levels. There was no evidence of an increased risk of adverse events (seven studies; 2892 participants). Risk of bias was assessed as low (eight studies; 3060 participants) or moderate (three studies; 2677 participants). There were no differences in effectiveness between studies using different types of professionals delivering the intervention (for example health professional, exercise specialist). There was no difference in pooled estimates between studies that generated the prescribed PA using an automated computer programme versus a human, nor between studies that used pedometers as part of their intervention compared to studies that did not. We found consistent evidence to support the effectiveness of remote and web 2.0 interventions for promoting PA. These interventions have positive, moderate sized effects on increasing self-reported PA and measured cardio-respiratory fitness, at least at 12 months. The effectiveness of these interventions was supported by moderate and high quality studies. However, there continues to be a paucity of cost effectiveness data and studies that include participants from varying socioeconomic or ethnic groups. To better understand the independent effect of individual programme components, longer term studies, with at least one year follow-up, are required.
We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS-I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS-I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis. Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias. Primary outcomes One study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes. The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low-quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low-quality evidence). Secondary outcomes In one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6-week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15-week trial) (very low-quality evidence). Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low-quality evidence). Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low-quality evidence). There were few or no data for our remaining secondary outcomes. Quality of evidence For the outcomes with available data, we downgraded the quality of the evidence by three levels to very low-quality due to too few data and the fact that the number of events was too small to be meaningful. This review identified only two small studies, with insufficient data for analysis. As we could undertake no meta-analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life. We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions.
Twenty-four eligible trials were included. Included trials were highly variable with regard to enrolment criteria (that is birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical relative risk (RR) 0.43, 95% confidence interval (CI) 0.33 to 0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.91, 95% CI 0.80 to 1.03; 19 studies, 5338 infants). The included trials reported no systemic infection with the supplemental probiotics organism. Probiotics preparations containing either lactobacillus alone or in combination with bifidobacterium were found to be effective. Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice. Head to head comparative studies are required to assess the most effective preparations, timing, and length of therapy to be utilized.
We identified 30 RCTs with 9177 participants. Sixteen trials were parallel two-arm RCTs, and seven were three-arm parallel trials. There were also seven cluster-randomised trials: two had four arms, and the remaining five had two arms. The median duration of the intervention was six months (range 1 week to 24 months), and the median follow-up period was 12 months (range 0 to 12 months). The trials included a wide spectrum of interventions and were both individual- and group-based. A meta-analysis of all psychological interventions combined versus usual care showed no firm effect on DRD (standardised mean difference (SMD) -0.07; 95% CI -0.16 to 0.03; P = 0.17; 3315 participants; 12 trials; low-quality evidence), HRQoL (SMD 0.01; 95% CI -0.09 to 0.11; P = 0.87; 1932 participants; 5 trials; low-quality evidence), all-cause mortality (11 per 1000 versus 11 per 1000; risk ratio (RR) 1.01; 95% CI 0.17 to 6.03; P = 0.99; 1376 participants; 3 trials; low-quality evidence) or adverse events (17 per 1000 versus 41 per 1000; RR 2.40; 95% CI 0.78 to 7.39; P = 0.13; 438 participants; 3 trials; low-quality evidence). We saw small beneficial effects on self-efficacy and HbA1c at medium-term follow-up (6 to 12 months): on self-efficacy the SMD was 0.15 (95% CI 0.00 to 0.30; P = 0.05; 2675 participants; 6 trials; low-quality evidence) in favour of psychological interventions; on HbA1c there was a mean difference (MD) of -0.14% (95% CI -0.27 to 0.00; P = 0.05; 3165 participants; 11 trials; low-quality evidence) in favour of psychological interventions. Our included trials did not report diabetes-related complications or socioeconomic effects. Many trials were small and were at high risk of bias for incomplete outcome data as well as possible performance and detection biases in the subjective questionnaire-based outcomes assessment, and some appeared to be at risk of selective reporting. There are four trials awaiting further classification. These are parallel RCTs with cognition-focused and emotion-cognition focused interventions. There are another 18 ongoing trials, likely focusing on emotion-cognition or cognition, assessing interventions such as diabetes self-management support, telephone-based cognitive behavioural therapy, stress management and a web application for problem solving in diabetes management. Most of these trials have a community setting and are based in the USA. Low-quality evidence showed that none of the psychological interventions would improve DRD more than usual care. Low-quality evidence is available for improved self-efficacy and HbA1c after psychological interventions. This means that we are uncertain about the effects of psychological interventions on these outcomes. However, psychological interventions probably have no substantial adverse events compared to usual care. More high-quality research with emotion-focused programmes, in non-US and non-European settings and in low- and middle-income countries, is needed.
The primary analysis of overall effect using hazard ratios derived from published survival curves involved six trials (692 women). No significant difference was seen (hazard ratio 0.94, 95% CI 0.79 to 1.12, P = 0.5). A test for heterogeneity gave a P value of 0.1. A pooled estimate of reported response rates in eight trials involving 817 women showed a significant advantage for chemotherapy over endocrine therapy with a relative risk of 1.25 (95% CI 1.01 to 1.54, P = 0.04). However the point estimates for the two largest trials were in opposite directions, and an overall test for heterogeneity gave a P value of 0.0009. There was little information available on toxicity and quality of life. Six of the seven fully published trials commented on increased toxicity with chemotherapy, mentioning nausea, vomiting and alopecia. Three of the seven trials mentioned aspects of quality of life, with differing results. Only one trial formally measured quality of life, concluding that it was better with chemotherapy. In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease.
We identified one randomised clinical trial eligible for inclusion in this review. This study compared the use of nebulised pentoxifylline versus placebo for prevention of BPD in 100 preterm infants and was at high risk of bias due to lack of blinding of intervention and outcome assessors, and incomplete outcome data. There was no statistically significant effect of nebulised pentoxifylline versus placebo on individual outcomes of BPD at 36 weeks PMA or on death prior to 36 weeks PMA. There was no significant effect of nebulised pentoxifylline on intraventricular haemorrhage, periventricular leukomalacia, sepsis, or patent ductus arteriosus (PDA) requiring ligation. The study did not report any of the other secondary outcomes considered for this review. Reporting of adverse events was very limited and did not allow for reliable judgement on the incidence of such events. No long-term outcomes were reported. There is insufficient evidence to determine the safety and efficacy of pentoxifylline for prevention of BPD in preterm neonates. We encourage researchers to conduct clinical trials to confirm or refute the role of pentoxifylline for prevention of BPD in preterm neonates. These trials should report on clinically important outcomes and, ideally, on long-term neurodevelopmental outcome.
Three studies (212 participants) were included in this review. The overall risk of bias was high for two trials and unclear for one. One trial (101 participants) compared ozone treatment with antibiotics for foot ulcers in people with DM. The study had a follow-up period of 20 days. This study showed that ozone treatment was associated with a greater reduction in ulcer area from baseline to the end of the study than treatment with antibiotics (MD -20.54 cm2, 95% CI -20.61 to -20.47), and a shorter duration of hospitalisation (MD -8.00 days, 95% CI -14.17 to -1.83), but did not appear to affect the number of ulcers healed over 20 days (RR 1.10, 95% CI 0.87 to 1.40). No side effects were observed in either group. The other two trials (111 participants) compared ozone treatment plus usual care with usual care for foot ulcers in people with DM. The meta-analysis results did not show evidence of a difference between groups for the outcomes of reduction of ulcer area (MD -2.11 cm2, 95% CI -5.29 to 1.07), the number of ulcers healed (RR 1.69, 95% CI 0.90 to 3.17), adverse events (RR 2.27, 95% CI 0.48 to 10.79), or amputation rate (RR 2.73, 95%CI 0.12, 64.42). The available evidence was three small RCTs with unclear methodology, so we are unable to draw any firm conclusions regarding the effectiveness of ozone therapy for foot ulcers in people with DM.
Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different. Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSβºthal genotypes. Of the remaining two studies, one (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events). The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea – there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported. The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties.
We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted. Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density. In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk. We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.
We included 160 studies with 54,109 enrolled participants; 53,713 participants started the studies and 50,034 completed the studies or data analysis (or both). We could not use 115 RCTs in meta-analytic comparisons because they had zero awareness events. We did not merge 27 of the remaining 45 studies because they had excessive clinical and methodological heterogeneity. We pooled the remaining 18 eligible RCTs in meta-analysis. There are 10 studies awaiting classification which we will process when we update the review. The meta-analyses included 18 trials with 36,034 participants. In the analysis of anaesthetic depth monitoring (either Bispectral Index or M-entropy) versus standard clinical and electronic monitoring, there were nine trials with 34,744 participants. The overall event rate was 0.5%. The effect favoured neither anaesthetic depth monitoring nor standard clinical and electronic monitoring, with little precision in the odds ratio (OR) estimate (OR 0.98, 95% confidence interval (CI) 0.59 to 1.62). In a five-study subset of Bispectral Index monitoring versus standard clinical and electronic monitoring, with 34,181 participants, 503 participants gave awareness reports to a blinded, expert panel who adjudicated or judged the outcome for each patient after reviewing the questionnaires: no awareness, possible awareness, or definite awareness. Experts judged 351 patient awareness reports to have no awareness, 87 to have possible awareness, and 65 to have definite awareness. The effect size favoured neither Bispectral Index monitoring nor standard clinical and electronic monitoring, with little precision in the OR estimate for the combination of definite and possible awareness (OR 0.96, 95% CI 0.35 to 2.65). The effect size favoured Bispectral Index monitoring for definite awareness, but with little precision in the OR estimate (OR 0.60, 95% CI 0.13 to 2.75). We performed three smaller meta-analyses of anaesthetic drugs. There were nine studies with 1290 participants. Wakefulness was reduced by ketamine and etomidate compared to thiopental. Wakefulness was more frequent than awareness. Benzodiazepines reduces awareness compared to thiopental, ketamine, and placebo., Also, higher doses of inhaled anaesthetics versus lower doses reduced the risk of awareness. We graded the quality of the evidence as low or very low in the 'Summary of findings' tables for the five comparisons. Most of the secondary outcomes in this review were not reported in the included RCTs. Anaesthetic depth monitors may have similar effects to standard clinical and electrical monitoring on the risk of awareness during surgery. In older studies comparing anaesthetics in a smaller portion of the patient sample, wakefulness occurred more frequently than awareness. Use of etomidate and ketamine lowered the risk of wakefulness compared to thiopental. Benzodiazepines compared to thiopental and ketamine, or higher doses of inhaled anaesthetics versus lower doses, reduced the risk of awareness.
We included three small studies with a cross-over design, involving a total of 20 participants (11 adults and 9 children), in this review. Our primary outcome was mortality, and there was one death by the time of follow-up 28 days after hospital admission. The trials did not measure the clinical secondary outcomes of quality of life, GCS, and disability. The included studies provided information only for the secondary outcomes intracranial pressure (ICP), cerebral perfusion pressure (CPP), and adverse effects. We were unable to pool the results as the data were either presented in different formats or no numerical data were provided. We included narrative interpretations of the available data. The overall risk of bias of the studies was unclear due to poor reporting of the methods. There was marked inconsistency across studies for the outcome of ICP and small sample sizes or wide confidence intervals for all outcomes. We therefore rated the quality of the evidence as very low for all outcomes and have not included the results of individual studies here. We do not have enough evidence to draw conclusions about the effect of HBE during intensive care management of people with TBI. The lack of consistency among studies, scarcity of data and the absence of evidence to show a correlation between physiological measurements such as ICP, CCP and clinical outcomes, mean that we are uncertain about the effects of HBE during intensive care management in people with severe TBI. Well-designed and larger trials that measure long-term clinical outcomes are needed to understand how and when different backrest positions can affect the management of severe TBI.
We included six trials with 1176 adolescents that measured outcomes at different follow-up periods in this review. Three studies with 732 adolescents compared brief interventions (Bls) with information provision only, and three studies with 444 adolescents compared Bls with assessment only. Reasons for downgrading the quality of evidence included risk of bias of the included studies, imprecision, and inconsistency. For outcomes that concern substance abuse, the retrieved studies only assessed alcohol and cannabis. We generally found moderate-quality evidence that, compared to information provision only, BIs did not have a significant effect on any of the substance use outcomes at short-, medium-, or long-term follow-up. They also did not have a significant effect on delinquent-type behaviour outcomes among adolescents. When compared to assessment-only controls, we found low- or very low-quality evidence that BIs reduced cannabis frequency at short-term follow-up in one study (standardised mean difference (SMD) -0.83; 95% confidence interval (CI) -1.14 to -0.53, n = 269). BIs also significantly reduced frequency of alcohol use (SMD -0.91; 95% CI -1.21 to -0.61, n = 242), alcohol abuse (SMD -0.38; 95% CI -0.7 to -0.07, n = 190) and dependence (SMD -0.58; 95% CI -0.9 to -0.26, n = 190), and cannabis abuse (SMD -0.34; 95% CI -0.65 to -0.02, n = 190) at medium-term follow-up in one study. At long-term follow-up, BIs also reduced alcohol abuse (SMD -0.72; 95% CI -1.05 to -0.40, n = 181), cannabis frequency (SMD -0.56; 95% CI -0.75 to -0.36, n = 181), abuse (SMD -0.62; 95% CI -0.95 to -0.29, n = 181), and dependence (SMD -0.96; 95% CI -1.30 to -0.63, n = 181) in one study. However, the evidence from studies that compared brief interventions to assessment-only conditions was generally of low quality. Brief interventions also had mixed effects on adolescents' delinquent or problem behaviours, although the effect at long-term follow-up on these outcomes in the assessment-only comparison was significant (SMD -0.78; 95% CI -1.11 to -0.45). We found low- or very low-quality evidence that brief school-based interventions may be more effective in reducing alcohol and cannabis use than the assessment-only condition and that these reductions were sustained at long-term follow-up. We found moderate-quality evidence that, when compared to information provision, brief interventions probably did not have a significant effect on substance use outcomes. It is premature to make definitive statements about the effectiveness of brief school-based interventions for reducing adolescent substance use. Further high-quality studies examining the relative effectiveness of BIs for substance use and other problem behaviours need to be conducted, particularly in low- and middle-income countries.
Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized. Four studies reported the responses to enzyme replacement therapy of previously untreated individuals with type 1 Gaucher disease. Two studies investigated maintenance enzyme replacement therapy in people with stable type 1 Gaucher disease previously treated for at least two years. One study compared substrate reduction therapy, enzyme replacement therapy and a combination thereof as maintenance therapy in people with type 1 Gaucher disease previously treated with enzyme replacement therapy. One study examined substrate reduction therapy in people with chronic neuronopathic (type 3) Gaucher disease who continued to receive enzyme replacement therapy. Treatment-naïve participants had similar increases in haemoglobin when comparing those receiving imiglucerase or alglucerase at 60 units/kg, imiglucerase or velaglucerase alfa at 60 U/kg, taliglucerase alfa at 30 units/kg or 60 units/kg, and velaglucerase alfa at 45 units/g or 60 units/kg. For platelet count response in participants with intact spleens, a benefit for imiglucerase over velaglucerase alfa at 60 units/kg was observed, mean difference -79.87 (95% confidence interval -137.57 to -22.17). There were no other significant differences in platelet count response when comparing different doses of velaglucerase alfa and of taliglucerase alfa, and when comparing imiglucerase to alglucerase. Spleen and liver volume reductions were not significantly different in any enzyme replacement therapy product or dose comparison study. Although a dose effect on serum biomarkers was not seen after nine months, a significantly greater reduction with higher dose was reported after 12 months in the velaglucerase study, mean difference 16.70 (95% confidence intervaI 1.51 to 31.89). In the two enzyme replacement therapy maintenance studies comparing infusions every two weeks and every four weeks, there were no significant differences in haemoglobin concentration, platelet count, and spleen and liver volumes over a 6 to 12 month period when participants were treated with the same cumulative dose. A total of 25 serious adverse events were reported, nearly all deemed unrelated to treatment. There are, as yet, no randomized trials of substrate reduction therapy in treatment-naïve patients that can be evaluated. Miglustat monotherapy appeared as effective as continued enzyme replacement therapy for maintenance of hematological, organ and biomarker responses in people with type 1 Gaucher disease previously treated with imiglucerase for at least two years. In those with neuronopathic Gaucher disease, no significant improvements in haemoglobin concentration, platelet count or organ volumes occurred when enzyme replacement therapy was augmented with miglustat. One randomized controlled study assessing substrate reduction therapy was published immediately prior to producing the final version of this review, and this, along with a further ongoing study (expected to be published in the near future), will be assessed for eligibility in a future update of the review. The results reflect the limitations of analysing evidence restricted to prospective randomized controlled trials, especially when dealing with chronic rare diseases. This analysis suggests that, during the first year of treatment, different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters. Enzyme replacement therapy given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for the assessed clinical outcomes. The analysis emphasise the need to determine whether it is realistic to carry out multi-decade prospective clinical trials for rare diseases such as type 1 Gaucher disease. With large treatment effects on the classical manifestations of the disorder, therapeutic investigations in Gaucher disease mandate innovative trial designs and methodology to secure decisive data concerning long-term efficacy and safety – with the realization that knowledge about disease-modifying actions that are sustained are of crucial importance to people with this chronic condition.
We identified 39 trials with 1827 participants. We considered the trials to be at a mixed risk of bias as the result of unreported allocation concealment and probable detection bias. Compared with no intervention, physiotherapy significantly improved the gait outcomes of speed (mean difference 0.04 m/s, 95% confidence interval (CI) 0.02 to 0.06, P = 0.0002); two- or six-minute walk test (13.37 m, 95% CI 0.55 to 26.20, P = 0.04) and Freezing of Gait questionnaire (-1.41, 95% CI -2.63 to -0.19, P = 0.02); functional mobility and balance outcomes of Timed Up & Go test (-0.63 s, 95% CI -1.05 to -0.21, P = 0.003), Functional Reach Test (2.16 cm, 95% CI 0.89 to 3.43, P = 0.0008), and Berg Balance Scale (3.71 points, 95% CI 2.30 to 5.11, P < 0.00001); and clinician-rated disability using the Unified Parkinson’s Disease Rating Scale (UPDRS) (total -6.15 points, 95% CI-8.57 to -3.73, P < 0.00001; activities of daily living: -1.36, 95% CI -2.41 to -0.30, P = 0.01; and motor: -5.01, 95% CI -6.30 to -3.72, P < 0.00001). No difference between arms was noted in falls (Falls Efficacy Scale: -1.91 points, 95% CI -4.76 to 0.94, P = 0.19) or patient-rated quality of life (PDQ-39 Summary Index: -0.38 points, 95% CI -2.58 to 1.81, P = 0.73). One study reported that adverse events were rare; no other studies reported data on this outcome. Indirect comparisons of the different physiotherapy interventions revealed no evidence that the treatment effect differed across physiotherapy interventions for any of the outcomes assessed. Benefit for physiotherapy was found in most outcomes over the short term (i.e. < 3 months) but was significant only for speed, two- or six-minute walk test, Freezing of Gait questionnaire, Timed Up & Go, Functional Reach Test, Berg Balance Scale, and clinician-rated UPDRS. Most of the observed differences between treatments were small. However, for some outcomes (e.g. speed, Berg Balance Scale, UPDRS), the differences observed were at, or approaching, what are considered minimal clinically important changes. These benefits should be interpreted with caution because the quality of most of the included trials was not high. Variation in measurements of outcome between studies meant that our analyses include a small proportion of the participants recruited. This review illustrates that a wide range of approaches are employed by physiotherapists to treat patients with PD. However, no evidence of differences in treatment effect was noted between the different types of physiotherapy interventions being used, although this was based on indirect comparisons. A consensus menu of 'best practice' physiotherapy is needed, as are large, well-designed randomised controlled trials undertaken to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.
We identified three studies involving 433 patients. Overall, the quality of studies was not high, and there was moderate to high risk of bias. Interventions of a pre-visit booklet and a pre-visit session (either combined or pre-visit session alone) led to more questioning behaviour and more self-reported active behaviour in the intervention group (3 studies). One study (booklet and pre-visit session) showed no difference in consultation length and time engaged in talk between the intervention and control groups. The booklet and pre-visit session in one study was associated with more satisfaction with interpersonal aspects of care for the intervention group although no difference in overall satisfaction between intervention and control. There was no long-term follow up to see if effects were sustained. No studies measured outcomes relating to the use of health care, health status and wellbeing, or health behaviour. Overall this review shows some positive effects of specific methods to improve the involvement of older people in primary care episodes. Because the evidence is limited, however, we can not recommend the use of the reviewed interventions in daily practice. There should be a balance between respecting patients' autonomy and stimulating their active participation in health care. Face-to-face coaching sessions, whether or not complemented with written materials, may be the way forward. As this is impractical for the whole population, it could be worthwhile to identify a subgroup of older patients who might benefit the most from enhanced involvement, ie. those who want to be involved, but lack the necessary skills. This group could be coached either individually or, more practically, in group sessions.
We included three randomized controlled trials (RCTs) and one cluster-RCT (with a total of 26,742 participants analysed). We identified one ongoing study. While predominantly adult patients, one study included children. Untrained bystander-administered CPR Three studies assessed CPR provided by untrained bystanders in urban areas of the USA, Sweden and the UK. Bystanders administered CPR under telephone instruction from emergency services. There was an unclear risk of selection bias in two trials and low risk of detection, attrition, and reporting bias in all three trials. Survival outcomes were unlikely to be affected by the unblinded design of the studies. We found high-quality evidence that continuous chest compression CPR without rescue breathing improved participants’ survival to hospital discharge compared with interrupted chest compression with pauses for rescue breathing (ratio 15:2) by 2.4% (14% versus 11.6%; RR 1.21, 95% confidence interval (CI) 1.01 to 1.46; 3 studies, 3031 participants). One trial reported survival to hospital admission, but the number of participants was too low to be certain about the effects of the different treatment strategies on survival to admission(RR 1.18, 95% CI 0.94 to 1.48; 1 study, 520 participants; moderate-quality evidence). There were no data available for survival at one year, quality of life, return of spontaneous circulation or adverse effects. There was insufficient evidence to determine the effect of the different strategies on neurological outcomes at hospital discharge (RR 1.25, 95% CI 0.94 to 1.66; 1 study, 1286 participants; moderate-quality evidence). The proportion of participants categorized as having good or moderate cerebral performance was 11% following treatment with interrupted chest compression plus rescue breathing compared with 10% to 18% for those treated with continuous chest compression CPR without rescue breathing. CPR administered by a trained professional In one trial that assessed OHCA CPR administered by emergency medical service professionals (EMS) 23,711 participants received either continuous chest compression CPR (100/minute) with asynchronous rescue breathing (10/minute) or interrupted chest compression with pauses for rescue breathing (ratio 30:2). The study was at low risk of bias overall. After OHCA, risk of survival to hospital discharge is probably slightly lower for continuous chest compression CPR with asynchronous rescue breathing compared with interrupted chest compression plus rescue breathing (9.0% versus 9.7%) with an adjusted risk difference (ARD) of -0.7%; 95% CI (-1.5% to 0.1%); moderate-quality evidence. There is high-quality evidence that survival to hospital admission is 1.3% lower with continuous chest compression CPR with asynchronous rescue breathing compared with interrupted chest compression plus rescue breathing (24.6% versus 25.9%; ARD -1.3% 95% CI (-2.4% to -0.2%)). Survival at one year and quality of life were not reported. Return of spontaneous circulation is likely to be slightly lower in people treated with continuous chest compression CPR plus asynchronous rescue breathing (24.2% versus 25.3%; -1.1% (95% CI -2.4 to 0.1)), high-quality evidence. There is high-quality evidence of little or no difference in neurological outcome at discharge between these two interventions (7.0% versus 7.7%; ARD -0.6% (95% CI -1.4 to 0.1). Rates of adverse events were 54.4% in those treated with continuous chest compressions plus asynchronous rescue breathing versus 55.4% in people treated with interrupted chest compression plus rescue breathing compared with the ARD being -1% (-2.3 to 0.4), moderate-quality evidence). Following OHCA, we have found that bystander-administered chest compression-only CPR, supported by telephone instruction, increases the proportion of people who survive to hospital discharge compared with conventional interrupted chest compression CPR plus rescue breathing. Some uncertainty remains about how well neurological function is preserved in this population and there is no information available regarding adverse effects. When CPR was performed by EMS providers, continuous chest compressions plus asynchronous rescue breathing did not result in higher rates for survival to hospital discharge compared to interrupted chest compression plus rescue breathing. The results indicate slightly lower rates of survival to admission or discharge, favourable neurological outcome and return of spontaneous circulation observed following continuous chest compression. Adverse effects are probably slightly lower with continuous chest compression. Increased availability of automated external defibrillators (AEDs), and AED use in CPR need to be examined, and also whether continuous chest compression CPR is appropriate for paediatric cardiac arrest.
A total of 29 trials (5489 patients) including 18 comparisons with placebo and 17 comparisons with synthetic standard antidepressants met the inclusion criteria. Results of placebo-controlled trials showed marked heterogeneity. In nine larger trials the combined response rate ratio (RR) for hypericum extracts compared with placebo was 1.28 (95% confidence interval (CI), 1.10 to 1.49) and from nine smaller trials was 1.87 (95% CI, 1.22 to 2.87). Results of trials comparing hypericum extracts and standard antidepressants were statistically homogeneous. Compared with tri- or tetracyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), respectively, RRs were 1.02 (95% CI, 0.90 to 1.15; 5 trials) and 1.00 (95% CI, 0.90 to 1.11; 12 trials). Both in placebo-controlled trials and in comparisons with standard antidepressants, trials from German-speaking countries reported findings more favourable to hypericum. Patients given hypericum extracts dropped out of trials due to adverse effects less frequently than those given older antidepressants (odds ratio (OR) 0.24; 95% CI, 0.13 to 0.46) or SSRIs (OR 0.53, 95% CI, 0.34-0.83). The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation.
Ten RCTs with 1378 women were identified. Of the seven RCTs on group psychological interventions, three were on cognitive behavioural therapy and four were on supportive-expressive group therapy. The remaining three studies were individual based and the types of psychological interventions were not common to either cognitive behavioural or supportive-expressive therapy. A clear pattern of psychological outcomes could not be discerned as a wide variety of outcome measures and durations of follow-up were used in the included studies. The overall effect of the psychological interventions across six studies, on one-year survival, favoured the psychological intervention group with an odds ratio (OR) of 1.46 (95% confidence interval (CI) 1.07 to 1.99). Pooled data from four studies did not show any survival benefit at five-years follow-up (OR 1.03, 95% CI 0.42 to 2.52). There was evidence of a short-term benefit for some psychological outcomes and improvement in pain scores. Psychological interventions appear to be effective in improving survival at 12 months but not at longer-term follow-up, and they are effective in reducing psychological symptoms only in some of the outcomes assessed in women with metastatic breast cancer. However, findings of the review should be interpreted with caution as there is a relative lack of data in this field, and the included trials had reporting or methodological weaknesses and were heterogeneous in terms of interventions and outcome measures.
Eight trials evaluated ursodeoxycholic acid versus placebo or no intervention (592 patients). The eight randomised clinical trials have a high risk of bias. Patients were treated for three months to six years (median three years). The dosage of ursodeoxycholic acid used in the trials ranged from low (10 mg/kg body weight/day) to high (28 to 30 mg/kg body weight/day). Ursodeoxycholic acid did not significantly reduce the risk of death (RR 1.00; 95% CI 0.46 to 2.20); treatment failure including liver transplantation, varices, ascites, and encephalopathy (RR 1.22; 95% CI 0.91 to 1.64); liver histological deterioration (RR 0.89; 95% CI 0.45 to 1.74); or liver cholangiographic deterioration (RR 0.60; 95% CI 0.23 to 1.57). Ursodeoxycholic acid significantly improved serum bilirubin (MD -14.6 µmol/litre; 95% CI -18.7 to -10.6), alkaline phosphatases (MD -506 IU/litre; 95% CI -583 to -430), aspartate aminotransferase (MD -46 IU/litre; 95% CI -77 to -16), and gamma-glutamyltranspeptidase (MD -260 IU/litre; 95% CI -315 to -205), but not albumin (MD -0.20 g/litre; 95% CI -1.91 to 1.50). Ursodeoxycholic acid was safe and well tolerated by patients with primary sclerosing cholangitis. We did not find enough evidence to support or refute the use of bile acids in the treatment of primary sclerosing cholangitis. However, bile acids seem to lead to a significant improvement in liver biochemistry. Therefore, more randomised trials are needed before any of the bile acids can be recommended for this indication.
We included 11 trials in the review, involving a total of 5974 participants. Four trials involving 4701 women compared weight loss programmes with a control intervention. Low quality evidence from one trial suggested that more women following weight loss programmes reported improvement in symptoms of incontinence at six months (163/214 (76%) versus 49/90 (54%), risk ratio (RR) 1.40, 95% confidence interval (CI) 1.14 to 1.71), and this effect was sustained at 18 months (N = 291, 75% versus 62%, RR not estimable, reported P value 0.02). No data were available for self-reported cure and quality of life. One of the weight loss trials involving 1296 women reported very low quality evidence for a reduction in weekly urinary incontinence a mean of 2.8 years after following a lifestyle weight loss intervention that had been compared with a pharmacological weight loss intervention. Three trials involving 181 women and 11 men compared change in fluid intake with no change. Limited, very low quality evidence suggested that symptom-specific quality of life scores improved when fluid intake was reduced, although some people reported headaches, constipation or thirst. A further three trials involving 160 women and nine men compared reduction in caffeinated drinks with no change, and one trial involving 42 women compared a soy-rich diet with soy-free diet. However, it was not possible to reach any conclusions about the effects of these changes, due to methodological limitations, that resulted in very low quality evidence. Adverse effects appeared relatively uncommon for all interventions studied. All included studies had a high or unclear risk of bias across all bias parameters, but most notably for allocation concealment. The main factors for our downgrading of the evidence were risk of bias, indirect evidence (less than 12 months of follow-up; and not all participants having confirmed urinary incontinence at baseline in some studies), and imprecise results with wide confidence intervals. Other interventions such as reduction in consumption of sweetened fizzy or diet drinks; reduction in alcohol consumption; avoiding constipation; smoking cessation; restricting strenuous physical forces; or reducing high levels of, or increasing low levels of, physical activity, could not be assessed in this review, as no evidence from randomized controlled trials or quasi-randomised trials was available. Evidence for the effect of weight loss on urinary incontinence is building and should be a research priority. Generally, there was insufficient evidence to inform practice reliably about whether lifestyle interventions are helpful in the treatment of urinary incontinence.
We found only one quasi-randomised trial with 30 participants that met our inclusion criteria. In the small trial, total and ionised serum calcium levels were measured immediately before and immediately after EBT. All the participants were included in the final analysis and all the important outcomes were reported. Primary outcomes There was one death in each group (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1). The study did not report the presence of cardiac arrhythmias within one week of EBT and the number of infants with serum calcium levels (total less than 8 mg/dL (2 mmol/L) or ionised less than 4.4 mg/dL (1.1 mmol/L)). Pair-wise comparison of EBT with intravenous 10% calcium gluconate versus EBT without intravenous calcium (change from baseline) showed mean total serum calcium was raised in the intervention group compared to the control group (MD -0.46, 95% CI -0.81 to -0.11; participants = 30; studies = 1). Very low-quality evidence also indicated an increase in the levels of mean ionised serum calcium in the intervention group compared to the control group (MD -0.22, 95% CI -0.33 to -0.11; participants = 30; studies = 1). Secondary outcomes Adverse reactions to intravenous calcium therapy included cardiac arrest in one neonate in the intervention arm (RR 3.00, 95% CI 0.13 to 68.26; RD 0.07, 95% CI -0.10 to 0.23; participants = 30; studies = 1). There was apnoea and hypoglycaemia (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1) in the two neonates who died. Data were not available for other major secondary outcomes such as the number of infants with reduced serum magnesium, reduced parathormone, increased calcitonin, presence of seizures, carpopedal spasm, jitteriness and prolonged QTc interval on electrocardiography within one week of EBT. Very low-quality data from one quasi-randomised controlled trial suggested that the mean serum total and ionised calcium increased in the study group but decreased in the control group immediately after EBT. However, the mean values of total and ionised calcium in both arms of studies remained within international reference ranges. Unfortunately, data were not available to assess the trend of total and ionised serum calcium to the end of the first week after EBT. Therefore, due to the very low quality of evidence available, it is difficult to support or reject the continual use of prophylactic intravenous calcium in newborn infants receiving EBT. Researchers are encouraged to conduct more robustly designed trials with larger numbers of participants, and particularly, addressing the pattern of differences based on gestational age of participants, type of anticoagulant used, and the volume of blood used.
Eight controlled trials (seven placebo controlled and one trial against an active treatment) with a total of 664 participants met the inclusion criteria. Three studied adverse effects of radiotherapy, three studied adverse effects of chemotherapy and two studied menopausal symptoms associated with breast cancer treatment. Two studies with low risk of bias demonstrated benefit: one with 254 participants demonstrated superiority of topical calendula over trolamine (a topical agent not containing corticosteroids) for prevention of radiotherapy-induced dermatitis, and another with 32 participants demonstrated superiority of Traumeel S (a proprietary complex homeopathic medicine) over placebo as a mouthwash for chemotherapy-induced stomatitis. Two other studies reported positive results, although the risk of bias was unclear, and four further studies reported negative results. No serious adverse effects or interactions were reported attributable to the homeopathic medicines used. This review found preliminary data in support of the efficacy of topical calendula for prophylaxis of acute dermatitis during radiotherapy and Traumeel S mouthwash in the treatment of chemotherapy-induced stomatitis. These trials need replicating. There is no convincing evidence for the efficacy of homeopathic medicines for other adverse effects of cancer treatments. Further research is required.
Seven studies, covering 1624 participants, met the inclusion criteria. All included studies investigated adults and compared dexmedetomidine with traditional sedatives, including propofol, midazolam and lorazepam. Compared with traditional sedatives, dexmedetomidine reduced the geometric mean duration of mechanical ventilation by 22% (95% CI 10% to 33%; four studies, 1120 participants, low quality evidence), and consequently the length of stay in the intensive care unit (ICU) by 14% (95% CI 1% to 24%; five studies, 1223 participants, very low quality evidence). There was no evidence that dexmedetomidine decreased the risk of delirium (RR 0.85; 95% CI 0.63 to 1.14; seven studies, 1624 participants, very low quality evidence) as results were consistent with both no effect and appreciable benefit. Only one study assessed the risk of coma, but lacked methodological reliability (RR 0.69; 95% CI 0.55 to 0.86, very low quality evidence). Of all the adverse events included, the most commonly reported one was bradycardia, and we observed a doubled (111%) increase in the incidence of bradycardia (RR 2.11; 95% CI 1.39 to 3.20; six studies, 1587 participants, very low quality evidence). Our meta-analysis provided no evidence that dexmedetomidine had any impact on mortality (RR 0.99; 95% CI 0.79 to 1.24; six studies, 1584 participants, very low quality evidence). We observed high levels of heterogeneity in risk of delirium (I² = 70%), but due to the limited number of studies we were unable to determine the source of heterogeneity through subgroup analyses or meta-regression. We judged six of the seven studies to be at high risk of bias. In this review, we found no eligible studies for children or for clonidine. Compared with traditional sedatives, long-term sedation using dexmedetomidine in critically ill adults reduced the duration of mechanical ventilation and ICU length of stay. There was no evidence for a beneficial effect on risk of delirium and the heterogeneity was high. The evidence for risk of coma was inadequate. The most common adverse event was bradycardia. No evidence indicated that dexmedetomidine changed mortality. The general quality of evidence ranged from very low to low, due to high risks of bias, serious inconsistency and imprecision, and strongly suspected publication bias. Future studies could pay more attention to children and to using clonidine.
We did not identify any new trials from the updated search so the results remain unchanged as follows. We included 13 randomised controlled trials (RCTs) with a total of 1551 women. We found no differences for admission to the neonatal intensive care unit when betamimetics were compared with placebo (risk ratio (RR) 1.28, 95% confidence interval (CI) 0.68 to 2.41; two RCTs of terbutaline with 2600 women) or with magnesium (RR 0.80, 95% CI 0.43 to 1.46; one RCT of 137 women). The rate of preterm birth (less than 37 weeks) showed no significant difference in six RCTs, four comparing ritodrine with placebo/no treatment and two comparing terbutaline with placebo/no treatment (RR 1.11, 95% CI 0.91 to 1.35; 644 women). We observed no differences between betamimetics and placebo, no treatment or other tocolytics for perinatal mortality and morbidity outcomes. Some adverse effects such as tachycardia were more frequent in the betamimetics groups than the groups allocated to placebo, no treatment or another type of tocolytic. Available evidence does not support the use of oral betamimetics for maintenance therapy after threatened preterm labour.
We included 13 trials involving 514 participants. There was a significant effect of treatment on subjective reports of memory in the short term (standard mean difference (SMD) 0.36, 95% confidence interval (CI) 0.08 to 0.64, P = 0.01, moderate quality of evidence), but not the long term (SMD 0.31, 95% CI -0.02 to 0.64, P = 0.06, low quality of evidence). The SMD for the subjective reports of memory had small to moderate effect sizes. The results do not show any significant effect of memory rehabilitation on performance in objective memory tests, mood, functional abilities, or quality of life. No information was available on adverse events. Participants who received cognitive rehabilitation for memory problems following a stroke reported benefits from the intervention on subjective measures of memory in the short term (i.e. the first assessment point after the intervention, which was a minimum of four weeks). This effect was not, however, observed in the longer term (i.e. the second assessment point after the intervention, which was a minimum of three months). There was, therefore, limited evidence to support or refute the effectiveness of memory rehabilitation. The evidence was limited due to the poor quality of reporting in many studies, lack of consistency in the choice of outcome measures, and small sample sizes. There is a need for more robust, well-designed, adequately powered, and better-reported trials of memory rehabilitation using common standardised outcome measures.
Three trials involving two different interventions were included. Two trials involving 680 children compared flushing CVC with urokinase (with or without heparin) versus heparin alone. Neither of these trials reported on the primary outcome of catheter-related blood stream infection (CRBSI). There was a non-significantly decreased rate of catheter-associated infection (CAI) (Rate Ratio 0.72, 95% confidence interval 0.12 to 4.41) in the urokinase (with or without heparin) arm compared with the heparin arm. One trial involving 113 children compared frequency of catheter dressing change every 15 days versus every 4 days. It did not report on CRBSI or CAI. There were no premature catheter removals for infection in either of the trial arms. Three RCTs for only two types of interventions to prevent CVC-related infections in children with cancer have been identified. Flushing CVC with urokinase (with or without heparin) compared to heparin alone possibly leads to decrease in CAI rates. Changing catheter dressings every 15 days versus every 4 days does not lead to more premature catheter removals due to infection although data were insufficient to assess if catheter-related infection rates were changed.
Three randomised controlled trials involving 2270 women from high-income countries were eligible for inclusion in the review. Outcomes were reported for 1280 infants in one study. The interventions assessed in the trials were designed to be used either independently by women or mediated through the involvement of independent support. No studies looked at shared decision supports, that is, interventions designed to facilitate shared decision-making with health professionals during clinical encounters. We found no difference in planned mode of birth: VBAC (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.97 to 1.10; I² = 0%) or caesarean birth (RR 0.96, 95% CI 0.84 to 1.10; I² = 0%). The proportion of women unsure about preference did not change (RR 0.87, 95% CI 0.62 to 1.20; I² = 0%). There was no difference in adverse outcomes reported between intervention and control groups (one trial, 1275 women/1280 babies): permanent (RR 0.66, 95% CI 0.32 to 1.36); severe (RR 1.02, 95% CI 0.77 to 1.36); unclear (0.66, 95% CI 0.27, 1.61). Overall, 64.8% of those indicating preference for VBAC achieved it, while 97.1% of those planning caesarean birth achieved this mode of birth. We found no difference in the proportion of women achieving congruence between preferred and actual mode of birth (RR 1.02, 95% CI 0.96 to 1.07) (three trials, 1921 women). More women had caesarean births (57.3%), including 535 women where it was unplanned (42.6% all caesarean deliveries and 24.4% all births). We found no difference in actual mode of birth between groups, (average RR 0.97, 95% CI 0.89 to 1.06) (three trials, 2190 women). Decisional conflict about preferred mode of birth was lower (less uncertainty) for women with decisional support (standardised mean difference (SMD) -0.25, 95% CI -0.47 to -0.02; two trials, 787 women; I² = 48%). There was also a significant increase in knowledge among women with decision support compared with those in the control group (SMD 0.74, 95% CI 0.46 to 1.03; two trials, 787 women; I² = 65%). However, there was considerable heterogeneity between the two studies contributing to this outcome ( I² = 65%) and attrition was greater than 15 per cent and the evidence for this outcome is considered to be moderate quality only. There was no difference in satisfaction between women with decision support and those without it (SMD 0.06, 95% CI -0.09 to 0.20; two trials, 797 women; I² = 0%). No study assessed decisional regret or whether women's information needs were met. Qualitative data gathered in interviews with women and health professionals provided information about acceptability of the decision support and its feasibility of implementation. While women liked the decision support there was concern among health professionals about their impact on their time and workload. Evidence is limited to independent and mediated decision supports. Research is needed on shared decision support interventions for women considering mode of birth in a pregnancy after a caesarean birth to use with their care providers.
We included 21 trials involving 4174 participants. Nine trials used a combination of venesection and plasma volume expander. Twelve trials used plasma volume expander alone. The plasma volume expander was plasma alone in one trial, dextran 40 in 12 trials, hydroxyethyl starch (HES) in five trials and albumin in three trials. Two trials tested haemodilution in combination with another therapy. Evaluation was blinded in 14 trials. Five trials probably included some participants with intracerebral haemorrhage. Haemodilution did not significantly reduce deaths within the first four weeks (risk ratio (RR) 1.10; 95% confidence interval (CI) 0.90 to 1.34). Similarly, haemodilution did not influence deaths within three to six months (RR 1.05; 95% CI 0.93 to 1.20), or death and dependency or institutionalisation (RR 0.96; 95% CI 0.85 to 1.07). The results were similar in confounded and unconfounded trials, and in trials of isovolaemic and hypervolaemic haemodilution. No statistically significant benefits were documented for any particular type of haemodiluting agents, but the statistical power to detect effects of HES was weak. Six trials reported venous thromboembolic events. There was a tendency towards reduction in deep venous thrombosis or pulmonary embolism or both at three to six months' follow-up (RR 0.68; 95% CI 0.37 to 1.24). There was no statistically significant increased risk of serious cardiac events among haemodiluted participants. The overall results of this review showed no clear evidence of benefit of haemodilution therapy for acute ischaemic stroke. These results are compatible with no persuasive beneficial evidence of haemodilution therapy for acute ischaemic stroke. This therapy has not been proven to improve survival or functional outcome.
A total of 131 studies with 10,514 randomised participants are now included. Overall only 8% of these studies were assessed as being at low risk of bias. Ten interventions, where there was more than one trial in the meta-analysis, showed some statistically significant evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis, compared to either a placebo or no treatment. These ten interventions were: aloe vera, amifostine, cryotherapy, granulocyte-colony stimulating factor (G-CSF), intravenous glutamine, honey, keratinocyte growth factor, laser, polymixin/tobramycin/amphotericin (PTA) antibiotic pastille/paste and sucralfate. Ten interventions were found to have some benefit with regard to preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specific for certain cancer types and treatment. There is a need for further well designed, and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.
Six randomized controlled trials were included (total 162 participants, age range 7 to 53 years).  Pimozide was compared with: placebo and haloperidol (two trials), placebo (one trial), haloperidol (one trial), and risperidone (two trials). Methodological quality was rated ‘fair’ for all studies. Studies used different outcome measurement scales for assessing tic severity and adverse effects. Significant clinical heterogeneity made meta-analysis inappropriate. Pimozide was superior to placebo in three studies, though it caused more side effects than placebo in one of these. Pimozide was inferior to haloperidol in one of three studies (the other two showed no significant difference between the drugs), which also showed significantly fewer side effects associated with pimozide. No significant differences between pimozide and risperidone were detected. Pimozide is an effective treatment for tics in Tourette Syndrome, though the number of trials comparing its effect to placebo and other drugs is limited. Trials of longer duration (minimum six months) are needed to investigate the longer-term effects of pimozide compared to atypical neuroleptics.  Future trials should use the Yale Global Tic Severity Scale to assess the main outcome measure, and quantify adverse events with the Extrapyramidal Symptoms Rating Scale.
The database search identified 3963 references. Nineteen trials with 1592 participants were included. Psychological intervention studies (eight trials, 1122 participants, duration of therapy three weeks to 12 months, follow-up after treatment zero to six months) showed beneficial effects on short (i.e. end of treatment), medium (i.e. one to six months after treatment) and long-term (i.e. more than six months after treatment) depression severity (range of standardised mean differences (SMD) -1.47 to -0.14; eight trials). However, between-study heterogeneity was substantial and meta-analyses were not conducted. Short-term depression remission rates (OR 2.88; 95% confidence intervals (CI) 1.58 to 5.25; P = 0.0006; 647 participants; four trials) and medium-term depression remission rates (OR 2.49; 95% CI 1.44 to 4.32; P = 0.001; 296 participants; two trials) were increased in psychological interventions compared to usual care. Evidence regarding glycaemic control in psychological intervention trials was heterogeneous and inconclusive. QoL did not improve significantly based on the results of three psychological intervention trials compared to usual care. Healthcare costs and adherence to diabetes and depression medication were examined in only one study and reliable conclusions cannot be drawn. Diabetes complications and death from any cause have not been investigated in the included psychological intervention trials. With regards to the comparison of pharmacological interventions versus placebo (eight trials; 377 participants; duration of intervention three weeks to six months, no follow-up after treatment) there was a moderate beneficial effect of antidepressant medication on short-term depression severity (all studies: SMD -0.61; 95% CI -0.94 to -0.27; P = 0.0004; 306 participants; seven trials; selective serotonin reuptake inhibitors (SSRI): SMD -0.39; 95% CI -0.64 to -0.13; P = 0.003; 241 participants; five trials). Short-term depression remission was increased in antidepressant trials (OR 2.50; 95% CI 1.21 to 5.15; P = 0.01; 136 participants; three trials). Glycaemic control improved in the short term (mean difference (MD) for glycosylated haemoglobin A1c (HbA1c) -0.4%; 95% CI -0.6 to -0.1; P = 0.002; 238 participants; five trials). HRQoL and adherence were investigated in only one trial each showing no statistically significant differences. Medium- and long-term depression and glycaemic control outcomes as well as healthcare costs, diabetes complications and mortality have not been examined in pharmacological intervention trials. The comparison of pharmacological interventions versus other pharmacological interventions (three trials, 93 participants, duration of intervention 12 weeks, no follow-up after treatment) did not result in significant differences between the examined pharmacological agents, except for a significantly ameliorated glycaemic control in fluoxetine-treated patients (MD for HbA1c -1.0%; 95% CI -1.9 to -0.2; 40 participants) compared to citalopram in one trial. Psychological and pharmacological interventions have a moderate and clinically significant effect on depression outcomes in diabetes patients. Glycaemic control improved moderately in pharmacological trials, while the evidence is inconclusive for psychological interventions. Adherence to diabetic treatment regimens, diabetes complications, death from any cause, health economics and QoL have not been investigated sufficiently. Overall, the evidence is sparse and inconclusive due to several low-quality trials with substantial risk of bias and the heterogeneity of examined populations and interventions.
We included four trials with a total of 924 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity. We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.02, 95% CI 0.77 to 1.35, I² = 0%; four RCTs; N = 924), live birth alone (OR 0.99, 95% CI 0.69 to 1.44, I² = 0%; three RCTs; N = 597), or miscarriage (OR 1.18, 95% CI 0.77 to 1.82; I² = 0%; three RCTs; N = 869). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.90, 95% CI 0.66 to 1.25, I² = 0%; two RCTs; N = 744). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics. We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.11, 95% CI 0.85 to 1.45; I²= 44%; four trials; N = 924) or multiple pregnancy (OR 1.50, 95% CI 0.70 to 3.19; I² = 0%; two RCTs, N = 180). Rates of cycle cancellation were higher in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744, low quality evidence). There was very low-quality evidence of little or no difference between groups in rates of ectopic pregnancy rates (OR 3.00, 95% CI 0.12 to 74.07; one RCT; N = 417), and foetal abnormality (no events; one RCT; N = 125). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.03, 95% CI 0.76 to 1.38; I² = 40%; two RCTs; N = 744). The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. According to current trials in women undergoing ART, there is no evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy or foetal abnormalities. The existing evidence varied from very low to low-quality. Data on other adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.
Nine completed RCTs met the inclusion criteria, of which four were cluster-randomised. We also identified five ongoing trials. The included studies had a high or unclear risk of bias, and the GRADE ratings of overall quality were low or very low. The length of follow-up varied from one year in four studies, three years in one study, five or six years in two studies, and ten years in two studies. Eight studies recruited participants from the general population, although there were differences in the age ranges targeted. One study recruited family members of cardiac patients (high risk assessment). There were considerable differences between the studies in the interventions received by the intervention and control groups. There was insufficient evidence to stratify by the types of risk assessment approaches. Limited data were available on all-cause mortality (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.93 to 1.03; 3 studies,103,571 participants, I² = 0%; low-quality evidence) and cardiovascular mortality (RR 1.00, 95% CI 0.90 to 1.11; 2 studies, 43,955 participants, I² = 0%), and suggest that screening has no effect on these outcomes. Data were also limited for combined non-fatal endpoints; overall, evidence indicates no difference in total coronary heart disease (RR 1.01, 95% CI 0.95 to 1.07; 4 studies, 5 comparisons, 110,168 participants, I² = 0%; low-quality evidence), non-fatal coronary heart disease (RR 0.98, 95% CI 0.89 to 1.09; 2 studies, 43,955 participants, I² = 39%), total stroke (RR 0.99, 95% CI 0.90 to 1.10; 2 studies, 79,631 participants, I² = 0%, low-quality evidence), and non-fatal stroke (RR 1.17, 95% CI 0.94 to 1.47; 1 study, 20,015 participants). Overall, systematic risk assessment appears to result in lower total cholesterol levels (mean difference (MD) -0.11 mmol/l, 95% CI -0.17 to -0.04, 6 studies, 7 comparisons, 12,591 participants, I² = 57%; very low-quality evidence), lower systolic blood pressure (MD -3.05 mmHg, 95% CI -4.84 to -1.25, 6 studies, 7 comparisons, 12,591 participants, I² = 82%; very low-quality evidence) and lower diastolic blood pressure (MD -1.34 mmHg, 95% CI -1.76 to -0.93, 6 studies, 7 comparisons, 12,591 participants, I² = 0%; low-quality evidence). One study assessed adverse effects and found no difference in psychological distress at five years (1126 participants). The results are limited by the heterogeneity between trials in terms of participants recruited, interventions and duration of follow-up. Limited data suggest that systematic risk assessment for CVD has no statistically significant effects on clinical endpoints. There is limited evidence to suggest that CVD systematic risk assessment may have some favourable effects on cardiovascular risk factors. The completion of the five ongoing trials will add to the evidence base.
We included 15 trials involving 17,674 women. We assessed the quality of the trial evidence for all primary outcomes (i.e. regional analgesia (epidural/spinal), caesarean birth, instrumental vaginal birth (forceps/vacuum), spontaneous vaginal birth, intact perineum, preterm birth (less than 37 weeks) and all fetal loss before and after 24 weeks plus neonatal death using the GRADE methodology: all primary outcomes were graded as of high quality. For the primary outcomes, women who had midwife-led continuity models of care were less likely to experience regional analgesia (average risk ratio (RR) 0.85, 95% confidence interval (CI) 0.78 to 0.92; participants = 17,674; studies = 14; high quality), instrumental vaginal birth (average RR 0.90, 95% CI 0.83 to 0.97; participants = 17,501; studies = 13; high quality), preterm birth less than 37 weeks (average RR 0.76, 95% CI 0.64 to 0.91; participants = 13,238; studies = eight; high quality) and less all fetal loss before and after 24 weeks plus neonatal death (average RR 0.84, 95% CI 0.71 to 0.99; participants = 17,561; studies = 13; high quality evidence). Women who had midwife-led continuity models of care were more likely to experience spontaneous vaginal birth (average RR 1.05, 95% CI 1.03 to 1.07; participants = 16,687; studies = 12; high quality). There were no differences between groups for caesarean births or intact perineum. For the secondary outcomes, women who had midwife-led continuity models of care were less likely to experience amniotomy (average RR 0.80, 95% CI 0.66 to 0.98; participants = 3253; studies = four), episiotomy (average RR 0.84, 95% CI 0.77 to 0.92; participants = 17,674; studies = 14) and fetal loss less than 24 weeks and neonatal death (average RR 0.81, 95% CI 0.67 to 0.98; participants = 15,645; studies = 11). Women who had midwife-led continuity models of care were more likely to experience no intrapartum analgesia/anaesthesia (average RR 1.21, 95% CI 1.06 to 1.37; participants = 10,499; studies = seven), have a longer mean length of labour (hours) (mean difference (MD) 0.50, 95% CI 0.27 to 0.74; participants = 3328; studies = three) and more likely to be attended at birth by a known midwife (average RR 7.04, 95% CI 4.48 to 11.08; participants = 6917; studies = seven). There were no differences between groups for fetal loss equal to/after 24 weeks and neonatal death, induction of labour, antenatal hospitalisation, antepartum haemorrhage, augmentation/artificial oxytocin during labour, opiate analgesia, perineal laceration requiring suturing, postpartum haemorrhage, breastfeeding initiation, low birthweight infant, five-minute Apgar score less than or equal to seven, neonatal convulsions, admission of infant to special care or neonatal intensive care unit(s) or in mean length of neonatal hospital stay (days). Due to a lack of consistency in measuring women's satisfaction and assessing the cost of various maternity models, these outcomes were reported narratively. The majority of included studies reported a higher rate of maternal satisfaction in midwife-led continuity models of care. Similarly, there was a trend towards a cost-saving effect for midwife-led continuity care compared to other care models. This review suggests that women who received midwife-led continuity models of care were less likely to experience intervention and more likely to be satisfied with their care with at least comparable adverse outcomes for women or their infants than women who received other models of care. Further research is needed to explore findings of fewer preterm births and fewer fetal deaths less than 24 weeks, and all fetal loss/neonatal death associated with midwife-led continuity models of care.
Six randomised controlled trials (overall 876 participants) lasting 6 to 24 months were included. Two studies (overall 312 participants) compared valproate with placebo, four studies (overall 618 participants) valproate with lithium, one study (overall 23 participants) valproate with olanzapine and one study (overall 220 participants) valproate with the combination of valproate plus lithium. In terms of study quality, most studies reported the methods used to generate random sequence; however, only one study reported enough details on allocation concealment. Four of six included studies described their design as “double blind”, but only two trials reported full details about blinding. Valproate was more effective than placebo in preventing study withdrawal due to any mood episode (RR 0.68, 95% CI 0.49 to 0.93; NNTB 8), but no difference in efficacy was found between valproate and lithium (RR 1.02, 95% CI 0.87 to 1.20). Valproate was associated with fewer participants dropping out of treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively). However, combination therapy with lithium plus valproate was more likely to prevent relapse than was monotherapy with valproate (RR 0.78, 95% CI 0.63 to 0.96). Significant differences in adverse event frequencies were found, and lithium was associated with more frequent diarrhoea, polyuria, increased thirst and enuresis, whereas valproate was associated with increased sedation and infection. Limited evidence supports the efficacy of valproate in the long-term treatment of bipolar disorder. Clinicians and patients should consider acceptability and tolerability profile when choosing between lithium and valproate—their combination or other agents—as long-term treatment for bipolar disorder.
Forty-five studies, randomising 1863 participants were included in this review. Thirty two studies presented data that could be meta-analysed. Types of exercise training included cardiovascular training, mixed cardiovascular and resistance training, resistance-only training and yoga. Some studies used supervised exercise interventions and others used unsupervised interventions. Exercise intensity was classed as 'high' or 'low', duration of individual exercise sessions ranged from 20 minutes/session to 110 minutes/session, and study duration was from two to 18 months. Seventeen per cent of studies were classed as having an overall low risk of bias, 33% as moderate, and 49% as having a high risk of bias. The results shows that regular exercise significantly improved: 1) physical fitness (aerobic capacity, 24 studies, 847 participants: SMD -0.56, 95% CI -0.70 to -0.42; walking capacity, 7 studies, 191 participants: SMD -0.36, 95% CI-0.65 to -0.06); 2) cardiovascular dimensions (resting diastolic blood pressure, 11 studies, 419 participants: MD 2.32 mm Hg, 95% CI 0.59 to 4.05; resting systolic blood pressure, 9 studies, 347 participants: MD 6.08 mm Hg, 95% CI 2.15 to 10.12; heart rate, 11 studies, 229 participants: MD 6 bpm, 95% CI 10 to 2); 3) some nutritional parameters (albumin, 3 studies, 111 participants: MD -2.28 g/L, 95% CI -4.25 to -0.32; pre-albumin, 3 studies, 111 participants: MD - 44.02 mg/L, 95% CI -71.52 to -16.53; energy intake, 4 studies, 97 participants: SMD -0.47, 95% CI -0.88 to -0.05); and 4) health-related quality of life. Results also showed how exercise should be designed in order to optimise the effect. Other outcomes had insufficient evidence. There is evidence for significant beneficial effects of regular exercise on physical fitness, walking capacity, cardiovascular dimensions (e.g. blood pressure and heart rate), health-related quality of life and some nutritional parameters in adults with CKD. Other outcomes had insufficient evidence due to the lack of data from RCTs. The design of the exercise intervention causes difference in effect size and should be considered when prescribing exercise with the aim of affecting a certain outcome. Future RCTs should focus more on the effects of resistance training interventions or mixed cardiovascular- and resistance training as these exercise types have not been studied as much as cardiovascular exercise.
Four RCTs (262 adult participants) met the inclusion criteria. One study (N = 33) compared an elemental diet to a non-elemental (polymeric) diet. One study (N = 51) compared a half elemental diet to a regular free diet. Another study (N = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group. One study (N= 83) compared a polymeric diet to mesalamine. Two studies were rated as high risk of bias due to lack of blinding or incomplete outcome data. The other two studies were judged to have an unclear risk of bias. The studies were not pooled due to differences in control interventions and the way outcomes were assessed. The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to adverse events is uncertain. Fifty-eight per cent (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57% (8/14) of participants in the polymeric diet group (RR 1.01, 95% CI 0.56 to 1.84; very low certainty evidence). Thirty-two per cent (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95% CI 0.59 to 159.93; low certainty evidence). Anthropometric measures, QoL, adverse events and serious adverse events were not reported as outcomes. The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates is uncertain. Thirty-five per cent (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64% (16/25) of participants in the free diet group (RR 0.54, 95% CI 0.30 to 0.99; very low certainty evidence). No adverse events were reported. This study reported no differences in weight change between the two diet groups. Height and QoL were not reported as outcomes. The effect of an elemental diet compared to 6-MP on relapse rates or adverse events is uncertain. Thirty-eight per cent (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23% (7/30) of participants in the 6-MP group (RR 1.61; 95% CI 0.73 to 3.53; very low certainty evidence). Three per cent (1/32) of participants in the elemental diet group had an adverse event compared to 13% (4/30) of participants in the 6-MP group (RR 0.23, 95% CI 0.03 to 1.98; low certainty evidence). Adverse events in the elemental diet group included surgery due to worsening CD. Adverse events in the 6-MP group included liver injury (n = 2), hair loss (n = 1) and surgery due to an abscess (n = 1). No serious adverse events or withdrawals due to adverse events were reported. Weight, height and QoL were not reported as outcomes The effect of a polymeric diet compared to mesalamine on relapse rates and weight is uncertain. Forty-two per cent (18/43) of participants in the polymeric diet group relapsed at 6 months compared to 55% (22/40) of participants in the mesalamine group (RR 0.76; 95% CI 0.49 to 1.19; low certainty evidence). The mean difference in weight gain over the study period was 1.9 kg higher in the polymeric diet group compared to mesalamine (95% CI -4.62 to 8.42; low certainty evidence). Two participants in the polymeric diet group experienced nausea and four had diarrhoea. It is unclear if any participants in the mesalamine group had an adverse event. Height, QoL, serious adverse events and withdrawal due to adverse events were not reported as outcomes. The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of enteral nutrition in quiescent CD can be drawn. More research is needed to determine the efficacy and safety of using enteral nutrition as maintenance therapy in CD. Currently, there are four ongoing studies (estimated enrolment of 280 participants). This review will be updated when the results of these studies are available.
We included 81 studies (69,094 participants), five of which are new to this update. We judged 22 studies to be at high risk of bias, 53 to be at unclear risk of bias, and six studies to be at low risk of bias. Fifty studies included abstainers, and 30 studies helped people to quit and then tested treatments to prevent relapse. Twenty-eight studies focused on special populations who were abstinent because of pregnancy (19 studies), hospital admission (six studies), or military service (three studies). Most studies used behavioural interventions that tried to teach people skills to cope with the urge to smoke, or followed up with additional support. Some studies tested extended pharmacotherapy. We focused on results from those studies that randomised abstainers, as these are the best test of relapse prevention interventions. Of the 12 analyses we conducted in abstainers, three pharmacotherapy analyses showed benefits of the intervention: extended varenicline in assisted abstainers (2 studies, n = 1297, risk ratio (RR) 1.23, 95% confidence interval (CI) 1.08 to 1.41, I2 = 82%; moderate-certainty evidence), rimonabant in assisted abstainers (1 study, RR 1.29, 95% CI 1.08 to 1.55), and nicotine replacement therapy (NRT) in unaided abstainers (2 studies, n = 2261, RR 1.24, 95% Cl 1.04 to 1.47, I2 = 56%). The remainder of analyses of pharmacotherapies in abstainers had wide confidence intervals consistent with both no effect and a statistically significant effect in favour of the intervention. These included NRT in hospital inpatients (2 studies, n = 1078, RR 1.23, 95% CI 0.94 to 1.60, I2 = 0%), NRT in assisted abstainers (2 studies, n = 553, RR 1.04, 95% CI 0.77 to 1.40, I2 = 0%; low-certainty evidence), extended bupropion in assisted abstainers (6 studies, n = 1697, RR 1.15, 95% CI 0.98 to 1.35, I2 = 0%; moderate-certainty evidence), and bupropion plus NRT (2 studies, n = 243, RR 1.18, 95% CI 0.75 to 1.87, I2 = 66%; low-certainty evidence). Analyses of behavioural interventions in abstainers did not detect an effect. These included studies in abstinent pregnant and postpartum women at the end of pregnancy (8 studies, n = 1523, RR 1.05, 95% CI 0.99 to 1.11, I2 = 0%) and at postpartum follow-up (15 studies, n = 4606, RR 1.02, 95% CI 0.94 to 1.09, I2 = 3%), studies in hospital inpatients (5 studies, n = 1385, RR 1.10, 95% CI 0.82 to 1.47, I2 = 58%), and studies in assisted abstainers (11 studies, n = 5523, RR 0.98, 95% CI 0.87 to 1.11, I2 = 52%; moderate-certainty evidence) and unaided abstainers (5 studies, n = 3561, RR 1.06, 95% CI 0.96 to 1.16, I2 = 1%) from the general population. Behavioural interventions that teach people to recognise situations that are high risk for relapse along with strategies to cope with them provided no worthwhile benefit in preventing relapse in assisted abstainers, although unexplained statistical heterogeneity means we are only moderately certain of this. In people who have successfully quit smoking using pharmacotherapy, there were mixed results regarding extending pharmacotherapy for longer than is standard. Extended treatment with varenicline helped to prevent relapse; evidence for the effect estimate was of moderate certainty, limited by unexplained statistical heterogeneity. Moderate-certainty evidence, limited by imprecision, did not detect a benefit from extended treatment with bupropion, though confidence intervals mean we could not rule out a clinically important benefit at this stage. Low-certainty evidence, limited by imprecision, did not show a benefit of extended treatment with nicotine replacement therapy in preventing relapse in assisted abstainers. More research is needed in this area, especially as the evidence for extended nicotine replacement therapy in unassisted abstainers did suggest a benefit.
Two trials (341 eyes of 238 children and adults) were included comparing efficacy and safety of laser photocoagulation to no therapy in people with proliferative sickle retinopathy. There were 121 males and 117 females with an age range from 13 to 67 years. The laser photocoagulation technique used was different in the two trials; one single-centre trial employed sectoral scatter laser photocoagulation using an argon laser; and the second, two-centre trial, employed feeder vessel coagulation using argon laser in one centre and xenon arc in the second centre. The follow-up period ranged from a mean of 21 to 32 months in one trial and 42 to 47 months in the second. Both trials were at risk of selection bias (random sequence generation) because of the randomisation method employed for participants with bilateral disease. One study was considered to be at risk of reporting bias. Using sectoral scatter laser photocoagulation, one trial (174 eyes) reported that complete regression of proliferative sickle retinopathy was seen in 30.2% in the laser group and 22.4% in the control group (no difference between groups). The same trial reported the development of new proliferative sickle retinopathy in 34.3% of laser-treated eyes and in 41.3% of eyes given no treatment; again, there was no difference between treatment groups. The second trial, using feeder vessel coagulation, did not present full data for either treatment group for these outcomes. There was evidence from both trials (341 eyes) that laser photocoagulation using scatter laser or feeder vessel coagulation may prevent the loss of vision in eyes with proliferative sickle retinopathy (at median follow up of 21 to 47 months). Data from both trials indicated that laser treatment prevented the occurrence of vitreous haemorrhage with both argon and xenon laser; with the protective effect being greater with feeder vessel laser treatment compared to scatter photocoagulation. Regarding adverse effects, the incidence of retinal tear was minimal, with only one event reported. Combined data from both trials were available for 341 eyes; there was no difference between the laser and control arms for retinal detachment. In relation to choroidal neovascularization, treatment with xenon arc was found to be associated with a significantly higher risk, but visual loss related to this complication is uncommon with long-term follow up of three years or more. Data regarding quality of life and other adverse effects were not reported in the included trials. Our conclusions are based on the data from two trials conducted over 20 years ago. In the absence of further evidence, laser treatment for sickle cell disease-related retinopathy should be considered as a one of therapeutic options for preventing visual loss and vitreous haemorrhage. However, it does not appear to have a significant different effect on other clinical outcomes such as regression of proliferative sickle retinopathy and development of new ones. No evidence is available assessing efficacy in relation to patient-important outcomes (such as quality of life or the loss of a driving licence). There is limited evidence on safety, overall, scatter argon laser photocoagulation is superior in terms of adverse effects, although feeder vessel coagulation has a better effect in preventing vitreous haemorrhage. Further research is needed to examine the safety of laser treatment compared to other interventions such as intravitreal injection of anti-vascular endothelial growth factors. In addition, patient-important outcomes as well as cost-effectiveness should be addressed.
Nine studies of 3449 participants were included. The rate of exchange transfusion was reduced in one study with liberal transfusion criteria (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) but not in the other two more recent studies with stringent criteria (typical RR 0.66; 95% CI 0.19 to 2.28). There was no statistically significant difference in the rate of cerebral palsy (typical RR 0.96; 95% CI 0.50 to 1.85; two studies, 756 participants). However, one large study that reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment with prophylactic phototherapy (RR 0.85; 95% CI 0.74 to 0.99; 1804 participants). The prophylactic phototherapy group had lower peak bilirubin levels (mean difference (MD) -2.73; 95% CI -2.89 to -2.57; six studies, 2319 participants) and had fewer neonates with peak unconjugated serum bilirubin levels > 10 mg/dl (typical RR 0.27; 95% CI 0.22 to 0.33; three studies, 1090 participants) or peak unconjugated serum bilirubin levels > 15 mg/dl (typical RR 0.13; 95% CI 0.07 to 0.23; four studies, 1116 participants). There was no statistically significant difference in the rate of all-cause mortality between the two groups (typical RR 1.08; 95% CI 0.93 to 1.26; four studies, 3044 participants). Prophylactic phototherapy helps to maintain a lower serum bilirubin concentration and may have an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment. However, further well-designed studies are needed to determine the efficacy and safety of prophylactic phototherapy on long-term outcomes including neurodevelopmental outcomes.
Nine trials (666 participants) evaluated nicotine for postoperative pain. Nicotine may reduce postoperative pain scores at 24 hours by a small amount compared with placebo (eight trials, mean difference -0.88 on a 0 to 10 scale, 95% confidence interval (CI) -1.58 to -0.18; low quality evidence). The effect on pain at one hour and 12 hours postoperatively was less certain (very low quality evidence). Statistical heterogeneity was substantial and not adequately explained by stratification of trials according to type of surgical procedure, smoking status, mode of nicotine administration, timing of administration, or assessed risk of bias. Excluding one trial at high risk of bias resulted in similar findings. The effect of nicotine on postoperative opioid use was uncertain due to small number of participants in the studies. Nicotine probably increases the risk of postoperative nausea (seven trials, RR 1.24, 95% CI 1.03 to 1.50; moderate quality evidence). Three trials assessed sedation but the effect is very uncertain due to the very low quality of evidence. We found no evidence that nicotine increased the risk of vomiting (seven studies, risk difference (RD) 0.03, 95% CI -0.04 to 0.09; low quality evidence). The results from one single small trial were insufficient to establish whether nicotine led to an earlier hospital discharge (very low quality evidence). Based on evidence of generally low quality, nicotine may reduce postoperative pain at 24 hours compared with placebo, but the effects were relatively small (less than 1 point on a 10 point pain scale) and there was substantial heterogeneity in the results of our analyses. Nicotine does not appear to reduce postoperative use of opioids or opioid-related adverse events but probably increases the risk of nausea. More research is needed to determine the effectiveness of nicotine for postoperative pain and to understand the optimal timing, dose, and method of delivery of nicotine.
Eleven trials that involved 3435 patients were identified. Of 3435 patients, 52 patients were randomised more than once for different painful bone metastasis sites. Altogether, 3487 painful sites were randomised. The trials included patients with painful bone metastases of any primary sites, but were mainly prostate, breast and lung. The overall pain response rates for single fraction radiotherapy and multifraction radiotherapy were 60% (1059/1779) and 59% (1038/1769) respectively, giving an odds ratio of 1.03 (95% confidence interval [CI], 0.89 to 1.19) indicating no difference between the two radiotherapy schedules. There was also no difference in complete pain response rates for single fraction radiotherapy (34% [497/1441]) and multifraction radiotherapy (32% [463/1435]) with an odds ratio of 1.11 (95% CI 0.94 to 1.30). Patients treated by single fraction radiotherapy had a higher re-treatment rate with 21.5% (267/1240) requiring re-treatment compared to 7.4% (91/1236) of patients in the multifraction radiotherapy arm (odds ratio 3.44 [95% CI 2.67 to 4.43]). The pathological fracture rate was also higher in single fraction radiotherapy arm patients. Three percent (37/1240) of patients treated by single fraction radiotherapy developed pathological fracture compared to 1.6% (20/1236) for those treated by multifraction radiotherapy (odds ratio 1.82 [95% CI 1.06 to 3.11]). The spinal cord compression rates were similar for both arms (odds ratio 1.41 [95% CI 0.72 to 2.75]). Repeated analyses excluding dropout patients gave similar results. Single fraction radiotherapy was as effective as multifraction radiotherapy in relieving metastatic bone pain. However, the retreatment rate and pathological fracture rates were higher after single fraction radiotherapy. Studies with quality of life and health economic end points are warranted to find out the optimal treatment option.
In this update, we found four new studies, for a total of ten studies. We included seven RCTs and three cluster-RCTs involving a total of 4527 participants, although we were unable to pool the data from one cluster-RCT. Three of the ten studies were conducted in low- or middle- income countries. All included studies compared face-to-face interventions with control. Most studies evaluated the effectiveness of a single intervention session delivered to individual parents. The interventions were an even mix of short (ten minutes or less) and longer sessions (15 minutes to several hours). Overall, elements of the study designs put them at moderate to high risk of bias. All studies but one were at low risk of bias for sequence generation (i.e. used a random number sequence). For allocation concealment (i.e. the person randomising participants was unaware of the study group to which participant would be allocated), three were at high risk and one was judged at unclear risk of bias. Due to the educational nature of the intervention, blinding of participants and personnel was not possible in any studies. The risk of bias due to blinding of outcome assessors was judged as low for four studies. Most studies were at unclear risk of bias for incomplete outcome data and selective reporting. Other potential sources of bias included failure to account for clustering in a cluster-RCT and significant unexplained baseline differences between groups. One cluster-RCT was at high risk for selective recruitment of participants. We judged the certainty of the evidence to be low for the outcomes of children's vaccination status, parents' attitudes or beliefs, intention to vaccinate, adverse effects (e.g. anxiety), and immunisation cost, and moderate for parents' knowledge or understanding. All studies had limitations in design. We downgraded the certainty of the evidence where we judged that studies had problems with randomisation or allocation concealment, or when outcomes were self-reported by participants who knew whether they'd received the intervention or not. We also downgraded the certainty for inconsistency (vaccination status), imprecision (intention to vaccinate and adverse effects), and indirectness (attitudes or beliefs, and cost). Low-certainty evidence from seven studies (3004 participants) suggested that face-to-face interventions to inform or educate parents may improve vaccination status (risk ratio (RR) 1.20, 95% confidence interval (CI) 1.04 to 1.37). Moderate-certainty evidence from four studies (657 participants) found that face-to-face interventions probably slightly improved parent knowledge (standardised mean difference (SMD) 0.19, 95% CI 0.00 to 0.38), and low-certainty evidence from two studies (179 participants) suggested they may slightly improve intention to vaccinate (SMD 0.55, 95% CI 0.24 to 0.85). Low-certainty evidence found the interventions may lead to little or no change in parent attitudes or beliefs about vaccination (SMD 0.03, 95% CI -0.20 to 0.27; three studies, 292 participants), or in parents’ anxiety (mean difference (MD) -1.93, 95% CI -7.27 to 3.41; one study, 90 participants). Only one study (365 participants) measured the intervention cost of a case management strategy, reporting that the estimated additional cost per fully immunised child for the intervention was approximately eight times higher than usual care (low-certainty evidence). No included studies reported outcomes associated with parents’ experience of the intervention (e.g. satisfaction). There is low- to moderate-certainty evidence suggesting that face-to-face information or education may improve or slightly improve children's vaccination status, parents' knowledge, and parents' intention to vaccinate. Face-to-face interventions may be more effective in populations where lack of awareness or understanding of vaccination is identified as a barrier (e.g. where people are unaware of new or optional vaccines). The effect of the intervention in a population where concerns about vaccines or vaccine hesitancy is the primary barrier is less clear. Reliable and validated scales for measuring more complex outcomes, such as attitudes or beliefs, are necessary in order to improve comparisons of the effects across studies.
Three trials, involving 233 women, are included. There was no evidence of differences in caesarean section rates between the two interventions in the two trials reporting this outcome (risk ratio (RR) 2.04, 95% confidence interval (CI) 0.92 to 4.55). There were no data presented on neonatal or maternal mortality or morbidity. There was no evidence of a difference between castor oil and placebo/no treatment for the rate of instrumental delivery, meconium-stained liquor, or Apgar score less than seven at five minutes. The number of participants was too small to detect all but large differences in outcome. All women who ingested castor oil felt nauseous (RR 59.92, 95% CI 8.46 to 424.52). The three trials included in the review contain small numbers of women. All three studies used single doses of castor oil. The results from these studies should be interpreted with caution due to the risk of bias introduced due to poor methodological quality. Further research is needed to attempt to quantify the efficacy of castor oil as an cervical priming and induction agent.
Two randomized controlled trials evaluated the no-scalpel technique and differed in their findings. The larger trial demonstrated less perioperative bleeding (OR 0.49; 95% CI 0.27 to 0.89) and pain during surgery (OR 0.75; 95% CI 0.61 to 0.93), scrotal pain (OR 0.63; 95% 0.50 to 0.80), and incisional infection (OR 0.21; 95% CI 0.06 to 0.78) during follow up than the standard incisional group. Both studies found less hematoma with the no-scalpel technique (OR 0.23; 95% CI 0.15 to 0.36). Operations using the no-scalpel approach were faster and had a quicker resumption of sexual activity. The smaller study did not find these differences; however, the study could have failed to detect differences due to a small sample size as well as a high loss to follow up. Neither trial found differences in vasectomy effectiveness between the two approaches to the vas. The no-scalpel approach to the vas resulted in less bleeding, hematoma, infection, and pain as well as a shorter operation time than the traditional incision technique. No difference in effectiveness was found between the two approaches.
We included three trials in which a total of 114 infants participated. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately severe encephalopathy. These studies were generally of good methodological quality, but were too small to exclude clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death (typical risk ratio 0.88; 95% confidence interval (95% CI) 0.56 to 1.38; risk difference -0.04; 95% CI -0.18 to 0.10) or a composite of death or severe neurodevelopmental disability (typical risk ratio 0.78; 95% CI 0.56 to 1.08; risk difference -0.14; 95% CI -0.31 to 0.04). The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy. Much larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude important effects on mortality and adverse long-term neurodevelopmental outcomes.
We only considered one study eligible for this review (20 participants). Assessments of risk of bias for most domains were unclear or low. Adverse events were only reported in participants from the zonisamide group, making it possible that they were aware of treatment group assignment. We are uncertain as to the effects of zonisamide on motor tasks (mean difference (MD) -0.00, 95% confidence interval (CI) -1.51 to 1.51, very low-quality evidence) and functional disabilities (MD -0.30, 95% CI -1.23 to 0.63, very low-quality evidence) when compared with placebo. Three participants in the zonisamide group (30%) and two participants in the placebo group (20%) discontinued the treatment and withdrew from the study for any reason (very low-quality evidence), however the increased risk of withdrawal in the zonisamide group was statistically non-significant (risk difference (RD) 0.1, 95% CI -0.28 to 0.48). Six participants in the zonisamide group (60%) and none of the participants in the placebo group (0%) developed adverse events (AEs), with a RD of 0.60 (95% CI 0.28 to 0.92; very low quality evidence). The most common AEs, experienced with zonisamide treatment, were headache, nausea, fatigue, sleepiness, and diarrhoea. Quality of life was not assessed in the study included. Based on currently available data, there is insufficient evidence to assess the efficacy and safety of zonisamide treatment for ET.
We found 21 RCTs including 2482 participants with migraine, and we extracted meta-analytic data from 14 of these studies. The majority of studies recruited participants through advertisements, included participants with migraine according to the International Classification of Headache Disorders (ICHD) criteria and those with and without aura. Most intervention arms were a form of behavioural or cognitive-behavioural therapy. The majority of comparator arms were no treatment, routine care or waiting list. Interventions varied from one 20-minute session to 14 hours of intervention. No study had unequivocally low risk of bias; all had at least one domain at high risk of bias, and 20 had two to five domains at high risk. Reporting of randomisation procedures and allocation concealment were at high or unclear risk of bias. We downgraded the quality of evidence for outcomes to very low, due to very serious limitations in study quality and imprecision. Reporting in trials was poor; we found no preregistrations stipulating the outcomes, or demonstrating equivalent expectations between groups. Few studies reported our outcomes of interest, most only reported outcomes post treatment; follow-up data were sparse. Post-treatment effects We found no evidence of an effect of psychological interventions for migraine frequency in number of migraines or days with migraine (standardised mean difference (SMD) −0.02, 95% confidence interval (CI) −0.17 to 0.13; 4 studies, 681 participants; very low-quality evidence). The responder rate (proportion of participants with migraine frequency reduction of more than 50%) was greater for those who received a psychological intervention compared to control: 101/186 participants (54%) with psychological therapy; 37/152 participants (24%) with control (risk ratio (RR) 2.21, 95% CI 1.63 to 2.98; 4 studies, 338 participants; very low-quality evidence). We found no effect of psychological therapies on migraine intensity (SMD −0.13, 95% CI −0.28 to 0.02; 4 studies, 685 participants). There were no data for migraine duration (hours of migraine per day). There was no effect on migraine medication usage (SMD −0.06, 95% CI −0.35 to 0.24; 2 studies, 483 participants), mood (mean difference (MD) 0.08, 95% CI −0.33 to 0.49; 4 studies, 432 participants), quality of life (SMD −0.02, 95% CI −0.30 to 0.26; 4 studies, 565 participants), or migraine-related disability (SMD −0.67, 95% CI −1.34 to 0.00; 6 studies, 952 participants). The proportion of participants reporting adverse events did not differ between those receiving psychological treatment (9/107; 8%) and control (30/101; 30%) (RR 0.16, 95% CI 0.00 to 7.85; 2 studies, 208 participants). Only two studies reported adverse events and so we were unable to draw any conclusions. We rated evidence from all studies as very low quality. Follow-up Only four studies reported any follow-up data. Follow-ups ranged from four months following intervention to 11 months following intervention. There was no evidence of an effect on any outcomes at follow-up (very low-quality evidence). This review identified 21 studies of psychological interventions for the management of migraine. We did not find evidence that psychological interventions affected migraine frequency, a result based on four studies of primarily brief treatments. Those who received psychological interventions were twice as likely to be classified as responders in the short term, but this was based on very low-quality evidence and there was no evidence of an effect of psychological intervention compared to control at follow-up. There was no evidence of an effect of psychological interventions on medication usage, mood, migraine-related disability or quality of life. There was no evidence of an effect of psychological interventions on migraine frequency in the short-term or long-term. In terms of adverse events, we were unable to draw conclusions as there was insufficient evidence. High and unclear risk of bias in study design and reporting, small numbers of participants, performance and detection bias meant that we rated all evidence as very low quality. Therefore, we conclude that there is an absence of high-quality evidence to determine whether psychological interventions are effective in managing migraine in adults and we are uncertain whether there is any difference between psychological therapies and controls.
We have no good-quality evidence of the absolute effectiveness of haloperidol for people with long-term aggression. One study randomising 110 chronically aggressive people to three different antipsychotic drugs met the inclusion criteria. When haloperidol was compared with olanzapine or clozapine, skewed data (n=83) at high risk of bias suggested some advantage in terms of scale scores of unclear clinical meaning for olanzapine/clozapine for 'total aggression'. Data were available for only one other outcome, leaving the study early. When compared with other antipsychotic drugs, people allocated to haloperidol were no more likely to leave the study (1 RCT, n=110, RR 1.37, CI 0.84 to 2.24, low-quality evidence). Although there were some data for the outcomes listed above, there were no data on most of the binary outcomes and none on service outcomes (use of hospital/police), satisfaction with treatment, acceptance of treatment, quality of life or economics. Only one study could be included and most data were heavily skewed, almost impossible to interpret and oflow quality. There were also some limitations in the study design with unclear description of allocation concealment and high risk of bias for selective reporting, so no firm conclusions can be made. This review shows how trials in this group of people are possible - albeit difficult. Further relevant trials are needed to evaluate use of haloperidol in treatment of long-term/persistent aggression in people living with psychosis.
Nine trials were included in the review. Seven trials, comparing antibiotics to placebo or no treatment, were meta-analysed. Systematic bias in design or publication is suggested by trial results. The randomisation results suggest that the probability that true randomisation took place in all trials is very small and the report of most trials regarding design was poor. The proportion of participants with spontaneous bacterial peritonitis varied between the trials from 15% to 50%. The calculated relative risks (95% confidence interval) of spontaneous bacterial peritonitis and mortality among patients treated with antibiotics compared with no treatment/placebo were 0.20 (0.11 to 0.37) and 0.61 (0.43 to 0.87). There were very few reports of adverse events. The pooled estimates suggest that antibiotic prophylaxis might be prudent among cirrhotic patients with ascites and no gastrointestinal bleeding. However, poor trial methodology and report coupled with findings suggesting systematic bias in publication and design reflect the fragility of these findings. Potential hazard to society and the patients themselves from resistant pathogens should be considered when promoting long-lasting antibiotic prophylaxis. It seems that recommending antibiotic prophylaxis is still far from being a substantiated prevention strategy. Trials of better design, well reported, and of longer follow-up are greatly needed.
We included two large trials. One trial compared three-weekly PLD and carboplatin (PLD/carbo) with PAC/carbo. The other trial included four experimental arms, one of which was PLD plus PAC/carbo, that were compared with the standard PAC/carbo regimen. We did not combine results of these two trials in the meta-analysis. We considered the two studies to be at low risk of bias. For the comparison PLD/carbo versus PAC/carbo (820 women; stages Ic to IV), no statistically significant differences in progression-free survival (PFS) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.85 to 1.19) or overall survival (OS) (HR 0.94, 95% CI 0.78 to 1.13) were noted between study arms. Severe anaemia (risk ratio [RR] 2.74, 95% CI 1.54 to 4.88) and thrombocytopenia (RR 8.09, 95% CI 3.93 to 16.67) were significantly more common with PLD/carbo, whereas alopecia (RR 0.09, 95% CI 0.06 to 0.14) and severe neurotoxicity (RR 0.09, 95% CI 0.01 to 0.66) were significantly more common with PAC/carbo. Quality of life scores were not significantly different. For the comparison PLD/PAC/carbo versus PAC/carbo (1726 women; stage III/IV), it is important to note that PLD was given for alternate cycles only (i.e. every 6 weeks). No statistically significant difference in PFS (HR 0.98, 95% CI 0.88 to 1.09) or OS (HR 0.95, 95% CI 0.84 to 1.08) between these two treatment arms was reported. However, women in the triplet arm experienced significantly more severe haematological adverse events (anaemia, thrombocytopenia, neutropenia and febrile neutropenia) compared with those given standard treatment. No RCTs evaluated single-agent PLD for first-line treatment of EOC. PLD/carbo is a reasonable alternative to PAC/carbo for the first-line treatment of EOC. Although three-weekly PLD/carbo may be associated with increased dose delays and discontinuations compared with the standard PAC/carbo regimen, it might be more acceptable to women who wish to avoid alopecia or those at high risk of neurotoxicity. No survival benefits appear to be associated with the alternating triplet regimen, and the additional toxicity associated with adding PLD to PAC/carbo limits further investigation. Further studies are needed to establish the safest, most effective PLD/carbo regimen for newly diagnosed disease.
We included two trials in this review, with 62 participants included in the analyses. Both trials were conducted in university dental schools in the USA and compared the effects of oral penicillin V potassium (penicillin VK) versus a matched placebo when provided in conjunction with a surgical intervention (total or partial pulpectomy) and analgesics to adults with acute apical abscess or symptomatic necrotic tooth. The patients included in these trials had no signs of spreading infection or systemic involvement (fever, malaise). We assessed one study as having a high risk of bias and the other study as having unclear risk of bias. The primary outcome variables reported in both studies were participant-reported pain and swelling (one trial also reported participant-reported percussion pain). One study reported the type and number of analgesics taken by participants. One study recorded the incidence of postoperative endodontic flare-ups (people who returned with symptoms that necessitated further treatment). Adverse effects, as reported in one study, were diarrhoea (one participant, placebo group) and fatigue and reduced energy postoperatively (one participant, antibiotic group). Neither study reported quality of life measurements. Objective 1: systemic antibiotics versus placebo with surgical intervention and analgesics for symptomatic apical periodontitis or acute apical abscess Two studies provided data for the comparison between systemic antibiotics (penicillin VK) and a matched placebo for adults with acute apical abscess or a symptomatic necrotic tooth when provided in conjunction with a surgical intervention. Participants in one study all underwent a total pulpectomy of the affected tooth, while participants in the other study had their tooth treated by either partial or total pulpectomy. Participants in both trials received oral analgesics. There were no statistically significant differences in participant-reported measures of pain or swelling at any of the time points assessed within the review. The MD for pain (short ordinal numerical scale 0 to 3) was -0.03 (95% CI -0.53 to 0.47) at 24 hours; 0.32 (95% CI -0.22 to 0.86) at 48 hours; and 0.08 (95% CI -0.38 to 0.54) at 72 hours. The SMD for swelling was 0.27 (95% CI -0.23 to 0.78) at 24 hours; 0.04 (95% CI -0.47 to 0.55) at 48 hours; and 0.02 (95% CI -0.49 to 0.52) at 72 hours. The body of evidence was assessed as at very low quality. Objective 2: systemic antibiotics without surgical intervention for adults with symptomatic apical periodontitis or acute apical abscess We found no studies that compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults. There is very low-quality evidence that is insufficient to determine the effects of systemic antibiotics on adults with symptomatic apical periodontitis or acute apical abscess.
A single study enrolling 68 non-intubated children was found eligible for inclusion in review. The study had low or unclear risk of bias. It demonstrated no significant difference in respiratory rate, oxygen saturation, hospital admission rate (odds ratio (OR) 0.77; 95% confidence interval (CI) 0.23 to 2.58) and need for mechanical ventilation between ketamine (0.2 mg/kg intravenous bolus over one to two minutes, followed by a 0.5 mg/kg per hour continuous infusion for two hours) and placebo group. There were no significant side effects of ketamine in the study. There was also no difference in need for other adjuvant therapy (OR 2.19; 95% CI 0.19 to 25.40) and in Pulmonary Index Score (mean difference (MD) -0.40; 95% CI -1.21 to 0.41) between the groups. The single study on non-intubated children with severe acute asthma did not show significant benefit and does not support the case studies and observational reports showing benefits of ketamine in both non-ventilated and ventilated children. There were no significant side effects of ketamine. We could not find any trials on ventilated children. To prove that ketamine is an effective treatment for acute asthma in children, there is need for sufficiently powered randomised trials of high methodological quality with objective outcome measures of clinical importance. Future trials should also explore different doses of ketamine and its role in children needing ventilation because of severe acute asthma.
Sixteen studies were eligible for inclusion (n = 1811 participants), 12 (n = 1366 participants) of which were suitable for meta-analysis. No significant heterogeneity was detected. There were no significant differences between depot GnRHa and daily GnRHa in live birth/ongoing pregnancy rates (OR 0.95, 95% CI 0.70 to 1.31, seven studies, 873 women), but substantial differences could not be ruled out. Thus for a woman with a 24% chance of achieving a live birth or ongoing pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 18% and 29%. There was no significant difference between the groups in clinical pregnancy rate (OR 0.96, 95% CI 0.75 to 1.23, 11 studies, 1259 women). For a woman with a 30% chance of achieving clinical pregnancy using daily GnRHa injections, the corresponding chance using GnRHa depot would be between 25% and 35%. There was no significant difference between the groups in the rate of severe OHSS (OR 0.84, 95% CI 0.29 to 2.42, five studies, 570 women), but substantial differences could not be ruled out. For a woman with a 3% chance of severe OHSS using daily GnRHa injections, the corresponding risk using GnRHa depot would be between 1% and 6%. Compared to women using daily GnRHa, those on depot administration required significantly more gonadotrophin units for ovarian stimulation (standardised mean difference (SMD) 0.26, 95% CI 0.08 to 0.43, 11 studies, 1143 women) and a significantly longer duration of gonadotrophin use (mean difference (MD) 0.65, 95% CI 0.46 to 0.84, 10 studies, 1033 women). Study quality was unclear due to poor reporting. Only four studies reported live births as an outcome and only five described adequate methods for concealment of allocation. We found no evidence of a significant difference between depot and daily GnRHa use for pituitary down regulation in IVF cycles using the long protocol, but substantial differences could not be ruled out. Since depot GnRHa requires more gonadotrophins and a longer duration of use, it may increase the overall costs of IVF treatment.
31 papers reporting the results of 26 trials were included in the review. For studies that compared a step down approach to a constant moderate/low ICS dose, there were no significant differences in lung function, symptoms, rescue medications or asthma control between the two treatment approaches. Significant but clinically small improvements in percent predicted FEV1 ( WMD 5.32, 95% CI 0.65 to 9.99) and non significant improvements in the change in morning PEF were found for high dose ICS compared to moderate dose ICS. There were no significant differences in efficacy between high and low dose ICS. For moderate dose ICS, compared to low dose ICS, there were significant improvements in the change in morning PEF L/min from baseline (WMD 11.14, 95% CI 1.34 to 20.93) and nocturnal symptoms (SMD -0.29, 95% CI -0.53 to -0.06 ) . Commencing ICS at double or quadruple a base moderate or low dose had no greater effect than commencing with the base dose. Several studies reported greater improvement in airway hyperresponsiveness for high dose ICS. For patients with asthma who require ICS, commencing with a moderate dose ICS is equivalent to commencing with a high dose ICS and down-titrating. The small significant benefits of commencing with a high ICS dose are not of sufficient clinical benefit to warrant its use when compared to moderate or low dose ICS. Initial moderate ICS dose appears to be more effective than initial low ICS dose. High dose ICS may be more effective than moderate or low dose ICS for airway hyperresponsiveness. There is no benefit in doubling or quadrupling ICS in subjects with stable asthma.
In this update, we did not identify any new RCT studies for inclusion. We identified two RCT studies as ongoing that we are likely to include in future updates. Accordingly, our results are unchanged and include three RCTs with a total of 316 participants. All three studies compared the effectiveness of VM in reverting SVT with that of other vagal manoeuvres in a cross-over design. Two studies induced SVT within a controlled laboratory environment. Participants had ceased all medications prior to engaging in these studies. The third study reported on people presenting to a hospital emergency department with an episode of SVT. These participants were not controlled for medications or other factors prior to intervention. The two laboratory studies demonstrated reversion rates of 45.9% and 54.3%, whilst the clinical study demonstrated reversion success of 19.4%. This discrepancy may be due to methodological differences between studies, the effect of induced SVT versus spontaneous episodic SVT, and participant factors such as medications and comorbidities. We were unable to assess any of these factors, or adverse effects, further, since they were either not described in enough detail or not reported at all. Statistical pooling was not possible due to heterogeneity between the included studies. We did not find sufficient evidence to support or refute the effectiveness of VM for termination of SVT. Further research is needed, and this research should include a standardised approach to performance technique and methodology.
Twenty two randomised controlled trials were included. Five studies analysed the use of a GnRH agonist versus control. No significant benefit was demonstrated when using GnRH agonists. No evidence of statistically significant benefit was found for one GnRH agonist over another, or vaginal over intramuscular progesterone administration. No difference in pregnancy rate was demonstrated when no treatment was compared to aspirin, steroids, ovarian stimulation, or human chorionic gonadotropin (hCG) prior to embryo transfer, although using hCG several times before the oocyte retrieval decreases the pregnancy rate. Finally, when oocyte recipients were studied further, starting progesterone on the day of oocyte pick-up (OPU) or the day after OPU produced a significantly higher pregnancy rate (OR 1.87, 95% CI 1.13 to 3.08) than when recipients started progesterone the day prior to OPU. There is insufficient evidence to recommend any one particular protocol for endometrial preparation over another with regard to pregnancy rates after embryo transfers. These were either frozen embryos or embryos derived from donor oocytes. However, there is evidence of a lower pregnancy rate and a higher cycle cancellation rate when the progesterone supplementation is commenced prior to oocyte retrieval in oocyte donation cycles. Adequately powered studies are needed to evaluate each treatment more accurately.
We included eight trials with a total of 5762 participants. The data showed that anticoagulants (in any intensity) are not more efficacious in the prevention of recurrent ischaemic stroke than antiplatelet therapy (medium intensity anticoagulation: relative risk (RR) 0.80, 95% confidence interval (CI) 0.56 to 1.14; high intensity anticoagulation: RR 1.02, 95% CI 0.49 to 2.13). There is no evidence that treatment with low intensity anticoagulation gives a higher bleeding risk than treatment with antiplatelet agents: RR 1.27 (95% CI 0.79 to 2.03). However, it was clear that medium and high intensity anticoagulation with vitamin K antagonists, with an INR of 2.0 to 4.5, were not safe because they yielded a higher risk of major bleeding complications (medium intensity anticoagulation: RR 1.93, 95% CI 1.27 to 2.94; high intensity anticoagulation: RR 9.0, 95% CI 3.9 to 21). For the secondary prevention of recurrent ischemic stroke after TIA or minor stroke of presumed arterial origin, there is sufficient evidence to conclude that vitamin K antagonists in any dose are not more efficacious than antiplatelet therapy and that medium and high intensity anticoagulation leads to a significant increase in major bleeding complications.
We included four studies involving 2302 children. One study was at unclear risk of bias and three were at high risk of bias. Included studies reported heterogeneity in both the intervention design and outcome measures used; this made statistical comparison difficult. Additionally this review is limited by poor reporting of intervention procedure and design. Several BCTs were identified in the trials: these included information around the consequences of twice daily brushing and controlling sugar snacking; information on consequences of adverse behaviour and instruction and demonstration regarding skill development of relevant oral health behaviours. Only one included study reported the primary outcome of development of caries. This small study at unclear risk of bias showed a prevented fraction of 0.65 (95% confidence interval (CI) 0.12 to 1.18) in the intervention group. However, as this is based on a single study, this finding should be interpreted with caution. Although no meta-analysis was performed with respect to plaque outcomes (due to differences in plaque reporting between studies), the three studies which reported plaque outcomes all found a statistically significant reduction in plaque in the intervention groups with respect to plaque outcomes. Two of these trials involved an 'active' home component where parents were given tasks relating to the school oral health programme (games and homework) to complete with their children. Secondary outcome measures from one study reported that the intervention had a positive impact upon children's oral health knowledge. Currently, there is insufficient evidence for the efficacy of primary school-based behavioural interventions for reducing caries. There is limited evidence for the effectiveness of these interventions on plaque outcomes and on children's oral health knowledge acquisition. None of the included interventions were reported as being based on or derived from behavioural theory. There is a need for further high quality research to utilise theory in the design and evaluation of interventions for changing oral health related behaviours in children and their parents.
We included one randomised clinical trial that compared four groups: electro-coagulation alone, electro-coagulation + dimethyl sulphoxide, electro-coagulation + allopurinol, and control (Salim 1993). The risk of bias in the trial is high. In three groups, patients had their metastases destroyed with diathermy electro-coagulation (current set at No 5) and received: 1) solution of allopurinol by mouth 5 mL 4 x a day or 2) allopurinol by mouth 5 mL (50 mg) 4 x a day or 3) dimethyl sulphoxide by mouth 5 mL (500 mg) 4 x a day. In the control group patients received a solution of allopurinol by mouth 5 mL 4 x a day. The treatment was started in the fifth postoperative day and was continued for five years. Three hundred and six patients who had undergone resection of the sigmoid colon and who had five or more hepatic metastases were included; 75 received electro-coagulation alone (58 were evaluable), 76 received electro-coagulation plus allopurinol (53 were evaluable), 78 received electro-coagulation plus dimethyl sulphoxide (57 were evaluable), and 77 were in the control group (55 evaluable). The authors reported the number of deaths due to disease spread (100% in the control, 98% in electro-coagulation, 87% in electro-coagulation + allopurinol, and 86% in the electro-coagulation + dimethyl sulphoxide groups). There was a significant benefit in favour of the electro-coagulation + allopurinol (risk ratio (RR) 0.87 (95% confidence interval (CI) 0.78 to 0.96)) and electro-coagulation + dimethyl sulphoxide (RR 0.86 (95% CI 0.77 to 0.95)) groups compared to the control group, but no such benefit in the electro-coagulation alone group (RR 0.98 (95% CI 0.95 to 1.02)) compared to the control group. There were no local recurrences, no positive tests for occult blood, and observed pulmonary metastases were always with ultrasonographic evidence of hepatic secondaries and were not significantly different for the experimental groups compared to the control group (electro-coagulation: RR 1.11 (95% CI 0.4 to 3.09)), electro-coagulation + allopurinol (RR 0.86 (95% CI 0.28 to 2.66)), electro-coagulation + dimethyl sulphoxide (RR 0.8 (95% CI 0.26 to 2.48)). None of the adverse events were significantly associated with treatment. On the basis of one randomised trial which did not describe its methodology in sufficient detail to assess risk of bias and quality, excluded 27% of patients after randomisation due to various reasons, and is probably not free from selective outcome reporting bias, there is insufficient evidence to conclude that in patients with colonic cancer liver metastases, electro-coagulation alone brings any significant benefit in terms of survival or recurrence compared with the control. In addition, there is insufficient evidence for the effectiveness of adding allopurinol or dimethyl sulphoxide to electro-coagulation. The probability for selective outcome reporting bias in the trial is high. More randomised trials are needed in order to sufficiently validate electro-coagulation with or without co-interventions.
We found no completed RCT and included 21 observational studies with 71,693 participants. The only eligible RCT is currently ongoing among MSM in China. The pooled effect estimate for HIV acquisition was not statistically significant (20 studies; 65,784 participants; OR 0.86, 95% CI 0.70 to 1.06) and showed significant heterogeneity (I²=53%). In a subgroup analysis, the results were statistically significant in studies of men reporting an insertive role (7 studies, 3465 participants; OR 0.27, 95% CI 0.17 to 0.44; I²=0%) but not in studies of men reporting a receptive role (3 studies, 1792 participants; OR 1.20, 95% CI 0.63 to 2.29; I² = 0%). There was no significant association between male circumcision and syphilis (8 studies; 34,999 participants: OR 0.96, 95% CI 0.82 to 1.13; I² = 0%), herpes simplex virus 1 (2 studies, 2740 participants; OR 0.90, 95% CI 0.53 to 1.52; I²=0%), or herpes simplex virus 2 (5 studies;10,285 participants; OR 0.86, 95% CI 0.62 to 1.21; I²=0%). The overall GRADE quality of evidence was low. None of the included studies assessed adverse effects associated with male circumcision. Current evidence suggests that male circumcision may be protective among MSM who practice primarily insertive anal sex, but the role of male circumcision overall in the prevention of HIV and other sexually transmitted infections among MSM remains to be determined. Therefore, there is not enough evidence to recommend male circumcision for HIV prevention among MSM at present. Further research should be of high quality and further explore interaction with the predominant sexual role.
We included 38 studies testing 58 different interventions and containing data on 15519 patients. The studies were conducted in nine countries between 1975 and 2000. The duration of follow-up ranged from two to 60 months. Due to heterogeneity between studies in terms of interventions and the methods used to measure adherence, we did not pool the results. Simplifying dosing regimens increased adherence in seven out of nine studies, with a relative increase in adherence of 8 per cent to 19.6 per cent. Motivational strategies were successful in 10 out of 24 studies with generally small increases in adherence up to a maximum of 23 per cent. Complex interventions involving more than one technique increased adherence in eight out of 18 studies, ranging from 5 per cent to a maximum of 41 per cent. Patient education alone seemed largely unsuccessful. Reducing the number of daily doses appears to be effective in increasing adherence to blood pressure lowering medication and should be tried as a first line strategy, although there is less evidence of an effect on blood pressure reduction. Some motivational strategies and complex interventions appear promising, but we need more evidence on their effect through carefully designed RCTs.
We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision. COCP versus placebo COCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I2 = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I2 = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment. COCP versus other medical treatments Non-steroidal anti-inflammatory drugs (NSAIDs) There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events. Levonorgestrel-releasing intrauterine system (LNG IUS) The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I2 = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL. Contraceptive vaginal ring (CVR) versus other medical treatments COCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL. Progestogens CVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events. Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.
Three cross-over studies, with 175 women were included in the review. All three studies had an unclear risk of bias with regards to trial design and overall, the quality of evidence generated was judged to be poor. Two of the studies (n = 59) compared desmopressin (1-deamino-8-D-arginine vasopressin) with placebo. Menstrual blood loss was the primary outcome for both of these studies. Neither study found clear evidence of a difference between groups. The first of these reported a mean difference in menstrual blood loss in the desmopressin versus placebo group of 21.20 mL (95% confidence interval -19.00 to 61.50) The second study reported that even though there was an improvement of pictorial bleeding assessment chart scores with desmopressin and placebo when compared to pretreatment assessment, there was no clear evidence of difference in these scores when the two were compared to each other (results presented graphically, P = 0.51). The data from these studies could not be combined. The third study (n = 116) compared desmopressin with tranexamic acid (n = 116). This study found a decrease in pictorial bleeding assessment chart scores after both treatments as compared to baseline. The decrease in these scores was greater for tranexamic acid than for desmopressin, with a mean difference of 41.6 mL (95% confidence interval 19.6 to 63) (P < 0.0002). In relation to adverse events, across two studies, there was no clear evidence of a difference when placebo was compared to desmopressin, risk ratio 1.17 (95% confidence interval 0.41 to 3.34) . The same was also true when desmopressin was compared to tranexamic acid, risk ratio 1.17 (95% confidence interval 0.41 to 3.34). Only the study that compared desmopressin to tranexamic acid assessed quality of life. However, we are unable to present any data from this study, since no differences in this outcome between the two intervention groups were reported. Evidence from randomised controlled studies on the effect of desmopressin when compared to placebo in reducing menstrual blood loss is very limited and inconclusive. Two studies, each with a very limited number of participants, have shown uncertain effects in menstrual blood loss and adverse effects. A non-randomised comparison in one of the studies points to the value of combining desmopressin and tranexamic acid, which needs to be tested in a formal randomised controlled study comparison. When tranexamic acid was compared to desmopressin, a single study showed a reduction in menstrual blood loss with tranexamic acid use compared to desmopressin. There is a need to evaluate non-surgical methods for treating of menorrhagia in women with bleeding disorders through randomised controlled studies. Such methods would be more acceptable than surgery for women wishing to retain their fertility. Given that women may need to use these treatments throughout their entire reproductive life, long-term side-effects should be evaluated.
We included three randomised controlled trials involving 212 participants. The evidence available does not demonstrate that FESS, as practised in the included trials, is superior to medical treatment with or without sinus irrigation in patients with chronic rhinosinusitis. A middle meatal antrostomy fashioned by FESS was also not shown to be superior to an inferior meatal antrostomy formed by traditional sinus surgery techniques, although the small sample size in the study does not exclude a type II error. In one study there was a relapse rate of 2.4% in the FESS and sinus irrigation group compared to 5.6% in the sinus irrigation only group. The relapse rates were not mentioned in the other studies. There were no major complications, such as orbital injury or cerebrospinal fluid leak, reported in any of the included trials. FESS as currently practised is a safe surgical procedure. The limited evidence available suggests that FESS as practised in the included trials has not been demonstrated to confer additional benefit to that obtained by medical treatment (+/- sinus irrigation) in chronic rhinosinusitis. More randomised controlled trials comparing FESS with medical and other treatments, with long-term follow up, are required.
One hundred thirty-seven studies involving 8333 eyes met the inclusion criteria. Placebo-controlled studies were heterogeneous in comparison with idoxuridine (RR 1.74; 95% CI 1.03 to 2.91) and few in number for vidarabine (RR 1.81; 95% CI 1.09 to 3.01), interferon (RR 1.32; 95% CI 1.06 to 1.64), and debridement. Vidarabine (RR 1.13; 95% CI 1.02 to 1.25), trifluridine (RR 1.30; 95% CI 1.18 to 1.43), acyclovir (RR 1.23; 95% CI 1.14 to 1.34), and brivudine (RR 1.34; 95% CI 1.18 to 1.51) were more effective than idoxuridine. Trifluridine (RR 1.17; 95% CI 1.03 to 1.32) and acyclovir (RR 1.11; 95% CI 1.03 to 1.19) were more effective than vidarabine. No significant differences in healing emerged among trifluridine, acyclovir, brivudine, and foscarnet although few studies compared brivudine or foscarnet with other antivirals. Any potential advantage of ganciclovir compared to acyclovir was mitigated by study heterogeneity and possible publication bias. Only one study evaluated the joint use of two topical antivirals. In a limited number of studies, oral acyclovir (RR 0.92; 95% CI 0.79 to 1.07) or the combination of oral acyclovir with a topical antiviral (RR 1.36; 95% CI 0.68 to 2.74) appeared as effective as a single topical antiviral agent. Compared to topical antiviral monotherapy, the combination of an antiviral with either interferon or debridement had inconsistent effects on expediting healing and improving outcome. Placebo-controlled studies of HSV epithelial keratitis are limited to superseded interventions. Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness. Brivudine and foscarnet do not substantially differ in effectiveness from trifluridine or acyclovir. Ganciclovir is at least as effective as acyclovir. The addition of interferon to a nucleoside antiviral agent and the combination of debridement with antiviral treatment need to be further assessed to substantiate any possible advantage in healing.
The results of twenty-five studies were used in the meta-analysis. The results suggest that speech and language therapy is effective for children with phonological (SMD=0.44, 95%CI: 0.01,0.86) or vocabulary difficulties (SMD=0.89, 95%CI: 0.21,1.56), but that there is less evidence that interventions are effective for children with receptive difficulties (SMD=-0.04, 95%CI: -0.64,0.56). Mixed findings were found concerning the effectiveness of expressive syntax interventions (n=233; SMD=1.02, 95%CI: 0.04-2.01). No significant differences were shown between clinician administered intervention and intervention implemented by trained parents, and studies did not show a difference between the effects of group and individual interventions (SMD=0.01, 95%CI: -0.26,1.17). The use of normal language peers in therapy was shown to have a positive effect on therapy outcome (SMD=2.29, 95%CI: 1.11,3.48). The review shows that overall there is a positive effect of speech and language therapy interventions for children with expressive phonological and expressive vocabulary difficulties. The evidence for expressive syntax difficulties is more mixed, and there is a need for further research to investigate intervention for receptive language difficulties. There is a large degree of heterogeneity in the results, and the sources of this need to be investigated.
We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2 studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2and 29.9 kg/m2, therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin in combination with another treatment. Two other studies are ongoing. All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women attending hospitals for antenatal care. Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low risk of attrition bias and other bias; we felt it was at a high risk of reporting bias. The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex). Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence). Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10; 3 studies, 899 women; low-quality evidence). Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence). One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage. In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2 studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission between women receiving metformin or placebo; no other admission data were reported to assess differences in costs. There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency. There were only a small number of studies included in this review. Furthermore, none of the included studies included women categorised as 'overweight' and no trials looked at metformin in combination with another treatment. Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.
We identified 18 RCTs examining a range of complex interventions for people with multimorbidity. Nine studies focused on defined comorbid conditions with an emphasis on depression, diabetes and cardiovascular disease. The remaining studies focused on multimorbidity, generally in older people. In 12 studies, the predominant intervention element was a change to the organisation of care delivery, usually through case management or enhanced multidisciplinary team work. In six studies, the interventions were predominantly patient-oriented, for example, educational or self-management support-type interventions delivered directly to participants. Overall our confidence in the results regarding the effectiveness of interventions ranged from low to high certainty. There was little or no difference in clinical outcomes (based on moderate certainty evidence). Mental health outcomes improved (based on high certainty evidence) and there were modest reductions in mean depression scores for the comorbidity studies that targeted participants with depression (standardized mean difference (SMD) −2.23, 95% confidence interval (CI) −2.52 to −1.95). There was probably a small improvement in patient-reported outcomes (moderate certainty evidence) although two studies that specifically targeted functional difficulties in participants had positive effects on functional outcomes with one of these studies also reporting a reduction in mortality at four year follow-up (Int 6%, Con 13%, absolute difference 7%). The intervention may make little or no difference to health service use (low certainty evidence), may slightly improve medication adherence (low certainty evidence), probably slightly improves patient-related health behaviours (moderate certainty evidence), and probably improves provider behaviour in terms of prescribing behaviour and quality of care (moderate certainty evidence). Cost data were limited. This review identifies the emerging evidence to support policy for the management of people with multimorbidity and common comorbidities in primary care and community settings. There are remaining uncertainties about the effectiveness of interventions for people with multimorbidity in general due to the relatively small number of RCTs conducted in this area to date, with mixed findings overall. It is possible that the findings may change with the inclusion of large ongoing well-organised trials in future updates. The results suggest an improvement in health outcomes if interventions can be targeted at risk factors such as depression, or specific functional difficulties in people with multimorbidity.
Forty-two studies were included in the review. There was evidence that MHWs caused significant reductions in PCP consultations (standardised mean difference -0.17, 95% CI -0.30 to -0.05), psychotropic prescribing (relative risk 0.67, 95% CI 0.56 to 0.79), prescribing costs (standardised mean difference -0.22, 95% CI -0.38 to -0.07), and rates of mental health referral (relative risk 0.13, 95% CI 0.09 to 0.20) for the patients they were seeing. In controlled before and after studies, the addition of MHWs to a practice did not affect prescribing behaviour towards the wider practice population and there was no consistent pattern to the impact on referrals in the wider patient population. This review provides some evidence that MHWs working in primary care to deliver psychological therapy and psychosocial interventions cause a significant reduction in PCP behaviours such as consultations, prescribing, and referrals to specialist care. However, the changes are modest in magnitude, inconsistent, do not generalise to the wider patient population, and their clinical or economic significance is unclear.
We identified 18 eligible primary publications (21 trial reports). A total of 3089 infants participated in the trials. The risk of bias varied with lack of clarity on methods to conceal allocation in half of the trials and lack of blinding of caregivers or investigators in all of the trials being the main potential sources of bias. Eight trials (2086 infants) examined the effect of topical ointments or creams. Most participants were very preterm infants cared for in health-care facilities in high-income countries. Meta-analyses did not show evidence of a difference in the incidence of invasive infection (typical risk ratio (RR) 1.13, 95% confidence interval (CI) 0.97 to 1.31; low quality evidence) or mortality (typical RR 0.87, 95% CI 0.75 to 1.03; low quality evidence). Eleven trials (1184 infants) assessed the effect of plant or vegetable oils. Nine of these trials were undertaken in low- or middle-income countries and all were based in health-care facilities rather than home or community settings. Meta-analyses did not show evidence of a difference in the incidence of invasive infection (typical RR 0.71, 95% CI 0.51 to 1.01; low quality evidence) or mortality (typical RR 0.94, 95% CI 0.81 to 1.08; moderate quality evidence). Infants massaged with vegetable oil had a higher rate of weight gain (about 2.55 g/kg/day; 95% CI 1.76 to 3.34), linear growth (about 1.22 mm/week; 95% CI 1.01 to 1.44), and head growth (about 0.45 mm/week; 95% CI 0.19 to 0.70). These meta-analyses contained substantial heterogeneity. The available data do not provide evidence that the use of emollient therapy prevents invasive infection or death in preterm infants in high-, middle- or low-income settings. Some evidence of an effect of topical vegetable oils on neonatal growth exists but this should be interpreted with caution because lack of blinding may have introduced caregiver or assessment biases. Since these interventions are low cost, readily accessible, and generally acceptable, further randomised controlled trials, particularly in both community- and health care facility-based settings in low-income countries, may be justified.
We included three randomised controlled trials, involving a total of 251 participants. All three trials were at high risk of performance bias reflecting the fact that surgeons could not be blinded. One trial was at low risk of selection bias but was undermined by a high attrition bias, in part resulting from post-randomisation exclusions. There were incomplete details of methodology for the other two trials, which usually resulted in unclear risk of bias judgements. Two trials compared radial head replacement with open reduction and internal fixation (ORIF) for treating Mason type III radial head fractures. The trial authors reported outcomes at a mean of 2.8 years and 15 months respectively. There were significant differences between the two groups in favour of radial head replacement in the Broberg and Morrey elbow scores (92.1 versus 72.4, mean difference (MD) 19.70; 95% confidence interval (CI) 15.64 to 23.76; one trial, 45 participants), excellent or good Broberg and Morrey elbow scores (33/36 versus 16/31, risk ratio (RR) 1.88; 95% CI 1.27 to 2.77; two trials), and overall adverse events (6/36 versus 15/31, RR 0.33; 95% CI 0.14 to 0.77; two trials). No statistically significant difference was found between the two groups in any of the reported individual adverse events. One trial compared biodegradable pins with standard metal screws in treating radial head fractures of AO-classification 21 B2. The two types of fixation devices yielded similar results, with no significant between-group differences in the Broberg and Morrey scores (93.3 versus 90.9, MD 2.40; 95% CI -0.10 to 4.90), excellent or good Broberg and Morrey elbow scores (72/74 versus 56/61, RR 1.06; 95% CI 0.97 to 1.15), and adverse events (13/82 versus 16/82, RR 0.81; 95% CI 0.42 to 1.58) at two-year follow-up. Only tentative conclusions can be drawn from the available evidence in this review. Compared with ORIF, there was some evidence that radial head replacement had better elbow function and fewer adverse events for Mason type III radial head fractures in the short term. However, the evidence is of low quality and it is unknown whether these results would apply in the longer term or more generally. Using biodegradable implants may be as good as metallic implants for fixation of some usually more stable fractures but more evidence is needed to confirm this. There is a need for good quality evidence for addressing the areas of uncertainty for the surgical treatment of radial head fractures.
We identified 16 trials involving a total of 616 participants. Eight different types of interventions were studied. Eight trials investigated the effects of electrical brain stimulation (transcranial direct current stimulation (tDCS) and cranial electrotherapy stimulation (CES); five trials) or repetitive transcranial magnetic stimulation (rTMS; three trials). Interventions in the remaining studies included exercise programmes (three trials); acupuncture (two trials); self-hypnosis (one trial); transcutaneous electrical nerve stimulation (TENS) (one trial); and a cognitive behavioural programme (one trial). None of the included trials were considered to have low overall risk of bias. Twelve studies had high overall risk of bias, and in four studies risk of bias was unclear. The overall quality of the included studies was weak. Their validity was impaired by methodological weaknesses such as inappropriate choice of control groups. An additional search in November 2014 identified more recent studies that will be included in an update of this review. For tDCS the pooled mean difference between intervention and control groups in pain scores on an 11-point visual analogue scale (VAS) (0-10) was a reduction of -1.90 units (95% confidence interval (CI) -3.48 to -0.33; P value 0.02) in the short term and of -1.87 (95% CI -3.30 to -0.45; P value 0.01) in the mid term. Exercise programmes led to mean reductions in chronic shoulder pain of -1.9 score points for the Short Form (SF)-36 item for pain experience (95% CI -3.4 to -0.4; P value 0.01) and -2.8 pain VAS units (95% CI -3.77 to -1.83; P value < 0.00001); this represented the largest observed treatment effects in the included studies. Trials using rTMS, CES, acupuncture, self-hypnosis, TENS or a cognitive behavioural programme provided no evidence that these interventions reduce chronic pain. Ten trials examined study endpoints other than pain, including anxiety, depression and quality of life, but available data were too scarce for firm conclusions to be drawn. In four trials no side effects were reported with study interventions. Five trials reported transient mild side effects. Overall, a paucity of evidence was found on any serious or long-lasting side effects of the interventions. Evidence is insufficient to suggest that non-pharmacological treatments are effective in reducing chronic pain in people living with SCI. The benefits and harms of commonly used non-pharmacological pain treatments should be investigated in randomised controlled trials with adequate sample size and study methodology.
There are no included studies in this review. The electronic search produced three relevant references, among which we identified two old planned trials that seem never to have started, and one which we excluded a study because it was a report of a case series. This is not an empty review - it is a review full of unanswered questions. Despite growing interest in women’s mental health, the literature in the area of postnatal psychosis is still very limited. It seems that clinicians have no choice but to continue with their current practices guided solely by varied clinical judgement. Women at risk of postnatal psychosis and their relatives are justified to be disappointed in the medical/research fraternity. A post hoc PubMed topic (not methodology-specific) search identified mainly case series. Policy makers have no trial-based evidence upon which to base their guidelines. Certainly, preventive interventions for postnatal psychosis are difficult to justify with confidence without well-designed, well-conducted, and well-reported randomised studies. Available publications suggest that such studies are possible and funders of research may wish to make this work a priority.
Eight trials, which included 1132 participants in total, met the inclusion criteria of this Cochrane review. These trials were at high risk of bias trials. One trial (which included five participants) did not contribute any data to this Cochrane review, and we excluded 13 participants in the remaining trials after randomisation; this left a total of 1114 participants, 510 randomised to non-surgical treatment and 604 to surgical treatment for analysis. The non-surgical treatment was definitive chemoradiotherapy in five trials and definitive radiotherapy in three trials. All participants were suitable for major surgery. Most of the data were from trials that compared chemoradiotherapy with surgery. There was no difference in long-term mortality between chemoradiotherapy and surgery (HR 0.88, 95% CI 0.76 to 1.03; 602 participants; four studies; low quality evidence). The long-term mortality was higher in radiotherapy than surgery (HR 1.39, 95% CI 1.18 to 1.64; 512 participants; three studies; very low quality evidence). There was no difference in long-term recurrence between non-surgical treatment and surgery (HR 0.96, 95% CI 0.80 to 1.16; 349 participants; two studies; low quality evidence). The difference between non-surgical and surgical treatments was imprecise for short-term mortality (RR 0.39, 95% CI 0.11 to 1.35; 689 participants; five studies; very low quality evidence), the proportion of participants with serious adverse in three months (RR 0.61, 95% CI 0.25 to 1.47; 80 participants; one study; very low quality evidence), and proportion of people with local recurrence at maximal follow-up (RR 0.89, 95% CI 0.70 to 1.12; 449 participants; three studies; very low quality evidence). The health-related quality of life was higher in non-surgical treatment between four weeks and three months after treatment (Spitzer Quality of Life Index; MD 0.93, 95% CI 0.24 to 1.62; 165 participants; one study; very low quality evidence). The difference between non-surgical and surgical treatments was imprecise for medium-term health-related quality of life (three months to two years after treatment) (Spitzer Quality of Life Index; MD −0.95, 95% CI −2.10 to 0.20; 62 participants; one study; very low quality of evidence). The proportion of people with dysphagia at the last follow-up visit prior to death was higher with definitive chemoradiotherapy compared to surgical treatment (RR 1.48, 95% CI 1.01 to 2.19; 139 participants; one study; very low quality evidence). Based on low quality evidence, chemoradiotherapy appears to be at least equivalent to surgery in terms of short-term and long-term survival in people with oesophageal cancer (squamous cell carcinoma type) who are fit for surgery and are responsive to induction chemoradiotherapy. However, there is uncertainty in the comparison of definitive chemoradiotherapy versus surgery for oesophageal cancer (adenocarcinoma type) and we cannot rule out significant benefits or harms of definitive chemoradiotherapy versus surgery. Based on very low quality evidence, the proportion of people with dysphagia at the last follow-up visit prior to death was higher with definitive chemoradiotherapy compared to surgery. Based on very low quality evidence, radiotherapy results in less long-term survival than surgery in people with oesophageal cancer who are fit for surgery. However, there is a risk of bias and random errors in these results, although the risk of bias in the studies included in this systematic review is likely to be lower than in non-randomised studies. Further trials at low risk of bias are necessary. Such trials need to compare endoscopic treatment with surgical treatment in early stage oesophageal cancer (carcinoma in situ and Stage Ia), and definitive chemoradiotherapy with surgical treatments in other stages of oesophageal cancer, and should measure and report patient-oriented outcomes. Early identification of responders to chemoradiotherapy and better second-line treatment for non-responders will also increase the need and acceptability of trials that compare definitive chemoradiotherapy with surgery.
Combining the results of five randomised clinical trials randomising 499 patients with alcoholic hepatitis and/or cirrhosis demonstrated no significant effects of anabolic-androgenic steroids on mortality (relative risk (RR) 1.01, 95% confidence interval (CI) 0.79 to 1.29), liver-related mortality (RR 0.83, 95% CI 0.60 to 1.15), complications of liver disease (RR 1.25, 95% CI 0.74 to 2.10), and liver histology. Anabolic-androgenic steroids did not significantly affect a number of other outcome measures, including sexual function and liver biochemistry. Anabolic-androgenic steroids were not associated with a significantly increased risk of non-serious adverse events (RR 1.14, 95% CI 0.50 to 2.59) or with serious adverse events (RR 4.54, 95% CI 0.57 to 36.30). This systematic review could not demonstrate any significant beneficial effects of anabolic-androgenic steroids on any clinically important outcomes (mortality, liver-related mortality, liver complications, and histology) of patients with alcoholic liver disease.
Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low-quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80). One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development. We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease-specific subgroups of patients. The included studies covered 25,290 participants, 11,801 of whom used varenicline. The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high-quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high-quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate-quality evidence). Four trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high-quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow-up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta-analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern. Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and three-fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research. Future trials of cytisine may test extended regimens and more intensive behavioural support.
We identified 16 qualifying randomised controlled trials (RCTs) (7 statin, 9 fibrate). Thirteen of these trials (involving 62,197 participants) provided data on incident melanomas (6 statin, 7 fibrate). A total of 66 melanomas were reported in groups receiving the experimental drug and 86 in groups receiving placebo or other control therapies. For statin trials this translated to an odds ratio of 0.90 (95% confidence interval 0.56 to 1.44) and for fibrate trials an odds ratio of 0.58 (95% confidence interval 0.19 to 1.82). Subgroup analyses failed to show statistically significant differences in melanoma outcomes by gender, melanoma occurrence after two years of participation in trial, stage or histology, or trial funding. Subgroup analysis by type of fibrate or statin also failed to show statistically significant differences, except for the statin subgroup analysis which showed reduced melanoma incidence for lovastatin, based on one trial only (odds ratio 0.52, 95% confidence interval 0.27 to 0.99). The melanoma outcomes data collected in this review of RCTs of statins and fibrates does not exclude the possibility that these drugs prevent melanoma. There was a 10% and 42% reduction for participants on statins and fibrates, respectively, however these results were not statistically significant. Until further evidence is established, limiting exposure to ultraviolet radiation remains the most effective way to reduce the risk of melanoma.
In updating the review, 49 new studies were identified for inclusion. A total of 81 trials involving more than 11,000 health professionals are now included in the review. Based on 30 trials (36 comparisons), the median adjusted RD in compliance with desired practice was 6% (interquartile range 1.8 to 15.9) when any intervention in which educational meetings were a component was compared to no intervention. Educational meetings alone had similar effects (median adjusted RD 6%, interquartile range 2.9 to 15.3; based on 21 comparisons in 19 trials). For continuous outcomes the median adjusted percentage change relative to control was 10% (interquartile range 8 to 32%; 5 trials). For patient outcomes the median adjusted RD in achievement of treatment goals was 3.0 (interquartile range 0.1 to 4.0; 5 trials). Based on univariate meta-regression analyses of the 36 comparisons with dichotomous outcomes for professional practice, higher attendance at the educational meetings was associated with larger adjusted RDs (P < 0.01); mixed interactive and didactic education meetings (median adjusted RD 13.6) were more effective than either didactic meetings (RD 6.9) or interactive meetings (RD 3.0). Educational meetings did not appear to be effective for complex behaviours (adjusted RD -0.3) compared to less complex behaviours; they appeared to be less effective for less serious outcomes (RD 2.9) than for more serious outcomes. Educational meetings alone or combined with other interventions, can improve professional practice and healthcare outcomes for the patients. The effect is most likely to be small and similar to other types of continuing medical education, such as audit and feedback, and educational outreach visits. Strategies to increase attendance at educational meetings, using mixed interactive and didactic formats, and focusing on outcomes that are likely to be perceived as serious may increase the effectiveness of educational meetings. Educational meetings alone are not likely to be effective for changing complex behaviours.
Fifteen studies (1644 elderly women) were included. Three studies compared single dose with short-course treatment (3 to 6 days), six compared single dose with long-course treatment (7 to 14 days) and six compared short- with long-course treatment. Methodological quality of all studies was low except for a more recent geriatric study. There was a significant difference for persistent UTI between single dose and short-course treatment (RR 2.01, 95% CI 1.05 to 3.84) and single versus long-course treatment (RR 1.93, 1.01 to 3.70 95% CI), in the short-term (< 2 weeks post-treatment) but not at long-term follow-up or on clinical outcomes. Patients preferred single dose treatment (RR 0.73, 95% CI 0.60 to 0.88) to long-course treatments, but this was based on one study comparing different antibiotics. Short versus longer treatments showed no significant difference in efficacy. Rate of adverse drug reactions increased significantly with longer treatment durations in only one study. Short-course treatment (3 to 6 days) could be sufficient for treating uncomplicated UTIs in elderly women, although more studies on specific commonly prescribed antibiotics are needed.
Nineteen studies (11 prevention, 8 treatment; 1,861 participants) were included. There was no difference in mortality between ANP and control in either the low or high dose prevention studies. Low (but not high) dose ANP was associated with a reduced need for RRT in the prevention studies (RR 0.32, 95% CI 0.14 to 0.71). Length of hospital and ICU stay were significantly shorter in the low dose ANP group. For established AKI, there was no difference in mortality with either low or high dose ANP. Low (but not high) dose ANP was associated with a reduction in the need for RRT (RR 0.54, 95% CI 0.30 to 0.98). High dose ANP was associated with more adverse events (hypotension, arrhythmias). After major surgery there was a significant reduction in RRT requirement with ANP in the prevention studies (RR 0.56, 95% CI 0.32 to 0.99), but not in the treatment studies. There was no difference in mortality between ANP and control in either the prevention or treatment studies. There was a reduced need for RRT with low dose ANP in patients undergoing cardiovascular surgery (RR 0.35, 95% CI 0.18 to 0.70). ANP was not associated with outcome improvement in either radiocontrast nephropathy or oliguric AKI. ANP may be associated with improved outcomes when used in low doses for preventing AKI and in managing postsurgery AKI and should be further explored in these two settings. There were no significant adverse events in the prevention studies, however in the high dose ANP treatment studies there were significant increases hypotension and arrhythmias.
We found no randomised trials for inclusion in this review. One study is ongoing. As we did not identify any randomised trials for inclusion in this review, we are unable to comment on implications for practice at this stage. Although evidence from animals studies has supported a fetal neuroprotective role for melatonin when administered to the mother during pregnancy, no trials assessing melatonin for fetal neuroprotection in pregnant women have been completed to date. However, there is currently one ongoing randomised controlled trial (with an estimated enrolment target of 60 pregnant women) which examines the dose of melatonin, administered to women at risk of imminent very preterm birth (less than 28 weeks' gestation) required to reduce brain damage in the white matter of the babies that were born very preterm. Further high-quality research is needed and research efforts should directed towards trials comparing melatonin with either no intervention (no treatment or placebo), or with alternative agents aimed at providing fetal neuroprotection (such as magnesium sulphate for the very preterm infant). Such trials should evaluate maternal and infant short- and longer-term outcomes (including neurosensory disabilities such as cerebral palsy), and consider the costs of care.
Ten studies enrolling 630 participants were included. Overall, the quality of evidence was suboptimal due to the small number of included studies enrolling small numbers of participants; short follow-up in each study; only a few studies in each comparison category; and major concerns with methodological bias. Four studies (293 participants) contributed to the comparison of TwHF versus non-TwHF. TwHF significantly increased complete remission (RR 1.46, 95% CI 1.18 to 1.80) and complete or partial remission (RR 1.26, 95% CI 1.10 to 1.44) without escalating the adverse events profile at the last follow-up (12 to 16 months). Four studies (223 participants) compared TwHF with prednisone. There were no statistically significant differences between complete remission, partial remission, and complete or partial remission. Two studies (114 participants) contributed to the comparison of TwHF versus cyclophosphamide (CPA) at the last follow-up (3 to 12 months). There were no statistically significant differences between complete, partial, or complete or partial remission. One study (46 participants) reported TwHF was associated with a significantly lower serum creatinine compared with CPA (MD -14.00 μmol/L, 95% CI -26.43 to -1.57). No serious adverse events of TwHF were observed. One study (37 participants) reported TwHF was associated with a significantly lower risk of psychosis when compared to prednisone (RR 0.11, 95% CI 0.01 to 0.75), and two studies showed a significantly lower risk of hair loss with TwHF when compared to CPA ((2 studies, 114 participants): RR 0.11, 95% CI 0.02 to 0.59). TwHF may have an add-on effect on remission in patients with primary NS. There was insufficient evidence to assess if TwHF was as effective as prednisone or CPA. More methodologically sound and sufficiently powered studies, with adequate follow-up would help to better inform management options for the use of TwHF for primary NS. TwHF should be further directly compared with other widely used immunosuppressive agents after the superiority over placebo or no treatment has been clearly established.
Our searches returned 546 trials, of which five met our inclusion criteria. These studies randomised 14,252 children to receive either an intervention or usual care. All studies were conducted in the Northern Hemisphere. Three interventions used a leukotriene receptor antagonist, one used omalizumab or a boost of inhaled corticosteroids, and the largest study, (12,179 children), used a medication reminder letter. Whilst the risk of bias within individual studies was generally low, we downgraded the evidence quality due to imprecision associated with low participant numbers, poor consistency between studies, and indirect outcome ascertainment. A US study of 513 children with mild/severe asthma and allergic sensitisation was the only study to provide data for our primary outcome. In this study, the proportion of participants experiencing an exacerbation requiring oral corticosteroids or hospital admission in the 90 days after school return was significantly reduced to 11.3% in those receiving omalizumab compared to 21.0% in those receiving placebo (odds ratio 0.48, 95% confidence interval 0.25 to 0.92, moderate-quality evidence). The remaining studies used alternative exacerbation definitions. When data from two leukotriene receptor antagonist studies with comparable outcomes were combined in a random-effects model, there was no evidence of an effect upon exacerbations. There was no evidence that a seasonal medication reminder letter decreased unscheduled contacts for a respiratory diagnosis between September and December. Four studies recorded adverse events. There was no evidence that the proportion of participants experiencing at least one adverse event differed between intervention and usual care groups. Lack of data prevented planned subgroup and sensitivity analyses. Seasonal omalizumab treatment from four to six weeks before school return might reduce autumn asthma exacerbations. We found no evidence that this strategy is associated with increased adverse effects other than injection site pain, but it is costly. There were no data upon which to judge the effect of this or other seasonal interventions on asthma control, quality of life, or asthma-related death. In future studies definitions of exacerbations should be provided, and standardised where possible. To investigate possible differential effects according to subgroup, participants in future trials should be well characterised with respect to baseline asthma severity and exacerbation history in addition to age and gender.
We included six published RCTs, conducted in the USA (5 RCTs) and Israel (1 RCT), with 1097 children and adolescents (11 to 18 years old), in the review. We are very uncertain about the effect of client feedback on improvement of symptoms, as reported by youth in the short term because we considered evidence to be of very low-certainty due to high risk of bias and very serious inconsistency in the effect estimates from the different studies. Similarly, we are very uncertain about the effect of client feedback on treatment acceptability, due to high risk of bias, imprecision in the results, and indirectness of measuring the outcome (RR 1.08, 95% CI 0.73 to 1.61; 2 studies, 237 participants; very low-certainty). Overall, most studies reported and carried out randomisation and allocation concealment adequately. None of the studies were blinded or attempted to blind participants and personnel and were at high risk of performance bias, and only one study had blind outcome assessors. All of the studies were at high or unclear risk of attrition bias mainly due to poor, non-transparent reporting of participants' flow through the studies. Due to the paucity of high-quality data and considerable inconsistency in results from different studies, there is currently insufficient evidence to reach any firm conclusions regarding the role of client feedback in psychological therapies for children and adolescents with mental health problems, and further research on this important topic is needed. Future studies should avoid risks of performance, detection and attrition biases, as seen in the studies included in this review. Studies from countries other than the USA are needed, as well as studies including children younger than 10 years.
We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise. All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses. In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain. For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.
Primary outcome  Mean improvement in the maintenance of wakefulness test was available for two of the five identified trials accounting for 48 participants. The mean difference +2.52(95% confidence interval (CI) -2.32 to +7.37), was not significant and there was marked heterogeneity across these studies (I2= 50%). Secondary outcomes  Mean improvement in the Epworth Sleepiness Scale was available in four trials accounting for 101 participants. The mean difference was -2.26 (95% CI -3.78to -0.73), significantly in favor of modafinil with marked heterogeneity across the studies (I2= 84%). There was no evidence for any treatment benefit on the multiple sleep latency test or quality of life. There is low quality evidence from two small trials that psychostimulants do not significantly improve the maintenance of wakefulness test in myotonic dystrophy. There is low quality evidence from four studies that modafinil significantly improves the Epworth Sleepiness Scale. More randomized trials are needed to evaluate the efficacy and safety of psychostimulants.
We identified 41 randomised controlled trials (RCTs) involving 194,035 participants from 6422 reports. We assessed studies as having high or unclear risk of bias across multiple domains. Low-quality evidence evidence suggests that providing CVD risk scores may have little or no effect on CVD events compared with usual care (5.4% versus 5.3%; RR 1.01, 95% confidence interval (CI) 0.95 to 1.08; I² = 25%; 3 trials, N = 99,070). Providing CVD risk scores may reduce CVD risk factor levels by a small amount compared with usual care. Providing CVD risk scores reduced total cholesterol (MD −0.10 mmol/L, 95% CI −0.20 to 0.00; I² = 94%; 12 trials, N = 20,437, low-quality evidence), systolic blood pressure (MD −2.77 mmHg, 95% CI −4.16 to −1.38; I² = 93%; 16 trials, N = 32,954, low-quality evidence), and multivariable CVD risk (SMD −0.21, 95% CI −0.39 to −0.02; I² = 94%; 9 trials, N = 9549, low-quality evidence). Providing CVD risk scores may reduce adverse events compared with usual care, but results were imprecise (1.9% versus 2.7%; RR 0.72, 95% CI 0.49 to 1.04; I² = 0%; 4 trials, N = 4630, low-quality evidence). Compared with usual care, providing CVD risk scores may increase new or intensified lipid-lowering medications (15.7% versus 10.7%; RR 1.47, 95% CI 1.15 to 1.87; I² = 40%; 11 trials, N = 14,175, low-quality evidence) and increase new or increased antihypertensive medications (17.2% versus 11.4%; RR 1.51, 95% CI 1.08 to 2.11; I² = 53%; 8 trials, N = 13,255, low-quality evidence). There is uncertainty whether current strategies for providing CVD risk scores affect CVD events. Providing CVD risk scores may slightly reduce CVD risk factor levels and may increase preventive medication prescribing in higher-risk people without evidence of harm. There were multiple study limitations in the identified studies and substantial heterogeneity in the interventions, outcomes, and analyses, so readers should interpret results with caution. New models for implementing and evaluating CVD risk scores in adequately powered studies are needed to define the role of applying CVD risk scores in primary CVD prevention.
We included 38 studies involving 9445 participants. Among studies that measured diet adherence outcomes between an intervention group and a control/usual care group, 32 out of 123 diet adherence outcomes favoured the intervention group, 4 favoured the control group whereas 62 had no significant difference between groups (assessment was impossible for 25 diet adherence outcomes since data and/or statistical analyses needed for comparison between groups were not provided). Interventions shown to improve at least one diet adherence outcome are: telephone follow-up, video, contract, feedback, nutritional tools and more complex interventions including multiple interventions. However, these interventions also shown no difference in some diet adherence outcomes compared to a control/usual care group making inconclusive results about the most effective intervention to enhance dietary advice. The majority of studies reporting a diet adherence outcome favouring the intervention group compared to the control/usual care group in the short-term also reported no significant effect at later time points. Studies investigating interventions such as a group session, individual session, reminders, restriction and behaviour change techniques reported no diet adherence outcome showing a statistically significant difference favouring the intervention group. Finally, studies were generally of short duration and low quality, and adherence measures varied widely. There is a need for further, long-term, good-quality studies using more standardized and validated measures of adherence to identify the interventions that should be used in practice to enhance adherence to dietary advice in the context of a variety of chronic diseases.
Twelve studies were identified in the searches and seven of these were eligible for inclusion in the review. Five studies, involving 260 participants, provided data for analysis. One study showed that cognitive behaviour therapy significantly reduced the affective component of pain (feelings about pain), mean difference -0.99 (95% confidence interval -1.62 to -0.36), but not the sensory component (pain intensity), mean difference 0.00 (95% confidence interval -9.39 to 9.39). One study of family psycho-education was not associated with a reduction in depression. Another study evaluating cognitive behavioural therapy had inconclusive results for the assessment of coping strategies, and showed no difference between groups assessed on health service utilisation. In addition, family home-based cognitive behavioural therapy did not show any difference compared to disease education. One study of patient education on health beliefs showed a significant improvement in attitudes towards health workers, mean difference -4.39 (95% CI -6.45 to -2.33) and medication, mean difference -1.74 (95% CI -2.98 to -0.50). Nonetheless, these results may not apply across all ages, severity of sickle cell disease, types of pain (acute or chronic), or setting. Evidence for the efficacy of psychological therapies in sickle cell disease is currently limited. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions in sickle cell disease.
Eighteen RCTs were included in the review, of which 14 were included in the meta-analyses (in total 2279 couples). The evidence was current to October 2013. The quality of the evidence was low or very low for most comparisons . The main limitations in the evidence were failure to describe study methods, serious imprecision and attrition bias. Ten RCTs compared different methods of timing for IUI. We found no evidence of a difference in live birth rates between hCG injection versus LH surge (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.06 to 18, 1 RCT, 24 women, very low quality evidence), urinary hCG versus recombinant hCG (OR 1.17, 95% CI 0.68 to 2.03, 1 RCT, 284 women, low quality evidence) or hCG versus GnRH agonist (OR 1.04, 95% CI 0.42 to 2.6, 3 RCTS, 104 women, I2 = 0%, low quality evidence). Two RCTs compared the optimum time interval from hCG injection to IUI, comparing different time frames that ranged from 24 hours to 48 hours. Only one of these studies reported live birth rates, and found no difference between the groups (OR 0.52, 95% CI 0.27 to 1.00, 1 RCT, 204 couples). One study compared early versus late hCG administration and one study compared different dosages of hCG, but neither reported the primary outcome of live birth. We found no evidence of a difference between any of the groups in rates of pregnancy or adverse events (multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS)). However, most of these data were very low quality. There is insufficient evidence to determine whether there is any difference in safety and effectiveness between different methods of synchronization of ovulation and insemination. More research is needed.
In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations. The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013). The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups. Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity. Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes. We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors. High-quality studies should be performed.
Seventeen studies (14 ITS and 3 CBA studies) met the inclusion criteria in this updated version of the review. The ITS studies evaluated the effects of: introducing or changing regulations that laid down safety and health requirements for the construction sites (nine studies), a safety campaign (two studies), a drug-free workplace programme (one study), a training programme (one study), and safety inspections (one study) on fatal and non-fatal occupational injuries. One CBA study evaluated the introduction of occupational health services such as risk assessment and health surveillance, one evaluated a training programme and one evaluated the effect of a subsidy for upgrading to safer scaffoldings. The overall risk of bias of most of the included studies was high, as it was uncertain for the ITS studies whether the intervention was independent from other changes and thus could be regarded as the main reason of change in the outcome. Therefore, we rated the quality of the evidence as very low for all comparisons. Compulsory interventions Regulatory interventions at national or branch level may or may not have an initial effect (effect size (ES) of −0.33; 95% confidence interval (CI) −2.08 to 1.41) and may or may not have a sustained effect (ES −0.03; 95% CI −0.30 to 0.24) on fatal and non-fatal injuries (9 ITS studies) due to highly inconsistent results (I² = 98%). Inspections may or may not have an effect on non-fatal injuries (ES 0.07; 95% CI −2.83 to 2.97; 1 ITS study). Educational interventions Safety training interventions may result in no significant reduction of non-fatal injuries (1 ITS study and 1 CBA study). Informational interventions We found no studies that had evaluated informational interventions alone such as campaigns for risk communication. Persuasive interventions We found no studies that had evaluated persuasive interventions alone such as peer feedback on workplace actions to increase acceptance of safe working methods. Facilitative interventions Monetary subsidies to companies may lead to a greater decrease in non-fatal injuries from falls to a lower level than no subsidies (risk ratio (RR) at follow-up: 0.93; 95% CI 0.30 to 2.91 from RR 3.89 at baseline; 1 CBA study). Multifaceted interventions A safety campaign intervention may result in an initial (ES −1.82; 95% CI −2.90 to −0.74) and sustained (ES −1.30; 95% CI −1.79 to −0.81) decrease in injuries at the company level (1 ITS study), but not at the regional level (1 ITS study). A multifaceted drug-free workplace programme at the company level may reduce non-fatal injuries in the year following implementation by −7.6 per 100 person-years (95% CI −11.2 to −4.0) and in the years thereafter by −2.0 per 100 person-years (95% CI −3.5 to −0.5) (1 ITS study). Introducing occupational health services may result in no decrease in fatal or non-fatal injuries (one CBA study). The vast majority of interventions to adopt safety measures recommended by standard texts on safety, consultants and safety courses have not been adequately evaluated. There is very low-quality evidence that introducing regulations as such may or may not result in a decrease in fatal and non-fatal injuries. There is also very low-quality evidence that regionally oriented safety campaigns, training, inspections or the introduction of occupational health services may not reduce non-fatal injuries in construction companies. There is very low-quality evidence that company-oriented safety interventions such as a multifaceted safety campaign, a multifaceted drug workplace programme and subsidies for replacement of scaffoldings may reduce non-fatal injuries among construction workers. More studies, preferably cluster-randomised controlled trials, are needed to evaluate different strategies to increase the employers' and workers' adherence to the safety measures prescribed by regulation.
Three studies met our inclusion criteria. In one study dichlorphenamide (DCP) vs placebo was tested in two groups of participants: 42 with hypokalemic periodic paralysis (HypoPP) and 31 with hyperkalemic periodic paralysis (HyperPP), based on clinical criteria. Thirty-four of 42 participants with hypokalemic periodic paralysis completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. Fifteen preferred DCP, three placebo and six their baseline medication. Twenty-four of 31 participants with hyperkalemic periodic paralysis completed both treatment phases: for the 16 participants who had attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.006) and in severity-weighted attack rate (P = 0.02) on DCP relative to placebo were significant. Fifteen preferred DCP, one placebo and five their baseline medication.  Acetazolamide proved to improve muscle strength in eight participants with HypoPP in one other study and pinacidil, a potassium channel opener, also improved muscle strength in 2/4 participants with HypoPP in a third study. The largest included study that met our inclusion criteria suggested that DCP was effective in the prevention of episodic weakness in both hypokalemic and hyperkalemic periodic paralyses. The other two studies provide some evidence that either acetazolamide or pinacidil may improve muscle strength. However we still lack sufficient evidence to provide full guidelines for the treatment of people with periodic paralysis.
Twenty-eight trials with 1273 menopausal women were included in this review. Data could be extracted from 16 trials to conduct the meta-analysis. The overall quality of the studies was moderate to low with the majority of studies that were included in the meta-analysis having reasonable methodology. Compared to placebo, DHEA did not improve quality of life (standardised mean difference (SMD) 0.16, 95% confidence interval (CI) -0.03 to 0.34, P = 0.10, 8 studies, 287 women (132 from parallel and 155 from crossover trials), I² = 0%, moderate quality evidence; one trial of the nine that reported on this outcome was removed in a sensitivity analysis as it was judged to be at high risk of bias). DHEA was found to be associated with androgenic side effects (mainly acne) (odds ratio (OR) 3.77, 95% CI 1.36 to 10.4, P = 0.01, 5 studies, 376 women, I² = 10%, moderate quality evidence) when compared to placebo. No associations were found with other adverse effects. It was unclear whether DHEA affected menopausal symptoms as the results from the trials were inconsistent and could not easily be pooled to provide an overall effect due to different types of measurement (for example continuous, dichotomous, change and end scores). DHEA was found to improve sexual function (SMD 0.31, 95% CI 0.07 to 0.55, P = 0.01, 5 studies, 261 women (239 women from parallel trials and 22 women from crossover trials), I² = 0%; one trial judged to be at high risk of bias was removed during sensitivity analysis) compared to placebo. There was no difference in the acne associated with DHEA when comparing studies that used oral DHEA (OR 2.16, 95% CI 0.47 to 9.96, P = 0.90, 3 studies, 136 women, I² = 5%, very low quality evidence) to one study that used skin application of DHEA (OR 2.74, 95% CI 0.10 to 74.87, P = 0.90, 1 study, 22 women, very low quality evidence). The effects did not differ for sexual function when studies using oral DHEA (SMD 0.11, 95% CI -0.13 to 0.35, P = 0.36, 5 studies, 340 women, I² = 0) were compared to a study using intravaginal DHEA (SMD 0.42, 95% CI 0.03 to 0.81, 1 study, 218 women). Test for subgroup differences: Chi² = 1.77, df = 1 (P = 0.18), I² = 43.4%. Insufficient data were available to assess quality of life and menopausal symptoms for this comparison. There were insufficient data available to compare the effects of DHEA to hormone therapy (HT) for quality of life, menopausal symptoms, and adverse effects. No large differences in treatment effects were found for sexual function when comparing DHEA to HT (mean difference (MD) 1.26, 95% CI -0.21 to 2.73, P = 0.09, 2 studies, 41 women, I² = 0%). There is no evidence that DHEA improves quality of life but there is some evidence that it is associated with androgenic side effects. There is uncertainty whether DHEA decreases menopausal symptoms, but DHEA may slightly improve sexual function compared with placebo.
Forty-one trials (10,681 participants) met the inclusion criteria. Trials were grouped according to similar interventions (changes to organisation of nutritional care (N = 13; 3456 participants), changes to the feeding environment (N = 5; 351 participants), modification of meal profile or pattern (N = 12; 649 participants), additional supplementation of meals (N = 10; 6022 participants) and home meal delivery systems (N = 1; 203 participants). Follow-up ranged from ‘duration of hospital stay’ to 12 months. The overall quality of evidence was moderate to very low, with the majority of trials judged to be at an unclear risk of bias in several risk of bias domains. The risk ratio (RR) for all-cause mortality was 0.78 (95% confidence interval (CI) 0.66 to 0.92); P = 0.004; 12 trials; 6683 participants; moderate-quality evidence. This translates into 26 (95% CI 9 to 41) fewer cases of death per 1000 participants in favour of supportive interventions. The RR for number of participants with any medical complication ranged from 1.42 in favour of control compared with 0.59 in favour of supportive interventions (very low-quality evidence). Only five trials (4451 participants) investigated health-related quality of life showing no substantial differences between intervention and comparator groups. Information on patient satisfaction was unreliable. The effects of supportive interventions versus comparators on hospitalisation showed a mean difference (MD) of -0.5 days (95% CI -2.6 to 1.6); P = 0.65; 5 trials; 667 participants; very low-quality evidence. Only three of 41 included trials (4108 participants; very low-quality evidence) reported on adverse events, describing intolerance to the supplement (diarrhoea, vomiting; 5/34 participants) and discontinuation of oral nutritional supplements because of refusal or dislike of taste (567/2017 participants). Meta-analysis across 17 trials with adequate data on weight change revealed an overall improvement in weight in favour of supportive interventions versus control: MD 0.6 kg (95% CI 0.21 to 1.02); 2024 participants; moderate-quality evidence. A total of 27 trials investigated nutritional intake with a majority of trials not finding marked differences in energy intake between intervention and comparator groups. Only three trials (1152 participants) reported some data on economic costs but did not use accepted health economic methods (very low-quality evidence). There is evidence of moderate to very low quality to suggest that supportive interventions to improve nutritional care results in minimal weight gain. Most of the evidence for the lower risk of all-cause mortality for supportive interventions comes from hospital-based trials and more research is needed to confirm this effect. There is very low-quality evidence regarding adverse effects; therefore whilst some of these interventions are advocated at a national level clinicians should recognise the lack of clear evidence to support their role. This review highlights the importance of assessing patient-important outcomes in future research.
This first update of the review identified two additional eligible studies, bringing the total number of included studies to 25 (forty seven randomised controlled comparisons involving 2543 children considered to be at normal risk of regurgitation or aspiration during anaesthesia). Only one incidence of aspiration and regurgitation was reported. Children permitted fluids up to 120 minutes preoperatively were not found to experience higher gastric volumes or lower gastric pH values than those who fasted. The children permitted fluids were less thirsty and hungry, better behaved and more comfortable than those who fasted. Clear fluids preoperatively did not result in a clinically important difference in children's gastric volume or pH. Evidence relating to the preoperative intake of milk was sparse. The volume of fluid permitted during the preoperative period did not appear to impact on children's intraoperative gastric volume or pH contents. There is no evidence that children who are denied oral fluids for more than six hours preoperatively benefit in terms of intraoperative gastric volume and pH compared with children permitted unlimited fluids up to two hours preoperatively. Children permitted fluids have a more comfortable preoperative experience in terms of thirst and hunger. This evidence applies only to children who are considered to be at normal risk of aspiration/regurgitation during anaesthesia.
We included 14 studies (747 participants). The studies included children (seven studies, 499 participants) and adults (seven studies, 248 participants). No studies reported outcomes beyond three months follow-up. Saline volumes ranged from 'very low' to 'high' volume. Where stated, studies used either hypertonic or isotonic saline solution. Nasal saline versus no saline treatment All seven studies (112 adults; 332 children) evaluating this comparison used different scoring systems for patient-reported disease severity, so we pooled the data using the standardised mean difference (SMD). Saline irrigation may improve patient-reported disease severity compared with no saline at up to four weeks (SMD -1.32, 95% confidence interval (CI) -1.84 to -0.81; 407 participants; 6 studies; low quality) and between four weeks and three months (SMD -1.44, 95% CI -2.39 to -0.48; 167 participants; 5 studies; low quality). Although the evidence was low quality the SMD values at both time points are considered large effect sizes. Subgroup analysis showed the improvement in both adults and children. Subgroup analyses for volume and tonicity were inconclusive due to heterogeneity. Two studies reported methods for recording adverse effects and five studies mentioned them. Two studies (240 children) reported no adverse effects (epistaxis or local discomfort) in either group and three only reported no adverse effects in the saline group. One study (48 children) reported disease-specific HRQL using a modified RCQ-36 scale. It was uncertain whether there was a difference between the groups at any of the specified time points (very low quality). No other secondary outcomes were reported. Nasal saline versus no saline with adjuvant use of intranasal steroids or oral antihistamines Three studies (40 adults; 79 children) compared saline with intranasal steroids versus intranasal steroids alone; one study (14 adults) compared saline with oral antihistamines versus oral antihistamines alone. It is uncertain if there is a difference in patient-reported disease severity at up to four weeks (SMD -0.60, 95% CI -1.34 to 0.15; 32 participants; 2 studies; very low quality) or from four weeks to three months (SMD -0.32, 95% CI -0.85 to 0.21; 58 participants; 2 studies; very low quality). Although none of the studies reported methods for recording adverse effects, three mentioned them: one study (40 adults; adjuvant intranasal steroids) reported no adverse effects (epistaxis or local discomfort) in either group; the other two only reported no adverse effects in the saline group. It is uncertain if saline irrigation in addition to pharmacological treatment improved disease-specific HRQL at four weeks to three months, compared with pharmacological treatment alone (SMD -1.26, 95% CI -2.47 to -0.05; 54 participants; 2 studies; very low quality). No other secondary outcomes were reported. Nasal saline versus intranasal steroids It is uncertain if there was a difference in patient-reported disease severity between nasal saline and intranasal steroids at up to four weeks (MD 1.06, 95% CI -1.65 to 3.77; 14 participants; 1 study), or between four weeks and three months (SMD 1.26, 95% CI -0.92 to 3.43; 97 participants; 3 studies), or indisease-specific HRQL between four weeks and three months (SMD 0.01, 95% CI -0.73 to 0.75; 83 participants; 2 studies). Only one study reported methods for recording adverse effects although three studies mentioned them. One (21 participants) reported two withdrawals due to adverse effects but did not describe these or state which group. Three studies reported no adverse effects (epistaxis or local discomfort) with saline, although one study reported that 27% of participants experienced local discomfort with steroid use. No other secondary outcomes were reported. Saline irrigation may reduce patient-reported disease severity compared with no saline irrigation at up to three months in both adults and children with allergic rhinitis, with no reported adverse effects. No data were available for any outcomes beyond three months. The overall quality of evidence was low or very low. The included studies were generally small and used a range of different outcome measures to report disease severity scores, with unclear validation. This review did not include direct comparisons of saline types (e.g. different volume, tonicity). Since saline irrigation could provide a cheap, safe and acceptable alternative to intranasal steroids and antihistamines further high-quality, adequately powered research in this area is warranted.
We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials), vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant heterogeneity (I2 = 54.0%, P = 0.003). The heterogeneity may have been explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96 to 1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43 to 0.80; test of interaction P < 0.0005), and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I2 = 53.5%), but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I2 = 0%). We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately conducted randomised trials.
We identified 11 trials that enrolled 687 eyes of 679 participants. The studies were conducted in the United States, Europe, Asia and Africa. Five studies enrolled participants at low risk of trabeculectomy failure, five studies enrolled participants at high risk of failure, and one study enrolled people with both high and low risk of failure. None of the included trials enrolled participants with combined trabeculectomy/cataract surgery. We considered one study to be at low risk of bias in all domains, six studies to be at high risk of bias in one or more domains, and the remaining four studies to be at an unclear risk of bias in all domains. The risk of failure of trabeculectomy at one year after surgery was less in those participants who received MMC compared to those who received 5-FU, however the confidence intervals were wide and are compatible with no effect (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.30 to 1.00; studies = 11; I2 = 40%). There was no evidence for any difference between groups at high and low risk of failure (test for subgroup differences P = 0.69). On average, people treated with MMC had lower intraocular pressure at one year (mean difference (MD) -3.05 mmHg, 95% CI -4.60 to -1.50), but the studies were inconsistent (I2 = 52%). The size of the effect was greater in the high-risk group (MD -4.18 mmHg, 95% CI -6.73 to -1.64) compared to the low-risk group (MD -1.72 mmHg, 95% CI -3.28 to -0.16), but again the test for interaction was not statistically significant (P = 0.11). Similar proportions of eyes treated with MMC lost 2 or more lines of visual acuity one year after surgery compared to 5-FU, but the confidence intervals were wide (RR 1.05, 95% CI 0.54 to 2.06). Adverse events occurred relatively rarely, and estimates of effect were generally imprecise. There was some evidence for less epitheliopathy in the MMC group (RR 0.23, 95% CI 0.11 to 0.47) and less hyphaema in the MMC group (RR 0.62, 95% CI 0.42 to 0.91). None of the studies reported quality of life. Overall, we graded the quality of the evidence as low largely because of risk of bias in the included studies and imprecision in the estimate of effect. We found low-quality evidence that MMC may be more effective in achieving long-term lower intraocular pressure than 5-FU. Further comparative research on MMC and 5-FU is needed to enhance reliability and validity of the results shown in this review. Furthermore, the development of new agents that control postoperative scar tissue formation without side effects would be valuable and is justified by the results of this review.
The comprehensive searches found one randomised controlled trial of treatment for amphetamine psychosis meeting the criteria for considering studies. The study involved 58 participants and compared the efficacy and tolerability of two antipsychotic drugs, olanzapine (a newer antipsychotic) and haloperidol (a commonly used antipsychotic medication used as a control condition), in treating amphetamine-induced psychosis. The results show that both olanzapine and haloperidol at clinically relevant doses were efficacious in resolving psychotic symptoms, with the olanzapine condition showing significantly greater safety and tolerability than the haloperidol control as measured by frequency and severity of extrapyramidal symptoms. Only one RCT of treatment for amphetamine psychosis has been published. Outcomes from this trial indicate that antipsychotic medications effectively reduce symptoms of amphetamine psychosis, the newer generation and more expensive antipsychotic medication, olanzapine, demonstrates significantly better tolerability than the more affordable and commonly used medication, haloperidol. There are other two studies that did not meet the inclusion criteria for this review. The results of these two studies show that agitation and some psychotic symptoms may be abated within an hour after antipsychotic injection. Whether this limited evidence can be applied for amphetamine psychotic patients is not yet known. The medications that should be further investigate are conventional antipsychotics, newer antipsychotics and benzodiazepines. However, naturalistic studies of amphetamine psychotic symptoms and the prevalence of relapse to psychosis in the presence of amphetamine, are also crucial for advising the development of study designs appropriate for further treatment studies of amphetamine psychosis.
We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes. Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials.
We found two small randomised controlled trails that fulfilled the eligibility criteria (Corbet 1977; Dixon 1999) and one unpublished pilot trial (Lawn 2005). Corbet 1977 compared treating infants with sodium bicarbonate infusion (N = 30) versus no treatment (N = 32) and did not find evidence of an effect on mortality [relative risk (RR) 1.39 (95% confidence interval 0.72 to 2.67)] or in the incidence of intra/periventricular haemorrhage [RR 1.24 (95% confidence interval 0.47 to 3.28)]. Addition of the unpublished data of Lawn 2005 does not change the overall estimate of effect on mortality [typical RR 1.45 (95%CI 0.82 to 2.56)]. Dixon 1999 compared treatment with sodium bicarbonate (N = 16) versus fluid bolus (N = 20). The primary outcome assessed was arterial blood pH/base excess two hours after the intervention. Other clinical outcomes were not reported. Neither trial assessed longer term neurodevelopmental outcomes. There is insufficient evidence from randomised controlled trials to determine whether infusion of base or fluid bolus reduces morbidity and mortality in preterm infants with metabolic acidosis. Further large randomised trials are needed.
We included seven trials involving 500 participants that studied the effect of hyaluronidase on intraoperative pain. Four of the seven trials with 289 participants reported the primary outcome in a dichotomous manner, and we proceeded to meta-analyse the findings which showed a moderate heterogeneity that could not be explained (I2 = 41% ). The pooled risk ratio (RR) for these four trials was 0.83 with the 95% confidence interval ranging from 0.48 to 1.42. The reduction in intraoperative pain scores in the hyaluronidase group were not statistically significant. Among the three trials that reported the primary outcome in a continuous manner, the presence of missing data made it difficult to conduct a meta-analysis. To further explore the data, we imputed standard deviations for the other studies from another included RCT (Sedghipour 2012). However, this resulted in substantial heterogeneity between study estimates (I² = 76% ). The lack of reported relevant data in two of the three remaining trials made it difficult to assess the direction of effect in a clinical setting. Overall, there was no statistical difference regarding the intraoperative reduction of pain scores between the hyaluronidase and control group. All seven included trials had a low risk of bias. According to GRADE, we found the quality of evidence was low and downgraded the trials for serious risk of inconsistency and imprecision. Therefore, the results should be analysed with caution. Participant satisfaction scores were significantly higher in the hyaluronidase group in two high quality trials with 122 participants. Surgical satisfaction was also superior in two of three high quality trials involving 141 participants. According to GRADE, the quality of evidence was moderate for participant and surgical satisfaction as the trials were downgraded for imprecision due to the small sample sizes. The risk of bias in these trials was low. There was no reported harm due to the addition of hyaluronidase in any of the studies. No study reported on the cost of hyaluronidase in the context of eye surgery. The effects of adding hyaluronidase to local anaesthetic fluid on pain outcomes in people undergoing eye surgery are uncertain due to the low quality of evidence available. A well designed RCT is required to address inconsistency and imprecision among the studies and to determine the benefit of hyaluronidase to improve analgesia during eye surgery. Participant and surgical satisfaction is higher with hyaluronidase compared to the control groups, as demonstrated in moderate quality studies. There was no harm attributed to the use of hyaluronidase in any of the studies. Considering that harm was only rarely defined as an outcome measure, and the overall small number of participants, conclusions cannot be drawn about the incidence of harmful effects of hyaluronidase. None of the studies undertook cost calculations with regards to use of hyaluronidase in local anaesthetic eye blocks.
Fifty-eight community coalition-driven intervention studies were included. No study was considered to be at low risk of bias. Behavioral change outcomes and health status change outcomes were analyzed separately. Outcomes are grouped by intervention type. Pooled effects across intervention types are not presented because the diverse community coalition-led intervention studies did not examine the same constructs or relationships, and they used dissimilar methodological designs. Broad-scale community system level change strategies led to little or no difference in measures of health behavior or health status (very low-certainty evidence). Broad health and social care system level strategies leds to small beneficial changes in measures of health behavior or health status in large samples of community residents (very low-certainty evidence). Lay community health outreach worker interventions led to beneficial changes in health behavior measures of moderate magnitude in large samples of community residents (very low-certainty evidence). Lay community health outreach worker interventions may lead to beneficial changes in health status measures in large samples of community residents; however, results were not consistent across studies (low-certainty evidence). Group-based health education led by professional staff resulted in moderate improvement in measures of health behavior (very low-certainty evidence) or health status (low-certainty evidence). Adverse outcomes of community coalition-led interventions were not reported. Coalition-led interventions are characterized by connection of multi-sectoral networks of health and human service providers with ethnic and racial minority communities. These interventions benefit a diverse range of individual health outcomes and behaviors, as well as health and social care delivery systems. Evidence in this review shows that interventions led by community coalitions may connect health and human service providers with ethnic and racial minority communities in ways that benefit individual health outcomes and behaviors, as well as care delivery systems. However, because information on characteristics of the coalitions themselves is insufficient, evidence does not provide an explanation for the underlying mechanisms of beneficial effects. Thus, a definitive answer as to whether a coalition-led intervention adds extra value to the types of community engagement intervention strategies described in this review remains unattainable.
We included 15 studies. The total number of participants included in the analyses was 3520. Most studies were small with fewer than 120 participants, although two larger studies with 2012 and 671 participants were included. There was considerable variation in many of the study characteristics, including the anaesthetics used. The concentrations of nitrous oxide varied between 50% and 70%, and half of the studies used clinical signs and haemodynamic changes to monitor depth of anaesthesia. As it was not possible to blind the anaesthetist to the anaesthetic used, we rated all studies at high risk of performance bias and we therefore downgraded the quality of evidence by one level for risk of bias using the GRADE approach. Other types of bias were generally low, or were rated unclear due to missing information. No studies were designed to measure AAGA as the primary outcome, and were therefore statistically underpowered to answer this review question. Despite the inclusion of 3520 participants, only three awareness events were reported by two studies. In one study the event was due to technical failure. Due to the rarity of the events, we did not consider it appropriate to pool the data, and we therefore downgraded the quality of evidence by a further level for imprecision using GRADE. It is not possible to draw any conclusions from this review. The included studies were mainly small (fewer than 120 participants) and there were limited estimates of effect, with only two studies reporting any events. We cannot therefore determine whether the use of nitrous oxide in general anaesthesia increases, decreases or has no effect on the risk of accidental awareness.
When compared to placebo, misoprostol (400-600 µg given vaginally or sublingually), gemeprost, mifepristone (200 or 600 mg), prostaglandin E and F2α (2.5 mg administered intracervically) demonstrated larger cervical preparation effects. When misoprostol was compared to gemeprost, misoprostol was more effective in preparing the cervix and was associated with fewer gastrointestinal side-effects. For vaginal administration, administration 2 hours prior was less effective than administration 3 hours prior to the abortion. Compared to oral misoprostol administration, the vaginal route was associated with significantly greater initial cervical dilation and lower rates of side-effects; however, sublingual administration 2-3 hours prior to the procedure demonstrated cervical effects superior to vaginal administration. When misoprostol (600 µg oral or 800 µg vaginal) was compared to mifepristone (200 mg administered 24 hours prior to procedure), misoprostol had inferior cervical preparatory effects. Compared to day-prior laminaria tents, 200 or 400 µg vaginal misoprostol showed no differences in the need for further mechanical dilation or length of the procedure; similarly, the osmotic dilators Lamicel and Dilapan showed no differences in cervical ripening when compared to gemeprost, although gemeprost had cervical effects which were superior to laminaria tents. Older prostaglandin regimens (sulprostone, prostaglandin E2 and F2α) were associated with high rates of gastrointestinal side-effects and unplanned pregnancy expulsions. Few studies reported women's satisfaction with cervical preparatory techniques. Modern methods of cervical ripening are generally safe, although efficacy and side-effects between methods vary. Reports of adverse events such as cervical laceration or uterine perforation are uncommon overall in this body of evidence and no published study has investigated whether cervical preparation impacts these rare outcomes. Cervical preparation decreases the length of the abortion procedure; this may become increasingly important with increasing gestational age, as mechanical dilation at later gestational ages takes longer and becomes more difficult. These data do not suggest a gestational age where the benefits of cervical dilation outweigh the side-effects, including pain, that women experience with cervical ripening procedures or the prolongation of the time interval before procedure completion. Mifepristone 200 mg, osmotic dilators and misoprostol, 400µg administered either vaginally or sublingually, are the most effective methods of cervical preparation.
We included three trials in this review, involving 134 patients who were 60 years of age or younger. The time window for the intervention was 30 hours from stroke onset in two studies and 96 hours in one study. All trials were stopped early. Surgical decompression reduced the risk of death at the end of follow-up (OR 0.19, 95% CI 0.09 to 0.37) and the risk of death or disability defined as mRS > 4 at 12 months (OR 0.26, 95% CI 0.13 to 0.51). Death or disability defined as mRS > 3 at the end of follow-up was no different between the treatment arms (OR 0.56, 95% CI 0.27 to 1.15). Surgical decompression lowers the risk of death and death or severe disability defined as mRS > 4 in selected patients 60 years of age or younger with a massive hemispheric infarction and oedema. Optimum criteria for patient selection and for timing of decompressive surgery are yet to be defined. Since survival may be at the expense of substantial disability, surgery should be the treatment of choice only when it can be assumed, based on their preferences, that it is in the best interest of patients. Since all the trials were stopped early, an overestimation of the effect size cannot be excluded.
We identified three trials with high risk of bias which compared veno-venous bypass (n = 65) versus no veno-venous bypass (n = 66). None of the trials reported patient or graft survival. There were no significant differences regarding renal failure or blood transfusion requirements between the two groups. None of the trials reported on the morbidity related to veno-venous bypass or the requirement of veno-venous bypass in the control group. We identified one trial with high risk of bias which compared percutaneous (n = 20) versus open technique (n =19) of veno-venous bypass. The patient or graft survival was not reported. There was no difference in veno-venous bypass related morbidity between the two groups. The operating time was significantly shorter in the percutaneous technique group (MD -59 minutes; 95% CI -102 to -16). There is no evidence to support or refute the use of veno-venous bypass in liver transplantation. There is no evidence to prefer any particular technique of veno-venous bypass in liver transplantation.
We included 13 articles reporting on nine studies with nine interventions. Four studies with 407 participants evaluated post-treatment programmes and five studies with 1113 participants evaluated exercise as a treatment modality. Four studies had a low risk of bias, one study a high risk and the remainder an unclear risk of bias. We found moderate quality evidence that post-treatment exercises were more effective than no intervention for reducing the rate of recurrences at one year (Rate Ratio 0.50; 95% Confidence Interval 0.34 to 0.73). There was moderate quality evidence that the number of recurrences was significantly reduced in two studies (Mean Difference -0.35; 95% CI -0.60 to -0.10) at one-half to two years follow-up. There was very low quality evidence that the days on sick leave were reduced by post-treatment exercises (Mean Difference -4.37; 95% CI -7.74 to -0.99) at one-half to two years follow-up. We found conflicting evidence for the effectiveness of exercise treatment in reducing the number of recurrences or the recurrence rate. There is moderate quality evidence that post-treatment exercise programmes can prevent recurrences of back pain but conflicting evidence was found for treatment exercise. Studies into the validity of measurement of recurrences and the effectiveness of post-treatment exercise are needed.
Five RCTs involving a total of 687 participants with a range of clinical indications were included. No new studies were included in this update. In one three-pronged study, vessel patency was greater with intra-arterial recombinant tissue plasminogen activator (rt-PA) than with intra-arterial streptokinase (P < 0.04) or intravenous rt-PA (P < 0.01). In participants with peripheral arterial occlusion there was no statistically significant difference in limb salvage at 30 days with either urokinase or rt-PA, though this may reflect the small numbers in the studies. Incidences of haemorrhagic complications varied with fibrinolytic regime but there was no statistically significant difference between intra-arterial urokinase and intra-arterial rt-PA. In the three-pronged study intravenous rt-PA and intra-arterial streptokinase were associated with a significantly higher risk of haemorrhagic complications than with intra-arterial rt-PA (P < 0.05). There is some evidence to suggest that intra-arterial rt-PA is more effective than intra-arterial streptokinase or intravenous rt-PA in improving vessel patency in people with peripheral arterial occlusion. There was no evidence that rt-PA was more effective than urokinase for patients with peripheral arterial occlusion and some evidence that initial lysis may be more rapid with rt-PA, depending on the regime. Incidences of haemorrhagic complications were not statistically significantly greater with rt-PA than with other regimes. However, all of the findings come from small studies and a general paucity of results means that it is not possible to draw clear conclusions.
We included three multifaceted and six monofaceted intervention studies (3271 children). Physician diagnosed asthma in children less than five years, and asthma as defined by respiratory symptoms and lung function criteria in children aged five years and older, both favoured treatment with a multifaceted intervention compared to usual care (< 5 years: odds ratio (OR) 0.72, 95% confidence interval (CI) 0.54 to 0.96, and > 5 years: OR 0.52, 95% CI 0.32 to 0.85). However, there was no significant difference in outcome between monofaceted intervention and control interventions (< 5 years: OR 1.12, 95% CI 0.76 to 1.64, and > 5 years: OR 0.83, 95% CI 0.59 to 1.16). Indirect comparison between these treatments did not demonstrate a significant difference between multiple interventions and mono-interventions in reducing the frequency of asthma diagnosis in children under five years (relative OR 0.64 (95% CI 0.40 to 1.04, P = 0.07) or five years and older (relative OR 0.63, 95% CI 0.35 to 1.13, P = 0.12). There was also no significant difference between either mono- and multifaceted intervention and control in reducing the likelihood of symptoms of nocturnal coughing at follow up. Wheezing, however, showed a significant difference between multifaceted and mono-interventions (relative OR 0.59, 95% CI 0.35 to 0.99, P = 0.04), but the significance was lost when data on treatment only was analysed. The available evidence suggests that the reduction of exposure to multiple allergens compared to usual care reduces the likelihood of a current diagnosis of asthma in children (at ages < 5 years and 5 years and older). Mono-intervention studies have not produced effects which are statistically significant compared with control. In children who are at risk of developing childhood asthma, multifaceted interventions, characterised by dietary allergen reduction and environmental remediation, reduce the odds of a physician diagnosis of asthma later in childhood by half. This translates to a number needed to treat (NNT) of 17. The effect of multi-faceted interventions on parent reported wheeze was inconsistent and had no significant impact on nocturnal coughing or dyspnoea. Data from monofaceted intervention exposed children studies were not significantly different from those of control groups for all outcomes. There remains uncertainty as to whether multiple interventions are more effective than mono-component interventions. The comparisons made were indirect, making the conclusions drawn uncertain. To our knowledge there are no ongoing studies in which both intervention strategies are randomly compared. The findings, however, warrant further direct comparison between multiple- and monofaceted interventions aimed at reducing the prevalence of asthma in children.
There were 15 trials with 11 included in the meta-analysis. Five trials showed relaxation reduced self-reported depression compared to wait-list, no treatment, or minimal treatment post intervention (SMD -0.59 (95% CI -0.94 to -0.24)). For clinician-rated depression, two trials showed a non-significant difference in the same direction (SMD -1.35 (95% CI -3.06 to 0.37)). Nine trials showed relaxation produced less effect than psychological (mainly cognitive-behavioural) treatment on self-reported depression (SMD = 0.38 (95% CI 0.14 to 0.62)). Three trials showed no significant difference between relaxation and psychological treatment on clinician-rated depression at post intervention (SMD 0.29 (95% CI -0.18 to 0.75)). Inconsistent effects were found when comparing relaxation training to medication and there were few data available comparing relaxation with complementary and lifestyle treatments. Relaxation techniques were more effective at reducing self-rated depressive symptoms than no or minimal treatment. However, they were not as effective as psychological treatment. Data on clinician-rated depressive symptoms were less conclusive. Further research is required to investigate the possibility of relaxation being used as a first-line treatment in a stepped care approach to managing depression, especially in younger populations and populations with subthreshold or first episodes of depression.
We included 16 studies with a total of 1146 participants in the meta-analysis. Only one study including 52 participants had a low risk of bias and low applicability concern in the patient selection domain. The median pre-test probability of unresectable disease after CT scanning across studies was 41.4% (that is 41 out of 100 participants who had resectable cancer after CT scan were found to have unresectable disease on laparotomy). The summary sensitivity of diagnostic laparoscopy was 64.4% (95% confidence interval (CI) 50.1% to 76.6%). Assuming a pre-test probability of 41.4%, the post-test probability of unresectable disease for participants with a negative test result was 0.20 (95% CI 0.15 to 0.27). This indicates that if a person is said to have resectable disease after diagnostic laparoscopy and CT scan, there is a 20% probability that their cancer will be unresectable compared to a 41% probability for those receiving CT alone. A subgroup analysis of people with pancreatic cancer gave a summary sensitivity of 67.9% (95% CI 41.1% to 86.5%). The post-test probability of unresectable disease after being considered resectable on both CT and diagnostic laparoscopy was 18% compared to 40.0% for those receiving CT alone. Diagnostic laparoscopy may decrease the rate of unnecessary laparotomy in people with pancreatic and periampullary cancer found to have resectable disease on CT scan. On average, using diagnostic laparoscopy with biopsy and histopathological confirmation of suspicious lesions prior to laparotomy would avoid 21 unnecessary laparotomies in 100 people in whom resection of cancer with curative intent is planned.
There are now 30 studies involving 6334 participants (6339 fractures) included in this review, which was published in 2011. There was considerable variation in the quality of trial methodology and generally inadequate reporting of methods and trial findings. Allocation concealment was confirmed in one trial only. The main outcome measures reported were fracture healing complications, re-operations and mortality. The reporting of functional outcomes was particularly poor. Few trials tested the same comparison. Most of the results for the 25 separate comparisons, frequently tested within one trial only, showed no statistically significant differences between the two implants under test. It was noted that the more rare findings of favourable results were often for implants developed within the same institutions as the trial. There was a consistent finding of less avascular necrosis with the sliding hip screw in comparison with five different types of cancellous screws but there was no significant difference found for re-operations. Additionally, the sliding hip screw was found to take longer to insert and to have an increased operative blood loss compared with multiple screws or pins. No clear conclusions can be made on the choice of implant for internal fixation of intracapsular fractures from the available evidence within randomised trials.
One study fulfilled inclusion criteria involving 113 children randomised to an asthma education programme involving an IHW, compared to a similar education programme without an IHW. Eighty eight of these children completed the trial. Parents' asthma knowledge score (mean difference (MD) (7.49; 95% CI 5.52 to 9.46), parents' asthma skill score (MD 0.98; 95% CI 0.52 to 1.44) and days absent from school (100% school-aged children in the intervention group missed <7 days, 21% of controls missed 7-14 days, difference = 21%, 95% CI 5-36%) were significantly better in the intervention group compared to controls. There was no significant difference in mean number of exacerbations (per year) between groups. There was no difference in quality of life or children's asthma skill score; both were limited to one study only and the direction favoured IHW group. There were no studies in adults. The involvement of IHW in asthma programs targeted for their own ethnic group in one small trial was beneficial in improving most, but not all asthma outcomes in children with asthma. It is very likely that involvement of an IHW is beneficial. However as exacerbation frequency was not significantly different between groups, we cannot be confident of the results in all settings. Nevertheless, given the complexity of health outcomes and culture as well as the importance of self-determination for indigenous peoples, the practice of including IHW in asthma education programs for indigenous children and adults with asthma is justified, but should be subject to further randomised controlled trials.
We included one trial reporting outcome at follow-up times ranging between two and 47 months for 81 participants with Mason type 1 and 2 radial head fractures. This poorly-reported trial was at particular high risk of detection and reporting biases. The trial found no significant differences between early and delayed mobilisation in the numbers of participants with pain or limitations in their range of elbow motion. All participants were reported as being able to use their arms for full activities of daily living and none had changed their occupation or lifestyle. There was no mention of fracture complications. There is a lack of robust evidence to inform on the timing of mobilisation, and specifically on the use of early mobilisation, after non-surgical or surgical treatment for adults with elbow fractures. There is a need for high quality, well-reported, adequately powered, randomised controlled trials that compare early versus delayed mobilisation in people with commonly-occurring elbow fractures, treated with or without surgery. Trials should use validated upper limb function scales, and assessment should be both short-term (to monitor recovery and early complications) and long-term (at least one year).
We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes. Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke. Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.
We only found studies (47 studies, 3581 participants) for 18 of the 29 eligible TCHMs as defined by our inclusion criteria. All were superiority trials conducted in China between 1997 and 2013, with most employing a two-arm parallel design with sample sizes ranging from 26 to 240 and a median treatment duration of 12 weeks (range: 2 to 24 weeks). We found that reporting and trial methodology were generally poor; in particular, there was a lack of information on randomisation, an absence of blinding of participants and outcome assessors and incomplete reporting of adverse events (AEs). None of the 30 trials published from 2007 onwards adopted the CONSORT recommendations for reporting RCTs of herbal interventions. We found seven TCHMs which each had potentially large benefits in studies estimating the TCHM versus 'no treatment' effect and in studies estimating the TCHM versus the WM effect. Two TCHMs (NaoXinTong and TongXinLuo) were common to both groups. Three of these TCHMs – Nao XinTong, NaoMaiTai and TongXinLuo – had the strongest evidence to justify further research. Two TCHMs (NaoMaiTai and TongXinLuo) had a 5% or more increased risk of AEs compared to the 'no Treatment' control, but the quality of this evidence was poor. We found moderate- to very low-quality evidence of benefit and harm of TCHMs for VaD. Methodological inadequacies need to be addressed by better conducted and reported trials. We identified NaoMaiTai, NaoXinTong and TongXinLuo as warranting special research priority.
In this review update, an additional three studies and 220 participants were added. A total of seven RCTs (two in adults, four in children, one in both children and adults) with 837 participants (aged from one to 63 years) with asthma from ethnic minority groups were eligible for inclusion in this review. The methodological quality of studies ranged from very low to low. For our primary outcome (asthma exacerbations during follow-up), the quality of evidence was low for all outcomes. In adults, use of a culture-specific programme, compared to generic programmes or usual care did not significantly reduce the number of participants from two studies with 294 participants for: exacerbations with one or more exacerbations during follow-up (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.50 to 1.26), hospitalisations over 12 months (OR 0.83, 95% CI 0.31 to 2.22) and exacerbations requiring oral corticosteroids (OR 0.97, 95% CI 0.55 to 1.73). However, use of a culture-specific programme, improved asthma quality of life scores in 280 adults from two studies (mean difference (MD) 0.26, 95% CI 0.17 to 0.36) (although the MD was less then the minimal important difference for the score). In children, use of a culture-specific programme was superior to generic programmes or usual care in reducing severe asthma exacerbations requiring hospitalisation in two studies with 305 children (rate ratio 0.48, 95% CI 0.24 to 0.95), asthma control in one study with 62 children and QoL in three studies with 213 children, but not for the number of exacerbations during follow-up (OR 1.55, 95% CI 0.66 to 3.66) or the number of exacerbations (MD 0.18, 95% CI -0.25 to 0.62) among 100 children from two studies. The available evidence showed that culture-specific education programmes for adults and children from minority groups are likely effective in improving asthma-related outcomes. This review was limited by few studies and evidence of very low to low quality. Not all asthma-related outcomes improved with culture-specific programs for both adults and children. Nevertheless, while modified culture-specific education programs are usually more time intensive, the findings of this review suggest using culture-specific asthma education programmes for children and adults from minority groups. However, more robust RCTs are needed to further strengthen the quality of evidence and determine the cost-effectiveness of culture-specific programs.
Nine trials with 882 participants were included in the review. In five trials the outcome assessors were blind to the participants' intervention condition and in the remainder of trials it was unclear. In the majority of trials, participants were either not blind to their intervention condition, or it was unclear whether they were or not. Allocation concealment was also unclear in the majority of trials. Although all trials treated participants in an outpatient setting, the designs implemented in trials was diverse, which limits the generalisability of the results. Three trials indicated participants treated with antidepressant medication had lower relapse-recurrence rates (40.9%) compared to those treated with placebo (66.6%) during a relapse prevention phase (odds ratio (OR) 0.34; 95% confidence interval (CI) 0.18 to 0.64, P = 0.02). One trial that compared a combination of psychological therapy and medication to medication alone favoured a combination approach over medication alone, however this result did not reach statistical significance (OR 0.26; 95% CI 0.06 to 1.15). The majority of trials that involved antidepressant medication reported adverse events including suicide-related behaviours. However, there were not enough data to show which treatment approach results in the most favourable adverse event profile. Currently, there is little evidence to conclude which type of treatment approach is most effective in preventing relapse or recurrence of depressive episodes in children and adolescents. Limited trials found that antidepressant medication reduces the chance of relapse-recurrence in the future, however, there is considerable diversity in the design of trials, making it difficult to compare outcomes across studies. Some of the research involving psychological therapies is encouraging, however at present more trials with larger sample sizes need to be conducted in order to explore this treatment approach further.
We excluded nine studies because they were non-randomised trials or were withdrawn before enrolment. We included one study, which was conducted in two phases. During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three-day course of oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms. This review included data from only one study, which had methodological limitations. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed.
The electronic literature search identified 1 original study that met the eligibility criteria. One unpublished study was also identified through manual searches. Therefore two randomized controlled trials met the inclusion criteria: Tscheikuna 2002 (via electronic searches) and Ruiz 1994 (via manual searches). Tscheikuna 2002, a double-blind RCT performed in Thailand, evaluated the effectiveness of tranexamic acid (TXA, an antifibrinolytic agent) administered orally in 46 hospital in- and outpatients with haemoptysis of various etiologies. Ruiz 1994, a double-blind RCT performed in Peru, evaluated the effectiveness of intravenous TXA in 24 hospitalised patients presenting with haemoptysis secondary to tuberculosis. Pooled together, results demonstrated a significant reduction in bleeding time between patients receiving TXA and patients receiving placebo with a weighted mean difference (WMD) of -19.47 (95% CI -26.90 to -12.03 hours), but with high heterogeneity (I² = 52%). TXA did not affect remission of haemoptysis evaluated at seven days after the start of treatment. Adverse effects caused by the drug's mechanism of action were not reported. There was no significant difference in the incidence of mild side effects between active and placebo groups (OR 3.13, 95% CI 0.80 to 12.24). There is insufficient evidence to judge whether antifibrinolytics should be used to treat haemoptysis from any cause, though limited evidence suggests they may reduce the duration of bleeding.
We included two studies, both comparing the effects of adding aspirin to standard antipsychotic treatment with adding placebo to standard antipsychotic treatment. We were hoping to find high-quality data for seven main outcomes of importance: clinically important change in global state, mental state, cognitive functioning and quality of life, numbers leaving the study early, incidence of gastrointestinal adverse events and hospital admission. Clinically important change data were not reported. Global state data were reported by one study as 'unspecified problem necessitating change in dose or type of antipsychotics'; there was no clear difference between treatment groups for this outcome (RR 0.75, 95% CI 0.30 to 1.88; studies = 1; participants = 70; very low-quality evidence). Both trials measured mental state using the Positive and Negative Symptom Scale (PANSS), and mean total PANSS endpoint scores favoured the adjunct aspirin group in the medium term (MD –6.56, 95% CI –12.04 to –1.08; studies = 2; participants = 130; very low-quality evidence). Less than 10% of each group's participants left the studies early (for any reason) and by around three months there was no clear difference between numbers leaving early from the aspirin group compared to numbers leaving early from the placebo group suggesting aspirin is acceptable (RR 1.12, 95% CI 0.40 to 3.14; studies = 2; participants = 130; very low-quality evidence). There was some gastric upset in both groups but rates were not clearly different between the treatment groups (RR 1.03, 95% CI 0.55 to 1.94; studies = 1; participants = 70; very low-quality evidence). We are unclear if 'change in hospital status' is an unfavourable outcome or not as one study reported equivocal data (RR 0.56, 95% CI 0.05 to 5.90; studies = 1; participants = 70; very low-quality evidence). It should be noted that all the above results were based on data of very low-quality and were difficult to interpret for clinicians or patients, and that the two studies, completed in the last decade, failed to report any usable outcomes on cognitive functioning or quality of life. We highlighted the evidence that some pioneering researchers feel this question is important enough to merit testing in randomised trials. However, we also highlighted that the evidence produced from these trials was weak and inconclusive. It was impossible to draw clear conclusions on the therapeutic value of aspirin for schizophrenia from these short, small and limited trials.
We included six trials with 520 patients comparing pre-operative biliary drainage (265 patients) versus no pre-operative biliary drainage (255 patients). Four trials used percutaneous transhepatic biliary drainage and two trials used endoscopic sphincterotomy and stenting as the method of pre-operative biliary drainage. The risk of bias was high in all trials. The proportion of patients with malignant obstruction varied between 60% and 100%. There was no significant difference in mortality (40/265, weighted proportion 14.9%) in the pre-operative biliary drainage group versus the direct surgery group (34/255, 13.3%) (RR 1.12; 95% CI 0.73 to 1.71; P = 0.60). The overall serious morbidity was higher in the pre-operative biliary drainage group (60 per 100 patients in the pre-operative biliary drainage group versus 26 per 100 patients in the direct surgery group) (RaR 1.66; 95% CI 1.28 to 2.16; P = 0.0002). The proportion of patients who developed serious morbidity was significantly higher in the pre-operative biliary drainage group (75/102, 73.5%) in the pre-operative biliary drainage group versus the direct surgery group (37/94, 37.4%) (P < 0.001). Quality of life was not reported in any of the trials. There was no significant difference in the length of hospital stay (2 trials, 271 patients; MD 4.87 days; 95% CI -1.28 to 11.02; P = 0.12) between the two groups. Trial sequential analysis showed that for mortality only a small proportion of the required information size had been obtained. There seemed to be no significant differences in the subgroup of trials assessing percutaneous compared to endoscopic drainage. There is currently not sufficient evidence to support or refute routine pre-operative biliary drainage for patients with obstructive jaundice. Pre-operative biliary drainage may increase the rate of serious adverse events. So, the safety of routine pre-operative biliary drainage has not been established. Pre-operative biliary drainage should not be used in patients undergoing surgery for obstructive jaundice outside randomised clinical trials.
One of 17 studies retrieved for full-text assessment for eligibility was included in the final analysis. This study included a total of 186 participants and investigated the effect of LMWH to prevent CVC-related thrombosis compared to standard care. The risk of bias of the study was assessed to be low, except for the unclear risk of selection bias (allocation concealment not reported) and detection bias since it was an open-label study. Nonetheless, outcome adjudication was blinded. However, overall the quality of the evidence was low due to the fact that the study was underpowered. The CIs for the risk of CVC-related thrombosis (symptomatic and asymptomatic events) were compatible with benefits of either LMWH (reviparin) or the control (RR for symptomatic thrombosis 1.03, 95% CI 0.21 to 4.93; RR for asymptomatic thrombosis 1.17, 95% CI 0.45 to 3.08). Similarly, only one patient in the standard care group suffered a major bleeding event, while minor bleeding was found in 53.3% of patients in the reviparin arm and in 44.7% of patients in the standard care arm (major bleeding RR 0.34, 95% CI 0.01 to 8.26; minor bleeding RR 1.20, 95% CI 0.91 to 1.58). Lastly, there were two deaths within the study and neither were the result of a venous thrombotic event (VTE), occurring in the standard care arm. No additional adverse effects were reported. Other pre-specified outcomes for this review were not reported. A single study reported imprecise effects for the risk of CVC-related thrombosis in children on a CVC anticoagulant prophylaxis regimen. The quality of the evidence was low due to the fact that the included study was clearly underpowered, hampering any conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombi in children. Further prospective randomised studies are highly encouraged.
This review included 10 studies with a total number of 686 participants featuring in 20 different outcomes of interest. Overall, there was significant clinical improvement in clinical global state at medium term amongst people receiving trifluoperazine (3 RCTs, n = 417, RR 4.61, CI 1.54 to 13.84, low quality evidence) and significantly fewer people receiving trifluoperazine left the studies early due to relapse or worsening at medium term (2 RCTs, n = 381, RR 0.34, CI 0.23 to 0.49, low quality evidence). However, results were equivocal for leaving the study early at medium term for any reason (2 RCTs, n = 391, RR 0.80, CI 0.17 to 3.81, very low quality evidence) and due to severe adverse effects (2 RCTs, n = 391, RR 1.54, CI 0.56 to 4.24, very low quality evidence). Equivocal data were also found for intensified symptoms at medium term (2 RCTs, n = 80, RR 1.05, CI 0.54 to 2.05, very low quality evidence) and rates of agitation or distress again at medium term (1 RCT, n = 52, RR 2.00, CI 0.19 to 20.72, very low quality evidence). Comparison between low and high-dose trifluoperazine with placebo from a single study provided equivocal evidence of effects. For economic outcomes, we valued outcomes in GBP terms and presented them in additional tables; there was an estimated saving of £3488.3 in favour of trifluoperazine. However, numerous assumptions were made and these savings need to be interpreted in light of those assumptions. Our results agree with existing evidence that compared to placebo, trifluoperazine is an effective antipsychotic for people with schizophrenia. Furthermore, our review provides supportive evidence that trifluoperazine increases the risk of extrapyramidal adverse effects. Although the effect sizes against placebo are similar to those observed with other agents, they are based on data from many small, pre-CONSORT trials with generally either a low or very low GRADE evidence that has limited implication for clinical practice. Large, independent trials are needed that adhere to the CONSORT statement to compare trifluoperazine with placebo used in the treatment of schizophrenia and schizophrenia-like illnesses.
We included 8 trials involving 263 people with PD in the review. Risk of bias was unclear or high for all but one of the included studies. Study sample sizes were small, and there was a large amount of heterogeneity between trials with regard to study design and the outcome measures used. As a result, we graded the quality of the evidence as low or very low. Most of the studies intended to improve motor function using commercially available devices, which were compared with physiotherapy. The interventions lasted for between 4 and 12 weeks. In comparison to physiotherapy, VR may lead to a moderate improvement in step and stride length (standardised mean difference (SMD) 0.69, 95% confidence interval (CI) 0.30 to 1.08; 3 studies; 106 participants; low-quality evidence). VR and physiotherapy interventions may have similar effects on gait (SMD 0.20, 95% CI -0.14 to 0.55; 4 studies; 129 participants; low-quality evidence), balance (SMD 0.34, 95% CI -0.04 to 0.71; 5 studies; 155 participants; low-quality evidence), and quality of life (mean difference 3.73 units, 95% CI -2.16 to 9.61; 4 studies; 106 participants). VR interventions did not lead to any reported adverse events, and exercise adherence did not differ between VR and other intervention arms. The evidence available comparing VR exercise with a passive control was more limited. The evidence for the main outcomes of interest was of very low quality due to the very small sample sizes of the two studies available for this comparison. We found low-quality evidence of a positive effect of short-term VR exercise on step and stride length. VR and physiotherapy may have similar effects on gait, balance, and quality of life. The evidence available comparing VR with passive control interventions was more limited. Additional high-quality, large-scale studies are needed to confirm these findings.
Thirteen studies were identified as possibly eligible for inclusion. The majority of studies were excluded as they did not separate data for early and late onset infection. Two studies are still awaiting assessment. Only one small study, in 24 neonates, was included in this review. It compared beta-lactam therapy with a combination of beta lactam plus aminoglycoside. The study did not meet our prespecified criteria for good methodological quality. In babies with suspected infection there was no significant difference in mortality (RR 0.17, 95% CI 0.01 to 3.23) or treatment failure (RR 0.17, 95% CI 0.01 to 3.23). Antibiotic resistance was assessed and there were no cases in either group. There is inadequate evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset neonatal sepsis. The available evidence is not of high quality. Although suspected sepsis and antibiotic use is common, quality research is required to specifically address both narrow and broad spectrum antibiotic use for late onset neonatal sepsis. Future research also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and lower gestational age groups.
We included 32 trials (1836 participants). No trial compared a combination of manual therapy and exercise versus placebo or no intervention. Seven trials compared a combination of manual therapy and exercise versus other interventions but were clinically heterogeneous, so opportunities for meta-analysis were limited. The overall impression gained from these trials is that the few outcome differences between interventions that were clinically important were detected only up to seven weeks. Evidence of moderate quality shows that a combination of manual therapy and exercise for six weeks probably results in less improvement at seven weeks but a similar number of adverse events compared with glucocorticoid injection. The mean change in pain with glucocorticoid injection was 58 points on a 100-point scale, and 32 points with manual therapy and exercise (mean difference (MD) 26 points, 95% confidence interval (CI) 15 points to 37 points; one RCT, 107 participants), for an absolute difference of 26% (15% to 37%). Mean change in function with glucocorticoid injection was 39 points on a 100-point scale, and 14 points with manual therapy and exercise (MD 25 points, 95% CI 35 points to 15 points; one RCT, 107 participants), for an absolute difference of 25% (15% to 35%). Forty-six per cent (26/56) of participants reported treatment success with manual therapy and exercise compared with 77% (40/52) of participants receiving glucocorticoid injection (risk ratio (RR) 0.6, 95% CI 0.44 to 0.83; one RCT, 108 participants), with an absolute risk difference of 30% (13% to 48%). The number reporting adverse events did not differ between groups: 56% (32/57) reported events with manual therapy and exercise, and 53% (30/57) with glucocorticoid injection (RR 1.07, 95% CI 0.76 to 1.49; one RCT, 114 participants), with an absolute risk difference of 4% (-15% to 22%). Group differences in improvement in overall pain and function at six months and 12 months were not clinically important. We are uncertain of the effect of other combinations of manual therapy and exercise, as most evidence is of low quality. Meta-analysis of two trials (86 participants) suggested no clinically important differences between a combination of manual therapy, exercise, and electrotherapy for four weeks and placebo injection compared with glucocorticoid injection alone or placebo injection alone in terms of overall pain, function, active range of motion and quality of life at six weeks, six months and 12 months (though the 95% CI suggested function may be better with glucocorticoid injection at six weeks). The same two trials found that adding a combination of manual therapy, exercise and electrotherapy for four weeks to glucocorticoid injection did not confer clinically important benefits over glucocorticoid injection alone at each time point. Based on one high quality trial (148 participants), following arthrographic joint distension with glucocorticoid and saline, a combination of manual therapy and supervised exercise for six weeks conferred similar effects to those of sham ultrasound in terms of overall pain, function and quality of life at six weeks and at six months, but provided greater patient-reported treatment success and active shoulder abduction at six weeks. One trial (119 participants) found that a combination of manual therapy, exercise, electrotherapy and oral non-steroidal anti-inflammatory drug (NSAID) for three weeks did not confer clinically important benefits over oral NSAID alone in terms of function and patient-reported treatment success at three weeks. On the basis of 25 clinically heterogeneous trials, we are uncertain of the effect of manual therapy or exercise when not delivered together, or one type of manual therapy or exercise versus another, as most reported differences between groups were not clinically or statistically significant, and the evidence is mostly of low quality. The best available data show that a combination of manual therapy and exercise may not be as effective as glucocorticoid injection in the short-term. It is unclear whether a combination of manual therapy, exercise and electrotherapy is an effective adjunct to glucocorticoid injection or oral NSAID. Following arthrographic joint distension with glucocorticoid and saline, manual therapy and exercise may confer effects similar to those of sham ultrasound in terms of overall pain, function and quality of life, but may provide greater patient-reported treatment success and active range of motion. High-quality RCTs are needed to establish the benefits and harms of manual therapy and exercise interventions that reflect actual practice, compared with placebo, no intervention and active interventions with evidence of benefit (e.g. glucocorticoid injection).
We included two trials that compared surgical with non-surgical treatment for patients with thoracolumbar burst fractures without neurological deficit. These recruited a total of 87 participants and reported outcomes for 79 participants at follow-up of two years or more. Both trials were judged at unclear risk of selection bias and at high risk of performance and detection biases, resulting from lack of blinding. The two trials reported contrasting results for pain and function-related outcomes at final follow-up, and numbers returning to work. One trial found less pain (mean difference (MD) -15.09 mm, 95% CI -27.81 to -2.37; 100 mm visual analogue scale), and better function based on the Roland and Morris disability questionnaire results (MD -5.87, 95% CI -10.10 to -1.64; 24 points = maximum disability) in the surgical group. Based on the same outcome measures, the other trial found the surgical group had more pain (MD 13.60 mm, 95% CI -0.31 to 27.51) and worse function (MD 4.31, 95% CI 0.54 to 8.08). Neither trial reported a statistically significant difference in return to work. There were greater numbers of participants with complications in the surgical group of both trials (21/41 versus 6/38; RR 2.85, 95% CI 0.83 to 9.75; 2 trials), and only participants of this group had subsequent surgery, involving implant removal either for complications or as a matter of course. One trial reported that surgery was over four times more costly than non-surgical treatment. The contradictory evidence provided by two small and potentially biased randomised controlled trials is insufficient to conclude whether surgical or non-surgical treatment yields superior pain and functional outcomes for people with thoracolumbar burst fractures without neurological deficit. It is likely, however, that surgery is associated with more early complications and the need for subsequent surgery, as well as greater initial healthcare costs.
We included eight studies with 957 participants. The mean age of participants in the studies ranged from 78 to 88 years and in seven studies the mean MMSE score was 12 or lower. Seven studies were randomised controlled trials (three individually randomised, parallel group studies, one individually randomised cross-over study and three cluster-randomised trials) and one study was a non-randomised clinical trial. Five studies included a control group receiving usual care, two studies an active control intervention (activities which were not personally tailored) and one study included both an active control and usual care. Personally tailored activities were mainly delivered directly to the participants; in one study the nursing staff were trained to deliver the activities. The selection of activities was based on different theoretical models but the activities did not vary substantially. We found low-quality evidence indicating that personally tailored activities may slightly improve challenging behaviour (standardised mean difference (SMD) −0.21, 95% confidence interval (CI) −0.49 to 0.08; I² = 50%; 6 studies; 439 participants). We also found low-quality evidence from one study that was not included in the meta-analysis, indicating that personally tailored activities may make little or no difference to general restlessness, aggression, uncooperative behaviour, very negative and negative verbal behaviour (180 participants). There was very little evidence related to our other primary outcome of quality of life, which was assessed in only one study. From this study, we found that quality of life rated by proxies was slightly worse in the group receiving personally tailored activities (moderate-quality evidence, mean difference (MD) −1.93, 95% CI −3.63 to −0.23; 139 participants). Self-rated quality of life was only available for a small number of participants, and there was little or no difference between personally tailored activities and usual care on this outcome (low-quality evidence, MD 0.26, 95% CI −3.04 to 3.56; 42 participants). We found low-quality evidence that personally tailored activities may make little or no difference to negative affect (SMD −0.02, 95% CI −0.19 to 0.14; I² = 0%; 6 studies; 589 participants). We found very low quality evidence and are therefore very uncertain whether personally tailored activities have any effect on positive affect (SMD 0.88, 95% CI 0.43 to 1.32; I² = 80%; 6 studies; 498 participants); or mood (SMD −0.02, 95% CI −0.27 to 0.23; I² = 0%; 3 studies; 247 participants). We were not able to undertake a meta-analysis for engagement and the sleep-related outcomes. We found very low quality evidence and are therefore very uncertain whether personally tailored activities improve engagement or sleep-related outcomes (176 and 139 participants, respectively). Two studies that investigated the duration of the effects of personally tailored activities indicated that the intervention effects persisted only during the delivery of the activities. Two studies reported information about adverse effects and no adverse effects were observed. Offering personally tailored activities to people with dementia in long-term care may slightly improve challenging behaviour. Evidence from one study suggested that it was probably associated with a slight reduction in the quality of life rated by proxies, but may have little or no effect on self-rated quality of life. We acknowledge concerns about the validity of proxy ratings of quality of life in severe dementia. Personally tailored activities may have little or no effect on negative affect and we are uncertain whether they improve positive affect or mood. There was no evidence that interventions were more likely to be effective if based on one specific theoretical model rather than another. Our findings leave us unable to make recommendations about specific activities or the frequency and duration of delivery. Further research should focus on methods for selecting appropriate and meaningful activities for people in different stages of dementia.
We included 27 studies involving 3048 participants. The main comparators were clonidine or lofexidine (14 studies). Six studies compared buprenorphine versus methadone, and seven compared different rates of buprenorphine dose reduction. We assessed 12 studies as being at high risk of bias in at least one of seven domains of methodological quality. Six of these studies compared buprenorphine with clonidine or lofexidine and two with methadone; the other four studies compared different rates of buprenorphine dose reduction. For the comparison of buprenorphine and methadone in tapered doses, meta-analysis was not possible for the outcomes of intensity of withdrawal or adverse effects. However, information reported by the individual studies was suggestive of buprenorphine and methadone having similar capacity to ameliorate opioid withdrawal, without clinically significant adverse effects. The meta-analyses that were possible support a conclusion of no difference between buprenorphine and methadone in terms of average treatment duration (mean difference (MD) 1.30 days, 95% confidence interval (CI) −8.11 to 10.72; N = 82; studies = 2; low quality) or treatment completion rates (risk ratio (RR) 1.04, 95% CI 0.91 to 1.20; N = 457; studies = 5; moderate quality). Relative to clonidine or lofexidine, buprenorphine was associated with a lower average withdrawal score (indicating less severe withdrawal) during the treatment episode, with an effect size that is considered to be small to moderate (standardised mean difference (SMD) −0.43, 95% CI −0.58 to −0.28; N = 902; studies = 7; moderate quality). Patients receiving buprenorphine stayed in treatment for longer, with an effect size that is considered to be large (SMD 0.92, 95% CI 0.57 to 1.27; N = 558; studies = 5; moderate quality) and were more likely to complete withdrawal treatment (RR 1.59, 95% CI 1.23 to 2.06; N = 1264; studies = 12; moderate quality). At the same time there was no significant difference in the incidence of adverse effects, but dropout due to adverse effects may be more likely with clonidine (RR 0.20, 95% CI 0.04 to 1.15; N = 134; studies = 3; low quality). The difference in treatment completion rates translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 6), indicating that for every four people treated with buprenorphine, we can expect that one additional person will complete treatment than with clonidine or lofexidine. For studies comparing different rates of reduction of the buprenorphine dose, meta-analysis was possible only for treatment completion, with separate analyses for inpatient and outpatient settings. The results were diverse, and we assessed the quality of evidence as being very low. It remains very uncertain what effect the rate of dose taper has on treatment outcome. Buprenorphine is more effective than clonidine or lofexidine for managing opioid withdrawal in terms of severity of withdrawal, duration of withdrawal treatment, and the likelihood of treatment completion. Buprenorphine and methadone appear to be equally effective, but data are limited. It remains possible that the pattern of withdrawal experienced may differ and that withdrawal symptoms may resolve more quickly with buprenorphine. It is not possible to draw any conclusions from the available evidence on the relative effectiveness of different rates of tapering the buprenorphine dose. The divergent findings of studies included in this review suggest that there may be multiple factors affecting the response to the rate of dose taper. One such factor could be whether or not the initial treatment plan includes a transition to subsequent relapse prevention treatment with naltrexone. Indeed, the use of buprenorphine to support transition to naltrexone treatment is an aspect worthy of further research. Most participants in the studies included in this review were male. None of the studies reported outcomes on the basis of sex, preventing any exploration of differences related to this variable. Consideration of sex as a factor influencing response to withdrawal treatment would be relevant research for selecting the most appropriate type of intervention for each individual.
We have included nine studies in this review. All were part of the original systematic review; no new trials meeting eligibility criteria were identified through our updated searches. The studies were conducted in eight different states of the USA, during the years 1967 to 1992. Nearly 1000 (946) juveniles or young adults of different races participated, almost all males. The average age of the participants in each study ranged from 15 to 17 years. Meta-analyses of seven studies show the intervention to be more harmful than doing nothing. The OR (fixed-effect) for effects on first post-treatment effect on officially measured criminal behavior indicated a negative program effect (OR 1.68, 95% confidence interval (CI) 1.20 to 2.36) and nearly identical regardless of the meta-analytic strategy (random-effects OR 1.72, 95% CI 1.13 to 2.62). Sensitivity analyses (random-effects) showed the findings were robust even when removing one study with an inadequate randomization strategy (OR 1.47, 95% CI 1.03 to 2.11), or when removing one study with high attrition (OR 1.96, 95% CI 1.25 to 3.08), or both (OR 1.68, 95% CI 1.10 to 2.58). We conclude that programs such as 'Scared Straight' increase delinquency relative to doing nothing at all to similar youths. Given these results, we cannot recommend this program as a crime prevention strategy. Agencies that permit such programs, therefore, must rigorously evaluate them, to ensure that they do not cause more harm than good to the very citizens they pledge to protect.
We were able to include two trials involving 321 people with severe mental illnesses. There was no significant difference in hospital admission (n=160, 1 RCT, RR 0.69 0.5 to 1.0), or number of psychiatric outpatient attendances between participants given advanced treatment directives or usual care. Similarly, no significant differences were found for compliance with treatment, self harm or number of arrests. Participants given advanced treatment directives needed less use of social workers time (n=160, 1 RCT, WMD -106.00 CI -156.2 to -55.8) than the usual care group, and violent acts were also lower in the advanced directives group (n=160, 1 RCT, RR 0.27 CI 0.1 to 0.9, NNT 8 CI 6 to 92). The number of people leaving the study early were not different between groups (n=321, 2 RCTs, RR 0.92 CI 0.6 to 1.6). The addition of 11 studies to awaiting classification section of the review may alter the conclusions of the review once assessed. There are too few data available to make definitive recommendations. More intensive forms of advance directive appear to show promise, but currently practice must be guided by evidence other than that derived from randomised trials. More trials are indicated to determine whether higher intensity interventions, such as joint crisis planning, have an effect on outcomes of clinical relevance.
Thirty-five trials (3573 women) with 15 comparisons were included. Women allocated calcium channel blockers were less likely to have persistent high blood pressure compared to those allocated hydralazine (six trials, 313 women; 8% versus 22%; risk ratio (RR) 0.37, 95% confidence interval (CI) 0.21 to 0.66). Ketanserin was associated with more persistent high blood pressure than hydralazine (three trials, 180 women; 27% versus 6%; RR 4.79, 95% CI 1.95 to 11.73), but fewer side-effects (three trials, 120 women; RR 0.32, 95% CI 0.19 to 0.53) and a lower risk of HELLP (haemolysis, elevated liver enzymes and lowered platelets) syndrome (one trial, 44 women; RR 0.20, 95% CI 0.05 to 0.81). Labetalol was associated with a lower risk of hypotension compared to diazoxide (one trial 90 women; RR 0.06, 95% CI 0.00 to 0.99) and a lower risk of caesarean section (RR 0.43, 95% CI 0.18 to 1.02), although both were borderline for statistical significance. Both nimodipine and magnesium sulphate were associated with a high incidence of persistent high blood pressure, but this risk was lower for nimodipine compared to magnesium sulphate (one trial, 1650 women; 47% versus 65%; RR 0.84, 95% CI 0.76 to 0.93). Nimodipine was associated with a lower risk of respiratory difficulties (RR 0.28, 95% CI 0.08 to 0.99), fewer side-effects (RR 0.68, 95% CI 0.55 to 0.85) and less postpartum haemorrhage (RR 0.41, 95% CI 0.18 to 0.92) than magnesium sulphate. Stillbirths and neonatal deaths were not reported. There are insufficient data for reliable conclusions about the comparative effects of any other drugs. Until better evidence is available the choice of antihypertensive should depend on the clinician's experience and familiarity with a particular drug; on what is known about adverse effects; and on women's preferences. Exceptions are nimodipine, magnesium sulphate (although this is indicated for women who require an anticonvulsant for prevention or treatment of eclampsia), diazoxide and ketanserin, which are probably best avoided.
Only two trials (60 participants) investigating the effect of metformin added to insulin therapy for three months in adolescents with poorly controlled type 1 diabetes could be included. Meta-analysis was not possible due to the clinical and methodological heterogeneity of data. Both studies suggested that metformin treatment lowered glycosylated haemoglobin A1c (HbA1c) in adolescents with type 1 diabetes and poor metabolic control. Improvements in insulin sensitivity, body composition or serum lipids were not documented in either study, however, one study showed a decrease in insulin dosage by 10%. Adverse effects were mainly gastrointestinal in both studies and hypoglycaemia in one study. No data on health-related quality of life, all-cause mortality or morbidity are currently available. There is some evidence suggesting improvement of metabolic control in poorly controlled adolescents with type 1 diabetes, on addition of metformin to insulin therapy. Stronger evidence is required from larger studies, carried out over longer time periods to document the long-term effects on metabolic control, health-related quality of life as well as morbidity and mortality in those patients.
A total of 3239 citations were identified through the searches. Only one RCT, with 15-year follow-up met the inclusion criteria (n = 13 clusters: 191,873 participants). There was no statistically significant difference in the oral cancer mortality rates for the screened group (15.4/100,000 person-years) and the control group (17.1/100,000 person-years), with a RR of 0.88 (95% CI 0.69 to 1.12). A 24% reduction in mortality was reported between the screening group (30/100,000 person-years) and the control group (39.0/100,000) for high-risk individuals who used tobacco or alcohol or both, which was statistically significant (RR 0.76; 95% CI 0.60 to 0.97). No statistically significant differences were found for incidence rates. A statistically significant reduction in the number of individuals diagnosed with stage III or worse oral cancer was found for those in the screening group (RR 0.81; 95% CI 0.70 to 0.93). No harms were reported. The study was assessed as at high risk of bias. There is evidence that a visual examination as part of a population-based screening programme reduces the mortality rate of oral cancer in high-risk individuals. In addition, there is a stage shift and improvement in survival rates across the population as a whole. However, the evidence is limited to one study, which has a high risk of bias and did not account for the effect of cluster randomisation in the analysis. There was no evidence to support the use of adjunctive technologies like toluidine blue, brush biopsy or fluorescence imaging as a screening tool to reduce oral cancer mortality. Further RCTs are recommended to assess the efficacy and cost-effectiveness of a visual examination as part of a population-based screening programme in low, middle and high-income countries.
We identified three eligible trials involving a total of 222 participants with 333 groin wounds. Suction drainage was compared with no drainage in all studies. Two studies were parallel-group, randomized controlled trials, and one was a split-body, randomized controlled trial. Trial settings were not clearly described. Patients undergoing bypass and endarterectomy procedures were included, but none of the studies provided details on the severity of the underlying arterial disease. We deemed all of the studies to be at a high risk of bias in three or more domains of the 'Risk of bias' assessment and overall the evidence was of very low quality. Two out of three studies had unit of analysis errors (with multiple wounds within patients analysed as independent) and it was not possible to judge the appropriateness of the analysis of the third. Meta-analysis was not appropriate, firstly because of clinical heterogeneity, and secondly because we were not able to adjust for the analysis errors in the individual trials. One trial yielded data on surgical site infections (SSI; the primary outcome of the review): there was no clear difference between drained and non-drained wounds for SSI (risk ratio 1.33; 95% confidence interval 0.30 to 5.94; 50 participants with bilateral groin wounds; very low quality evidence). It was not possible to evaluate any other outcomes from this trial. The results from the other two studies are unreliable because of analysis errors and reporting omissions. The data upon which to base practice in this area are limited and prone to biases. Complete uncertainty remains regarding the potential benefits and harms associated with the use of wound drains in lower limb arterial surgery due to the small number of completed studies and weaknesses in their design and conduct. Higher quality evidence is needed to inform clinical decision making. To our knowledge, no trials on this topic are currently active.
We included 11 studies (674 participants). The risk of bias was high or unclear in all of the included studies. All studies compared needle aspiration to incision and drainage. All but one of the 11 studies reported on the primary outcome of recurrence. When we pooled data from the 10 studies the recurrence rate was higher in the needle aspiration group compared with incision and drainage: risk ratio (RR) 3.74 (95% confidence interval (CI) 1.63 to 8.59; 612 participants). We detected moderate heterogeneity in this analysis (I2 = 48%). In interpreting the pooled result it is important to note that the evidence for this outcome was of very low quality. None of the other outcomes (adverse effects of the intervention, time to resumption of normal diet, complications of the disease process and symptom scores) were consistently measured across all studies. Only three studies reported on adverse effects/events associated with the intervention and only one such event in a single patient was reported (post-procedure bleeding following incision and drainage: 1/28, 3.6%) (very low-quality evidence). Time to resumption of normal diet was compared in two studies; neither found an obvious difference between needle aspiration and incision and drainage (very low-quality evidence). Only three studies stated that they would report complications of the disease process. In these three studies, the only complication reported was admission to hospital for dehydration in two patients who underwent incision and drainage (2/13, 6.7%). Symptom scores were measured in four studies; three evaluated pain using different scales and one other symptoms. The data could not be pooled in a meta-analysis. Two studies evaluating procedural pain reported this to be lower in the needle aspiration groups. One study found comparable rates of pain resolution at five days post-intervention between groups. The quality of the evidence for symptom scores was very low. Although a number of studies have sought to evaluate whether or not needle aspiration or incision and drainage is more effective in patients with peritonsillar abscess, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain. Very low-quality evidence suggests that incision and drainage may be associated with a lower chance of recurrence than needle aspiration. There is some very low-quality evidence to suggest that needle aspiration is less painful.
We included five studies involving 419 randomized participants with APS. Only one study was at low risk of bias in all domains. One study was at low risk of bias in all domains for objective outcomes but not for quality of life (measured using the EQ-5D-5L questionnaire). We judged the other three studies to be at unclear or high risk of bias in three or more domains. The duration of intervention ranged from 180 days to a mean of 3.9 years. One study compared rivaroxaban (a novel oral anticoagulant: NOAC) with standard warfarin treatment and reported no thrombotic or major bleeding events, but it was not powered to detect such differences (low-quality evidence). Investigators reported similar rates of clinically relevant non-major bleeding (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.25 to 8.33; moderate-quality evidence) and minor bleeding (RR 1.21, 95% CI 0.51 to 2.83) for participants receiving rivaroxaban and the standard vitamin K antagonists (VKA). This study also reported some small benefit with rivaroxaban over the standard VKA treatment in terms of quality of life health state measured at 180 days with the EQ-5D-5L 100 mm visual analogue scale (mean difference (MD) 7 mm, 95% CI 2.01 to 11.99; low-quality evidence) but not measured as health utility (MD 0.04, 95% CI −0.02 to 0.10 [on a scale from 0 to 1]). Two studies compared high dose VKA (warfarin) with moderate/standard intensity VKA and found no differences in the rates of any thrombotic events (RR 2.22, 95% CI 0.79 to 6.23) or major bleeding (RR 0.74, 95% CI 0.24 to 2.25) between the groups (low-quality evidence). Minor bleeding analyzed using the RR and any bleeding using the hazard ratio (HR) were more frequent in participants receiving high-intensity warfarin treatment compared to the standard-intensity therapy (RR 2.55, 95% CI 1.07 to 6.07; and HR 2.03, 95% CI 1.12 to 3.68; low-quality evidence). In one study, it was not possible to estimate the RR for stroke with a combination of VKA plus antiplatelet agent compared to a single antiplatelet agent, while for major bleeding, a single event occurred in the single antiplatelet agent group. In one study, comparing combined VKA plus antiplatelet agent with dual antiplatelet therapy, the RR of the risk of stroke over three years of observation was 5.00 (95% CI 0.26 to 98.0). In a single small study, the RR for stroke during one year of observation with a dual antiplatelet therapy compared to single antiplatelet drug was 0.14 (95% CI 0.01 to 2.60). There is not enough evidence for or against NOACs or for high-intensity VKA compared to the standard VKA therapy in the secondary prevention of thrombosis in people with APS. There is some evidence of harm for high-intensity VKA regarding minor and any bleeding. The evidence was also not sufficient to show benefit or harm for VKA plus antiplatelet agent or dual antiplatelet therapy compared to a single antiplatelet drug. Future studies should be adequately powered, with proper adherence to treatment, in order to evaluate the effects of anticoagulants, antiplatelets, or both, for secondary thrombosis prevention in APS. We have identified five ongoing trials mainly using NOACs in APS, so increasing experimental efforts are likely to yield additional evidence of clinical relevance in the near future.
We included six randomised clinical trials with 173 participants. All participants had Child-Pugh stage A or B cirrhosis. The intervention groups participated in eight to 14 weeks of physical exercise (aerobic: three trials; resistance: one trial; or aerobic plus resistance training: two trials). Control groups underwent sham exercise (supervised relaxation: one trial) or no intervention (five trials). None of the 89 participants allocated to exercise versus two of 84 participants in the control group died (RR 0.19, 95% CI 0.01 to 3.73; moderate-quality evidence). The cause of death was acute-on-chronic liver disease for both participants. Nine participants in the exercise group and 13 in the control group experienced serious adverse events (RR 0.61, 95% CI 0.19 to 1.94; low-quality evidence). Physical exercise showed no beneficial or detrimental effect on health-related quality of life assessed by the Chronic Liver Disease Questionnaire (MD 0.11, 95% CI –0.44 to 0.67; low-quality evidence). Likewise, physical exercise had no clear effect on physical fitness measured by peak exercise oxygen uptake (MD 0.3 mL/kg/minute, 95 % CI –2.74 to 3.35; low-quality evidence) and Six-Minute Walk Test (MD 56.06 min, 95% CI –9.14 to 121.26; very low-quality evidence). Physical exercise showed no clear effect on mid-thigh circumference (MD 1.76 cm, 95% CI –0.26 to 3.77; low-quality evidence), but showed an increase in mid-arm circumference (MD 2.61 cm, 95% CI 0.36 to 4.85; low-quality evidence). We found no clear beneficial or harmful effect of physical exercise on mortality, morbidity, or health-related quality of life. Further evidence is needed to evaluate the beneficial and harmful effects of physical exercise on clinical outcomes.
We included four RCTs with a total of 453 participants and determined that none of these trials had overall low risk of bias. We found six ongoing trials from which we were unable to retrieve further data. Three trials provided data on mortality. Meta-analysis showed no statistical effect on overall mortality (RR 0.93, 95% CI 0.37 to 2.33; very low quality of evidence). We were unable to associate use of PCC with the number of complications probably related to the intervention (RR 0.92, 95% CI 0.78 to 1.09; very low quality of evidence). Lack of transfusion data and apparent differences in study design prevented review authors from finding a beneficial effect of PCC in reducing the volume of fresh frozen plasma (FFP) transfused to reverse the effect of vitamin K antagonist treatment. The number of new occurrences of transfusion of red blood cells (RBCs) did not seem to be associated with the use of PCC (RR 1.08, 95% CI 0.82 to 1.43; very low quality of evidence). Still, the included studies demonstrate the possibility of equally reversing vitamin K-induced coagulopathy using PCC without the need for transfusion of FFP. No effect on other predefined outcomes was observed. In the four included RCTs, use of prothrombin complex concentrate does not appear to reduce mortality or transfusion requirements but demonstrates the possibility of reversing vitamin K-induced coagulopathy without the need for transfusion of fresh frozen plasma. All included trials have high risk of bias and are underpowered to detect mortality, benefit or harm. Clinical and statistical heterogeneity is high, and definitions of clinically important outcomes such as adverse events are highly dissimilar between trials. Only weak observational evidence currently supports the use of PCC in vitamin K antagonist-treated bleeding and non-bleeding patients, and the current systematic review of RCTs does not support the routine use of PCC over FFP. Additional high-quality research is urgently needed.
We included 32 studies that involved a total of 2601 participants. Acupuncture was either manually stimulated (24 studies) or electrically stimulated (8 studies). The aetiology of gastroparesis was diabetes (31 studies) or surgery (1 study). All studies provided data on the proportion of people with symptoms 'improved', although the definition or categorisation of improvement varied among the studies. Most measured only short-term outcomes (28 studies), and only one study employed validated instruments to assess subjective changes in symptoms or reported data on quality of life or the use of medication. Reporting of harm was incomplete; minor adverse events were reported in only seven trials. Most studies had unclear risk of bias in terms of allocation concealment (29/32), outcome assessor blinding (31/32) and selective reporting (31/32), as well as high risk of bias in terms of participant/personnel blinding (31/32). Acupuncture was compared with sham acupuncture (needling on non-acupuncture points), three different types of gastrokinetic drugs (domperidone, mosapride, cisapride), and a histamine H₂ receptor antagonist (cimetidine). There was low-certainty evidence that symptom scores of participants receiving acupuncture did not differ from those of participants receiving sham acupuncture at three months when measured by a validated scale. There was very low-certainty evidence that a greater proportion of participants receiving acupuncture had 'improved' symptoms in the short term compared to participants who received gastrokinetic medication (4 to 12 weeks) (12 studies; 963 participants; risk ratio (RR) 1.25; 95% confidence interval (CI) 1.17 to 1.33, I² = 8%). Short-term improvement in overall symptom scores favouring acupuncture was also reported in five studies with considerable heterogeneity. Acupuncture in combination with other treatments, including gastrokinetics, non-gastrokinetics and routine care, was compared with the same treatment alone. There was very low-certainty evidence in favour of acupuncture for the proportion of participants with 'improved' symptoms in the short term (4 to 12 weeks) (17 studies; 1404 participants; RR 1.22; 95% CI 1.16 to 1.28; I² = 0%). Short-term improvement in overall symptom scores, favouring acupuncture, were also reported (two studies, 132 participants; MD -1.96, 95% CI -2.42 to -1.50; I² = 0%). Seven studies described adverse events, including minor bleeding and hematoma, dizziness, xerostomia, loose stool, diarrhoea, abdominal pain, skin rash and fatigue. The rest of the trials did not report whether adverse events occurred. Subgroup analyses revealed that short-term benefits in terms of the proportion of people with 'improved' symptoms did not differ according to the type of acupuncture stimulation (i.e. manual or electrical). The sensitivity analysis revealed that use of a valid method of random sequence generation, and the use of objective measurements of gastric emptying, did not alter the overall effect estimate in terms of the proportion of people with 'improved' symptoms. The asymmetric funnel plot suggests small study effects and publication bias towards positive reporting. There is very low-certainty evidence for a short-term benefit with acupuncture alone or acupuncture combined with gastrokinetic drugs compared with the drug alone, in terms of the proportion of people who experienced improvement in diabetic gastroparesis. There is evidence of publication bias and a positive bias of small study effects. The reported benefits should be interpreted with great caution because of the unclear overall risk of bias, unvalidated measurements of change in subjective symptoms, publication bias and small study reporting bias, and lack of data on long-term outcomes; the effects reported in this review may therefore differ significantly from the true effect. One sham-controlled trial provided low-certainty evidence of no difference between real and sham acupuncture in terms of short-term symptom improvement in diabetic gastroparesis, when measured by a validated scale. No studies reported changes in quality of life or the use of medication. Due to the absence of data, no conclusion can be made regarding effects of acupuncture on gastroparesis of other aetiologies. Reports of harm have remained largely incomplete, precluding assessments of the safety of acupuncture in this population. Future research should focus on reducing the sources of bias in the trial design as well as transparent reporting. Harms of interventions should be explicitly reported.
We included 12 RCTs (743 people). Among these RCTs, flexibility exercise training was compared to an untreated control group, land-based aerobic training, resistance training, or other interventions (i.e. Tai Chi, Pilates, aquatic biodanza, friction massage, medications). Studies were at risk of selection, performance, and detection bias (due to lack of adequate randomization and allocation concealment, lack of participant or personnel blinding, and lack of blinding for self-reported outcomes). With the exception of withdrawals and adverse events, major outcomes were self-reported and were expressed on a 0-to-100 scale (lower values are best, negative mean differences (MDs) indicate improvement). We prioritized the findings of flexibility exercise training compared to land-based aerobic training and present them fully here. Very low-certainty evidence showed that compared with land-based aerobic training, flexibility exercise training (five trials with 266 participants) provides no clinically important benefits with regard to HRQoL, pain intensity, fatigue, stiffness, and physical function. Low-certainty evidence showed no difference between these groups for withdrawals at completion of the intervention (8 to 20 weeks). Mean HRQoL assessed on the Fibromyalgia Impact Questionnaire (FIQ) Total scale (0 to 100, higher scores indicating worse HRQoL) was 46 mm and 42 mm in the flexibility and aerobic groups, respectively (2 studies, 193 participants); absolute change was 4% worse (6% better to 14% worse), and relative change was 7.5% worse (10.5% better to 25.5% worse) in the flexibility group. Mean pain was 57 mm and 52 mm in the flexibility and aerobic groups, respectively (5 studies, 266 participants); absolute change was 5% worse (1% better to 11% worse), and relative change was 6.7% worse (2% better to 15.4% worse). Mean fatigue was 67 mm and 71 mm in the aerobic and flexibility groups, respectively (2 studies, 75 participants); absolute change was 4% better (13% better to 5% worse), and relative change was 6% better (19.4% better to 7.4% worse). Mean physical function was 23 points and 17 points in the flexibility and aerobic groups, respectively (1 study, 60 participants); absolute change was 6% worse (4% better to 16% worse), and relative change was 14% worse (9.1% better to 37.1% worse). We found very low-certainty evidence of an effect for stiffness. Mean stiffness was 49 mm to 79 mm in the flexibility and aerobic groups, respectively (1 study, 15 participants); absolute change was 30% better (8% better to 51% better), and relative change was 39% better (10% better to 68% better). We found no evidence of an effect in all-cause withdrawal between the flexibility and aerobic groups (5 studies, 301 participants). Absolute change was 1% fewer withdrawals in the flexibility group (8% fewer to 21% more), and relative change in the flexibility group compared to the aerobic training intervention group was 3% fewer (39% fewer to 55% more). It is uncertain whether flexibility leads to long-term effects (36 weeks after a 12-week intervention), as the evidence was of low certainty and was derived from a single trial. Very low-certainty evidence indicates uncertainty in the risk of adverse events for flexibility exercise training. One adverse effect was described among the 132 participants allocated to flexibility training. One participant had tendinitis of the Achilles tendon (McCain 1988), but it is unclear if the tendinitis was a pre-existing condition. When compared with aerobic training, it is uncertain whether flexibility improves outcomes such as HRQoL, pain intensity, fatigue, stiffness, and physical function, as the certainty of the evidence is very low. Flexibility exercise training may lead to little or no difference for all-cause withdrawals. It is also uncertain whether flexibility exercise training has long-term effects due to the very low certainty of the evidence. We downgraded the evidence owing to the small number of trials and participants across trials, as well as due to issues related to unclear and high risk of bias (selection, performance, and detection biases). While flexibility exercise training appears to be well tolerated (similar withdrawal rates across groups), evidence on adverse events was scarce, therefore its safety is uncertain.
We identified three trials (κ = 1.00) involving 1272 participants. Comparing the capnography group to the standard monitoring group, there were no differences in the rates of oxygen desaturation (RR 0.89, 95% CI 0.48 to 1.63; n = 1272, 3 trials; moderate quality evidence) and hypotension (RR 2.36, 95% CI 0.98 to 5.69; n = 986, 1 trial; moderate quality evidence). There was only one episode of emesis recorded without significant difference between the groups (RR 3.10, 95% CI 0.13 to 75.88, n = 986, 1 trial; moderate quality evidence). The quality of evidence for the primary outcomes was moderate with downgrades primarily due to heterogeneity and reporting bias. There were no differences in the rate of airway interventions performed (RR 1.26, 95% CI 0.94 to 1.69; n = 1272, 3 trials; moderate quality evidence). In the subgroup analysis, we found a higher rate of airway interventions for adults in the capnography group (RR 1.44, 95% CI 1.16 to 1.79; n = 1118, 2 trials; moderate quality evidence) with a number needed to treat for an additional harmful outcome of 12. Although statistical heterogeneity was reduced, there was moderate quality of evidence due to outcome definition heterogeneity and limited reporting bias. None of the studies reported recovery time. There is a lack of convincing evidence that the addition of capnography to standard monitoring in ED PSA reduces the rate of clinically significant adverse events. Evidence was deemed to be of moderate quality due to population and outcome definition heterogeneity and limited reporting bias. Our review was limited by the small number of clinical trials in this setting.
We included 38 RCTs. Twenty-two had a split-mouth design, and 16 had a parallel design. The overall evaluated data included 1402 defects. Two studies were at unclear overall risk of bias, while the remaining 36 studies had a high overall risk of bias. 1. APC + OFD versus OFD alone Twelve studies were included in this comparison, with a total of 510 infrabony defects. There is evidence of an advantage in using APC globally from split-mouth and parallel studies for all three primary outcomes: PD (mean difference (MD) 1.29 mm, 95% confidence interval (CI) 1.00 to 1.58 mm; P < 0.001; 12 studies; 510 defects; very low-quality evidence); CAL (MD 1.47 mm, 95% CI 1.11 to 1.82 mm; P < 0.001; 12 studies; 510 defects; very low-quality evidence); and RBF (MD 34.26%, 95% CI 30.07% to 38.46%; P < 0.001; 9 studies; 401 defects; very low-quality evidence). 2. APC + OFD + BG versus OFD + BG Seventeen studies were included in this comparison, with a total of 569 infrabony defects. Considering all follow-ups, as well as 3 to 6 months and 9 to 12 months, there is evidence of an advantage in using APC from both split-mouth and parallel studies for all three primary outcomes: PD (MD 0.54 mm, 95% CI 0.33 to 0.75 mm; P < 0.001; 17 studies; 569 defects; very low-quality evidence); CAL (MD 0.72 mm, 95% CI 0.43 to 1.00 mm; P < 0.001; 17 studies; 569 defects; very low-quality evidence); and RBF (MD 8.10%, 95% CI 5.26% to 10.94%; P < 0.001; 11 studies; 420 defects; very low-quality evidence). 3. APC + GTR versus GTR alone Seven studies were included in this comparison, with a total of 248 infrabony defects. Considering all follow-ups, there is probably a benefit for APC for both PD (MD 0.92 mm, 95% CI -0.02 to 1.86 mm; P = 0.05; very low-quality evidence) and CAL (MD 0.42 mm, 95% CI -0.02 to 0.86 mm; P = 0.06; very low-quality evidence). However, given the wide confidence intervals, there might be a possibility of a slight benefit for the control. When considering a 3 to 6 months and a 9 to 12 months follow-up there were no benefits evidenced, except for CAL at 3 to 6 months (MD 0.54 mm, 95% CI 0.18 to 0.89 mm; P = 0.003; 3 studies; 134 defects). No RBF data were available. 4. APC + EMD versus EMD Two studies were included in this comparison, with a total of 75 infrabony defects. There is insufficient evidence of an overall advantage of using APC for all three primary outcomes: PD (MD 0.13 mm, 95% CI -0.05 to 0.30 mm; P = 0.16; 2 studies; 75 defects; very low-quality evidence), CAL (MD 0.10 mm, 95% CI -0.13 to 0.32 mm; P = 0.40; 2 studies; 75 defects; very low-quality evidence), and RBF (MD -0.60%, 95% CI -6.21% to 5.01%; P = 0.83; 1 study; 49 defects; very low-quality evidence). All studies in all groups reported a survival rate of 100% for the treated teeth. No complete pocket closure was reported. No quantitative analysis regarding patients' quality of life was possible. There is very low-quality evidence that the adjunct of APC to OFD or OFD + BG when treating infrabony defects may improve probing pocket depth, clinical attachment level, and radiographic bone defect filling. For GTR or EMD, insufficient evidence of an advantage in using APC was observed.
Five RCTs with 202 participants met the inclusion criteria. The women participants were typically in their 50s, and the majority of them (about 82%) received reconstructive surgery following breast cancer, while the others had reconstructive surgery after prophylactic mastectomy. The studies were heterogenous in terms of implant comparisons, which prevented us from pooling the data. The studies were judged as being at an unclear risk of bias for most risk of bias items owing to poor quality of reporting in the trial publications. Three of the five RCTs were judged to be at high risk of attrition bias, and one at high risk of detection bias. Textured silicone versus smooth silicone implants: textured implants were associated with worse outcomes when compared to smooth implants (capsular contracture: risk ratio (RR) 0.82, 95% CI 0.14 to 4.71; 1 study, 20 participants; very low quality evidence; reintervention: RR 0.82, 95% CI 0.14 to 4.71; 1 study, 20 participants; very low quality evidence). No results in this comparison were statistically significant. Silicone versus saline implants: saline-filled implants performed better than silicone-filled implants for some outcomes; specifically, they produced less severe capsular contracture (RR 3.25, 95% CI 1.24 to 8.51; 1 study, 60 participants; very low quality evidence) and increased patient satisfaction (RR 0.60, 95% CI 0.41 to 0.88; 1 study, 58 participants; very low quality evidence). However reintervention was significantly more frequent in the saline-filled implant group than in the silicone-filled group (OR 0.08, 95% CI 0.01 to 0.43; 1 study, 60 participants; very low quality evidence). Poly(N-vinyl-2-pyrrolidone) hydrogel-filled (PVP-hydrogel) versus saline-filled implants: PVP-hydrogel-filled implants were associated with worse outcomes when compared to saline-filled implants (capsular contracture: RR 3.50, 95% CI 0.83 to 14.83; 1 study, 40 participants; very low quality evidence; short-term complications: RR 2.10, 95% CI 0.21 to 21.39; 1 study, 41 participants; very low quality evidence). Anatomical versus round implants: anatomical implants were associated with worse outcomes than round implants (capsular contracture: RR 2.00, 95% CI 0.20 to 20.15; 1 study, 36 participants; very low quality evidence; short-term complications: RR 2.00, 95% CI 0.42 to 9.58; 1 study, 36 participants; very low quality evidence; reintervention: RR 1.50, 95% CI 0.51 to 4.43; 1 study, 36 participants; very low quality evidence). No results in this comparison were statistically significant. Variable-volume versus fixed-volume implants: data about one-stage reconstruction using variable-volume implants were compared with data about fixed-volume implants positioned during the second surgical procedure of two-stage reconstructions. Fixed-volume implant reconstructions were possibly associated with a greater number of women reporting that their reconstruction corresponded with expected results (RR 0.25, 95% CI 0.10 to 0.62; 1 study, 40 participants; very low quality evidence) and fewer reinterventions (RR 7.00, 95% CI 1.82 to 26.89; 1 study, 40 participants; very low quality evidence) when compared to variable-volume implants. A higher patient satisfaction level (rated from 1 to 6, with 1 being very bad and 6 being very good) was found with the fixed-volume implants for overall aesthetic result (mean difference (MD) -1.10, 95% CI -1.59 to -0.61; 1 study, 40 participants; very low quality evidence). There were no studies that examined the effects of recent (fifth) generation silicone implants versus previous generations or different implant manufacturing companies. Despite the central role of breast reconstruction in women with breast cancer, the best implants to use in reconstructive surgery have been studied rarely in the context of RCTs. Furthermore the quality of these studies and the overall evidence they provide is largely unsatisfactory. Some of our results can be interpreted as early evidence of potentially large differences between different surgical approaches, which should be confirmed in new high-quality RCTs that include a larger number of women. These days - even after a few million women have had breasts reconstructed - surgeons cannot inform women about the risks and complications of different implant-based breast reconstructive options on the basis of results derived from RCTs.
Ten trials (9 RCTs and 1 CCT) (954 participants and 73 caregivers) met the inclusion criteria. Eight RCTs scored well; while one RCT and one CCT scored poorly on the methodological quality assessment. Despite no change in the level of impairment, there was ’strong evidence’ to support inpatient MD rehabilitation in producing short-term gains at the levels of activity (disability) and participation in patients with MS. There is ‘moderate evidence’ to support inpatient or outpatient rehabilitation programmes (compared with control wait-list groups) in improving disability; and bladder related activity and participation outcomes up to 12 months following MD rehabilitation intervention. For outpatient and home-based rehabilitation programmes there was 'limited evidence' for short-term improvements in symptoms and disability with high intensity programmes, which translated into improvement in participation and quality of life. For low intensity programmes conducted over a longer period there was 'strong evidence' for longer-term gains in quality of life; and also 'limited evidence' for benefits to carers. Although some studies reported potential for cost-savings, there is no convincing evidence regarding the long-term cost-effectiveness of these programmes. It was not possible to suggest best 'dose' of therapy or supremacy of one therapy over another. This review highlights the limitations of RCTs in rehabilitation settings and need for better designed randomized and multiple centre trials. MD rehabilitation programmes do not change the level of impairment, but can improve the experience of people with MS in terms of activity and participation. Regular evaluation and assessment of these persons for rehabilitation is recommended. Further research into appropriate outcome measures, optimal intensity, frequency, cost and effectiveness of rehabilitation therapy over a longer time period is needed. Future research in rehabilitation should focus on improving methodological and scientific rigour of clinical trials.
The search retrieved 16 studies (from 17 reports). Ten studies were excluded and one study is awaiting assessment. We included five studies involving 1065 women (1090 recruited). The five included studies were at moderate risk of bias. Data relating to one of our primary outcomes (UTI) was reported in four studies but did not meet our definition of UTI (as prespecified in our protocol). The included studies did not report on our other primary outcome – intraoperative bladder injury (this outcome was not prespecified in our protocol). Two secondary outcomes were not reported in the included studies: need for postoperative analgesia and women’s satisfaction. The included studies did provide limited data relating to this review’s secondary outcomes. Indwelling bladder catheter versus no catheter - three studies (840 women) Indwelling bladder catheterisation was associated with a reduced incidence of bladder distension (non-prespecified outcome) at the end of the operation (risk ratio (RR) 0.02, 95% confidence interval (CI) 0.00 to 0.35; one study, 420 women) and fewer cases of retention of urine (RR 0.06, 95% CI 0.01 to 0.47; two studies, 420 women) or need for catheterisation (RR 0.03, 95% CI 0.01 to 0.16; three studies 840 participants). In contrast, indwelling bladder catheterisation was associated with a longer time to first voiding (mean difference (MD) 16.81 hours, 95% CI 16.32 to 17.30; one study, 420 women) and more pain or discomfort due to catheterisation (and/or at first voiding) (average RR 10.47, 95% CI 4.71 to 23.25, two studies, 420 women) although high levels of heterogeneity were observed. Similarly, compared to women in the ‘no catheter’ group, indwelling bladder catheterisation was associated with a longer time to ambulation (MD 4.34 hours, 95% CI 1.37 to 7.31, three studies, 840 women) and a longer stay in hospital (MD 0.62 days, 95% CI 0.15 to 1.10, three studies, 840 women). However, high levels of heterogeneity were observed for these two outcomes and the results should be interpreted with caution. There was no difference in postpartum haemorrhage (PPH) due to uterine atony. There was also no difference in the incidence of UTI (as defined by trialists) between the indwelling bladder catheterisation and no catheterisation groups (two studies, 570 women). However, high levels of heterogeneity were observed for this non-prespecified outcome and results should be considered in this context. Indwelling bladder catheter versus bladder drainage – two studies (225 women) Two studies (225 women) compared the use of an indwelling bladder catheter versus bladder drainage. There was no difference between groups in terms of retention of urine following CS, length of hospital stay or the non-prespecified outcome of UTI (as defined by the trialist). There is some evidence (from one small study involving 50 women), that the need for catheterisation was reduced in the group of women with an indwelling bladder catheter (RR 0.04, 95% CI 0.00 to 0.70) compared to women in the bladder drainage group. Evidence from another small study (involving 175 women) suggests that women who had an indwelling bladder catheter had a longer time to ambulation (MD 0.90, 95% CI 0.25 to 1.55) compared to women who received bladder drainage. This review includes limited evidence from five RCTs of moderate quality. The review's primary outcomes (bladder injury during operation and UTI), were either not reported or reported in a way not suitable for our analysis. The evidence in this review is based on some secondary outcomes, with heterogeneity present in some of the analyses. There is insufficient evidence to assess the routine use of indwelling bladder catheters in women undergoing CS. There is a need for more rigorous RCTs, with adequate sample sizes, standardised criteria for the diagnosis of UTI and other common outcomes.
We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I2 = 47%). This suggests that among subfertile women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%. Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I2 = 66%). This suggests that among subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and 33%. Heterogeneity was moderately high. There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I2 = 23%, very low quality evidence). This suggests that, among subfertile women with an expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I2 = 4%, very low quality evidence). This suggests that among subfertile women with an expected multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise, there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I2 = 0%, very low quality evidence). This suggests that among subfertile women with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%. Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions. Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no conclusions could be drawn. Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I2 = 0%). This suggests that among subfertile women with an expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%. There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95% CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I2 = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
No RCTs meeting the selection criteria were identified. Since it is unlikely, for ethical and practical reasons that an RCT of SCUs will be conducted, a systematic review of non-RCTs using the same protocol and criteria was conducted. There were eight non-RCTs that fulfilled the criteria for inclusion. Only four studies had data which could be extracted for pooling in meta-analysis.  Differences between comparator groups in these nonRCTs ? for example in severity of dementia - were not adequately adjusted for and were common in the trial which accounted for almost all of the positive outcomes of SCUs (Nobili, 2006) All of the results of the outcomes came only from single studies except for "physical restraint use" at 6 months, which included data from two studies.  A small improvement in total Neuropsychiatric Inventory scores, favouring SCU was noted in one study at 6, 12 and 18 months.  The use of physical restraints was less common in SCUs at 6 and 12 months (OR= 0.46 (95% CI 0.27 to 0.80), p=0.006; and OR=0.49 (0.27 to 0.88), p=0.02 respectively).  Patients in SCUs were less depressed at 3 months than those in traditional nursing home (WMD -6.30 (-7.88 to -4.72) Cornell points, p<0.00001). There was only one observation that favoured the control group: a small but significant effect favouring traditional nursing home care was observed at 6 months in the mean number of psychotropic medications used (WMD 0.20, CI 0.00 to 0.40, z=1.96, P=0.05). There are no identified RCTs investigating the effects of SCUs on behavioural symptoms in dementia, and  no strong evidence of benefit from the available non-RCTs.  It is probably more important to implement best practice than to provide a specialized care environment.  The routine collection of data on behaviour, restraint and psychotropic drug use across multiple nursing home settings offers the best modality for formal evaluation of the benefit or otherwise of SCUs.
Nine safety and efficacy trials, and two safety trials, with over 3000 participants were included. In semi-immune children, RTS,S vaccine reduced clinical episodes of malaria by 26% (95% CI 13% to 37%) and severe malaria by 58% (95% CI 15% to 79%) for up to 18 months. Prevalence of parasitaemia was also reduced by 26% (95% CI 11% to 38%) at six months after immunization. RTS,S also reduced clinical malaria episodes by 63% (95% CI 18% to 83%) in semi-immune adult men in the second year of follow up after a booster dose. No severe adverse events were judged to be related to RTS,S vaccine, although the frequencies of injection site pain, swelling, arm motion limitation, headache, and malaise were increased in the vaccine groups. There was no evidence for effect of the CS-NANP vaccines (307 participants, 3 trials), CS102 peptide vaccine (14 participants, 1 trial), or the ME-TRAP vaccine (372 participants, 1 trial). RTS,S vaccine was effective in preventing a significant number of clinical malaria episodes, including good protection against severe malaria in children for 18 months. No severe adverse events were attributable to the vaccine. Progression of this vaccine towards licensing is justified while efforts to increase its efficacy continue. The other vaccines do not look promising and further research is a priority.
We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. The majority of the included data (approximately 90%) was from apixaban, edoxaban, and rivaroxaban. The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in all of the included studies. Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin in participants with AF (OR 0.89, 95% CI 0.82 to 0.97; 13 studies; 67,477 participants; high-quality evidence). Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.78, 95% CI 0.73 to 0.84; 13 studies; 67,396 participants; moderate-quality evidence). There was, however, statistically significant and high heterogeneity (I2 = 83%). When we repeated this analysis using a random-effects model, it did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). A pre-specified sensitivity analysis excluding all open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81), but high heterogeneity was also observed in this analysis (I2 = 72%). The same sensitivity analysis using a random-effects model also showed a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96). Treatment with a factor Xa inhibitor significantly reduced the risk of intracranial haemorrhages (ICHs) compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high-quality evidence). We observed moderate, but statistically significant heterogeneity (I2 = 55%). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non-statistically significant heterogeneity (I2 = 27%). Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate-quality evidence). Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in people with AF. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Factor Xa inhibitors also reduced the number of ICHs, all-cause deaths and major bleedings compared with warfarin, although the evidence for a reduction in the latter is less robust.
Only one study evaluating lamotrigine in secondary progressive MS was eligible. One hundred and twenty people were included, 61 randomly assigned to lamotrigine treatment and 59 to placebo treatment. The average age of participants in the two groups was 51.9 years and 50.1 years, respectively. The proportion of male participants was 27.5%. The period of follow-up was 2 years. No data were found on disability progression and people who experienced relapses. No significant differences were found for serious adverse events between the two groups. Treatment with lamotrigine was associated with more rashes (20% vs 5%, P value 0.03) and transient, dose-related deterioration of mobility (66% vs 34%, P value 0.001) than placebo. Furthermore, no significant difference between the two groups was found in the magnetic resonance imaging (MRI) measurements of cerebral atrophy, Expanded Disability Status Score changes, Multiple Sclerosis Functional Composite score changes. This study was judged to be at high risk of bias. This review will be updated when the three ongoing studies we identified are completed. The quality of evidence was judged to be very low due to the low number of available studies and included participants. There is a lack of evidence to address the review question on the efficacy of sodium channel blockers for people with MS. Assessment of the three ongoing trials might change this conclusion. Further high-quality large scale studies are needed.
The review included 27 studies reported in 30 articles. The studies had 73,557 participants with 12 studies from the US; four from China; two from each of Australia, Canada, the Netherlands and the UK; and one from each of Israel, Greece and Brazil. Thirteen studies were RCTs, six were non-RCTs and eight were CBAs. Of the included studies, 18 provided some element of the intervention in children aged four to 11 years, 17 studies included children aged 11 to 14 years and nine studies included children aged 14 to 18 years. The overall quality of the results was poor, with the all studies assessed as being at high or unclear risks of bias across multiple domains, and varied interventions and data collection methods employed. Interventions comprised information-giving, peer education or were multi-component. Seven studies reported the primary outcome of injury occurrence and only three of these were similar enough to combine in a meta-analysis, with a pooled incidence rate ratio of 0.73 (95% confidence interval (CI) 0.49 to 1.08; 2073 children) and substantial statistical heterogeneity (I2 = 63%). However, this body of evidence was low certainty, due to concerns over this heterogeneity (inconsistency) and imprecision. This heterogeneity may be explained by the non-RCT study design of one of the studies, as a sensitivity analysis with this study removed found stronger evidence of an effect and no heterogeneity (I2 = 0%). Two studies report an improvement in safety skills in the intervention group. Likewise, the four studies measuring observed safety behaviour reported an improvement in the intervention group relative to the control. Thirteen out of 19 studies describing self-reported behaviour and safety practices showed improvements, and of the 21 studies assessing changes in safety knowledge, 19 reported an improvement in at least one question domain in the intervention compared to the control group. However, we were unable to pool data for our secondary outcomes, so our conclusions were limited, as they were drawn from highly diverse single studies and the body of evidence was low (safety skills) or very low (behaviour, safety knowledge) certainty. Only one study reported intervention costs but did not undertake a full economic evaluation (very low certainty evidence). There is insufficient evidence to determine whether school-based educational programmes can prevent unintentional injuries. More high-quality studies are needed to evaluate the impact of educational programmes on injury occurrence. There is some weak evidence that such programmes improve safety skills, behaviour/practices and knowledge, although the evidence was of low or very low quality certainty. We found insufficient economic studies to assess cost-effectiveness.
We included 35 RCTs analysing 3102 participants. Thirteen studies were at low risk of bias, 12 studies were at unclear risk of bias, and 10 studies were at high risk of bias. Our main findings were regarding keratinocyte growth factor (KGF) and are summarised as follows. There might be a reduction in the risk of moderate to severe oral mucositis in adults receiving bone marrow/stem cell transplantation after conditioning therapy for haematological cancers (RR 0.89, 95% CI 0.80 to 0.99; 6 studies; 852 participants; low-quality evidence). We would need to treat 11 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 6 to 112). There might be a reduction in the risk of severe oral mucositis in this population, but there is also some possibility of an increase in risk (RR 0.85, 95% CI 0.65 to 1.11; 6 studies; 852 participants; low-quality evidence). We would need to treat 10 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 5 to prevent the outcome to 14 to cause the outcome). There is probably a reduction in the risk of moderate to severe oral mucositis in adults receiving radiotherapy to the head and neck with cisplatin or fluorouracil (RR 0.91, 95% CI 0.83 to 1.00; 3 studies; 471 participants; moderate-quality evidence). We would need to treat 12 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 7 to infinity). It is very likely that there is a reduction in the risk of severe oral mucositis in this population (RR 0.79, 95% CI 0.69 to 0.90; 3 studies; 471 participants; high-quality evidence). We would need to treat 7 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 5 to 15). It is likely that there is a reduction in the risk of moderate to severe oral mucositis in adults receiving chemotherapy alone for mixed solid and haematological cancers (RR 0.56, 95% CI 0.45 to 0.70; 4 studies; 344 participants; moderate-quality evidence). We would need to treat 4 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 3 to 6). There might be a reduction in the risk of severe oral mucositis in this population (RR 0.30, 95% CI 0.14 to 0.65; 3 studies; 263 participants; low -quality evidence). We would need to treat 10 adults with KGF in order to prevent one additional adult from developing this outcome (95% CI 8 to 19). Due to the low volume of evidence, single-study comparisons and insufficient sample sizes, we found no compelling evidence of a benefit for any other cytokines or growth factors and there was no evidence on children. There did not appear to be any serious adverse effects of any of the interventions assessed in this review. We are confident that KGF is beneficial in the prevention of oral mucositis in adults who are receiving: a) radiotherapy to the head and neck with cisplatin or fluorouracil; or b) chemotherapy alone for mixed solid and haematological cancers. We are less confident about a benefit for KGF in adults receiving bone marrow/stem cell transplant after conditioning therapy for haematological cancers because of multiple factors involved in that population, such as whether or not they received total body irradiation (TBI) and whether the transplant was autologous (the patients' own cells) or allogeneic (cells from a donor). KGF appears to be a relatively safe intervention. Due to limited research, we are not confident that there are any beneficial effects of other cytokines and growth factors. There is currently insufficient evidence to draw any conclusions about the use of cytokines and growth factors in children.
We included seven RCTs and five CBA studies. Six studies evaluated the effectiveness of educational materials alone, one study evaluated educational meetings, four studies evaluated a combination of the two, and one study evaluated a multifaceted educational campaign for increasing the reporting of occupational diseases by physicians. We judged all the included studies to have a high risk of bias. We did not find any studies evaluating the effectiveness of Internet-based interventions or interventions on procedures or techniques of reporting, or the use of financial incentives. Moreover, we did not find any studies evaluating large-scale interventions like the introduction of new laws, existing or new specific disease registries, newly established occupational health services, or surveillance systems. Educational materials We found moderate-quality evidence that the use of educational materials did not considerably increase the number of physicians reporting occupational diseases compared to no intervention (risk ratio of 1.11, 95% confidence interval (CI) 0.74 to 1.67). We also found moderate-quality evidence showing that sending a reminder message of a legal obligation to report increased the number of physicians reporting occupational diseases (risk ratio of 1.32, 95% CI 1.05 to 1.66) when compared to a reminder message about the benefits of reporting. We found low-quality evidence that the use of educational materials did not considerably increase the rate of reporting when compared to no intervention. Educational materials plus meetings We found moderate-quality evidence that the use of educational materials combined with meetings did not considerably increase the number of physicians reporting when compared to no intervention (risk ratio of 1.22, 95% CI 0.83 to 1.81). We found low-quality evidence that educational materials plus meetings did not considerably increase the rate of reporting when compared to no intervention (rate ratio of 0.77, 95% CI 0.42 to 1.41). Educational meetings We found very low-quality evidence showing that educational meetings increased the number of physicians reporting occupational diseases (risk ratio at baseline: 0.82, 95% CI 0.47 to 1.41 and at follow-up: 1.74, 95% CI 1.11 to 2.74) when compared to no intervention. We found very low-quality evidence that educational meetings did not considerably increase the rate of reporting occupational diseases when compared to no intervention (rate ratio at baseline: 1.57, 95% CI 1.22 to 2.02 and at follow-up: 1.92, 95% CI 1.48 to 2.47). Educational campaign We found very low-quality evidence showing that the use of an educational campaign increased the number of physicians reporting occupational diseases when compared to no intervention (risk ratio at baseline: 0.53, 95% CI 0.19 to 1.50 and at follow-up: 11.59, 95% CI 5.97 to 22.49). We found 12 studies to include in this review. They provide evidence ranging from very low to moderate quality showing that educational materials, educational meetings, or a combination of the two do not considerably increase the reporting of occupational diseases. The use of a reminder message on the legal obligation to report might provide some positive results. We need high-quality RCTs to corroborate these findings. Future studies should investigate the effects of large-scale interventions like legislation, existing or new disease-specific registries, newly established occupational health services, or surveillance systems. When randomisation or the identification of a control group is impractical, these large-scale interventions should be evaluated using an interrupted time-series design. We also need studies assessing online reporting and interventions aimed at simplifying procedures or techniques of reporting and the use of financial incentives.
We included one randomised trial of 55 children aged between 16 months to 15 years. It compared anatomically-guided FICB versus systemic analgesia with intravenous morphine sulphate. The small sample size and the high risk of bias relating to lack of blinding resulted in a low quality rating for all outcomes. Overall, the trial provided low quality evidence for better pain management in the FICB group. Fewer children in the FICB group had analgesia failure at 30 minutes than in the morphine group (2/26 (8%) versus 8/28 (29%); risk ratio (RR) 0.33, 95% confidence interval (CI) 0.09 to 1.20; P value 0.09). The trial did not report on pain during procedures or transfers, or application of analgesia. The trial provided low quality evidence that FICB has a better safety profile than morphine, with only four (15%) reports of redness and pain at the injection site, and no reports of the type of adverse effects of systematic analgesia that occurred in the morphine group, such as respiratory depression (six cases (21%)) and vomiting (four cases (14%)). No long-term adverse events were reported for either intervention. Clinically significant pain relief was achieved in both groups at five minutes; with limited evidence of greater initial pain relief in the FICB group. Based on an inspection of graphically-presented data, at least 46% (12/26) of children in the FICB group had no supplementary medication (mainly analgesia) for the six hours of the study, while only 5% (1 or 2/28) of children in the intravenous morphine group went without additional analgesia. There was insufficient evidence to determine whether child or parental satisfaction with the method of analgesia favoured either method. Resource use was not measured. Low quality evidence from one small trial suggests that FICB provides better and longer lasting pain relief with fewer adverse events than intravenous opioids for femur fractures in children. Well conducted and reported randomised trials that compare nerve blocks (both FNB and FICB) with systemic analgesia and that use validated pain scores are needed.
We included 26 trials with 2084 participants analysed. Most of the studies were conducted in the United Kingdom (UK) and United States (US), and involved men and women experiencing their first episode of genital herpes, with the exception of three studies which included only women. We rated the majority of these studies as having an unclear risk of bias; largely due to lack of information supplied in the publications, and due to the age of the trials. This review found low quality evidence from two studies of oral acyclovir, when compared to placebo, reduced the duration of symptoms in individuals undergoing their first episode of genital herpes (mean difference (MD) -3.22, 95% confidence interval (CI) -5.91 to -0.54; I2 = 52%). In two studies (112 participants), intravenous acyclovir decreased the median number of days that patients with first-episode herpes suffered symptoms. Oral valaciclovir (converted to acyclovir) also showed a similar length of symptom duration when compared to acyclovir in two studies. There is currently no evidence that topical acyclovir reduces symptoms (MD -0.61 days, 95% CI -2.16 to 0.95; 3 RCTs, 195 participants, I2 statistic = 56%). There is also no current evidence that the topical treatments of cicloxolone cream, carbenoxolone sodium cream, adenosine arabinoside, idoxuridine in dimethyl sulfoxide, when compared to placebo reduced the duration of symptoms in people undergoing their first episode of herpes. Two studies reported no evidence of a reduction in the number of median days to recurrence following treatment with oral acyclovir versus placebo. Adverse events were generally poorly reported by all of the included studies and we were unable to quantitatively analyse this outcome. For those taking acyclovir, there were no serious adverse events; the most common adverse events reported for oral acyclovir were coryza, dizziness, tiredness, diarrhoea and renal colic. For intravenous acyclovir these were phlebitis, nausea and abnormal liver function tests and for topical acyclovir there was pain with the topical application.Those undergoing interferon treatment had significantly more adverse events compared to those taking placebo. There is low quality evidence from this review that oral acyclovir reduced the duration of symptoms for genital herpes. However, there is low quality evidence which did not show that topical antivirals reduced symptom duration for patients undergoing their first episode of genital herpes. This review was limited by the inclusion of skewed data, resulting in few trials that we were able to meta-analyse.
We included nine randomised trials, published between 1998 and 2014, involving 662 participants. The population consisted of both children and adolescents in four trials, only adults in four trials, and both children/adolescents and adults in one trial. Four studies examined only permanent teeth, and five studies evaluated both deciduous and permanent teeth. Six trials used Er:YAG (erbium-doped yttrium aluminium garnet) lasers, two trials employed Er,Cr:YSGG (erbium, chromium: yttrium-scandium-gallium-garnet) lasers, and one trial used Nd:YAG (neodymium-doped yttrium aluminium garnet) laser. Overall, the trials had small sample sizes, and the majority were at unclear or high risk of bias. The primary outcomes were evaluated in a limited number of trials (removal of caries (four trials (but only two reported quantitative data)); episodes of pain (five studies)). There was insufficient evidence to suggest that either lasers or drill were better at caries removal (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.99 to 1.01; 2 studies; 256 treated caries; P = 0.75; I2 = 0%; low-quality evidence). The incidence of moderate or high pain was greater in the drill group compared to the laser group (RR 0.40, 95% CI 0.28 to 0.57; 2 studies; 143 participants; P < 0.001; I2 = 50%). Similarly, the need for anaesthesia was significantly higher in the drill group than in the laser group (RR 0.25, 95% CI 0.10 to 0.65; 3 studies; 217 children/adolescents; P = 0.004; I2 = 0%). In terms of marginal integrity of restoration, there was no evidence of a difference between laser and drill comparisons evaluated at 6 months (RR 1.00, 95% CI 0.21 to 4.78; 3 studies), 1 year (RR 1.59, 95% CI 0.34 to 7.38; 2 studies), or 2 years (RR 1.00, 95% CI 0.21 to 4.74; 1 study). There was no evidence of a difference for durability of restoration between laser therapy or drill at 6 months' follow-up (RR 2.40, 95% CI 0.65 to 8.77; 4 studies), at 1 year (RR 1.40, 95% CI 0.29 to 6.78; 2 studies) or at 2 years' follow-up (RR 0.50, 95% CI 0.02 to 14.60; 1 study). Only two trials investigated the recurrence of caries, but no events occurred during 6 months' follow-up. There was insufficient evidence of a difference between laser or drill in terms of pulpal inflammation or necrosis at 1 week (RR 1.51, 95% CI 0.26 to 8.75; 3 studies) and at 6 months (RR 0.99, 95% CI 0.10 to 9.41; 2 studies). Given the low quality of the body of evidence, we concluded that evidence was insufficient to support the use of laser as an alternative to traditional drill therapy for caries removal. We found some evidence in favour of laser therapy for pain control, need of anaesthesia and patient discomfort, but, again, the body of evidence was of low quality. Additional well-designed, randomised trials investigating the most relevant outcomes are needed.
Three randomised controlled trials (340 patients) and 12 non-randomised studies (4081 patients) were included. There was significant statistical heterogeneity in the analysis of many of the outcomes. We found no significant difference between care pathway and control groups in terms of death or discharge destination. Patients managed with a care pathway were: (1) more dependent at discharge (P = 0.04); (2) less likely to suffer a urinary tract infection (Odds Ratio (OR) 0.51, 95% Confidence Interval (CI) 0.34 to 0.79); (3) less likely to be readmitted (OR 0.11, 95% CI 0.03 to 0.39); and (4) more likely to have neuroimaging (OR 2.42, 95% CI 1.12 to 5.25). Evidence from randomised trials suggested that patient satisfaction and quality of life were significantly lower in the care pathway group (P = 0.02 and P < 0.005 respectively). Use of stroke care pathways may be associated with positive and negative effects. Since most of the results have been derived from non-randomised studies, they are likely to be influenced by potential biases and confounding factors. There is currently insufficient supporting evidence to justify the routine implementation of care pathways for acute stroke management or stroke rehabilitation.
Three trials, conducted between 1982 and 1984, met the inclusion criteria (n=17,965). Two trials examined the effect of driver education on licensing. In the trial by Stock (USA) 87% of students in the driver education group obtained their driving licence as compared to 84.3% in the control group (RR 1.04; 95% CI 1.02 to 1.05). In the trial by Wynne-Jones (New Zealand) the time from trial enrolment to licensing was 111 days in males receiving driver education compared with 300 days in males who did not receive driver education, and 105 days in females receiving driver education compared with 415 days in females who did not receive driver education. All three trials examined the effect of driver education on road traffic crashes. In the trial by Strang (Australia), 42% of students in each group had one or more crashes since being licensed (RR 1.01, 95% CI 0.83 to 1.23). In the trial by Stock, the number of students involved in one or more crashes as a driver was 27.5% in the driver education group compared to 26.7% in the control group (RR 1.03; 95% CI 0.98 to 1.09). In the trial by Wynne-Jones, the number of students who experienced crashes was 16% in the driver education group as compared to 14.5% in the control group (RR 1.10; 95% CI 0.76 to 1.59). The results show that driver education leads to early licensing. They provide no evidence that driver education reduces road crash involvement, and suggest that it may lead to a modest but potentially important increase in the proportion of teenagers involved in traffic crashes.
We identified four randomised controlled trials, using different intraoperative imaging technologies: iMRI (2 trials including 58 and 14 participants, respectively); fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) (1 trial, 322 participants); and neuronavigation (1 trial, 45 participants). We identified one ongoing trial assessing iMRI with a planned sample size of 304 participants for which results are expected to be published around autumn 2018. We identified no trials for ultrasound. Meta-analysis was not appropriate due to differences in the tumours included (eloquent versus non-eloquent locations) and variations in the image guidance tools used in the control arms (usually selective utilisation of neuronavigation). There were significant concerns regarding risk of bias in all the included studies. All studies included people with high-grade glioma only. Extent of resection was increased in one trial of iMRI (risk ratio (RR) of incomplete resection 0.13, 95% confidence interval (CI) 0.02 to 0.96; 1 study, 49 participants; very low-quality evidence) and in the trial of 5-ALA (RR of incomplete resection 0.55, 95% CI 0.42 to 0.71; 1 study, 270 participants; low-quality evidence). The other trial assessing iMRI was stopped early after an unplanned interim analysis including 14 participants, therefore the trial provides very low-quality evidence. The trial of neuronavigation provided insufficient data to evaluate the effects on extent of resection. Reporting of adverse events was incomplete and suggestive of significant reporting bias (very low-quality evidence). Overall, reported events were low in most trials. There was no clear evidence of improvement in overall survival with 5-ALA (hazard ratio 0.83, 95% CI 0.62 to 1.07; 1 study, 270 participants; low-quality evidence). Progression-free survival data were not available in an appropriate format for analysis. Data for quality of life were only available for one study and suffered from significant attrition bias (very low-quality evidence). Intra-operative imaging technologies, specifically iMRI and 5-ALA, may be of benefit in maximising extent of resection in participants with high grade glioma. However, this is based on low to very low quality evidence, and is therefore very uncertain. The short- and long-term neurological effects are uncertain. Effects of image-guided surgery on overall survival, progression-free survival, and quality of life are unclear. A brief economic commentary found limited economic evidence for the equivocal use of iMRI compared with conventional surgery. In terms of costs, a non-systematic review of economic studies suggested that compared with standard surgery use of image-guided surgery has an uncertain effect on costs and that 5-aminolevulinic acid was more costly. Further research, including studies of ultrasound-guided surgery, is needed.
Two randomised controlled trials contributed to this literature, enrolling 586 participants, and found no critical difference between TDF and AZT in regards to serious adverse events or virologic response. The trials did find higher rates of adherence and immunologic response in TDF-containing regimens compared with those containing AZT. The quality of the literature to support this conclusion is moderate to high. Drug resistance was more common for TDF than AZT, but the quality of this literature is low, with only one study reporting this outcome. It should be noted that the two studies compared two different drugs in addition to TDF and AZT; one had lamivudine (3TC) and nevirapine (NVP) and the other had emtricitabine (FTC) and efavirenz (EFV). We conclude that for the critical outcomes of virologic response and serious adverse events initial ART regimens containing TDF are equivalent to those containing AZT. However, TDF is superior to AZT in terms of immunologic response and adherence and more frequent emergence of resistance. How much the other drugs in the regimens contributed to these findings is unclear, and true head-to-head trials are still warranted. The role of each drug in initial ART will likely be driven by their specific toxicities.
We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66). Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.
We examined 1430 records, scrutinized 14 full-text publications and included four RCTs. Altogether 1305 participants entered the four trials, 543 participants were randomised to TT and 762 participants to ST. A total of 98% and 97% of participants finished the trials in the TT and ST groups, respectively. Two trials had a duration of follow-up between 12 and 39 months and two trials a follow-up of 5 and 10 years, respectively. Risk of bias across studies was mainly unknown for selection, performance and detection bias. Attrition bias was generally low and reporting bias high for some outcomes. In the short-term postoperative period no deaths were reported for both TT and ST groups. However, longer-term data on all-cause mortality were not reported (1284 participants; 4 trials; moderate quality evidence). Goiter recurrence was lower in the TT group compared to ST. Goiters recurred in 0.2% (1/425) of the TT group compared to 8.4% (53/632) of the ST group (OR 0.05 (95% CI 0.01 to 0.21); P < 0.0001; 1057 participants; 3 trials; moderate quality evidence). Re-intervention due to goitre recurrence was lower in the TT group compared to ST. Re-intervention was necessary in 0.5% (1/191) of TT patients compared to 0.8% (3/379)of ST patients (OR 0.66 (95% CI 0.07 to 6.38); P = 0.72; 570 participants; 1 trial; low quality evidence). The incidence of permanent recurrent laryngeal nerve palsy was lower for ST compared with TT. Permanent recurrent laryngeal nerve palsy occurred in 0.8% (6/741) of ST patients compared to 0.7% (4/543) of TT patients (OR 1.28, (95% CI 0.38 to 4.36); P = 0.69; 1275 participants; 4 trials; low quality evidence). The incidence of permanent hypoparathyroidism was lower for ST compared with TT. Permanent hypoparathyroidism occurred in 0.1% (1/741) of ST patients compared to 0.6% (3/543) of TT patients (OR 3.09 (95% CI 0.45 to 21.36); P = 0.25; 1275 participants: 4 trials; low quality evidence). The incidence of thyroid cancer was lower for ST compared with TT. Thyroid cancer occurred in 6.1% (41/669) of ST patients compared to 7.3% (34/465)of TT patients (OR 1.32 (95% CI 0.81 to 2.15); P = 0.27; 1134 participants; 3 trials; low quality evidence). No data on health-related quality of life or socioeconomic effects were reported in the included studies. The body of evidence on TT compared with ST is limited. Goiter recurrence is reduced following TT. The effects on other key outcomes such as re-interventions due to goitre recurrence, adverse events and thyroid cancer incidence are uncertain. New long-term RCTs with additional data such as surgeons level of experience, treatment volume of surgical centres and details on techniques used are needed.
We included 59 studies with a total of 13,342 participants. Compared to no treatment control MI showed a significant effect on substance use which was strongest at post-intervention SMD 0.79, (95% CI 0.48 to 1.09) and weaker at short SMD 0.17 (95% CI 0.09 to 0.26], and medium follow-up SMD 0.15 (95% CI 0.04 to 0.25]). For long follow-up, the effect was not significant SMD 0.06 (95% CI-0.16 to 0.28). There were no significant differences between MI and treatment as usual for either follow-up post-intervention, short and medium follow up. MI did better than assessment and feedback for medium follow-up SMD 0.38 (95% CI 0.10 to 0.66). For short follow-up, there was no significant effect . For other active intervention there were no significant effects for either follow-up. There was not enough data to conclude about effects of MI on the secondary outcomes. MI can reduce the extent of substance abuse compared to no intervention. The evidence is mostly of low quality, so further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Two studies met the inclusion criteria. No study looked at our main outcome: dog bite rates. The included studies were randomised controlled trials conducted in kindergarten and primary schools. Their methodology was of moderate quality. One study showed that the intervention group showed less 'inappropriate behaviour' when observed in the presence of a dog after a 30-minute educational intervention. Another study showed an increase in knowledge and in caution after an information programme. There is no direct evidence that educational programmes can reduce dog bite rates in children and adolescents. Educating children who are less than 10 years old in school settings could improve their knowledge, attitude and behaviour towards dogs. Educating children and adolescents in settings other than schools should also be evaluated. There is a need for high quality studies that measure dog bite rates as an outcome. To date, evidence does not suggest that educating children and adolescents is effective as a unique public health strategy to reduce dog bite injuries and their consequences.
We included in this systematic review 4745 participants who were randomly assigned in 21 trials. Trials were conducted in a wide variety of clinical settings. Most trials included participants with mild to moderate anaemia and excluded participants who were allergic to iron therapy. All trials were at high risk of bias for one or more domains. We compared both oral iron and parenteral iron versus inactive controls and compared different iron preparations. The comparison between oral iron and inactive control revealed no evidence of clinical benefit in terms of mortality (RR 1.05, 95% CI 0.68 to 1.61; four studies, N = 659; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged from 0.3 to 3.1 g/dL higher in the oral iron group than in the inactive control group. The proportion of participants who required blood transfusion was lower with oral iron than with inactive control (RR 0.74, 95% CI 0.55 to 0.99; three studies, N = 546; very low-quality evidence). Evidence was inadequate for determination of the effect of parenteral iron on mortality versus oral iron (RR 1.49, 95% CI 0.56 to 3.94; 10 studies, N = 2141; very low-quality evidence) or inactive control (RR 1.04, 95% CI 0.63 to 1.69; six studies, N = 1009; very low-quality evidence). Haemoglobin levels were higher with parenteral iron than with oral iron (MD -0.50 g/dL, 95% CI -0.73 to -0.27; six studies, N = 769; very low-quality evidence). The point estimate of the mean difference in haemoglobin levels in individual studies ranged between 0.3 and 3.0 g/dL higher in the parenteral iron group than in the inactive control group. Differences in the proportion of participants requiring blood transfusion between parenteral iron and oral iron groups (RR 0.61, 95% CI 0.24 to 1.58; two studies, N = 371; very low-quality evidence) or between parenteral iron groups and inactive controls (RR 0.84, 95% CI 0.66 to 1.06; eight studies, N = 1315; very low-quality evidence) were imprecise. Average blood volume transfused was less in the parenteral iron group than in the oral iron group (MD -0.54 units, 95% CI -0.96 to -0.12; very low-quality evidence) based on one study involving 44 people. Differences between therapies in quality of life or in the proportion of participants with serious adverse events were imprecise (very low-quality evidence). No trials reported severe allergic reactions due to parenteral iron, suggesting that these are rare. Adverse effects related to oral iron treatment included nausea, diarrhoea and constipation; most were mild. Comparisons of one iron preparation over another for mortality, haemoglobin or serious adverse events were imprecise. No information was available on quality of life. Thus, little evidence was found to support the use of one preparation or regimen over another. Subgroup analyses did not reveal consistent results; therefore we were unable to determine whether iron is useful in specific clinical situations, or whether iron therapy might be useful for people who are receiving erythropoietin. • Very low-quality evidence suggests that oral iron might decrease the proportion of people who require blood transfusion, and no evidence indicates that it decreases mortality. Oral iron might be useful in adults who can tolerate the adverse events, which are usually mild. • Very low-quality evidence suggests that intravenous iron results in a modest increase in haemoglobin levels compared with oral iron or inactive control without clinical benefit. • No evidence can be found to show any advantage of one iron preparation or regimen over another. • Additional randomised controlled trials with low risk of bias and powered to measure clinically useful outcomes such as mortality, quality of life and blood transfusion requirements are needed.
We included 17 RCTs involving 3488 children, of which 16 RCTs were included in the meta-analyses. Of the 16 RCTs that reported the mean age of children, mean age overall was 2.4 years; in 4 RCTs the mean age of children participating in the trial was less than 1 year old; in 2 RCTs the mean age was between 1 and 2 years old; and in 10 RCTs the mean age was older than 2 years. Probiotic strains evaluated by the trials varied, with 11 of the included RCTs evaluating Lactobacillus-containing probiotics, and six RCTs evaluating Streptococcus-containing probiotics. The proportion of children (i.e. the number of children in each group) experiencing one or more episodes of AOM during the treatment was lower for those taking probiotics (RR 0.77, 95% confidence interval (CI) 0.63 to 0.93; 16 trials; 2961 participants; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-certainty evidence). Post hoc subgroup analysis found that among children not prone to otitis media, a lower proportion of children receiving probiotics experienced AOM (RR 0.64, 95% CI 0.49 to 0.84; 11 trials; 2227 participants; NNTB = 9; moderate-certainty evidence). However, among children who were otitis prone, there was no difference between probiotic and comparator groups (RR 0.97, 95% CI 0.85 to 1.11; 5 trials; 734 participants; high-certainty evidence). The test for subgroup differences was significant (P = 0.007). None of the included trials reported on the severity of AOM. The proportion of children experiencing adverse events did not differ between the probiotic and comparator groups (OR 1.54, 95% CI 0.60 to 3.94; 4 trials; 395 participants; low-certainty evidence). Probiotics decreased the proportion of children taking antibiotics for any infection (RR 0.66, 95% CI 0.51 to 0.86; 8 trials; 1768 participants; NNTB = 8; moderate-certainty evidence). Test for subgroup differences (use of antibiotic specifically for AOM, use of antibiotic for infections other than AOM) was not significant. There was no difference in the mean number of school days lost (MD −0.95, 95% CI −2.47 to 0.57; 5 trials; 1280 participants; moderate-certainty evidence). There was no difference between groups in the level of compliance in taking the intervention (RR 1.02, 95% CI 0.99 to 1.05; 5 trials; 990 participants). Probiotics decreased the proportion of children having other infections (RR 0.75, 95% CI 0.65 to 0.87; 11 trials; 3610 participants; NNTB = 12; moderate-certainty evidence). Test for subgroup differences (acute respiratory infections, gastrointestinal infections) was not significant. Probiotic strains trialled and their dose, frequency, and duration of administration varied considerably across studies, which likely contributed to the substantial levels of heterogeneity. Sensitivity testing of funnel plots did not reveal publication bias. Probiotics may prevent AOM in children not prone to AOM, but the inconsistency of the subgroup analyses suggests caution in interpreting these results. Probiotics decreased the proportion of children taking antibiotics for any infection. The proportion of children experiencing adverse events did not differ between the probiotic and comparator groups. The optimal strain, duration, frequency, and timing of probiotic administration still needs to be established.
We have included 18 studies with 1087 participants of whom 545 received HS compared to 542 who received IS. All participants were over 18 years of age and all trials excluded high-risk patients (ASA IV). All trials assessed haematological parameters peri-operatively and up to three days post-operatively. There were three (< 1%) deaths reported in the IS group and four (< 1%) in the HS group, as assessed at 90 days in one study. There were no reports of serious adverse events. Most participants were in a positive fluid balance postoperatively (4.4 L IS and 2.5 L HS), with the excess significantly less in HS participants (MD -1.92 L, 95% confidence interval (CI) -2.61 to -1.22 L; P < 0.00001). IS participants received a mean volume of 2.4 L and HS participants received 1.49 L, significantly less fluid than IS-treated participants (MD -0.91 L, 95% CI -1.24 to -0.59 L; P < 0.00001). The maximum average serum sodium ranged between 138.5 and 159 in HS groups compared to between 136 and 143 meq/L in the IS groups. The maximum serum sodium was significantly higher in HS participants (MD 7.73, 95% CI 5.84 to 9.62; P < 0.00001), although the level remained within normal limits (136 to 146 meq/L). A high degree of heterogeneity appeared to be related to considerable differences in the dose of HS between studies. The quality of the evidence for the outcomes reported ranged from high to very low. The risk of bias for many of the studies could not be determined for performance and detection bias, criteria that we assess as likely to impact the study outcomes. HS reduces the volume of intravenous fluid required to maintain people undergoing surgery but transiently increases serum sodium. It is not known if HS affects survival and morbidity, but this should be examined in randomized controlled trials that are designed and powered to test these outcomes.
We included five completed trials, involving 4197 participants; all tested transdermal glyceryl trinitrate (GTN), an NO donor. The assessed risk of bias was low across the included studies; one study was double-blind, one open-label and three were single-blind. All included studies had blinded outcome assessment. Overall, GTN did not improve the primary outcome of death or dependency at the end of trial (modified Rankin Scale (mRS) > 2, OR 0.97, 95% CI 0.86 to 1.10, 4195 participants, high-quality evidence). GTN did not improve secondary outcomes, including death (OR 0.78, 95% CI 0.40 to 1.50) and quality of life (MD -0.01, 95% CI -0.17 to 0.15) at the end of trial overall (high-quality evidence). Systolic/diastolic blood pressure (BP) was lower in people treated with GTN (MD -7.2 mmHg (95% CI -8.6 to -5.9) and MD -3.3 (95% CI -4.2 to -2.5) respectively) and heart rate was higher (MD 2.0 beats per minute (95% CI 1.1 to 2.9)). Headache was more common in those randomised to GTN (OR 2.37, 95% CI 1.55 to 3.62). We did not find any trials assessing other nitrates, L-arginine, or NOS-I. There is currently insufficient evidence to recommend the use of NO donors, L-arginine or NOS-I in acute stroke, and only one drug (GTN) has been assessed. In people with acute stroke, GTN reduces blood pressure, increases heart rate and headache, but does not alter clinical outcome (all based on high-quality evidence).
Two cohort studies and four case control studies met the inclusion criteria for the primary prevention review. The two cohort studies found no effect of exposure to calcium channel blockers on the risk of developing PD. Three case control studies looked at the effects of exposure to calcium channel blockers and beta blockers on the risk of developing PD but the assessment periods of exposure were markedly different prior to PD onset, and different subclasses of drugs were examined, so results were not comparable. A protective effect of centrally acting calcium channel blockers was found in one study. Two trials and one ongoing trial met the inclusion criteria for the secondary prevention review. Each completed trial examined a different class of anti-hypertensive drug. The ongoing trial is examining the effects of the calcium channel blocker isradipine on motor symptoms and disease progression. It follows an earlier tolerability study. The results are due in the year 2012. Adverse effects were noted in all included trials and included intolerability to the drugs and worsening PD symptoms. There is currently a lack of evidence for the use of antihypertensive drugs for either the primary or secondary prevention of PD. More observational studies are required to identify potential drugs to go forward for safety and tolerability studies in people with early PD. The results of the ongoing trial will help inform further research.
A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials. Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.
Three trials were included, all of which evaluated doxycyline use. Trial quality suffered from a lack of intention-to-treat analysis and variability across trials in methodology and targeted outcomes. One trial assessed post-exposure prophylaxis in an indigenous population after a flood without apparent efficacy in reduction of clinical or laboratory identified Leptospira infection. Two trials assessed pre-exposure prophylaxis, one among deployed soldiers and another in an indigenous population. Despite an odds ratio of 0.05 (95% CI 0.01 to 0.36) for laboratory-identified infection among deployed soldiers on doxycyline in one of these two trials, pooled data showed no statistically significant reduction in Leptospira infection among participants (Odds ratio 0.28 (95% CI 0.01 to 7.48). Minor adverse events (predominantly nausea and vomiting) were more common among those on doxycycline with an odds ratio of 11 (95% CI 2.1 to 60). Regular use of weekly oral doxycycline 200 mg increases the odds for nausea and vomiting with unclear benefit in reducing Leptospira seroconversion or clinical consequences of infection.
Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow-mesenchymal stem cells (BM-MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies. The only study that contributed to the outcome data in the review involved 64 participants, comparing BM-MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions. Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to six months after cell injection was slightly reduced (better) in the BM-MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low-certainty evidence). ALSFRS-R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM-MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD –0.53, 95% CI –5.37 to 4.31; 1 RCT, 56 participants; low-certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low-certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low-certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low-certainty evidence). The study did not measure muscle strength. Currently, there is a lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low-certainty evidence that BM-MSC may slightly reduce functional impairment measured on the ALSFRS-R after four to six months, this was a small phase II trial that cannot be used to establish efficacy. We need large, prospective RCTs with long-term follow-up to establish the efficacy and safety of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.
Thirteen randomised clinical trials assessed milk thistle in 915 patients with alcoholic and/or hepatitis B or C virus liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered adequately double-blinded. Milk thistle versus placebo or no intervention had no significant effect on mortality (RR 0.78, 95% CI 0.53 to 1.15), complications of liver disease (RR 0.95, 95% CI 0.83 to 1.09), or liver histology. Liver-related mortality was significantly reduced by milk thistle in all trials (RR 0.50, 95% CI 0.29 to 0.88), but not in high-quality trials (RR 0.57, 95% CI 0.28 to 1.19). Milk thistle was not associated with a significantly increased risk of adverse events (RR 0.83, 95% CI 0.46 to 1.50). Our results question the beneficial effects of milk thistle for patients with alcoholic and/or hepatitis B or C virus liver diseases and highlight the lack of high-quality evidence to support this intervention. Adequately conducted and reported randomised clinical trials on milk thistle versus placebo are needed.
We included 57 RCTs (74 randomised comparisons) involving 3002 participants in this review (some appearing in more than one comparison). Twenty-seven randomised comparisons (1620 participants) assessed SLT versus no SLT; SLT resulted in clinically and statistically significant benefits to patients' functional communication (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.49, P = 0.01), reading, writing, and expressive language, but (based on smaller numbers) benefits were not evident at follow-up. Nine randomised comparisons (447 participants) assessed SLT with social support and stimulation; meta-analyses found no evidence of a difference in functional communication, but more participants withdrew from social support interventions than SLT. Thirty-eight randomised comparisons (1242 participants) assessed two approaches to SLT. Functional communication was significantly better in people with aphasia that received therapy at a high intensity, high dose, or over a long duration compared to those that received therapy at a lower intensity, lower dose, or over a shorter period of time. The benefits of a high intensity or a high dose of SLT were confounded by a significantly higher dropout rate in these intervention groups. Generally, trials randomised small numbers of participants across a range of characteristics (age, time since stroke, and severity profiles), interventions, and outcomes. Our review provides evidence of the effectiveness of SLT for people with aphasia following stroke in terms of improved functional communication, reading, writing, and expressive language compared with no therapy. There is some indication that therapy at high intensity, high dose or over a longer period may be beneficial. HIgh-intensity and high dose interventions may not be acceptable to all.
Only one RCT, providing very low-quality evidence, was identified and included. Thirteen patients received HBO therapy while another 13 did not. Two to six implants were placed in people with fully edentulous mandibles to be rehabilitated with bar-retained overdentures. One year after implant loading, four patients had died from each group. One patient, treated with HBO, developed an osteoradionecrosis and lost all implants so the prosthesis could not be provided. Five patients in the HBO group had at least one implant failure versus two in the control group. There were no statistically significant differences for prosthesis and implant failures, postoperative complications and patient satisfaction between the two groups. Despite the limited amount of clinical research available, it appears that HBO therapy in irradiated patients requiring dental implants may not offer any appreciable clinical benefits. There is a definite need for more RCTs to ascertain the effectiveness of HBO in irradiated patients requiring dental implants. These trials ought to be of a high quality and reported as recommended by the CONSORT statement (www.consort-statement.org/). Each clinical centre may have limited numbers of patients and it is likely that trials will need to be multicentred.
We included 52 studies with 41,331 participants; two studies were quasi-randomized and the remaining studies were RCTs. All studies included participants undergoing surgery under general anaesthesia. Three studies recruited only participants who were at high risk of intraoperative awareness, whilst two studies specifically recruited an unselected participant group. We analysed the data according to two comparison groups: BIS versus clinical signs; and BIS versus ETAG. Forty-eight studies used clinical signs as a comparison method, which included titration of anaesthesia according to criteria such as blood pressure or heart rate and, six studies used ETAG to guide anaesthesia. Whilst BIS target values differed between studies, all were within a range of values between 40 to 60. BIS versus clinical signs We found low-certainty evidence that BIS-guided anaesthesia may reduce the risk of intraoperative awareness in a surgical population that were unselected or at high risk of awareness (Peto odds ratio (OR) 0.36, 95% CI 0.21 to 0.60; I2 = 61%; 27 studies; 9765 participants). However, events were rare with only five of 27 studies with reported incidences; we found that incidences of intraoperative awareness when BIS was used were three per 1000 (95% CI 2 to 6 per 1000) compared to nine per 1000 when anaesthesia was guided by clinical signs. Of the five studies with event data, one included participants at high risk of awareness and one included unselected participants, four used a structured questionnaire for assessment, and two used an adjudication process to identify confirmed or definite awareness. Early recovery times were also improved when BIS was used. We found low-certainty evidence that BIS may reduce the time to eye opening by mean difference (MD) 1.78 minutes (95% CI -2.53 to -1.03 minutes; 22 studies; 1494 participants), the time to orientation by MD 3.18 minutes (95% CI -4.03 to -2.33 minutes; 6 studies; 273 participants), and the time to discharge from the postanaesthesia care unit (PACU) by MD 6.86 minutes (95% CI -11.72 to -2 minutes; 13 studies; 930 participants). BIS versus ETAG Again, events of intraoperative awareness were extremely rare, and we found no evidence of a difference in incidences of intraoperative awareness according to whether anaesthesia was guided by BIS or by ETAG in a surgical population at unselected or at high risk of awareness (Peto OR 1.13, 95% CI 0.56 to 2.26; I2 = 37%; 5 studies; 26,572 participants; low-certainty evidence). Incidences of intraoperative awareness were one per 1000 in both groups. Only three of five studies reported events, two included participants at high risk of awareness and one included unselected participants, all used a structured questionnaire for assessment and an adjudication process to identify confirmed or definite awareness. One large study (9376 participants) reported a reduced time to discharge from the PACU by a median of three minutes less, and we judged the certainty of this evidence to be low. No studies measured or reported the time to eye opening and the time to orientation. Certainty of the evidence We used GRADE to downgrade the evidence for all outcomes to low certainty. The incidence of intraoperative awareness is so infrequent such that, despite the inclusion of some large multi-centre studies in analyses, we believed that the effect estimates were imprecise. In addition, analyses included studies that we judged to have limitations owing to some assessments of high or unclear bias and in all studies, it was not possible to blind anaesthetists to the different methods of monitoring depth of anaesthesia. Studies often did not report a clear definition of intraoperative awareness. Time points of measurement differed, and methods used to identify intraoperative awareness also differed and we expected that some assessment tools were more comprehensive than others. Intraoperative awareness is infrequent and, despite identifying a large number of eligible studies, evidence for the effectiveness of using BIS to guide anaesthetic depth is imprecise. We found that BIS-guided anaesthesia compared to clinical signs may reduce the risk of intraoperative awareness and improve early recovery times in people undergoing surgery under general anaesthesia but we found no evidence of a difference between BIS-guided anaesthesia and ETAG-guided anaesthesia. We found six studies awaiting classification and two ongoing studies; inclusion of these studies in future updates may increase the certainty of the evidence.
Thirty-four trials reporting on 46 treatment comparisons were identified. All trials published results for tumour response and 27 trials published time-to-event data for overall survival. The observed 4244 deaths in 5605 randomised women did not demonstrate a statistically significant difference in survival between regimens that contained antitumour antibiotics and those that did not (HR 0.96, 95% CI 0.90 to 1.02, P = 0.22) and no significant heterogeneity. Antitumour antibiotic regimens were favourably associated with time-to-progression (HR 0.84, 95% CI 0.77 to 0.91) and tumour response rates (odds ratio (OR) 1.33, 95% CI 1.21 to 1.48) although statistically significant heterogeneity was observed for these outcomes. These associations were consistent when the analysis was restricted to the 30 trials that reported on anthracyclines. Patients receiving anthracycline containing regimens were also more likely to experience toxic events compared to patients receiving non-antitumour antibiotic regimens. No statistically significant difference was observed in any outcome between mitoxantrone containing and non-antitumour antibiotic-containing regimens. Compared to regimens without antitumour antibiotics, regimens that contained these agents showed a statistically significant advantage for tumour response and time to progression in women with metastatic breast cancer but were not associated with an improvement in overall survival. The favourable effect on tumour response and time to progression observed in anthracycline containing regimens was also associated with greater toxicity.
One study (186 infants up to two years old) comparing five monthly doses of palivizumab (N = 92) to placebo (N = 94) over one respiratory syncytial virus season was identified and met our inclusion criteria. We judged there to be a low risk of bias with respect to the concealment of the randomization schedule (although it was not clear how this was generated) and to blinding of participants and study personnel. There is also a low risk of bias with regards to incomplete outcome data. However, we judged there to be a high risk of bias from selective reporting (summary statements presented but no data) and the fact that this industry-supported study has not been published as a full report in a peer-reviewed journal. At six months follow-up, one participant in each group was hospitalised due to respiratory syncytial virus; there were no deaths in either group. In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while five and four children had related adverse events respectively. Nineteeen children receiving palivizumab and 16 receiving placebo suffered serious adverse events; one participant receiving palivizumab discontinued due to this. At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio. We identified one randomised controlled trial comparing five monthly doses of palivizumab to placebo in infants up to two years old with cystic fibrosis. While the overall incidence of adverse events was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of respiratory syncytial virus prophylaxis with palivizumab in infants with cystic fibrosis. Six months after treatment, the authors reported no clinically meaningful differences in outcomes. Additional randomised studies are needed to establish the safety and efficacy of palivizumab in children with cystic fibrosis.
We included nine trials with 1007 participants. Three trials compared rotator cuff repair with subacromial decompression followed by exercises with exercise alone. These trials included 339 participants with full-thickness rotator cuff tears diagnosed with magnetic resonance imaging (MRI) or ultrasound examination. One of the three trials also provided up to three glucocorticoid injections in the exercise group. All surgery groups received tendon repair with subacromial decompression and the postoperative exercises were similar to the exercises provided for the non-operative groups. Five trials (526 participants) compared repair with acromioplasty versus repair alone; and one trial (142 participants) compared repair with subacromial decompression versus subacromial decompression alone. The mean age of trial participants ranged between 56 and 68 years, and females comprised 29% to 56% of the participants. Symptom duration varied from a mean of 10 months up to 28 months. Two trials excluded tears with traumatic onset of symptoms. One trial defined a minimum duration of symptoms of six months and required a trial of conservative therapy before inclusion. The trials included mainly repairable full-thickness supraspinatus tears, six trials specifically excluded tears involving the subscapularis tendon. All trials were at risk of bias for several criteria, most notably due to lack of participant and personnel blinding, but also for other reasons such as unclearly reported methods of random sequence generation or allocation concealment (six trials), incomplete outcome data (three trials), selective reporting (six trials), and other biases (six trials). Our main comparison was rotator cuff repair with or without subacromial decompression versus non-operative treatment. We identified three trials for this comparison, that compared rotator cuff repair with subacromial decompression followed by exercises with exercise alone with or without glucocorticoid injections, and results are reported here for the 12 month follow up. At one year, moderate-certainty evidence (downgraded for bias) from 3 trials with 258 participants indicates that surgery probably provides little or no improvement in pain; mean pain (range 0 to 10, higher scores indicate more pain) was 1.6 points with non-operative treatment and 0.87 points better (0.43 better to 1.30 better) with surgery. Mean function (zero to 100, higher score indicating better outcome) was 72 points with non-operative treatment and 6 points better (2.43 better to 9.54 better) with surgery (3 trials; 269 participants), low-certainty evidence (downgraded for bias and imprecision). Participant-rated global success rate was 48/55 after non-operative treatment and 52/55 after surgery corresponding to risk ratio (RR) 1.08, 95% confidence interval (CI) 0.96 to 1.22; low-certainty evidence (downgraded for bias and imprecision). Health-related quality of life was 57.5 points (SF-36 mental component score, 0 to 100, higher score indicating better quality of life) with non-operative treatment and 1.3 points worse (4.5 worse to 1.9 better) with surgery (1 trial; 103 participants), low-certainty evidence (downgraded for bias and imprecision). We were unable to estimate the risk of adverse events and serious adverse events as only one event was reported across the trials (very low-certainty evidence; downgraded once due to bias and twice due to very serious imprecision). At the moment, we are uncertain whether rotator cuff repair surgery provides clinically meaningful benefits to people with symptomatic tears; it may provide little or no clinically important benefits with respect to pain, function, overall quality of life or participant-rated global assessment of treatment success when compared with non-operative treatment. Surgery may not improve shoulder pain or function compared with exercises, with or without glucocorticoid injections. The trials included have methodology concerns and none included a placebo control. They included participants with mostly small degenerative tears involving the supraspinatus tendon and the conclusions of this review may not be applicable to traumatic tears, large tears involving the subscapularis tendon or young people. Furthermore, the trials did not assess if surgery could prevent arthritic changes in long-term follow-up. Further well-designed trials in this area that include a placebo-surgery control group and long follow-up are needed to further increase certainty about the effects of surgery for rotator cuff tears.
We included no new trials in this update. The results are unchanged from the previous review and are based on the data of six RCTs with 223 participants. All six RCTs compared cognitive rehabilitation with a usual care control. Meta-analyses demonstrated no convincing effect of cognitive rehabilitation on subjective measures of attention either immediately after treatment (standardised mean difference (SMD) 0.53, 95% confidence interval (CI) –0.03 to 1.08; P = 0.06; 2 studies, 53 participants; very low-quality evidence) or at follow-up (SMD 0.16, 95% CI –0.23 to 0.56; P = 0.41; 2 studies, 99 participants; very low-quality evidence). People receiving cognitive rehabilitation (when compared with control) showed that measures of divided attention recorded immediately after treatment may improve (SMD 0.67, 95% CI 0.35 to 0.98; P < 0.0001; 4 studies, 165 participants; low-quality evidence), but it is uncertain that these effects persisted (SMD 0.36, 95% CI –0.04 to 0.76; P = 0.08; 2 studies, 99 participants; very low-quality evidence). There was no evidence for immediate or persistent effects of cognitive rehabilitation on alertness, selective attention, and sustained attention. There was no convincing evidence for immediate or long-term effects of cognitive rehabilitation for attentional problems on functional abilities, mood, and quality of life after stroke. The effectiveness of cognitive rehabilitation for attention deficits following stroke remains unconfirmed. The results suggest there may be an immediate effect after treatment on attentional abilities, but future studies need to assess what helps this effect persist and generalise to attentional skills in daily life. Trials also need to have higher methodological quality and better reporting.
We included nine studies (1614 participants) in this review. Symptomatic UTI (RR 1.11, 95% CI 0.51 to 2.43), complications (RR 0.78, 95% CI 0. 35 to 1.74), and death (RR 0.99, 95% CI 0.70 to 1.41) were similar between the antibiotic and placebo or no treatment arms. Antibiotics were more effective for bacteriological cure (RR 2.67, 95% CI 1.85 to 3.85) but also more adverse events developed in this group (RR 3.77, 95% CI 1.40 to 10.15). No decline in the kidney function was observed across the studies; minimal data were available on the emergence of resistant strains after antimicrobial treatment. The included studies were of medium and high quality, used different treatments for different durations of treatment and follow-up, different populations, but this did not appear to influence the results of review. No differences were observed between antibiotics versus no treatment of asymptomatic bacteriuria for the development of symptomatic UTI, complications or death. Antibiotics were superior to no treatment for the bacteriological cure but with significantly more adverse events. There was no clinical benefit from treating asymptomatic bacteriuria in the studies included in this review.
Twelve trials of six to 14 months duration involving 350 people were included. Eleven trials investigated levothyroxine replacement with placebo, one study compared levothyroxine replacement with no treatment. We did not identify any trial that assessed (cardiovascular) mortality or morbidity. Seven studies evaluated symptoms, mood and quality of life with no statistically significant improvement. One study showed a statistically significant improvement in cognitive function. Six studies assessed serum lipids, there was a trend for reduction in some parameters following levothyroxine replacement. Some echocardiographic parameters improved after levothyroxine replacement therapy, like myocardial relaxation, as indicated by a significant prolongation of the isovolumic relaxation time as well as diastolic dysfunction. Only four studies reported adverse events with no statistically significant differences between groups. In current RCTs, levothyroxine replacement therapy for subclinical hypothyroidism did not result in improved survival or decreased cardiovascular morbidity. Data on health-related quality of life and symptoms did not demonstrate significant differences between intervention groups. Some evidence indicates that levothyroxine replacement improves some parameters of lipid profiles and left ventricular function.
Sixteen randomised controlled trials, recruiting a total of 2027 perimenopausal or postmenopausal women, were identified. All studies used oral monopreparations of black cohosh at a median daily dose of 40 mg, for a mean duration of 23 weeks. Comparator interventions included placebo, hormone therapy, red clover and fluoxetine. Reported outcomes included vasomotor symptoms, vulvovaginal symptoms, menopausal symptom scores and adverse effects. There was no significant difference between black cohosh and placebo in the frequency of hot flushes (mean difference (MD) 0.07 flushes per day; 95% confidence interval (CI) -0.43 to 0.56 flushes per day; P=0.79; 393 women; three trials; moderate heterogeneity: I2 = 47%) or in menopausal symptom scores (standardised mean difference (SMD) -0.10; 95% CI -0.32 to 0.11; P = 0.34; 357 women; four trials; low heterogeneity: I2 = 21%). Compared to black cohosh, hormone therapy significantly reduced daily hot flush frequency (three trials; data not pooled) and menopausal symptom scores (SMD 0.32; 95% CI 0.13 to 0.51; P=0.0009; 468 women; five trials; substantial heterogeneity: I2 = 69%). These findings should be interpreted with caution given the heterogeneity between studies. Comparisons of the effectiveness of black cohosh and other interventions were either inconclusive (because of considerable heterogeneity or an insufficient number of studies) or not statistically significant. Similarly, evidence on the safety of black cohosh was inconclusive, owing to poor reporting. There were insufficient data to pool results for health-related quality of life, sexuality, bone health, vulvovaginal atrophic symptoms and night sweats. No trials reported cost-effectiveness data. The quality of included trials was generally unclear, owing to inadequate reporting. There is currently insufficient evidence to support the use of black cohosh for menopausal symptoms. However, there is adequate justification for conducting further studies in this area. The uncertain quality of identified trials highlights the need for improved reporting of study methods, particularly with regards to allocation concealment and the handling of incomplete outcome data. The effect of black cohosh on other important outcomes, such as health-related quality of life, sexuality, bone health, night sweats and cost-effectiveness also warrants further investigation.
The experimental intervention was cup feeding and the control intervention was bottle feeding in all five studies included in this review. One study reported weight gain as g/kg/day and there was no statistically significant difference between the two groups (MD −0.60, 95% CI −3.21 to 2.01); while a second study reported weight gain in the first seven days as grams/day and also showed no statistically significant difference between the two groups (MD −0.10, 95% CI −0.36 to 0.16). There was substantial variation in results for the majority of breastfeeding outcomes, except for not breastfeeding at three months (three studies) (typical RR 0.83, 95% CI 0.71 to 0.97) which favoured cup feeding. Where there was moderate heterogeneity meta-analysis was performed: not breastfeeding at six months (two studies) (typical RR 0.83, 95% CI 0.72 to 0.95); not fully breastfeeding at hospital discharge (four studies) (typical RR 0.61, 95% CI 0.52 to 0.71). Two studies reported average time to feed which showed no difference between the two groups. Two studies assessed length of hospital stay and there was considerable variation in results and in the direction of effect. Only one study has reported gestational age at discharge, which showed no difference between the two groups (MD −0.10, 95% CI −0.54 to 0.34). As the majority of infants in the included studies are preterm infants, no recommendations can be made for cup feeding term infants due to the lack of evidence in this population. From the studies of preterm infants, cup feeding may have some benefits for late preterm infants and on breastfeeding rates up to six months of age. Self-reported breastfeeding status and compliance to supplemental interventions may over-report exclusivity and compliance, as societal expectations of breastfeeding and not wishing to disappoint healthcare professionals may influence responses at interview and on questionnaires. The results for length of stay are mixed, with the study involving lower gestational age preterm infants finding that those fed by cup spent approximately 10 days longer in hospital, whereas the study involving preterm infants at a higher gestational age, who did not commence cup feeding until 35 weeks' gestation, did not have a longer length of stay, with both groups staying on average 26 days. This finding may have been influenced by gestational age at birth and gestational age at commencement of cup feeding, and their mothers' visits; (a large number of mothers of these late preterm infants lived regionally from the hospital and could visit at least twice per week). Compliance to the intervention of cup feeding remains a challenge. The two largest studies have both reported non-compliance, with one study analysing data by intention to treat and the other excluding those infants from the analysis. This may have influenced the findings of the trial. Non-compliance issues need consideration before further large randomised controlled trials are undertaken as this influences power of the study and therefore the statistical results. In addition larger studies with better-quality (especially blinded) outcome assessment with 100% follow-up are needed.
Seventeen trials including 1817 patients were identified. Vasoactive drugs were vasopressin (one trial), terlipressin (one trial), somatostatin (five trials), and octreotide (ten trials). No significant differences were found comparing sclerotherapy with each vasoactive drug for any outcome. Combining all the trials irrespective of the vasoactive drug, the risk differences (95% confidence intervals) were failure to control bleeding -0.02 (-0.06 to 0.02), five-day failure rate -0.05 (-0.10 to 0.01), rebleeding 0.01 (-0.03 to 0.05), mortality (17 randomised trials, 1817 patients) -0.02 (-0.06 to 0.02), and transfused blood units (8 randomised trials, 849 patients) (weighted mean difference) -0.24 (-0.54 to 0.07). Adverse events 0.08 (0.03 to 0.14) and serious adverse events 0.05 (0.02 to 0.08) were significantly more frequent with sclerotherapy. We found no convincing evidence to support the use of emergency sclerotherapy for variceal bleeding in cirrhosis as the first, single treatment when compared with vasoactive drugs. Vasoactive drugs may be safe and effective whenever endoscopic therapy is not promptly available and seems to be associated with less adverse events than emergency sclerotherapy. Other meta-analyses and guidelines advocate that combined vasoactive drugs and endoscopic therapy is superior to either intervention alone.
Three studies were identified, 2 published as full papers and one in abstract form (537 patients). The risk of bias was low for the 3 included studies. There was no statistically significant difference in the proportion of patients (GM-CSF 25.3% versus placebo 17.5%) who achieved clinical remission (RR 1.67; 95% CI 0.80 to 3.50; P = 0.17; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 38.3% versus placebo 24.8%) who achieved a 100-point clinical response (RR 1.71 95% CI 0.98 to 2.97; P = 0.06; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 54.3% versus placebo 44.2%) who achieved a 70 point clinical response (RR 1.23; 95% CI 0.83 to 1.82; P = 0.30; 1 study; 124 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 95.8% versus placebo 89.3%) who experienced at least one adverse event (RR 1.07; 95% CI 0.99 to 1.16; P = 0.08; 2 studies; 251 patients), or serious adverse events (GM-CSF 12.0% versus placebo 4.8%; RR 2.21; 95% CI 0.84 to 5.81; P = 0.11; 2 studies; 251 patients). The incidence of bone pain, musculoskeletal chest pain, and dyspnea were higher in patients treated with sargramostim compared to placebo. Other adverse events commonly associated with sargramostim such as pulmonary capillary leak syndrome, pulmonary edema, heart failure, fever, and neurotoxicity were not reported in these studies. Sargramostim does not appear to be more effective than placebo for induction of clinical remission or clinical improvement in patients with active Crohn's disease. However, the GRADE analysis indicates that the overall quality of the evidence for the primary (clinical remission) and secondary outcomes (clinical response) was low indicating that further research is likely to have an impact on the effect estimates.
We included 41 studies (4224 participants). Participants underwent ambulatory or short length of stay surgical procedures, and were predominantly American Society of Anesthesiology (ASA) class I or II. There is one study awaiting classification and three ongoing studies. All studies took place in surgical centres, and were conducted in geographically diverse settings. Risk of bias was generally unclear across all domains. Supplemental intravenous crystalloid administration probably reduces the cumulative risk of postoperative nausea (PON) (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.51 to 0.75; 18 studies; 1766 participants; moderate-certainty evidence). When the postoperative period was divided into early (first six hours postoperatively) and late (at the time point closest to or including 24 hours postoperatively) time points, the intervention reduced the risk of early PON (RR 0.67, 95% CI 0.58 to 0.78; 20 studies; 2310 participants; moderate-certainty evidence) and late PON (RR 0.47, 95% CI 0.32 to 0.69; 17 studies; 1682 participants; moderate-certainty evidence). Supplemental intravenous crystalloid administration probably reduces the risk of postoperative vomiting (POV) (RR 0.50, 95% CI 0.40 to 0.63; 20 studies; 1970 participants; moderate-certainty evidence). The intervention specifically reduced both early POV (RR 0.56, 95% CI 0.41 to 0.76; 19 studies; 1998 participants; moderate-certainty evidence) and late POV (RR 0.48, 95% CI 0.29 to 0.79; 15 studies; 1403 participants; moderate-certainty evidence). Supplemental intravenous crystalloid administration probably reduces the need for pharmacologic treatment of PONV (RR 0.62, 95% CI 0.51 to 0.76; 23 studies; 2416 participants; moderate-certainty evidence). The effect of supplemental intravenous crystalloid administration on the risk of unplanned postoperative admission to hospital is unclear (RR 1.05, 95% CI 0.77 to 1.43; 3 studies; 235 participants; low-certainty evidence). No studies reported serious adverse events that may occur following supplemental perioperative intravenous crystalloid administration (i.e. admission to high-dependency unit, postoperative cardiac or respiratory complication, or death). There is moderate-certainty evidence that supplemental perioperative intravenous crystalloid administration reduces PON and POV, in ASA class I to II patients receiving general anaesthesia for ambulatory or short length of stay surgical procedures. The intervention probably also reduces the risk of pharmacologic treatment for PONV. The effect of the intervention on the risk of unintended postoperative admission to hospital is unclear. The risk of serious adverse events resulting from supplemental perioperative intravenous crystalloid administration is unknown as no studies reported this outcome. The one study awaiting classification may alter the conclusions of the review once assessed.
Fifteen studies (733 patients) were suitable for analysis. All studies were small and had variable methodology. Fish oil did not significantly affect patient or graft survival, acute rejection rates, or calcineurin inhibitor toxicity when compared to placebo. Overall SCr was significantly lower in the fish oil group compared to placebo (5 studies, 237 participants: MD -30.63 µmol/L, 95% CI -59.74 to -1.53; I2 = 88%). In the subgroup analysis, this was only significant in the long-course (six months or more) group (4 studies, 157 participants: MD -37.41 µmol/L, 95% CI -69.89 to -4.94; I2 = 82%). Fish oil treatment was associated with a lower diastolic blood pressure (4 studies, 200 participants: MD -4.53 mm Hg, 95% CI -7.60 to -1.45) compared to placebo. Patients receiving fish oil for more than six months had a modest increase in HDL (5 studies, 178 participants: MD 0.12 mmol/L, 95% CI 0.03 to 0.21; I2 = 47%) compared to placebo. Fish oil effects on lipids were not significantly different from low-dose statins. There was insufficient data to analyse cardiovascular outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant patient drop-out. There is insufficient evidence from currently available RCTs to recommend fish oil therapy to improve kidney function, rejection rates, patient survival or graft survival. The improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use. To determine a benefit in clinical outcomes, future RCTs will need to be adequately powered with these outcomes in mind.
We included 19 studies (six paediatric, 13 adults). None of the paediatric studies could be combined for meta-analysis. A single RCT in infants found that PPI (compared to placebo) was not efficacious for cough outcomes (favouring placebo OR 1.61; 95% CI 0.57 to 4.55) but those on PPI had significantly increased adverse events (OR 5.56; 95% CI 1.18 to 26.25) (number needed to treat for harm in four weeks was 11 (95% CI 3 to 232)). In adults, analysis of H2 antagonist, motility agents and conservative treatment for GORD was not possible (lack of data) and there were no controlled studies of fundoplication. We analysed nine adult studies comparing PPI (two to three months) to placebo for various outcomes in the meta-analysis. Using intention-to-treat, pooled data from studies resulted in no significant difference between treatment and placebo in total resolution of cough (OR 0.46; 95% CI 0.19 to 1.15). Pooled data revealed no overall significant improvement in cough outcomes (end of trial or change in cough scores). We only found significant differences in sensitivity analyses. We found a significant improvement in change of cough scores at end of intervention (two to three months) in those receiving PPI (standardised mean difference -0.41; 95% CI -0.75 to -0.07) using generic inverse variance analysis on cross-over trials. Two studies reported improvement in cough after five days to two weeks of treatment. PPI is not efficacious for cough associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for cough associated with GORD. Clinicians should be cognisant of the period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Future paediatric and adult studies should be double-blind, randomised controlled and parallel-design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non-acid reflux.
Thirty seven studies (2185 participants) were included in this review. There was no significant difference in the risk for CMV disease (16 studies, 770 patients: RR 0.80, 95% CI 0.61 to 1.05), CMV infection (14 studies, 775 patients: RR 0.94, 95% CI 0.80 to 1.10) or all-cause mortality (8 studies, 502 patients: RR 0.57, 95% CI 0.32 to 1.03) with IgG compared with placebo/no treatment. However IgG significantly reduced the risk of death from CMV disease (6 studies, 346 patients: RR 0.33, 95% CI 0.14 to 0.80). There was no difference in the risk for CMV disease (4 studies, 298 patients: RR 1.17, 95% CI 0.74 to 1.86), CMV infection (4 studies, 298 patients: RR 1.16, 95% CI 0.89 to 1.52) or all-cause mortality (2 studies, 217 patients: RR 0.92, 95% CI 0.37 to 2.29) between antiviral medication combined with IgG and antiviral medication alone. There was no significant difference in the risk of CMV disease with anti CMV vaccine or interferon compared with placebo or no treatment. Currently there are no indications for IgG in the prophylaxis of CMV disease in recipients of solid organ transplants.
We included seven trials (1789 participants). Four studies had high risk of bias and the risk of bias in the other three trials was unclear. In addition, it was difficult to assess possible reporting bias. We pooled 1070 participants from four RCTs to evaluate corporal atrophy development revealing an insignificantly increased OR of 1.50 (95% CI 0.59 to 3.80; P value = 0.39; low-quality evidence) for long-term PPI users relative to non-PPI users. In five eligible trials, corporal intestinal metaplasia was assessed among 1408 participants, also with uncertain results (OR 1.46; 95% CI 0.43 to 5.03; P value = 0.55; low-quality evidence). However, by pooling data of 1705 participants from six RCTs, our meta-analysis showed that participants with PPI maintenance treatment were more likely to experience either diffuse (simple) (OR 5.01; 95% CI 1.54 to 16.26; P value = 0.007; very-low-quality evidence) or linear/micronodular (focal) ECL hyperplasia (OR 3.98; 95% CI 1.31 to 12.16; P value = 0.02; low-quality evidence) than controls. No participant showed any dysplastic or neoplastic change in any included studies. There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain.
4 RCTs were included and analysed. Methodological quality of included studies was considered low, when scored according to GRADE methodology. Total numbers of inclusion were limited. The trials included in primary analysis reported 237 patients, (119 ERAS vs 118 conventional). Baseline characteristics were comparable. The primary outcome measure, complications, showed a significant risk reduction for all complications (RR 0.50; 95% CI 0.35 to 0.72). This difference was not due to reduction in major complications. Length of hospital stay was significantly reduced in the ERAS group (MD -2.94 days; 95% CI -3.69 to -2.19), and readmission rates were equal in both groups. Other outcome parameters were unsuitable for meta-analysis, but seemed to favour ERAS. The quantity and especially quality of data are low. Analysis shows a reduction in overall complications, but major complications were not reduced. Length of stay was reduced significantly. We state that ERAS seems safe, but the quality of trials and lack of sufficient other outcome parameters do not justify implementation of ERAS as the standard of care. Within ERAS protocols included, no answer regarding the role for minimally invasive surgery (i.e. laparoscopy) was found. Furthermore, protocol compliance within ERAS programs has not been investigated, while this seems a known problem in the field. Therefore, more specific and large RCT's are needed.
A total of 16 randomised trials with 1326 patients were included. One trial with 42 participants compared phyllanthus with placebo. The trial found no significant difference in HBeAg seroconversion after the end of treatment (RR 0.9; 95% CI 0.73 to 1.25) or follow-up (RR 1.00; 95% CI 0.63 to 1.60). No other outcomes could be assessed. Fifteen trials compared phyllanthus plus an antiviral drug like interferon alpha, lamivudine, adefovir dipivoxil, thymosin, vidarabine, or conventional treatment with the same antiviral drug alone. Phyllanthus did significantly affect serum HBV DNA (RR 0.69; 95% CI 0.52 to 0.91, P = 0.008; I2 = 71%), serum HBeAg (RR 0.70; 95% CI 0.60 to 0.81, P < 0.00001; I2 = 68%), and HBeAg seroconversion (RR 0.77; 95% CI 0.63 to 0.92, P = 0.005; I2 = 78%), but the heterogeneity was substantial. The result obtained regarding serum HBV DNA was not supported by trial sequential analysis. None of the trials reported mortality and hepatitis B-related morbidity, quality of life, or liver histology. Only two trials reported adverse events with numbers without significant differences. No serious adverse events were reported. There is no convincing evidence that phyllanthus compared with placebo benefits patients with chronic HBV infection. Phyllanthus plus an antiviral drug may be better than the same antiviral drug alone. However, heterogeneity, systematic errors, and random errors question the validity of the results. Clinical trials with large sample size and low risk of bias are needed to confirm our findings. Species of phyllanthus should be reported in future trials, and a dose-finding design is warranted.
We identified seven RCTs, one register, and five ongoing trials from a total of 347 references. The published trials for VEGF-targeting drugs in MBC were limited to bevacizumab. Four trials, including a total of 2886 patients, were available for the comparison of first-line chemotherapy, with versus without bevacizumab. PFS (HR 0.67; 95% confidence interval (CI) 0.61 to 0.73) and response rate were significantly better for patients treated with bevacizumab, with moderate heterogeneity regarding the magnitude of the effect on PFS. For second-line chemotherapy, a smaller, but still significant benefit in terms of PFS could be demonstrated for patients treated with bevacizumab (HR 0.85; 95% CI 0.73 to 0.98), as well as a benefit in tumour response. However, OS did not differ significantly, neither in first- (HR 0.93; 95% CI 0.84 to 1.04), nor second-line therapy (HR 0.98; 95% CI 0.83 to 1.16). Quality of life (QoL) was evaluated in four trials but results were published for only two of these with no relevant impact. Subgroup analysis stated a significant greater benefit for patients with previous (taxane) chemotherapy and patients with hormone-receptor negative status. Regarding toxicity, data from RCTs and registry data were consistent and in line with the known toxicity profile of bevacizumab. While significantly higher rates of adverse events (AEs) grade III/IV (odds ratio (OR) 1.77; 95% CI 1.44 to 2.18) and serious adverse events (SAEs) (OR 1.41; 95% CI 1.13 to 1.75) were observed in patients treated with bevacizumab, rates of treatment-related deaths were lower in patients treated with bevacizumab (OR 0.60; 95% CI 0.36 to 0.99). The overall patient benefit from adding bevacizumab to first- and second-line chemotherapy in metastatic breast cancer can at best be considered as modest. It is dependent on the type of chemotherapy used and limited to a prolongation of PFS and response rates in both first- and second-line therapy, both surrogate parameters. In contrast, bevacizumab has no significant impact on the patient-related secondary outcomes of OS or QoL, which indicate a direct patient benefit. For this reason, the clinical value of bevacizumab for metastatic breast cancer remains controversial.
We included eight studies in this updated review but could retain in the analysis only seven studies on 742 operated eyes of 617 participants. Two cross-over trials included 125 participants, and five parallel trials included 492 participants. These studies were published between 1997 and 2005. The mean age of participants varied from 71.5 years to 83.5 years. The female proportion of participants varied from 54% to 76%. Compared with sub-Tenon's anaesthesia, topical anaesthesia (with or without intracameral injection) for cataract surgery increases intraoperative pain but decreases postoperative pain at 24 hours. The amplitude of the effect (equivalent to 1.1 on a score from 0 to 10 for intraoperative pain, and to 0.2 on the same scale for postoperative pain at 24 hours), although statistically significant, was probably too small to be of clinical relevance. The quality of the evidence was rated as high for intraoperative pain and moderate for pain at 24 hours. We did find differences in pain during administration of local anaesthetic (low level of evidence), and indications that surgeon satisfaction (low level of evidence) and participant satisfaction (moderate level of evidence) were less with topical anaesthesia. There was not enough evidence to say that one technique would result in a higher or lower incidence of intraoperative complications compared with the other. Both topical anaesthesia and sub-Tenon's anaesthesia are accepted and safe methods of providing anaesthesia for cataract surgery. An acceptable degree of intraoperative discomfort has to be expected with either of these techniques. Randomized controlled trials on the effects of various strategies to prevent intraoperative pain during cataract surgery could prove useful.
We included four randomised controlled trials involving 1933 participants. For the primary outcome category of health, there was moderate quality evidence from one study that women who received prenatal support via mobile phone messages had significantly higher satisfaction than those who did not receive the messages, both in the antenatal period (mean difference (MD) 1.25, 95% confidence interval (CI) 0.78 to 1.72) and perinatal period (MD 1.19, 95% CI 0.37 to 2.01). Their confidence level was also higher (MD 1.12, 95% CI 0.51 to 1.73) and anxiety level was lower (MD -2.15, 95% CI -3.42 to -0.88) than in the control group in the antenatal period. In this study, no further differences were observed between groups in the perinatal period. There was low quality evidence that the mobile phone messaging intervention did not affect pregnancy outcomes (gestational age at birth, infant birth weight, preterm delivery and route of delivery). For the primary outcome category of health behaviour, there was moderate quality evidence from one study that mobile phone message reminders to take vitamin C for preventive reasons resulted in higher adherence (risk ratio (RR) 1.41, 95% CI 1.14 to 1.74). There was high quality evidence from another study that participants receiving mobile phone messaging support had a significantly higher likelihood of quitting smoking than those in a control group at 6 weeks (RR 2.20, 95% CI 1.79 to 2.70) and at 12 weeks follow-up (RR 1.55, 95% CI 1.30 to 1.84). At 26 weeks, there was only a significant difference between groups if, for participants with missing data, the last known value was carried forward. There was very low quality evidence from one study that mobile phone messaging interventions for self-monitoring of healthy behaviours related to childhood weight control did not have a statistically significant effect on physical activity, consumption of sugar-sweetened beverages or screen time. For the secondary outcome of acceptability, there was very low quality evidence from one study that user evaluation of the intervention was similar between groups. There was moderate quality evidence from one study of no difference in adverse effects of the intervention, measured as rates of pain in the thumb or finger joints, and car crash rates. None of the studies reported the secondary outcomes of health service utilisation or costs of the intervention. We found very limited evidence that in certain cases mobile phone messaging interventions may support preventive health care, to improve health status and health behaviour outcomes. However, because of the low number of participants in three of the included studies, combined with study limitations of risk of bias and lack of demonstrated causality, the evidence for these effects is of low to moderate quality. The evidence is of high quality only for interventions aimed at smoking cessation. Furthermore, there are significant information gaps regarding the long-term effects, risks and limitations of, and user satisfaction with, such interventions.
Five studies (338 patients) were included, four studies compared ESWL to PCNL and one compared ESWL with RIRS. Random sequence generation was reported in three studies and unclear in two. Allocation concealment was not reported in any of the included studies. Blinding of participants and investigators could not be undertaken due to the nature of the interventions; blinding of outcome assessors was not reported. Reporting bias was judged to be low risk in all studies. One study was funded by industry and in one study the number of participants in each group was unbalanced. The success of treatment at three months was significantly greater in the PCNL compared to the ESWL group (3 studies, 201 participants: RR 0.46, 95% CI 0.35 to 0.62). Re-treatment (1 study, 122 participants: RR 1.81, 95% CI 0.66 to 4.99) and using auxiliary procedures (2 studies, 184 participants: RR 9.06, 95% CI 1.20 to 68.64) was significantly increased with ESWL group compared to PCNL. The efficiency quotient (EQ; used to assess the effectiveness of procedures) higher for PCNL than ESWL; however EQ decreased when stone size increased. Duration of treatment (MD -36.00 min, 95% CI -54.10 to -17.90) and hospital stay (1 study, 49 participants: MD -3.30 days, 95% CI -5.45 to -1.15) were significantly shorter in the ESWL group. Overall more complications were reported with PCNL, however we were unable to meta-analyse the included studies due to the differing outcomes reported and the timing of the outcome measurements. One study compared ESWL versus RIRS for lower pole kidney stones. The success of treatment was not significantly different at the end of the third month (58 participants: RR 0.91, 95% CI 0.64 to 1.30). Mean procedural time and mean hospital stay was reported to be longer in the RIRS group. Results from five small studies, with low methodological quality, indicated ESWL is less effective for kidney stones than PCNL but not significantly different from RIRS. Hospital stay and duration of treatment was less with ESWL. Larger RCTs with high methodological quality are required to investigate the effectiveness and complications of ESWL for kidney stones compared to PCNL if there is any technological progress in the non-invasive elimination of the residual fragments. Moreover, further research is required for the outcomes of ESWL and RIRS in lower and non-lower pole studies including PCNL versus RIRS.
We included 20 RCTs, including 3057 participants. The number of participants ranged per trial between 15 and 645. Follow-up ranged between 24 weeks and two years. Eighteen trials were parallel RCTs and two were cluster RCTs. Twelve RCTs had two comparisons and eight RCTs had three comparisons. The interventions varied widely; the duration, content, delivery and follow-up of the interventions were heterogeneous. The comparators also differed. This review categorised the comparisons into four groups: parent-only versus parent-child, parent-only versus waiting list controls, parent-only versus minimal contact interventions and parent-only versus other parent-only interventions. Trial quality was generally low with a large proportion of trials rated as high risk of bias on individual risk of bias criteria. In trials comparing a parent-only intervention with a parent-child intervention, the body mass index (BMI) z score change showed a mean difference (MD) at the longest follow-up period (10 to 24 months) of -0.04 (95% confidence interval (CI) -0.15 to 0.08); P = 0.56; 267 participants; 3 trials; low quality evidence. In trials comparing a parent-only intervention with a waiting list control, the BMI z score change in favour of the parent-only intervention at the longest follow-up period (10-12 months) had an MD of -0.10 (95% CI -0.19 to -0.01); P = 0.04; 136 participants; 2 trials; low quality evidence. BMI z score change of parent-only interventions when compared with minimal contact control interventions at the longest follow-up period (9 to 12 months) showed an MD of 0.01 (95% CI -0.07 to 0.09); P = 0.81; 165 participants; 1 trial; low quality evidence. There were few similarities between interventions and comparators across the included trials in the parent-only intervention versus other parent-only interventions and we did not pool these data. Generally, these trials did not show substantial differences between their respective parent-only groups on BMI outcomes. Other outcomes such as behavioural measures, parent-child relationships and health-related quality of life were reported inconsistently. Adverse effects of the interventions were generally not reported, two trials stated that there were no serious adverse effects. No trials reported on all-cause mortality, morbidity or socioeconomic effects. All results need to be interpreted cautiously because of their low quality, the heterogeneous interventions and comparators, and the high rates of non-completion. Parent-only interventions may be an effective treatment option for overweight or obese children aged 5 to 11 years when compared with waiting list controls. Parent-only interventions had similar effects compared with parent-child interventions and compared with those with minimal contact controls. However, the evidence is at present limited; some of the trials had a high risk of bias with loss to follow-up being a particular issue and there was a lack of evidence for several important outcomes. The systematic review has identified 10 ongoing trials that have a parent-only arm, which will contribute to future updates. These trials will improve the robustness of the analyses by type of comparator, and may permit subgroup analysis by intervention component and the setting. Trial reports should provide adequate details about the interventions to be replicated by others. There is a need to conduct and report cost-effectiveness analyses in future trials in order to establish whether parent-only interventions are more cost-effective than parent-child interventions.
There were two small randomised controlled trials including a total of 23 infants eligible for inclusion in the review. Only one trial involving 16 infants included in the analysis reported on either of the primary outcomes of the review. This found no difference in failure of modality between NIV-NAVA and NIPPV (RR 0.33, 95% CI 0.02 to 7.14; RD −0.13, 95% CI -0.41 to 0.16; 1 study, 16 infants; heterogeneity not applicable). Both trials reported on secondary outcomes of the review, specific for cross-over trials (total 22 infants; 1 excluded due to failure of initial modality). One study involving seven infants reported a significant reduction in maximum FiO₂ with NIV-NAVA compared to NIPPV (MD −4.29, 95% CI −5.47 to −3.11; heterogeneity not applicable). There was no difference in maximum electric activity of the diaphragm (Edi) signal between modalities (MD −1.75, 95% CI −3.75 to 0.26; I² = 0%) and a significant increase in respiratory rate with NIV-NAVA compared to NIPPV (MD 7.22, 95% CI 0.21 to 14.22; I² = 72%) on a meta-analysis of two studies involving a total of 22 infants. The included studies did not report on other outcomes of interest. Due to limited data and very low certainty evidence, we were unable to determine if diaphragm-triggered non-invasive respiratory support is effective or safe in preventing respiratory failure in preterm infants. Large, adequately powered randomised controlled trials are needed to determine if diaphragm-triggered non-invasive respiratory support in preterm infants is effective or safe.
We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients. No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence). No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence). There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.
Twenty-seven trials (2485 analyzed /3005 randomized participants) met our inclusion criteria. For acute neck pain only, no evidence was found. For chronic neck pain, moderate quality evidence supports 1) cervico-scapulothoracic and upper extremity strength training to improve pain of a moderate to large amount immediately post treatment [pooled SMD (SMDp) -0.71 (95% CI: -1.33 to -0.10)] and at short-term follow-up; 2) scapulothoracic and upper extremity endurance training for slight beneficial effect on pain at immediate post treatment and short-term follow-up; 3) combined cervical, shoulder and scapulothoracic strengthening and stretching exercises varied from a small to large magnitude of beneficial effect on pain at immediate post treatment [SMDp -0.33 (95% CI: -0.55 to -0.10)] and up to long-term follow-up and a medium magnitude of effect improving function at both immediate post treatment and at short-term follow-up [SMDp -0.45 (95%CI: -0.72 to -0.18)]; 4) cervico-scapulothoracic strengthening/stabilization exercises to improve pain and function at intermediate term [SMDp -14.90 (95% CI:-22.40 to -7.39)]; 5) Mindfulness exercises (Qigong) minimally improved function but not global perceived effect at short term. Low evidence suggests 1) breathing exercises; 2) general fitness training; 3) stretching alone; and 4) feedback exercises combined with pattern synchronization may not change pain or function at immediate post treatment to short-term follow-up. Very low evidence suggests neuromuscular eye-neck co-ordination/proprioceptive exercises may improve pain and function at short-term follow-up. For chronic cervicogenic headache, moderate quality evidence supports static-dynamic cervico-scapulothoracic strengthening/endurance exercises including pressure biofeedback immediate post treatment and probably improves pain, function and global perceived effect at long-term follow-up. Low grade evidence supports sustained natural apophyseal glides (SNAG) exercises. For acute radiculopathy, low quality evidence suggests a small benefit for pain reduction at immediate post treatment with cervical stretch/strengthening/stabilization exercises. No high quality evidence was found, indicating that there is still uncertainty about the effectiveness of exercise for neck pain. Using specific strengthening exercises as a part of routine practice for chronic neck pain, cervicogenic headache and radiculopathy may be beneficial. Research showed the use of strengthening and endurance exercises for the cervico-scapulothoracic and shoulder may be beneficial in reducing pain and improving function. However, when only stretching exercises were used no beneficial effects may be expected. Future research should explore optimal dosage.
We included 20 RCTs involving a total of 1681 individual participants and 1172 individual legs (2853 analytic units). Of these 20 trials, 10 included patients undergoing general surgery; six included patients undergoing orthopaedic surgery; three individual trials included patients undergoing neurosurgery, cardiac surgery, and gynaecological surgery, respectively; and only one trial included medical patients. Graduated compression stockings were applied on the day before surgery or on the day of surgery and were worn up until discharge or until the participants were fully mobile. In the majority of the included studies DVT was identified by the radioactive I125 uptake test. Duration of follow-up ranged from seven to 14 days. The included studies were at an overall low risk of bias. We were able to pool the data from 20 studies reporting the incidence of DVT. In the GCS group, 134 of 1445 units developed DVT (9%) in comparison to the control group (without GCS), in which 290 of 1408 units developed DVT (21%). The Peto odds ratio (OR) was 0.35 (95% confidence interval (CI) 0.28 to 0.43; 20 studies; 2853 units; high-quality evidence), showing an overall effect favouring treatment with GCS (P < 0.001). Based on results from eight included studies, the incidence of proximal DVT was 7 of 517 (1%) units in the GCS group and 28 of 518 (5%) units in the control group. The Peto OR was 0.26 (95% CI 0.13 to 0.53; 8 studies; 1035 units; moderate-quality evidence) with an overall effect favouring treatment with GCS (P < 0.001). Combining results from five studies, all based on surgical patients, the incidence of PE was 5 of 283 (2%) participants in the GCS group and 14 of 286 (5%) in the control group. The Peto OR was 0.38 (95% CI 0.15 to 0.96; 5 studies; 569 participants; low-quality evidence) with an overall effect favouring treatment with GCS (P = 0.04). We downgraded the quality of the evidence for proximal DVT and PE due to low event rate (imprecision) and lack of routine screening for PE (inconsistency). We carried out subgroup analysis by speciality (surgical or medical patients). Combining results from 19 trials focusing on surgical patients, 134 of 1365 (9.8%) units developed DVT in the GCS group compared to 282 of 1328 (21.2%) units in the control group. The Peto OR was 0.35 (95% CI 0.28 to 0.44; high-quality evidence), with an overall effect favouring treatment with GCS (P < 0.001). Based on results from seven included studies, the incidence of proximal DVT was 7 of 437 units (1.6%) in the GCS group and 28 of 438 (6.4%) in the control group. The Peto OR was 0.26 (95% CI 0.13 to 0.53; 875 units; moderate-quality evidence) with an overall effect favouring treatment with GCS (P < 0.001). We downgraded the evidence for proximal DVT due to low event rate (imprecision). Based on the results from one trial focusing on medical patients admitted following acute myocardial infarction, 0 of 80 (0%) legs developed DVT in the GCS group and 8 of 80 (10%) legs developed DVT in the control group. The Peto OR was 0.12 (95% CI 0.03 to 0.51; low-quality evidence) with an overall effect favouring treatment with GCS (P = 0.004). None of the medical patients in either group developed a proximal DVT, and the incidence of PE was not reported. Limited data were available to accurately assess the incidence of adverse effects and complications with the use of GCS as these were not routinely quantitatively reported in the included studies. There is high-quality evidence that GCS are effective in reducing the risk of DVT in hospitalised patients who have undergone general and orthopaedic surgery, with or without other methods of background thromboprophylaxis, where clinically appropriate. There is moderate-quality evidence that GCS probably reduce the risk of proximal DVT, and low-quality evidence that GCS may reduce the risk of PE. However, there remains a paucity of evidence to assess the effectiveness of GCS in diminishing the risk of DVT in medical patients.
We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin α1). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10  for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin α1 the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I² = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23,  P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias. Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin α1, there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy.
Six trials (1343 participants) of risperidone as monotherapy or as adjunctive treatment to lithium, or an anticonvulsant, were identified. Permitted doses were consistent  with those recommended by the manufacturers of Haldol (haloperidol) and Risperdal (risperidone) for treatment of mania and trials involving haloperidol allowed antiparkinsonian treatment. Risperidone monotherapy was more effective than placebo in reducing manic symptoms, using the Young Mania Rating Scale (YMRS) (weighted mean difference (WMD) -5.75, 95% confidence interval (CI) -7.46 to -4.04, P<0.00001; 2 trials) and in leading to response, remission and sustained remission. Effect sizes for monotherapy and adjunctive treatment comparisons were similar. Low levels of baseline depression precluded reliable assessment of efficacy for treatment of depressive symptoms. Risperidone as monotherapy and as adjunctive treatment was more acceptable than placebo, with lower incidence of failure to complete treatment (RR 0.66, 95% CI 0.52 to 0.82, P = 0.0003; 5 trials). Overall risperidone caused more weight gain, extrapyramidal disorder, sedation and increase in prolactin level than placebo. There was no evidence of a difference in efficacy between risperidone and haloperidol either as monotherapy or as adjunctive treatment. The acceptability of risperidone and haloperidol in incidence of failure to complete treatment was comparable. Overall risperidone caused more weight gain than haloperidol but less extrapyramidal disorder and comparable sedation. Risperidone, as monotherapy and adjunctive treatment, is effective in reducing manic symptoms. The main adverse effects are weight gain, extrapyramidal effects and sedation. Risperidone is comparable in efficacy to haloperidol. Higher quality trials are required to provide more reliable and precise estimates of its costs and benefits.
Along with the three RCTs included in the original version of this review (2013), we identified an additional five RCTs in this update, resulting in a total of eight RCTs involving 450 participants (180 (40%) females). The risk of selection bias in the included studies was low and the risk of performance bias high. Six studies explored the effects of combined aerobic and resistance training; one explored the effects of combined aerobic and inspiratory muscle training; and one explored the effects of combined aerobic, resistance, inspiratory muscle training and balance training. On completion of the intervention period, compared to the control group, exercise capacity expressed as the peak rate of oxygen uptake (VO2peak) and six-minute walk distance (6MWD) was greater in the intervention group (VO2peak: MD 2.97 mL/kg/min, 95% confidence interval (CI) 1.93 to 4.02 mL/kg/min, 4 studies, 135 participants, moderate-certainty evidence; 6MWD: MD 57 m, 95% CI 34 to 80 m, 5 studies, 182 participants, high-certainty evidence). One adverse event (hip fracture) related to the intervention was reported in one of the included studies. The intervention group also achieved greater improvements in the physical component of general HRQoL (MD 5.0 points, 95% CI 2.3 to 7.7 points, 4 studies, 208 participants, low-certainty evidence); improved force-generating capacity of the quadriceps muscle (SMD 0.75, 95% CI 0.4 to 1.1, 4 studies, 133 participants, moderate-certainty evidence); and less dyspnoea (SMD −0.43, 95% CI −0.81 to −0.05, 3 studies, 110 participants, very low-certainty evidence). We observed uncertain effects on the mental component of general HRQoL, disease-specific HRQoL, handgrip force, fatigue, and lung function. There were insufficient data to comment on the effect of exercise training on maximal inspiratory and expiratory pressures and feelings of anxiety and depression. Mortality was not reported in the included studies. Exercise training increased exercise capacity and quadriceps muscle force of people following lung resection for NSCLC. Our findings also suggest improvements on the physical component score of general HRQoL and decreased dyspnoea. This systematic review emphasises the importance of exercise training as part of the postoperative management of people with NSCLC.
We included ten RCTs, six in adults (628 participants) and four in children (366 participants). We found no clear evidence of a difference in treatment failure between the outpatient and inpatient groups, either in adults (RR 1.23, 95% CI 0.82 to 1.85, I2 0%; six studies; moderate-certainty evidence) or children (RR 1.04, 95% CI 0.55 to 1.99, I2 0%; four studies; moderate-certainty evidence). For mortality, we also found no clear evidence of a difference either in studies in adults (RR 1.04, 95% CI 0.29 to 3.71; six studies; 628 participants; moderate-certainty evidence) or in children (RR 0.63, 95% CI 0.15 to 2.70; three studies; 329 participants; moderate-certainty evidence). According to the type of intervention (early discharge or exclusively outpatient), meta-analysis of treatment failure in four RCTs in adults with early discharge (RR 1.48, 95% CI 0.74 to 2.95; P = 0.26, I2 0%; 364 participants; moderate-certainty evidence) was similar to the results of the exclusively outpatient meta-analysis (RR 1.15, 95% CI 0.62 to 2.13; P = 0.65, I2 19%; two studies; 264 participants; moderate-certainty evidence). Regarding the secondary outcome measures, we found no clear evidence of a difference between outpatient and inpatient groups in duration of fever (adults: mean difference (MD) 0.2, 95% CI -0.36 to 0.76, 1 study, 169 participants; low-certainty evidence) (children: MD -0.6, 95% CI -0.84 to 0.71, 3 studies, 305 participants; low-certainty evidence) and in duration of neutropaenia (adults: MD 0.1, 95% CI -0.59 to 0.79, 1 study, 169 participants; low-certainty evidence) (children: MD -0.65, 95% CI -1.86 to 0.55, 2 studies, 268 participants; moderate-certainty evidence). With regard to adverse drug reactions, although there was greater frequency in the outpatient group, we found no clear evidence of a difference when compared to the inpatient group, either in adult participants (RR 8.39, 95% CI 0.38 to 187.15; three studies; 375 participants; low-certainty evidence) or children (RR 1.90, 95% CI 0.61 to 5.98; two studies; 156 participants; low-certainty evidence). Four studies compared the hospitalisation time and found that the mean number of days of hospital stay was lower in the outpatient treated group by 1.64 days in adults (MD -1.64, 95% CI -2.22 to -1.06; 3 studies, 251 participants; low-certainty evidence) and by 3.9 days in children (MD -3.90, 95% CI -5.37 to -2.43; 1 study, 119 participants; low-certainty evidence). In the 3 RCTs of children in which days of antimicrobial treatment were analysed, we found no difference between outpatient and inpatient groups (MD -0.07, 95% CI -1.26 to 1.12; 305 participants; low-certainty evidence). We identified two studies that measured QoL: one in adults and one in children. QoL was slightly better in the outpatient group than in the inpatient group in both studies, but there was no consistency in the domains included. Outpatient treatment for low-risk febrile neutropaenia in people with cancer probably makes little or no difference to treatment failure and mortality compared with the standard hospital (inpatient) treatment and may reduce time that patients need to be treated in hospital.
Our prespecified primary outcomes were maternal and neonatal mortality, maternal and neonatal severe infection, and duration of maternal and neonatal hospital stay. We included 11 studies (involving 1296 women) and assessed them as having low to moderate risk of bias - mainly because allocation concealment methods were not adequately reported, most studies were open, and outcome reporting was incomplete. The quality of the evidence was low to very low for most outcomes, as per the GRADE approach. The following antibiotics were assessed in the included trials: ampicillin, ampicillin/sulbactam, gentamicin, clindamycin, and cefotetan. During labor: meta-analysis of two studies found no clear differences in rates of neonatal sepsis (163 neonates; risk ratio (RR) 1.07, 95% confidence interval (CI) 0.40 to 2.86; I² = 9%; low quality of evidence), treatment failure (endometritis) (163 participants; RR 0.86, 95% CI 0.27 to 2.70; I² = 0%; low quality of evidence), and postpartum hemorrhage (RR 1.39, 95% CI 0.76 to 2.56; I² = 0%; low quality of evidence) when two different dosages/regimens of gentamicin were assessed. No clear differences between groups were found for any reported maternal or neonatal outcomes. The review did not identify data for a comparison of antibiotics versus no treatment/placebo. Postpartum: meta-analysis of two studies that evaluated use of antibiotics versus placebo after vaginal delivery showed no significant differences between groups in rates of treatment failure or postpartum endometritis. No significant differences were found in rates of neonatal death and postpartum endometritis when use of antibiotics was compared with no treatment. Four trials assessing two different dosages/regimens of gentamicin or dual-agent therapy versus triple-agent therapy, or comparing antibiotics, found no significant differences in most reported neonatal or maternal outcomes; the duration of hospital stay showed a difference in favor of the group of women who received short-duration antibiotics (one study, 292 women; mean difference (MD) -0.90 days, 95% CI -1.64 to -0.16; moderate quality of evidence). Intrapartum versus postpartum: one small study (45 women) evaluating use of ampicillin/gentamicin during intrapartum versus immediate postpartum treatment found significant differences favoring the intrapartum group in the mean number of days of maternal postpartum hospital stay (one trial, 45 women; MD -1.00 days, 95% CI -1.94 to - 0.06; very low quality of evidence) and the mean number of neonatal hospital stay days (one trial, 45 neonates; MD -1.90 days, 95% CI -3.91 to -0.49; very low quality of evidence). Although no significant differences were found in the rate of maternal bacteremia or early neonatal sepsis, for the outcome of neonatal pneumonia or sepsis we observed a significant difference favoring intrapartum treatment (one trial, 45 neonates; RR 0.06, 95% CI 0.00 to 0.95; very low quality of evidence). This review included 11 studies (having low to moderate risk of bias). The quality of the evidence was low to very low for most outcomes, as per the GRADE approach. Only one outcome (duration of hospital stay) was considered to provide moderate quality of evidence when antibiotics (short duration) were compared with antibiotics (long duration) during postpartum management of intra-amniotic infection. Our main reasons for downgrading the quality of evidence were limitations in study design or execution (risk of bias), imprecision, and inconsistency of results. Currently, limited evidence is available to reveal the most appropriate antimicrobial regimen for the treatment of patients with intra-amniotic infection; whether antibiotics should be continued during the postpartum period; and which antibiotic regimen or what treatment duration should be used. Also, no evidence was found on adverse effects of the intervention (not reported in any of the included studies). One small RCT showed that use of antibiotics during the intrapartum period is superior to their use during the postpartum period in reducing the number of days of maternal and neonatal hospital stay.
This update included 49 trials containing 12,045 participants. Risk of treatment failure was higher with short courses of antibiotics (OR 1.34, 95% CI 1.15 to 1.55) at one month after initiation of therapy (21% failure with short-course treatment and 18% with long-course; absolute difference of 3% between groups). There were no differences found when examining treatment with ceftriaxone for less than seven days (30% failure in those receiving ceftriaxone and 27% in short-acting antibiotics administered for seven days or more) or azithromycin for less than seven days (18% failure in both those receiving azithromycin and short-acting antibiotics administered for seven days or more) with respect to risk of treatment failure at one month or less. Significant reductions in gastrointestinal adverse events were observed for treatment with short-acting antibiotics and azithromycin. Clinicians need to evaluate whether the minimal short-term benefit from longer treatment of antibiotics is worth exposing children to a longer course of antibiotics.
We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline. We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence. We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects. The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.
We found 28 published studies and one unpublished study. Only two studies were sufficiently similar to allow pooling of data for statistical analyses. Studies were divided into three groups; children, older people and the general population/mixed age group. None of the studies focusing on children or older people demonstrated a reduction in injuries that were a direct result of environmental modification in the home. One study in older people demonstrated a reduction in falls and one a reduction in falls and injurious falls that may have been due to hazard reduction. One meta-analysis was performed which examined the effects on falls of multifactorial interventions consisting of home hazard assessment and modification, medication review, health and bone assessment and exercise (RR 1.09, 95% CI 0.97 to 1.23). There is insufficient evidence to determine whether interventions focused on modifying environmental home hazards reduce injuries. Further interventions to reduce hazards in the home should be evaluated by adequately designed randomised controlled trials measuring injury outcomes. Recruitment of large study samples to measure effect must be a major consideration for future trials. Researchers should also consider using factorial designs to allow the evaluation of individual components of multifactorial interventions.
Twenty-nine trials were included, with 23019 participants, among whom 1503 vascular deaths and 3438 fatal and non-fatal vascular events occurred during follow up. Compared with control, dipyridamole had no clear effect on vascular death (relative risk (RR) 0.99, 95% confidence interval (CI) 0.87 to 1.12). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81 to 0.95). This effect was only statistically significant in patients presenting with cerebral ischaemia. For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug reduced the risk of vascular death, though it reduces the risk of further vascular events. This benefit was found only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.
One trial with 103 participants studied the effect of impaction of the fracture at the time of surgery. The only outcome measure reported was bone scintimetry. There was some evidence that impaction, particularly of displaced fractures, resulted in a reduction of blood flow to the femoral head as assessed by bone scintimetry. One quasi-randomised trial with 220 participants compared compression of the fracture with no compression. Results for 156 individuals at one year showed a tendency to a lower incidence of non-union for those fractures treated without compression. Two trials, one involving 102 young adults under 50 years old and the other involving 49 older people aged 65 years or over, compared open versus closed reduction of the fracture. Both found open reduction significantly increased length of surgery. None of the other differences between open and closed reduction in the outcomes reported by the two trials were statistically significant. Insufficient evidence exists from randomised trials to confirm the relative effects of open versus closed reduction of intracapsular fractures, or the effects of intra-operative impaction or compression of an intracapsular fracture treated by internal fixation.
We included 11 studies with 212 participants with cervical SCI. The meta-analysis revealed a statistically significant effect of RMT for three outcomes: vital capacity (MD mean end point 0.4 L, 95% CI 0.12 to 0.69), maximal inspiratory pressure (MD mean end point 10.50 cm/H2O, 95% CI 3.42 to 17.57), and maximal expiratory pressure (MD mean end point 10.31 cm/H2O, 95% CI 2.80 to 17.82). There was no effect on forced expiratory volume in one second or dyspnoea. We could not combine the results from quality of life assessment tools from three studies for meta-analysis. Respiratory complication outcomes were infrequently reported and thus we could not include them in the meta-analysis. Instead, we described the results narratively. We identified no adverse effects as a result of RMT in cervical SCI. In spite of the relatively small number of studies included in this review, meta-analysis of the pooled data indicates that RMT is effective for increasing respiratory muscle strength and perhaps also lung volumes for people with cervical SCI. Further research is needed on functional outcomes following RMT, such as dyspnoea, cough efficacy, respiratory complications, hospital admissions, and quality of life. In addition, longer-term studies are needed to ascertain optimal dosage and determine any carryover effects of RMT on respiratory function, quality of life, respiratory morbidity, and mortality.
Of the 51 studies identified, three met the inclusion criteria, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups (low-quality evidence). A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease. While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red blood cell survival (depending on dose), this did not lead to fewer painful crises. Given this is no longer an active area of research, this review will no longer be regularly updated.
Eighty-six trials (10,716 participants) were included. Ten trials (4,950 participants) were considered to be low risk of bias. Pooled analysis of all trials showed that off-pump CABG increased all-cause mortality compared with on-pump CABG (189/5,180 (3.7%) versus 160/5144 (3.1%); RR 1.24, 95% CI 1.01 to 1.53; P =.04). In the trials at low risk of bias the effect was corroborated (154/2,485 (6.2%) versus 113/2,465 (4.5%), RR 1.35,95% CI 1.07 to 1.70; P =.01). TSA showed that the risk of random error on the result was unlikely. Off-pump CABG resulted in fewer distal anastomoses (MD -0.28; 95% CI -0.40 to -0.16, P <.00001). No significant differences in myocardial infarction, stroke, renal insufficiency, or coronary re-intervention were observed. Off-pump CABG reduced post-operative atrial fibrillation compared with on-pump CABG, however, in trials at low risk of bias, the estimated effect was not significantly different. Our systematic review did not demonstrate any significant benefit of off-pump compared with on-pump CABG regarding mortality, stroke, or myocardial infarction. In contrast, we observed better long-term survival in the group of patients undergoing on-pump CABG with the use of cardiopulmonary bypass and cardioplegic arrest. Based on the current evidence, on-pump CABG should continue to be the standard surgical treatment. However, off-pump CABG may be acceptable when there are contraindications for cannulation of the aorta and cardiopulmonary bypass. Further randomised clinical trials should address the optimal treatment in such patients.
Eleven studies met the criteria, providing 14 comparisons, and capturing data on 4317 participants. Seven studies were RCTs, three were cluster non-RCTs, and one was a randomised cross-over design. Seven studies were carried out among school children (N = 3636), three among women of reproductive age (N = 648), and one among infants (N = 33). The studies used diverse types of food as vehicle for iodine delivery: biscuits, milk, fish sauce, drinking water, yoghourt, fruit beverage, seasoning powder, and infant formula milk. Daily amounts of iodine provided ranged from 35 µg/day to 220 µg/day; trial duration ranged from 11 days to 48 weeks. Five studies examined the effect of iodine fortification alone, two against the same unfortified food, and three against no intervention. Six studies evaluated the effect of cofortification of iodine with other micronutrients versus the same food without iodine but with different levels of other micronutrients. We assessed one study to be at low risk of bias for all bias domains, three at low risk of bias for all domains apart from selective reporting, and seven at an overall rating of high risk of bias. No study assessed the primary outcomes of death, mental development, cognitive function, cretinism, or hypothyroidism, or secondary outcomes of TSH or serum thyroglobulin concentration. Two studies reported the effects on goitre, one on physical development measures, and one on adverse effects. All studies assessed urinary iodine concentration. The effects of iodine fortification compared to control on goitre prevalence (OR 1.60, 95% CI 0.60 to 4.31; 1 non-RCT, 83 participants; very low-quality evidence), and five physical development measures were uncertain (1 non-RCT, 83 participants; very low-quality evidence): weight (MD 0.23 kg, 95% CI -6.30 to 6.77); height (MD -0.66 cm, 95% CI -4.64 to 3.33); weight-for-age (MD 0.05, 95% CI -0.59 to 0.69); height-for-age (MD -0.30, 95% CI -0.75 to 0.15); and weight-for-height (MD -0.21, 95% CI -0.51 to 0.10). One study reported that there were no adverse events observed during the cross-over trial (low-quality evidence). Pooled results from RCTs showed that urinary iodine concentration significantly increased following iodine fortification (SMD 0.59, 95% CI 0.37 to 0.81; 6 RCTs, 2032 participants; moderate-quality evidence). This is equivalent to an increase of 38.32 µg/L (95% CI 24.03 to 52.61 µg/L). This effect was not observed in the meta-analysis of non-RCTs (SMD 0.25, 95% CI -0.16 to 0.66; 3 non-RCTs, 262 participants; very low-quality evidence). Sensitivity analyses did not change the effect observed in the primary analyses. The evidence on the effect of iodine fortification of foods, beverages, condiments, or seasonings other than salt on reducing goitre, improving physical development measures, and any adverse effects is uncertain. However, our findings suggest that the intervention likely increases urinary iodine concentration. Additional, adequately powered, high-quality studies on the effects of iodine fortification of foods on these, and other important outcomes, as well as its efficacy and safety, are required.
Three RCTs (68 participants) were identified. All treatment comparisons contained only one study. No significant difference was found between prednisone compared with placebo for complete (RR 1.44, CI 0.95 to 2.19) and partial remission (RR 1.00, CI 0.07 to 14.45) of the nephrotic syndrome due to minimal change disease. There was no difference between intravenous methylprednisolone plus oral prednisone compared with oral prednisone alone for complete remission (RR 0.74, CI 0.50 to 1.08). Prednisone, compared with short-course intravenous methylprednisolone, increased the number of subjects who achieved complete remission (RR 4.95, CI 1.15 to 21.26). The lack of statistical evidence of efficacy associated with prednisone therapy was based on data derived from a single study that compared 'alternate-day prednisone' to no immunosuppression' with only a small number of participants in each group. No RCTs were identified comparing regimens in adults with a steroid-dependent or relapsing disease course or comparing treatments comprising alkylating agents, cyclosporine, tacrolimus, levamisole, or mycophenolate mofetil. Further comparative studies are required to examine the efficacy of immunosuppressive agents for achievement of sustained remission of nephrotic syndrome caused by minimal change disease. Studies are also needed to evaluate treatments for adults with steroid-dependent or relapsing disease.
Twenty trials involving 902 people were included. Oral medications There was evidence from individual small trials that people with Parkinson's disease had a statistically significant improvement in the number of bowel motions or successful bowel care routines per week when fibre (psyllium) (mean difference (MD) -2.2 bowel motions, 95% confidence interval (CI) -3.3 to -1.4) or oral laxative (isosmotic macrogol electrolyte solution) (MD 2.9 bowel motions per week, 95% CI 1.48 to 4.32) are used compared with placebo. One trial in people with spinal cord injury showed statistically significant improvement in total bowel care time comparing intramuscular neostigmine-glycopyrrolate (anticholinesterase plus an anticholinergic drug) with placebo (MD 23.3 minutes, 95% CI 4.68 to 41.92). Five studies reported the use of cisapride and tegaserod in people with spinal cord injuries or Parkinson's disease. These drugs have since been withdrawn from the market due to adverse effects; as they are no longer available they have been removed from this review. Rectal stimulants One small trial in people with spinal cord injuries compared two bisacodyl suppositories, one polyethylene glycol-based (PGB) and one hydrogenated vegetable oil-based (HVB). The trial found that the PGB bisacodyl suppository significantly reduced the mean defaecation period (PGB 20 minutes versus HVB 36 minutes, P < 0.03) and mean total time for bowel care (PGB 43 minutes versus HVB 74.5 minutes, P < 0.01) compared with the HVB bisacodyl suppository. Physical interventions There was evidence from one small trial with 31 participants that abdominal massage statistically improved the number of bowel motions in people who had a stroke compared with no massage (MD 1.7 bowel motions per week, 95% CI 2.22 to 1.18). A small feasibility trial including 30 individuals with multiple sclerosis also found evidence to support the use of abdominal massage. Constipation scores were statistically better with the abdominal massage during treatment although this was not supported by a change in outcome measures (for example the neurogenic bowel dysfunction score). One small trial in people with spinal cord injury showed statistically significant improvement in total bowel care time using electrical stimulation of abdominal muscles compared with no electrical stimulation (MD 29.3 minutes, 95% CI 7.35 to 51.25). There was evidence from one trial with a low risk of bias that for people with spinal cord injury transanal irrigation, compared against conservative bowel care, statistically improved constipation scores, neurogenic bowel dysfunction score, faecal incontinence score and total time for bowel care (MD 27.4 minutes, 95% CI 7.96 to 46.84). Patients were also more satisfied with this method. Other interventions In one trial in stroke patients, there appeared to be a short term benefit (less than six months) to patients in terms of the number of bowel motions per week with a one-off educational intervention from nurses (a structured nurse assessment leading to targeted education versus routine care), but this did not persist at 12 months. A trial in individuals with spinal cord injury found that a stepwise protocol did not reduce the need for oral laxatives and manual evacuation of stool. Finally, one further trial reported in abstract form showed that oral carbonated water (rather than tap water) improved constipation scores in people who had had a stroke. There is still remarkably little research on this common and, to patients, very significant issue of bowel management. The available evidence is almost uniformly of low methodological quality. The clinical significance of some of the research findings presented here is difficult to interpret, not least because each intervention has only been addressed in individual trials, against control rather than compared against each other, and the interventions are very different from each other. There was very limited evidence from individual trials in favour of a bulk-forming laxative (psyllium), an isosmotic macrogol laxative, abdominal massage, electrical stimulation and an anticholinesterase-anticholinergic drug combination (neostigmine-glycopyrrolate) compared to no treatment or controls. There was also evidence in favour of transanal irrigation (compared to conservative management), oral carbonated (rather than tap) water and abdominal massage with lifestyle advice (compared to lifestyle advice alone). However, these findings need to be confirmed by larger well-designed controlled trials which should include evaluation of the acceptability of the intervention to patients and the effect on their quality of life.
In total, we included 23 RCTs (N = 1309), 13 of which (56%) had low RoB. We included both men and women with a mean age of 50.6 years. We assessed the overall quality of the evidence as very low to moderate. Twelve studies examined suspected facet joint pain, five studies disc pain, two studies SI joint pain, two studies radicular CLBP, one study suspected radiating low back pain and one study CLBP with or without suspected radiation. Overall, moderate evidence suggests that facet joint RF denervation has a greater effect on pain compared with placebo over the short term (mean difference (MD) -1.47, 95% confidence interval (CI) -2.28 to -0.67). Low-quality evidence indicates that facet joint RF denervation is more effective than placebo for function over the short term (MD -5.53, 95% CI -8.66 to -2.40) and over the long term (MD -3.70, 95% CI -6.94 to -0.47). Evidence of very low to low quality shows that facet joint RF denervation is more effective for pain than steroid injections over the short (MD -2.23, 95% CI -2.38 to -2.08), intermediate (MD -2.13, 95% CI -3.45 to -0.81), and long term (MD -2.65, 95% CI -3.43 to -1.88). RF denervation used for disc pain produces conflicting results, with no effects for RF denervation compared with placebo over the short and intermediate term, and small effects for RF denervation over the long term for pain relief (MD -1.63, 95% CI -2.58 to -0.68) and improved function (MD -6.75, 95% CI -13.42 to -0.09). Lack of evidence of short-term effectiveness undermines the clinical plausibility of intermediate-term or long-term effectiveness. When RF denervation is used for SI joint pain, low-quality evidence reveals no differences from placebo in effects on pain (MD -2.12, 95% CI -5.45 to 1.21) and function (MD -14.06, 95% CI -30.42 to 2.30) over the short term, and one study shows a small effect on both pain and function over the intermediate term. RF denervation is an invasive procedure that can cause a variety of complications. The quality and size of original studies were inadequate to permit assessment of how often complications occur. The review authors found no high-quality evidence suggesting that RF denervation provides pain relief for patients with CLBP. Similarly, we identified no convincing evidence to show that this treatment improves function. Overall, the current evidence for RF denervation for CLBP is very low to moderate in quality; high-quality evidence is lacking. High-quality RCTs with larger patient samples are needed, as are data on long-term effects.
For this update, 15 additional studies fulfilled selection criteria. We included in this review 33 randomised controlled trials with 4477 participants; 21 compared different prostanoids versus placebo, seven compared prostanoids versus other agents, and five conducted head-to-head comparisons using two different prostanoids. We found low-quality evidence that suggests no clear difference in the incidence of cardiovascular mortality between patients receiving prostanoids and those given placebo (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.41 to 1.58). We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared with placebo (RR 0.97, 95% CI 0.86 to 1.09). Adverse events were more frequent with prostanoids than with placebo (RR 2.11, 95% CI 1.79 to 2.50; moderate-quality evidence). The most commonly reported adverse events were headache, nausea, vomiting, diarrhoea, flushing, and hypotension. We found moderate-quality evidence showing that prostanoids reduced rest-pain (RR 1.30, 95% CI 1.06 to 1.59) and promoted ulcer healing (RR 1.24, 95% CI 1.04 to 1.48) when compared with placebo, although these small beneficial effects were diluted when we performed a sensitivity analysis that excluded studies at high risk of bias. Additionally, we found evidence of low to very low quality suggesting the effects of prostanoids versus other active agents or versus other prostanoids because studies conducting these comparisons were few and we judged them to be at high risk of bias. None of the included studies assessed quality of life. We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared against placebo. Moderate-quality evidence showed small beneficial effects of prostanoids for rest-pain relief and ulcer healing when compared with placebo. Additionally, moderate-quality evidence showed a greater incidence of adverse effects with the use of prostanoids, and low-quality evidence suggests that prostanoids have no effect on cardiovascular mortality when compared with placebo. None of the included studies reported quality of life measurements. The balance between benefits and harms associated with use of prostanoids in patients with critical limb ischaemia with no chance of reconstructive intervention is uncertain; therefore careful assessment of therapeutic alternatives should be considered. Main reasons for downgrading the quality of evidence were high risk of attrition bias and imprecision of effect estimates.
Results should be interpreted with caution because risk of bias of the included trials was variable. We included eleven new trials for this update; there are now 32 included studies, and one trial is ongoing. Thirty trials involving 9015 women contributed to the analysis. Comparisons include any upright position, birth or squat stool, birth cushion, and birth chair versus supine positions. In all women studied (primigravid and multigravid), when compared with supine positions, the upright position was associated with a reduction in duration of second stage in the upright group (MD -6.16 minutes, 95% CI -9.74 to -2.59 minutes; 19 trials; 5811 women; P = 0.0007; random-effects; I² = 91%; very low-quality evidence); however, this result should be interpreted with caution due to large differences in size and direction of effect in individual studies. Upright positions were also associated with no clear difference in the rates of caesarean section (RR 1.22, 95% CI 0.81 to 1.81; 16 trials; 5439 women; low-quality evidence), a reduction in assisted deliveries (RR 0.75, 95% CI 0.66 to 0.86; 21 trials; 6481 women; moderate-quality evidence), a reduction in episiotomies (average RR 0.75, 95% CI 0.61 to 0.92; 17 trials; 6148 women; random-effects; I² = 88%), a possible increase in second degree perineal tears (RR 1.20, 95% CI 1.00 to 1.44; 18 trials; 6715 women; I² = 43%; low-quality evidence), no clear difference in the number of third or fourth degree perineal tears (RR 0.72, 95% CI 0.32 to 1.65; 6 trials; 1840 women; very low-quality evidence), increased estimated blood loss greater than 500 mL (RR 1.48, 95% CI 1.10 to 1.98; 15 trials; 5615 women; I² = 33%; moderate-quality evidence), fewer abnormal fetal heart rate patterns (RR 0.46, 95% CI 0.22 to 0.93; 2 trials; 617 women), no clear difference in the number of babies admitted to neonatal intensive care (RR 0.79, 95% CI 0.51 to 1.21; 4 trials; 2565 infants; low-quality evidence). On sensitivity analysis excluding trials with high risk of bias, these findings were unchanged except that there was no longer a clear difference in duration of second stage of labour (MD -4.34, 95% CI -9.00 to 0.32; 21 trials; 2499 women; I² = 85%). The main reasons for downgrading of GRADE assessment was that several studies had design limitations (inadequate randomisation and allocation concealment) with high heterogeneity and wide CIs. The findings of this review suggest several possible benefits for upright posture in women without epidural anaesthesia, such as a very small reduction in the duration of second stage of labour (mainly from the primigravid group), reduction in episiotomy rates and assisted deliveries. However, there is an increased risk blood loss greater than 500 mL and there may be an increased risk of second degree tears, though we cannot be certain of this. In view of the variable risk of bias of the trials reviewed, further trials using well-designed protocols are needed to ascertain the true benefits and risks of various birth positions.
Thirteen trials met the inclusion criteria, comprising women with stress urinary incontinence (SUI), urgency urinary incontinence (UUI) or mixed urinary incontinence (MUI); they compared PFMT added to another active treatment (585 women) with the same active treatment alone (579 women). The pre-specified comparisons were reported by single trials, except bladder training, which was reported by two trials, and electrical stimulation, which was reported by three trials. However, only two of the three trials reporting electrical stimulation could be pooled, as one of the trials did not report any relevant data. We considered the included trials to be at unclear risk of bias for most of the domains, predominantly due to the lack of adequate information in a number of trials. This affected our rating of the quality of evidence. The majority of the trials did not report the primary outcomes specified in the review (cure or improvement, quality of life) or measured the outcomes in different ways. Effect estimates from small, single trials across a number of comparisons were indeterminate for key outcomes relating to symptoms, and we rated the quality of evidence, using the GRADE approach, as either low or very low. More women reported cure or improvement of incontinence in two trials comparing PFMT added to electrical stimulation to electrical stimulation alone, in women with SUI, but this was not statistically significant (9/26 (35%) versus 5/30 (17%); risk ratio (RR) 2.06, 95% confidence interval (CI) 0.79 to 5.38). We judged the quality of the evidence to be very low. There was moderate-quality evidence from a single trial investigating women with SUI, UUI or MUI that a higher proportion of women who received a combination of PFMT and heat and steam generating sheet reported a cure compared to those who received the sheet alone: 19/37 (51%) versus 8/37 (22%) with a RR of 2.38, 95% CI 1.19 to 4.73). More women reported cure or improvement of incontinence in another trial comparing PFMT added to vaginal cones to vaginal cones alone, but this was not statistically significant (14/15 (93%) versus 14/19 (75%); RR 1.27, 95% CI 0.94 to 1.71). We judged the quality of the evidence to be very low. Only one trial evaluating PFMT when added to drug therapy provided information about adverse events (RR 0.84, 95% CI 0.45 to 1.60; very low-quality evidence). With regard to condition-specific quality of life, there were no statistically significant differences between women (with SUI, UUI or MUI) who received PFMT added to bladder training and those who received bladder training alone at three months after treatment, on either the Incontinence Impact Questionnaire-Revised scale (mean difference (MD) -5.90, 95% CI -35.53 to 23.73) or on the Urogenital Distress Inventory scale (MD -18.90, 95% CI -37.92 to 0.12). A similar pattern of results was observed between women with SUI who received PFMT plus either a continence pessary or duloxetine and those who received the continence pessary or duloxetine alone. In all these comparisons, the quality of the evidence for the reported critical outcomes ranged from moderate to very low. This systematic review found insufficient evidence to state whether or not there were additional effects by adding PFMT to other active treatments when compared with the same active treatment alone for urinary incontinence (SUI, UUI or MUI) in women. These results should be interpreted with caution as most of the comparisons were investigated in small, single trials. None of the trials in this review were large enough to provide reliable evidence. Also, none of the included trials reported data on adverse events associated with the PFMT regimen, thereby making it very difficult to evaluate the safety of PFMT.
The search identified 1366 references. Twenty-two RCTs meeting the inclusion criteria of this review were identified. The results of the meta-analyses (across all age groups) indicate benefit of CGM for patients starting on CGM sensor augmented insulin pump therapy compared to patients using multiple daily injections of insulin (MDI) and standard monitoring blood glucose (SMBG). After six months there was a significant larger decline in HbA1c level for real-time CGM users starting insulin pump therapy compared to patients using MDI and SMBG (mean difference (MD) in change in HbA1c level -0.7%, 95% confidence interval (CI) -0.8% to -0.5%, 2 RCTs, 562 patients, I2=84%). The risk of hypoglycaemia was increased for CGM users, but CIs were wide and included unity (4/43 versus 1/35; RR 3.26, 95% CI 0.38 to 27.82 and 21/247 versus 17/248; RR 1.24, 95% CI 0.67 to 2.29). One study reported the occurrence of ketoacidosis from baseline to six months; there was however only one event. Both RCTs were in patients with poorly controlled diabetes. For patients starting with CGM only, the average decline in HbA1c level six months after baseline was also statistically significantly larger for CGM users compared to SMBG users, but much smaller than for patients starting using an insulin pump and CGM at the same time (MD change in HbA1c level -0.2%, 95% CI -0.4% to -0.1%, 6 RCTs, 963 patients, I2=55%). On average, there was no significant difference in risk of severe hypoglycaemia or ketoacidosis between CGM and SMBG users. The confidence interval however, was wide and included a decreased as well as an increased risk for CGM users compared to the control group (severe hypoglycaemia: 36/411 versus 33/407; RR 1.02, 95% CI 0.65 to 1.62, 4 RCTs, I2=0% and ketoacidosis: 8/411 versus 8/407; RR 0.94, 95% CI 0.36 to 2.40, 4 RCTs, I2=0%). Health-related quality of life was reported in five of the 22 studies. In none of these studies a significant difference between CGM and SMBG was found. Diabetes complications, death and costs were not measured. There were no studies in pregnant women with diabetes type 1 and in patients with hypoglycaemia unawareness. There is limited evidence for the effectiveness of real-time continuous glucose monitoring (CGM) use in children, adults and patients with poorly controlled diabetes. The largest improvements in glycaemic control were seen for sensor-augmented insulin pump therapy in patients with poorly controlled diabetes who had not used an insulin pump before. The risk of severe hypoglycaemia or ketoacidosis was not significantly increased for CGM users, but as these events occurred infrequent these results have to be interpreted cautiously.There are indications that higher compliance of wearing the CGM device improves glycosylated haemoglobin A1c level (HbA1c) to a larger extent.
We included 78 studies (59,216 women) and excluded 34 studies.There was no statistically significant difference in maternal mortality for misoprostol compared with control groups overall (31 studies; 11/19,715 versus 4/20,076 deaths; risk ratio (RR) 2.08, 95% confidence interval (CI) 0.82 to 5.28); or for the trials of misoprostol versus placebo: 10 studies, 6/4626 versus 1/4707 ; RR 2.70; 95% CI 0.72 to 10.11; or for misoprostol versus other uterotonics: 21 studies, 5/15,089 versus 3/15,369 (19/100,000); RR 1.54; 95% CI 0.40 to 5.92. All 11 deaths in the misoprostol arms occurred in studies of misoprostol ≥ 600 µg. There was a statistically significant difference in the composite outcome ‘maternal death or severe morbidity’ for the comparison of misoprostol versus placebo (12 studies; average RR 1.70, 95% CI 1.02 to 2.81; Tau² = 0.00, I² = 0%) but not for the comparison of misoprostol versus other uterotonics (17 studies; average RR 1.50, 95% CI 0.50 to 4.52; Tau² = 1.81, I² = 69%). When we excluded hyperpyrexia from the composite outcome in exploratory analyses, there was no significant difference in either of these comparisons. Pyrexia > 38°C was increased with misoprostol compared with controls (56 studies, 2776/25,647 (10.8%) versus 614/26,800 (2.3%); average RR 3.97, 95% CI 3.13 to 5.04; Tau² = 0.47, I² = 80%). The effect was greater for trials using misoprostol 600 µg or more (27 studies; 2197/17,864 (12.3%) versus 422/18,161 (2.3%); average RR 4.64; 95% CI 3.33 to 6.46; Tau² = 0.51, I² = 86%) than for those using misoprostol 400 µg or less (31 studies; 525/6751 (7.8%) versus 185/7668 (2.4%); average RR 3.07; 95% CI 2.25 to 4.18; Tau² = 0.29, I² = 58%). Misoprostol does not appear to increase or reduce severe morbidity (excluding hyperpyrexia) when used to prevent or treat PPH. Misoprostol did not increase or decrease maternal mortality. However, misoprostol is associated with an increased risk of pyrexia, particularly in dosages of 600 µg or more. Given that misoprostol is used prophylactically in very large numbers of healthy women, the greatest emphasis should be placed on limiting adverse effects. In this context, the findings of this review support the use of the lowest effective dose. As for any new medication being used on a large scale, continued vigilance for adverse effects is essential and there is a need for large randomised trials to further elucidate both the relative effectiveness and the risks of various dosages of misoprostol.
We included six trials involving 1270 participants in the review: three trials involving 686 participants compared routine shunting with no shunting, one trial involving 200 participants compared routine shunting with selective shunting, one trial involving 253 participants compared selective shunting with and without near-infrared refractory spectroscopy monitoring, and the other trial involving 131 participants compared shunting with a combination of electroencephalographic and carotid pressure measurement with shunting by carotid pressure measurement alone. In general, reporting of methodology in the included studies was poor. For most studies, the blinding of outcome assessors and the report of prespecified outcomes were unclear. For routine versus no shunting, there was no significant difference in the rate of all stroke, ipsilateral stroke or death up to 30 days after surgery, although data were limited. No significant difference was found between the groups in terms of postoperative neurological deficit between selective shunting with and without near-infrared refractory spectroscopy monitoring, However, this analysis was inadequately powered to reliably detect the effect. There was no significant difference between the risk of ipsilateral stroke in participants selected for shunting with the combination of electroencephalographic and carotid pressure assessment compared with pressure assessment alone, although again the data were limited. This review concluded that the data available were too limited to either support or refute the use of routine or selective shunting in carotid endarterectomy. Large scale randomised trials of routine shunting versus selective shunting are required. No method of monitoring in selective shunting has been shown to produce better outcomes.
Four studies involving 1642 participants made three eligible comparisons: (i) personal assistance versus usual care, (ii) personal assistance versus nursing homes, and (iii) personal assistance versus 'cluster care'. One was an RCT, three were non-randomised. Personal assistance was generally preferred over other services; however, some people prefer other models of care. This review indicates that personal assistance probably has some benefits for some recipients and caregivers. Paid assistance probably substitutes for informal care and may cost government more than alternatives; however, the total costs to recipients and society are currently unknown. Research in this field is limited. Personal assistance is expensive and difficult to organise, especially in places that do not already have services in place. When implementing new programmes, recipients could be randomly assigned to different forms of assistance. While advocates may support personal assistance for myriad reasons, this review demonstrates that further studies are required to determine which models of personal assistance are most effective and efficient.
We included 42 studies involving 1453 participants. The trials included participants who had some residual motor power of the paretic arm, the potential for further motor recovery and with limited pain or spasticity, but tended to use the limb little, if at all. The majority of studies were underpowered (median number of included participants was 29) and we cannot rule out small-trial bias. Eleven trials (344 participants) assessed disability immediately after the intervention, indicating a non-significant standard mean difference (SMD) 0.24 (95% confidence interval (CI) -0.05 to 0.52) favouring CIMT compared with conventional treatment. For the most frequently reported outcome, arm motor function (28 studies involving 858 participants), the SMD was 0.34 (95% CI 0.12 to 0.55) showing a significant effect (P value 0.004) in favour of CIMT. Three studies involving 125 participants explored disability after a few months of follow-up and found no significant difference, SMD -0.20 (95% CI -0.57 to 0.16) in favour of conventional treatment. CIMT is a multi-faceted intervention where restriction of the less affected limb is accompanied by increased exercise tailored to the person’s capacity. We found that CIMT was associated with limited improvements in motor impairment and motor function, but that these benefits did not convincingly reduce disability. This differs from the result of our previous meta-analysis where there was a suggestion that CIMT might be superior to traditional rehabilitation. Information about the long-term effects of CIMT is scarce. Further trials studying the relationship between participant characteristics and improved outcomes are required.
Fifteen RCTs were included in the review. Six of these had been included in the previous review of RO. The studies included participants from a variety of settings, interventions that were of varying duration and intensity, and were from several different countries. The quality of the studies was generally low by current standards but most had taken steps to ensure assessors were blind to treatment allocation. Data were entered in the meta-analyses for 718 participants (407 receiving cognitive stimulation, 311 in control groups). The primary analysis was on changes that were evident immediately at the end of the treatment period. A few studies provided data allowing evaluation of whether any effects were subsequently maintained. A clear, consistent benefit on cognitive function was associated with cognitive stimulation (standardised mean difference (SMD) 0.41, 95% CI 0.25 to 0.57). This remained evident at follow-up one to three months after the end of treatment. In secondary analyses with smaller total sample sizes, benefits were also noted on self-reported quality of life and well-being (standardised mean difference: 0.38 [95% CI: 0.11, 0.65]); and on staff ratings of communication and social interaction (SMD 0.44, 95% CI 0.17 to 0.71). No differences in relation to mood (self-report or staff-rated), activities of daily living, general behavioural function or problem behaviour were noted. In the few studies reporting family caregiver outcomes, no differences were noted. Importantly, there was no indication of increased strain on family caregivers in the one study where they were trained to deliver the intervention. There was consistent evidence from multiple trials that cognitive stimulation programmes benefit cognition in people with mild to moderate dementia over and above any medication effects. However, the trials were of variable quality with small sample sizes and only limited details of the randomisation method were apparent in a number of the trials. Other outcomes need more exploration but improvements in self-reported quality of life and well-being were promising. Further research should look into the potential benefits of longer term cognitive stimulation programmes and their clinical significance.
Of a total of 216 citations identified by the systematic literature search, we included six randomised controlled trials (reported in nine publications), with a total of 576 participants. We identified a moderate heterogeneity of methodological quality and risk of bias of the included trials. None of the pooled results for our main outcomes of interest showed significant differences: delayed gastric emptying (OR 0.60; 95% CI 0.31 to 1.18; P = 0.14), mortality (RD -0.01; 95% CI -0.03 to 0.02; P = 0.72), postoperative pancreatic fistula (OR 0.98; 95% CI 0.65 to 1.47; P = 0.92), postoperative haemorrhage (OR 0.79; 95% CI 0.38 to 1.65; P = 0.53), intra-abdominal abscess (OR 0.93; 95% CI 0.52 to 1.67; P = 0.82), bile leakage (OR 0.89; 95% CI 0.36 to 2.15; P = 0.79), reoperation rate (OR 0.59; 95% CI 0.27 to 1.31; P = 0.20), and length of hospital stay (MD -0.67; 95%CI -2.85 to 1.51; P = 0.55). Furthermore, the perioperative outcomes duration of operation, intraoperative blood loss and time to NGT removal showed no relevant differences. Only one trial reported quality of life, on a subgroup of participants, also without a significant difference between the two groups at any time point. The overall quality of the evidence was only low to moderate, due to heterogeneity, some inconsistency and risk of bias in the included trials. There was low to moderate quality evidence suggesting no significant differences in morbidity, mortality, length of hospital stay, or quality of life between antecolic and retrocolic reconstruction routes for gastro- or duodenojejunostomy. Due to heterogeneity in definitions of the endpoints between trials, and differences in postoperative management, future research should be based on clearly defined endpoints and standardised perioperative management, to potentially elucidate differences between these two procedures. Novel strategies should be evaluated for prophylaxis and treatment of common complications, such as delayed gastric emptying.
Thirty-one trials involving 17,771 women are included in this review. This review found that folic acid supplementation has no impact on pregnancy outcomes such as preterm birth (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.38; three studies, 2959 participants), and stillbirths/neonatal deaths (RR 1.33, 95% CI 0.96 to 1.85; three studies, 3110 participants). However, improvements were seen in the mean birthweight (mean difference (MD) 135.75, 95% CI 47.85 to 223.68). On the other hand, the review found no impact on improving pre-delivery anaemia (average RR 0.62, 95% CI 0.35 to 1.10; eight studies, 4149 participants; random-effects), mean pre-delivery haemoglobin level (MD -0.03, 95% CI -0.25 to 0.19; 12 studies, 1806 participants), mean pre-delivery serum folate levels (standardised mean difference (SMD) 2.03, 95% CI 0.80 to 3.27; eight studies, 1250 participants; random-effects), and mean pre-delivery red cell folate levels (SMD 1.59, 95% CI -0.07 to 3.26; four studies, 427 participants; random-effects). However, a significant reduction was seen in the incidence of megaloblastic anaemia (RR 0.21, 95% CI 0.11 to 0.38, four studies, 3839 participants). We found no conclusive evidence of benefit of folic acid supplementation during pregnancy on pregnancy outcomes.
We included 16 studies out of the 243 identified. Most of the included studies showed methodological weaknesses that hamper the strength and reliability of their findings. When fees were introduced or increased, we found the use of health services decreased significantly in most studies. Two studies found increases in health service use when quality improvements were introduced at the same time as user fees. However, these studies have a high risk of bias. We found no evidence of effects on health outcomes or health expenditure. The review suggests that reducing or removing user fees increases the utilisation of certain healthcare services. However, emerging evidence suggests that such a change may have unintended consequences on utilisation of preventive services and service quality. The review also found that introducing or increasing fees can have a negative impact on health services utilisation, although some evidence suggests that when implemented with quality improvements these interventions could be beneficial. Most of the included studies suffered from important methodological weaknesses. More rigorous research is needed to inform debates on the desirability and effects of user fees.
Six trials involving 849 patients satisfied the inclusion criteria. Pharmacological interventions included aprotinin, desmopressin, recombinant factor VIIa, antithrombin III, and tranexamic acid. One or two trials could be included under most comparisons. All trials had a high risk of bias. There was no significant difference in the peri-operative mortality, survival at maximal follow-up, liver failure, or other peri-operative morbidity. The risk ratio of requiring allogeneic blood transfusion was significantly lower in the aprotinin and tranexamic acid groups than the respective control groups. Other interventions did not show significant decreases of allogeneic transfusion requirements. None of the interventions seem to decrease peri-operative morbidity or offer any long-term survival benefit. Aprotinin and tranexamic acid show promise in the reduction of blood transfusion requirements in liver resection surgery. However, there is a high risk of type I (erroneously concluding that an intervention is beneficial when it is actually not beneficial) and type II errors (erroneously concluding that an intervention is not beneficial when it is actually beneficial) because of the few trials included, the small sample size in each trial, and the high risk of bias. Further randomised clinical trials with low risk of bias and random errors assessing clinically important outcomes such as peri-operative mortality are necessary to assess any pharmacological interventions aimed at decreasing blood loss and blood transfusion requirements in liver resections. Trials need to be designed to assess the effect of a combination of different interventions in liver resections.
We included seven trials including 521 patients for this review. The sample size in the trials varied from 12 to 180 patients. All the trials were of high risks of systematic errors and of random errors. Four trials included patients who underwent liver resection only. In the remaining three trials, patients underwent combined liver resection with extrahepatic biliary resection resulting in a biliary enteric anastomosis. Four trials included only major liver resection. The remaining three trials included a mixture of major and minor liver resections. It appears that the proportion of cirrhotic patients in the trials was very low. The comparisons performed included whether antibiotics are necessary routinely during the peri-operative period of liver resection, the duration of antibiotics, the use of prebiotics and probiotics in the perioperative period, use of recombinant bactericidal-permeability increasing protein 21 (rBPI21), and the use of topical povidone iodine gel at the time of wound closure. Only one or two trials were included under each comparison. There was no significant differences in mortality or severe morbidity in any of the comparisons. Quality of life was not reported in any of the trials. There is currently no evidence to support or refute the use of any treatment to reduce infectious complications after liver resections. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.
Five trials involving 836 participants randomised to peritoneal closure (410 participants) and no peritoneal closure (426 participants) were included in this review. All the trials were at high risk of bias. All the trials included participants undergoing laparotomy (open surgery). Four of the five trials used catgut or chromic catgut for peritoneal closure. Three trials involved vertical incisions and two trials involved transverse incisions. None of the trials reported 30-day mortality. There was no significant difference in the one-year mortality between the two groups (RR 1.11; 95% CI 0.56 to 2.19) in the only trial that reported this outcome. The only serious peri-operative adverse event reported was burst abdomen, which was reported by three trials. Overall, 10/663 (1.5%) of participants developed burst abdomen. There was no significant difference in the proportion of participants who developed burst abdomen between the two groups (RR 0.71; 95% CI 0.22 to 2.35). The same three trials reported the proportion of participants who developed incisional hernia. Details of the follow-up period were only available for one trial, and so we were unable to calculate the incidence rate. Overall, 17/663 (2.5%) of participants developed incisional hernia. There was no significant difference in the proportion of participants who developed incisional hernia between the two groups (RR 0.92; 95% CI 0.37 to 2.28). None of the trials reported quality of life; the incidence rate of, or proportion of participants who developed, intestinal obstruction due to adhesions; or re-operation due to incisional hernia or adhesions. Only one trial reported the length of hospital stay, and this trial did not include readmissions in its calculations. There was no significant difference in the length of hospital stay between the two groups (MD 0.40 days; 95% CI -0.51 to 1.31). There is no evidence for any short-term or long-term advantage in peritoneal closure for non-obstetric operations. If further trials are performed on this topic, they should have an adequate period of follow-up and adequate measures should be taken to ensure that the results are not subject to bias.
Twenty three trials are included, allocation concealment was adequate in nine. Sixteen trials compared artemisinin drugs with quinine in 2653 patients. Artemisinin drugs were associated with better survival (mortality odds ratio 0.61, 95% confidence interval 0.46 to 0.82, random effects model). In trials where concealment of allocation was adequate (2261 patients), this was barely statistically significant (odds ratio 0.72, 95% CI 0.54 to 0.96, random effects model). In 1939 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (odds ratio 0.63, 95% CI 0.44 to 0.88, random effects model). The difference was not significant however when only trials reporting adequate concealment of allocation were analysed (odds ratio 0.78, 95% CI 0.55 to 1.10, random effects model) based on 1607 patients. No difference in neurological sequelae was shown. Compared with quinine, artemisinin drugs showed faster parasite clearance from the blood and similar adverse effects. The evidence suggests that artemisinin drugs are no worse than quinine in preventing death in severe or complicated malaria. No artemisinin derivative appears to be better than the others. This review summarizes trials up to 1999. For the reasons in the 'What's new' section, this review will no longer be updated.
We included five trials (involving 960 women). In three trials of 471 women, we found no significant differences in the incidence of mastitis between use of antibiotics and no antibiotics (risk ratio (RR) 0.43; 95% confidence interval (CI) 0.11 to 1.61; or in one trial of 99 women comparing two doses (RR 0.38; 95% CI 0.02 to 9.18). We found no significant differences for mastitis in three trials of specialist breastfeeding education with usual care (one trial); anti-secretory factor cereal (one trial); and mupirocin, fusidic acid ointment or breastfeeding advice (one trial). Generally we found no differences in any of the trials for breastfeeding initiation or duration; or symptoms of mastitis. There was insufficient evidence to show effectiveness of any of the interventions, including breastfeeding education, pharmacological treatments and alternative therapies, regarding the occurrence of mastitis or breastfeeding exclusivity and duration. While studies reported the incidence of mastitis, they all used different interventions. Caution needs to be applied when considering the findings of this review as the conclusion is based on studies, often with small sample sizes. An urgent need for further adequately powered research is needed into this area to conclusively determine the effectiveness of these interventions.
Five studies met the inclusion criteria. All five studies showed that published trials showed an overall greater treatment effect than grey trials. This difference was statistically significant in one of the five studies. Data could be combined for three of the five studies. This showed that, on average, published trials showed a 9% greater treatment effect than grey trials (ratio of odds ratios for grey versus published trials 1.09; 95% CI 1.03-1.16). Overall there were more published trials included in the meta-analyses than grey trials (median 224 (IQR 108-365) versus 45(IQR 40-102)). Published trials had more participants on average. The most common types of grey literature were abstracts (55%) and unpublished data (30%). There is limited evidence to show whether grey trials are of poorer methodological quality than published trials. This review shows that published trials tend to be larger and show an overall greater treatment effect than grey trials. This has important implications for reviewers who need to ensure they identify grey trials, in order to minimise the risk of introducing bias into their review.
Thirteen studies (254 individuals) met our inclusion criteria. These included 75 individuals with type 1 diabetes and 158 individuals with type 2 diabetes. The median reduction in urinary sodium was 203 mmol/24 h (11.9 g/day) in type 1 diabetes and 125 mmol/24 h (7.3 g/day) in type 2 diabetes. The median duration of salt restriction was one week in both type 1 and type 2 diabetes. BP was reduced in both type 1 and type 2 diabetes. In type 1 diabetes (56 individuals), salt restriction reduced BP by -7.11/-3.13 mm Hg (systolic/diastolic); 95% CI: systolic BP (SBP) -9.13 to -5.10; diastolic BP (DBP) -4.28 to -1.98). In type 2 diabetes (56 individuals), salt restriction reduced BP by -6.90/-2.87 mm Hg (95% CI: SBP -9.84 to -3.95; DBP -4.39 to -1.35). There was a greater reduction in BP in normotensive patients, possibly due to a larger decrease in salt intake in this group. Although the studies are not extensive, this meta-analysis shows a large fall in BP with salt restriction, similar to that of single drug therapy. All diabetics should consider reducing salt intake at least to less than 5-6 g/day in keeping with current recommendations for the general population and may consider lowering salt intake to lower levels, although further studies are needed.
We included five studies with a total of 1296 participants under two years of age hospitalised with bronchiolitis. Two studies with low risk of bias compared 4 mg montelukast (a leukotriene inhibitor) daily use from admission until discharge with a matching placebo. Both selected length of hospital stay as a primary outcome and clinical severity score as a secondary outcome. However, the effects of leukotriene inhibitors on length of hospital stay and clinical severity score were uncertain due to considerable heterogeneity between the study results and wide confidence intervals around the estimated effects (hospital stay: mean difference (MD) -0.95 days, 95% confidence interval (CI) -3.08 to 1.19, P value = 0.38, low quality evidence; clinical severity score on day two: MD -0.57, 95% CI -2.37 to 1.23, P value = 0.53, low quality evidence; clinical severity score on day three: MD 0.17, 95% CI -1.93 to 2.28, P value = 0.87, low quality evidence). The other three studies compared montelukast for several weeks for preventing post-bronchiolitis symptoms with placebo. We assessed one study as low risk of bias, whereas we assessed the other two studies as having a high risk of attrition bias. Due to the significant clinical heterogeneity in severity of disease, duration of treatment, outcome measurements and timing of assessment, we did not pool the results. Individual analyses of these studies did not show significant differences between the leukotriene inhibitors group and the control group in symptom-free days and incidence of recurrent wheezing. One study of 952 children reported two deaths in the leukotriene inhibitors group: neither was determined to be drug-related. No data were available on the percentage of children requiring ventilation, oxygen saturation and respiratory rate. Finally, three studies reported adverse events including diarrhoea, wheezing shortly after administration and rash. No differences were reported between the study groups. The current evidence does not allow definitive conclusions to be made about the effects of leukotriene inhibitors on length of hospital stay and clinical severity score in infants and young children with bronchiolitis. The quality of the evidence was low due to inconsistency (unexplained high levels of statistical heterogeneity) and imprecision arising from small sample sizes and wide confidence intervals, which did not rule out a null effect or harm. Data on symptom-free days and incidence of recurrent wheezing were from single studies only. Further large studies are required. We identified one registered ongoing study, which may make a contribution in the updates of this review.
We identified two eligible studies, both comparing the use of one model of SAD, the ProSeal laryngeal mask airway (PLMA) with a TT, with a total study population of 232. One study population underwent laparoscopic surgery. The included studies were generally of high quality, but there was an unavoidable high risk of bias in the main airway variables, such as change of device or laryngospasm, as the intubator could not be blinded. Many outcomes included data from one study only. A total of 5/118 (4.2%) participants randomly assigned to PLMA across both studies were changed to TT insertion because of failed or unsatisfactory placement of the device. Postoperative episodes of hypoxaemia (oxygen saturation < 92% whilst breathing air) were less common in the PLMA groups (RR 0.27, 95% CI 0.10 to 0.72). We found a significant postoperative difference in mean oxygen saturation, with saturation 2.54% higher in the PLMA group (95% CI 1.09% to 4.00%). This analysis showed high levels of heterogeneity between results (I2 = 71%). The leak fraction was significantly higher in the PLMA group, with the largest difference seen during abdominal insufflation－a 6.4% increase in the PLMA group (95% CI 3.07% to 9.73%). No cases of pulmonary aspiration of gastric contents, mortality or serious respiratory complications were reported in either study. We are therefore unable to present effect estimates for these outcomes. In all, 2/118 participants with a PLMA suffered laryngospam or bronchospasm compared with 4/114 participants with a TT. The pooled estimate shows a non-significant reduction in laryngospasm in the PLMA group (RR 0.48, 95% CI 0.09 to 2.59). Postoperative coughing was less common in the PLMA group (RR 0.10, 95% CI 0.03 to 0.31), and there was no significant difference in the risk of sore throat or dysphonia (RR 0.25, 95% CI 0.03 to 2.13). On average, PLMA placement took 5.9 seconds longer than TT placement (95% CI 3 seconds to 8.8 seconds). There was no significant difference in the proportion of successful first placements of a device, with 33/35 (94.2%) first-time successes in the PLMA group and 32/35 (91.4%) in the TT group. We have inadequate information to draw conclusions about safety, and we can only comment on one design of SAD (the PLMA) in obese patients. We conclude that during routine and laparoscopic surgery, PLMAs may take a few seconds longer to insert, but this is unlikely to be a matter of clinical importance. A failure rate of 3% to 5% can be anticipated in obese patients. However, once fitted, PLMAs provide at least as good oxygenation, with the caveat that the leak fraction may increase, although in the included studies, this did not affect ventilation. We found significant improvement in oxygenation during and after surgery, indicating better pulmonary performance of the PLMA, and reduced postoperative coughing, suggesting better recovery for patients.
A total of 14 trials were included in this review; 4970 patient results were analysed. Four trials evaluating vitamin K antagonists (VKA) versus no VKA suggested that oral anticoagulation may favour autologous venous, but not artificial, graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin (ASA) or aspirin and dipyridamole provided evidence to support a positive effect of VKA on the patency of venous but not artificial grafts. Three trials comparing low molecular weight heparin (LMWH) to unfractionated heparin (UFH) failed to demonstrate a significant difference on patency. One trial comparing LMWH with placebo found no significant improvement in graft patency over the first postoperative year in a population receiving aspirin. One trial showed an advantage for LMWH versus aspirin and dipyridamol at one year for patients undergoing limb salvage procedures. Perioperative administration of ancrod showed no greater benefit when compared to unfractionated heparin. Dextran 70 showed similar graft patency rates to LMWH but a significantly higher proportion of patients developed heart failure with dextran. Patients undergoing infrainguinal venous graft are more likely to benefit from treatment with VKA than platelet inhibitors. Patients receiving an artificial graft benefit from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers are needed in the future to compare antithrombotic therapies with either placebo or antiplatelet therapies.
Fifteen trials involving 3781 participants were included. No studies reported the effect of meglitinides on mortality or morbidity. In the eleven studies comparing meglitinides to placebo, both repaglinide and nateglinide resulted in a reductions in glycosylated haemoglobin (0.1% to 2.1% reduction in HbA1c for repaglinide; 0.2% to 0.6% for nateglinide). Only two trials compared repaglinide to nateglinide (342 participants), with greater reduction in glycosylated haemoglobin in those receiving repaglinide. Repaglinide (248 participants in three trials) had a similar degree of effect in reducing glycosylated haemoglobin as metformin. Nateglinide had a similar or slightly less marked effect on glycosylated haemoglobin than metformin (one study, 355 participants). Weight gain was generally greater in those treated with meglitinides compared with metformin (up to three kg in three months). Diarrhoea occurred less frequently and hypoglycaemia occurred more frequently but rarely severely enough as to require assistance. Meglitinides may offer an alternative oral hypoglycaemic agent of similar potency to metformin, and may be indicated where side effects of metformin are intolerable or where metformin is contraindicated. However, there is no evidence available to indicate what effect meglitinides will have on important long-term outcomes, particularly mortality.
We found six RCTs (1412 participants overall) conducted to evaluate the effects of therapeutic hypothermia - five on neurological outcome and survival, one on only neurological outcome. The quality of the included studies was generally moderate, and risk of bias was low in three out of six studies. When we compared conventional cooling methods versus no cooling (four trials; 437 participants), we found that participants in the conventional cooling group were more likely to reach a favourable neurological outcome (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.18 to 3.21). The quality of the evidence was moderate. Across all studies that used conventional cooling methods rather than no cooling (three studies; 383 participants), we found a 30% survival benefit (RR 1.32, 95% CI 1.10 to 1.65). The quality of the evidence was moderate. Across all studies, the incidence of pneumonia (RR 1.15, 95% CI 1.02 to 1.30; two trials; 1205 participants) and hypokalaemia (RR 1.38, 95% CI 1.03 to 1.84; two trials; 975 participants) was slightly increased among participants receiving therapeutic hypothermia, and we observed no significant differences in reported adverse events between hypothermia and control groups. Overall the quality of the evidence was moderate (pneumonia) to low (hypokalaemia). Evidence of moderate quality suggests that conventional cooling methods provided to induce mild therapeutic hypothermia improve neurological outcome after cardiac arrest, specifically with better outcomes than occur with no temperature management. We obtained available evidence from studies in which the target temperature was 34°C or lower. This is consistent with current best medical practice as recommended by international resuscitation guidelines for hypothermia/targeted temperature management among survivors of cardiac arrest. We found insufficient evidence to show the effects of therapeutic hypothermia on participants with in-hospital cardiac arrest, asystole or non-cardiac causes of arrest.
We included eight parallel-design RCTs, involving a total of 640 participants. We did not assess any of the studies as being at low risk of bias across all domains, with the main limitation being lack of blinding. Using GRADE methodology, the quality of the evidence ranged from very low to low quality. Long-term GnRH agonist therapy versus no pretreatment We are uncertain whether long-term GnRH agonist therapy affects the live birth rate (RR 0.48, 95% CI 0.26 to 0.87; 1 RCT, n = 147; I2 not calculable; very low-quality evidence) or the overall complication rate (Peto OR 1.23, 95% CI 0.37; to 4.14; 3 RCTs, n = 318; I2 = 73%; very low-quality evidence) compared to standard IVF/ICSI. Further, we are uncertain whether this intervention affects the clinical pregnancy rate (RR 1.13, 95% CI 0.91 to 1.41; 6 RCTs, n = 552, I2 = 66%; very low-quality evidence), multiple pregnancy rate (Peto OR 0.14, 95% CI 0.03 to 0.56; 2 RCTs, n = 208, I2 = 0%; very low-quality evidence), miscarriage rate (Peto OR 0.45, 95% CI 0.10 to 2.00; 2 RCTs, n = 208; I2 = 0%; very low-quality evidence), mean number of oocytes (MD 0.72, 95% CI 0.06 to 1.38; 4 RCTs, n = 385; I2 = 81%; very low-quality evidence) or mean number of embryos (MD -0.76, 95% CI -1.33 to -0.19; 2 RCTs, n = 267; I2 = 0%; very low-quality evidence). Long-term GnRH agonist therapy versus long-term continuous COC No studies reported on this comparison. Long-term GnRH agonist therapy versus surgical therapy of endometrioma No studies reported on this comparison. This review raises important questions regarding the merit of long-term GnRH agonist therapy compared to no pretreatment prior to standard IVF/ICSI in women with endometriosis. Contrary to previous findings, we are uncertain as to whether long-term GnRH agonist therapy impacts on the live birth rate or indeed the complication rate compared to standard IVF/ICSI. Further, we are uncertain whether this intervention impacts on the clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, mean number of oocytes and mean number of embryos. In light of the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes, not only compared to no pretreatment, but also compared to other proposed alternatives to endometriosis management.
Fifteen trials including a total of 1219 participants met the inclusion criteria. No trial to date has measured the effect of chitosan on mortality or morbidity. Analyses indicated that chitosan preparations result in a significantly greater weight loss (weighted mean difference -1.7 kg; 95% confidence interval (CI) -2.1 to -1.3 kg, P < 0.00001), decrease in total cholesterol (-0.2 mmol/L [95% CI -0.3 to -0.1], P < 0.00001), and a decrease in systolic and diastolic blood pressure compared with placebo. There were no clear differences between intervention and control groups in terms of frequency of adverse events or in faecal fat excretion. However, the quality of many studies was sub-optimal and analyses restricted to studies that met allocation concealment criteria, were larger, or of longer duration showed that such trials produced substantially smaller decreases in weight and total cholesterol. There is some evidence that chitosan is more effective than placebo in the short-term treatment of overweight and obesity. However, many trials to date have been of poor quality and results have been variable. Results obtained from high quality trials indicate that the effect of chitosan on body weight is minimal and unlikely to be of clinical significance.
Six studies were included, with a total of 440 participants. The interventions examined were cognitive therapy (CT), behavioural therapy (BT), cognitive behavioural therapy (CBT), behavioural stress management (BSM) and psychoeducation. All forms of psychotherapy except psychoeducation showed a significant improvement in hypochondriacal symptoms compared to waiting list control (SMD (random) [95% CI] = -0.86 [-1.25 to -0.46]). For some therapies, significant improvements were found in the secondary outcomes of general functioning (CBT), resource use (psychoeducation), anxiety (CT, BSM), depression (CT, BSM) and physical symptoms (CBT). These secondary outcome findings were based on smaller numbers of participants and there was significant heterogeneity between studies. Cognitive therapy, behavioural therapy, cognitive behavioural therapy and behavioural stress management are effective in reducing symptoms of hypochondriasis. However, studies included in the review used small numbers of participants and do not allow estimation of effect size, comparison between different types of psychotherapy or whether people are "cured". Most long-term outcome data were uncontrolled. Further studies should make use of validated rating scales, assess treatment acceptability and effect on resource use, and determine the active ingredients and nonspecific factors that are important in psychotherapy for hypochondriasis.
This review identified three studies (from four reports) involving a total of 22 children that investigated the efficacy of NSOMT as adjunctive treatment to conventional speech intervention versus conventional speech intervention for children with speech sound disorders. One study, a randomised controlled trial (RCT), included four boys aged seven years one month to nine years six months - all had speech sound disorders, and two had additional conditions (one was diagnosed as "communication impaired" and the other as "multiply disabled"). Of the two quasi-randomised controlled trials, one included 10 children (six boys and four girls), aged five years eight months to six years nine months, with speech sound disorders as a result of tongue thrust, and the other study included eight children (four boys and four girls), aged three to six years, with moderate to severe articulation disorder only. Two studies did not find NSOMT as adjunctive treatment to be more effective than conventional speech intervention alone, as both intervention and control groups made similar improvements in articulation after receiving treatments. One study reported a change in postintervention articulation test results but used an inappropriate statistical test and did not report the results clearly. None of the included studies examined the effects of NSOMTs on any other primary outcomes, such as speech intelligibility, speech physiology and adverse effects, or on any of the secondary outcomes such as listener acceptability. The RCT was judged at low risk for selection bias. The two quasi-randomised trials used randomisation but did not report the method for generating the random sequence and were judged as having unclear risk of selection bias. The three included studies were deemed to have high risk of performance bias as, given the nature of the intervention, blinding of participants was not possible. Only one study implemented blinding of outcome assessment and was at low risk for detection bias. One study showed high risk of other bias as the baseline characteristics of participants seemed to be unequal. The sample size of each of the included studies was very small, which means it is highly likely that participants in these studies were not representative of its target population. In the light of these serious limitations in methodology, the overall quality of the evidence provided by the included trials is judged to be low. Therefore, further research is very likely to have an important impact on our confidence in the estimate of treatment effect and is likely to change the estimate. The three included studies were small in scale and had a number of serious methodological limitations. In addition, they covered limited types of NSOMTs for treating children with speech sound disorders of unknown origin with the sounds /s/ and /z/. Hence, we judged the overall applicability of the evidence as limited and incomplete. Results of this review are consistent with those of previous reviews: Currently no strong evidence suggests that NSOMTs are an effective treatment or an effective adjunctive treatment for children with developmental speech sound disorders. Lack of strong evidence regarding the treatment efficacy of NSOMTs has implications for clinicians when they make decisions in relation to treatment plans. Well-designed research is needed to carefully investigate NSOMT as a type of treatment for children with speech sound disorders.
Four RCTs, 13 prospective cohort studies, and one unpublished ongoing cohort study met our inclusion criteria, and included a total of 2098 participants with TBM. None of the included RCTs directly compared six months versus longer regimens, so we analysed all data as individual cohorts to obtain relapse rates in each set of cohorts. We included 20 cohorts reported in 18 studies. One of these was reported separately, leaving 19 cohorts in the main analysis. We included seven cohorts of participants treated for six months with a total of 458 participants. Three studies were conducted in Thailand, two in South Africa, and one each in Ecuador and Papua New Guinea between the 1980s and 2009. We included 12 cohorts of participants treated for longer than six months (ranging from eight to 16 months), with a total of 1423 participants. Four studies were conducted in India, three in Thailand and one each in China, South Africa, Romania, Turkey, and Vietnam, between the late 1970s and 2011. The unpublished ongoing cohort study is conducted in India and included 217 participants. The proportion of participants classified as having stage III disease (severe) was higher in the cohorts treated for six months (33.2% versus 16.9%), but the proportion with known concurrent HIV was higher in the cohorts treated for longer (0/458 versus 122/1423). Although there were variations in the treatment regimens, most cohorts received isoniazid, rifampicin, and pyrazinamide during the intensive phase. Investigators achieved follow-up beyond 18 months after completing treatment in three out of the seven cohorts treated for six months, and five out of the 12 cohorts treated for eight to 16 months. All studies had potential sources of bias in their estimation of the relapse rate, and comparisons between the cohorts could be confounded. Relapse was an uncommon event across both groups of cohorts (3/369 (0.8%) with six months treatment versus 7/915 (0.8%) with longer), with only one death attributed to relapse in each group. Overall, the proportion of participants who died was higher in the cohorts treated for longer than six months (447/1423 (31.4%) versus 58/458 (12.7%)). However, most deaths occurred during the first six months in both treatment cohorts, which suggested that the difference in death rate was not directly related to duration of ATT but was due to confounding. Clinical cure was higher in the group of cohorts treated for six months (408/458 (89.1%) versus longer than six months (984/1336 (73.7%)), consistent with the observations for deaths. Few participants defaulted from treatment with six months treatment (4/370 (1.1%)) versus longer treatment (8/355 (2.3%)), and adherence was not well reported. In all cohorts most deaths occurred in the first six months; and relapse was uncommon in all participants irrespective of the regimen. Further inferences are probably inappropriate given this is observational data and confounding is likely. These data are almost all from participants who are HIV-negative, and thus the inferences will not apply to the efficacy and safety of the six months regimens in HIV-positive people. Well-designed RCTs, or large prospective cohort studies, comparing six months with longer treatment regimens with long follow-up periods established at initiation of ATT are needed to resolve the uncertainty regarding the safety and efficacy of six months regimens for TBM.
Fifteen trials involving 2022 people were included. Compared to placebo, haloperidol was more effective at reducing manic symptoms, both as monotherapy (Weighted Mean Difference (WMD) -5.85, 95% Confidence Interval (CI) -7.69 to -4.00) and as adjunctive treatment to lithium or valproate (WMD -5.20, 95% CI -9.26 to -1.14). There was a statistically significant difference, with haloperidol being less effective than aripiprazole (Relative Risk (RR) 1.45, 95% CI 1.22 to 1.73). No significant differences between haloperidol and risperidone, olanzapine, carbamazepine or valproate were found. Compared with placebo, a statistically significant difference in favour of haloperidol in failure to complete treatment (RR 0.74, 95% Cl 0.57 to 0.96) was reported. Haloperidol was associated with less weight gain than olanzapine (RR: 0.28, 95% CI 0.12 to 0.67), but with a higher incidence of tremor (RR: 3.01, 95% CI 1.55 to 5.84) and other movement disorders. There is some evidence that haloperidol is an effective treatment for acute mania. From the limited data available, there was no difference in overall efficacy of treatment between haloperidol and olanzapine or risperidone. Some evidence suggests that haloperidol could be less effective than aripiprazole. Referring to tolerability, when considering the poor evidence comparing drugs, clinicians and patients should consider different side effect profiles as an important issue to inform their choice.
The five included trials led to the following results:  1. There was no significant improvement in agitation among haloperidol treated patients, compared with controls.  2. Aggression decreased among patients with agitated dementia treated with haloperidol; other aspects of agitation were not affected significantly in treated patients compared with controls.  3. Although two studies showed increased drop-outs due to adverse effects among haloperidol patients, there was no significant difference in drop-out rates, comparing all haloperidol treated patients with controls.  4. The data were insufficient to examine response to treatment in relation to length of treatment, degree of dementia, age or sex of patients, and cause of dementia. 1. Evidence suggests that haloperidol was useful in reducing aggression, but was associated with adverse effects; there was no evidence to support the routine use of this drug for other manifestations of agitation in dementia.  2. Similar drop-out rates among haloperidol and placebo treated patients suggested that poorly controlled symptoms, or other factors, may be important in causing treatment discontinuation.  3. Variations in degree of dementia, dosage and length of haloperidol treatment, and in ways of assessing response to treatment suggested caution in the interpretation of reported effects of haloperidol in the management of agitation in dementia.  4. The present study confirmed that haloperidol should not be used routinely to treat patients with agitated dementia. Treatment of agitated dementia with haloperidol should be individualized and patients should be monitored for adverse effects of therapy.
Five randomised trials and four controlled before and after studies were included. The interventions were complex. Five studies added an additional component, or linked a new component, to an existing service, for example, adding family planning or HIV counselling and testing to routine services. The evidence from these studies indicated that adding on services probably increases service utilisation but probably does not improve health status outcomes, such as incident pregnancies. Four studies compared integrated services to single, special services. Based on the included studies, fully integrating sexually transmitted infection (STI) and family planning, and maternal and child health services into routine care as opposed to delivering them as special 'vertical' services may decrease utilisation, client knowledge of and satisfaction with the services and may not result in any difference in health outcomes, such as child survival. Integrating HIV prevention and control at facility and community level improved the effectiveness of certain services (STI treatment in males) but resulted in no difference in health seeking behaviour, STI incidence, or HIV incidence in the population. There is some evidence that 'adding on' services (or linkages) may improve the utilisation and outputs of healthcare delivery. However, there is no evidence to date that a fuller form of integration improves healthcare delivery or health status. Available evidence suggests that full integration probably decreases the knowledge and utilisation of specific services and may not result in any improvements in health status. More rigorous studies of different strategies to promote integration over a wider range of services and settings are needed. These studies should include economic evaluation and the views of clients as clients' views will influence the uptake of integration strategies at the point of delivery and the effectiveness on community health of these strategies.
We found 16 randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis. We classed seven trials as low risk of bias and nine trials as high risk of bias (mainly due to lack of blinding or for-profit funding). In a random-effects meta-analysis of mortality, we found no difference between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA on mortality. Trial sequential analysis showed that the required information size was not reached, suggesting that additional evidence was needed. BCAA had a beneficial effect on hepatic encephalopathy (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials; high quality of evidence). We found no small-study effects and confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). The trial sequential analysis showed that firm evidence was reached. In a fixed-effect meta-analysis, we found that BCAA increased the risk of nausea and vomiting (RR 5.56; 2.93 to 10.55; moderate quality of evidence). We found no beneficial or detrimental effects of BCAA on nausea or vomiting in a random-effects meta-analysis or on quality of life or nutritional parameters. We did not identify predictors of the intervention effect in the subgroup, sensitivity, or meta-regression analyses. In sensitivity analyses that excluded trials with a lactulose or neomycin control, BCAA had a beneficial effect on hepatic encephalopathy (RR 0.76, 95% CI 0.63 to 0.92). Additional sensitivity analyses found no difference between BCAA and lactulose or neomycin (RR 0.66, 95% CI 0.34 to 1.30). In this updated review, we included five additional trials. The analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. We found no effect on mortality, quality of life, or nutritional parameters, but we need additional trials to evaluate these outcomes. Likewise, we need additional randomised clinical trials to determine the effect of BCAA compared with interventions such as non-absorbable disaccharides, rifaximin, or other antibiotics.
We included four trials in this review and did not identify new studies from the search in April 2015. Home-based end-of-life care increased the likelihood of dying at home compared with usual care (risk ratio (RR) 1.33, 95% confidence interval (CI) 1.14 to 1.55, P = 0.0002; Chi2 = 1.72, df = 2, P = 0.42, I2 = 0%; 3 trials; N = 652; high quality evidence). Admission to hospital while receiving home-based end-of-life care varied between trials, and this was reflected by a high level of statistical heterogeneity in this analysis (range RR 0.62 to RR 2.61; 4 trials; N = 823; moderate quality evidence). Home-based end-of-life care may slightly improve patient satisfaction at one-month follow-up and reduce it at six-month follow-up (2 trials; low quality evidence). The effect on caregivers is uncertain (2 trials; low quality evidence). The intervention may slightly reduce healthcare costs (2 trials, low quality evidence). No trial reported costs to patients and caregivers. The evidence included in this review supports the use of home-based end-of-life care programmes for increasing the number of people who will die at home, although the numbers of people admitted to hospital while receiving end-of-life care should be monitored. Future research should systematically assess the impact of home-based end-of-life care on caregivers.
Twenty-six trials met inclusion criteria. The number, site and dosage of injections varied widely between studies. The number of participants per trial ranged from 20 to 114 (median 52 participants). Methodological quality was variable. For rotator cuff disease, subacromial steroid injection was demonstrated to have a small benefit over placebo in some trials however no benefit of subacromial steroid injection over NSAID was demonstrated based upon the pooled results of three trials.   For adhesive capsulitis, two trials suggested a possible early benefit of intra-articular steroid injection over placebo but there was insufficient data for pooling of any of the trials. One trial suggested short-term benefit of intra-articular corticosteroid injection over physiotherapy in the short-term (success at seven weeks RR=1.66 (1.21, 2.28). Despite many RCTs of corticosteroid injections for shoulder pain, their small sample sizes, variable methodological quality and heterogeneity means that there is little overall evidence to guide treatment. Subacromial corticosteroid injection for rotator cuff disease and intra-articular injection for adhesive capsulitis may be beneficial although their effect may be small and not well-maintained. There is a need for further trials investigating the efficacy of corticosteroid injections for shoulder pain. Other important issues that remain to be clarified include whether the accuracy of needle placement, anatomical site, frequency, dose and type of corticosteroid influences efficacy.
Our update search identified 465 citations, which we assessed for eligibility. Three new studies met the criteria for inclusion, giving a total of 14 included studies (n = 3370). The definition of partner varied among the studies. We compared partner support versus control interventions at six- to nine-month follow-up and at 12 or more months follow-up. We also examined outcomes among three subgroups: interventions targeting relatives, friends or coworkers; interventions targeting spouses or cohabiting partners; and interventions targeting fellow cessation programme participants. All studies gave self-reported smoking cessation rates, with limited biochemical verification of abstinence. The pooled risk ratio (RR) for abstinence was 0.97 (95% confidence interval (CI) 0.83 to 1.14; 12 studies; 2818 participants) at six to nine months, and 1.04 (95% CI 0.88 to 1.22; 7 studies; 2573 participants) at 12 months or more post-treatment. Of the 11 studies that measured partner support at follow-up, only two reported a significant increase in partner support in the intervention groups. One of these studies reported a significant increase in partner support in the intervention group, but smokers' reports of partner support received did not differ significantly. We judged one of the included studies to be at high risk of selection bias, but a sensitivity analysis suggests that this did not have an impact on the results. There were also potential issues with detection bias due to a lack of validation of abstinence in five of the 14 studies; however, this is not apparent in the statistically homogeneous results across studies. Using the GRADE system we rated the overall quality of the evidence for the two primary outcomes as low. We downgraded due to the risk of bias, as we judged studies with a high weighting in analyses to be at a high risk of detection bias. In addition, a study in both analyses was insufficiently randomised. We also downgraded the quality of the evidence for indirectness, as very few studies provided any evidence that the interventions tested actually increased the amount of partner support received by participants in the relevant intervention group. Interventions that aim to enhance partner support appear to have no impact on increasing long-term abstinence from smoking. However, most interventions that assessed partner support showed no evidence that the interventions actually achieved their aim and increased support from partners for smoking cessation. Future research should therefore focus on developing behavioural interventions that actually increase partner support, and test this in small-scale studies, before large trials assessing the impact on smoking cessation can be justified.
Eight trials are included in this review, seven used methylprednisolone. Methylprednisolone sodium succinate has been shown to improve neurologic outcome up to one year post-injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial results were replicated in a Japanese trial but not in the one from France. Data was obtained from the latter studies to permit appropriate meta-analysis of all three trials. This indicated significant recovery in motor function after methylprednisolone therapy, when administration commenced within eight hours of injury. A more recent trial indicates that, if methylprednisolone therapy is given for an additional 24 hours (a total of 48 hours), additional improvement in motor neurologic function and functional status are observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries. A modified regimen was found to improve recovery after surgery for lumbar disc disease. The risk of bias was low in the largest methyprednisolone trials. Overall, there was no evidence of significantly increased complications or mortality from the 23 or 48 hour therapy. High-dose methylprednisolone steroid therapy is the only pharmacologic therapy shown to have efficacy in a phase three randomized trial when administered within eight hours of injury. One trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours, if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacologic therapy for acute spinal cord injury.
Five RCTs with a total of 292 babies, were included in the review. Comparisons made within the RCTs were squeezable versus rigid feeding bottles (two studies), breastfeeding versus spoon-feeding (one study) and maxillary plate versus no plate (two studies). No statistically significant differences were shown for any of the primary outcomes when comparing bottle types, although squeezable bottles were less likely to require modification. No difference was shown for infants fitted with a maxillary plate compared to no plate. However, there was some evidence of an effect on weight at 6 weeks post-surgery in favour of breastfeeding when compared to spoon-feeding (mean difference 0.47; 95% confidence interval 0.20 to 0.74). Squeezable bottles appear easier to use than rigid feeding bottles for babies born with clefts of the lip and/or palate, however, there is no evidence of a difference in growth outcomes between the bottle types. There is weak evidence that breastfeeding is better than spoon-feeding following surgery for cleft. There was no evidence to suggest that maxillary plates assist growth in babies with clefts of the palate. No evidence was found to assess the use of any types of maternal advice and/or support for these babies.
Eight studies met inclusion criteria. They were heterogeneous in terms of participants, study designs, and interventions. Five of eight studies had high risk of bias. In 3 RCTs (312 participants), classroom-based didactic and experiential programs increased short-term knowledge of suicide (SMD = 1.51, 95% CI 0.57 to 2.45; moderate quality evidence) and knowledge of suicide prevention (SMD = 0.72, 95% CI 0.36 to 1.07; moderate quality evidence). The effect on suicide prevention self-efficacy in one RCT (152 participants) was uncertain (SMD = 0.20, 95% CI -0.13 to 0.54; low quality evidence). One CBA analysed the effects of an institutional policy that restricted student access to laboratory cyanide and mandated professional assessment for suicidal students. The incidence of student suicide decreased significantly at one university with the policy relative to 11 control universities, 2.00 vs. 8.68 per 100,000 (Z = 5.90; P < 0.05). Four CBAs explored effects of training 'gatekeepers' to recognize and respond to warning signs of emotional crises and suicide risk in students they encountered. The magnitude of effect sizes varied between studies. Gatekeeper training enhanced short-term suicide knowledge in students, peer advisors residing in student accommodation, and faculty and staff, and suicide prevention self-efficacy among peer advisors. There was no evidence of an effect on participants' suicide-related attitudes or behaviors. One CBA found no evidence of effects of gatekeeper training of peer advisors on suicide-related knowledge, self-efficacy, or gatekeeper behaviors measured four to six months after intervention. We found insufficient evidence to support widespread implementation of any programs or policies for primary suicide prevention in post-secondary educational settings. As all evaluated interventions combined primary and secondary prevention components, we were unable to determine the independent effects of primary preventive interventions. Classroom instruction and gatekeeper training increased short-term suicide-related knowledge. We found no studies that tested the effects of classroom instruction on suicidal behavior or long-term outcomes. Limited evidence suggested minimal longer-term effects of gatekeeper training on suicide-related knowledge, while no evidence was found evaluating its effect on suicidal behavior. A policy-based suicide intervention reduced student suicide, but findings have not been replicated. Our findings are limited by the overall low quality of the evidence and the lack of studies from middle- and low-income countries. Rigorously designed studies should test the effects of preventive interventions on important health outcomes, including suicidal ideation and behavior, in varying post-secondary settings.
Of 2313 participants without prior cerebral ischemia from five randomized trials, the mean age was 69 years. Participant features and study quality were similar between trials: the OAC in all five trials was warfarin. About half of participants (N = 1154) were randomized to adjusted-dose warfarin with mean achieved INRs ranging between 2.0 to 2.6. During 1.5 years mean follow up, warfarin was associated with large, highly statistically significant reductions in all strokes (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.26 to 0.59), ischemic stroke (OR 0.34, 95% CI 0.23 to 0.52), all disabling or fatal stroke (OR 0.47, 95% CI 0.28 to 0.80), death (OR 0.69, 95% CI 0.50 to 0.94) and the combined endpoint of all stroke, myocardial infarction or vascular death (OR 0.56, 95% CI 0.42 to 0.76). The observed rates of intracranial and extracranial hemorrhage were not significantly increased by OAC therapy, but the confidence intervals were wide. Treatment with adjusted-dose warfarin to achieved INRs of 2 to 3 reduces stroke, disabling or fatal stroke, and death for patients with non-valvular AF. The benefits were not substantially offset by increased bleeding among these participants in randomized clinical trials. Limitations include relatively short follow up and imprecise estimates of bleeding risks from the selected participants enrolled in the trials. For primary prevention of stroke in AF patients, about 25 strokes and about 12 disabling or fatal strokes would be prevented yearly for every 1000 atrial fibrillation patients given OACs.
We identified one new study for this update, resulting in six trials (561 patients) meeting the inclusion criteria. Five of the six trials reported on the main outcome, migraine frequency. Although five of the trials were generally of good methodological quality, all studies were either of unclear or high risk of bias with regards to sample size. Pooled analysis of the results was not possible due to the lack of common outcome measures and heterogeneity between studies in terms of participants, interventions and designs. The most recent trial added to this version of the review is rigorous and larger (n = 218), using a stable feverfew extract at a dose determined by a previous dose-finding trial. It reports that feverfew reduced migraine frequency by 1.9 attacks from 4.8 to 2.9 and placebo by 1.3 from to 4.8 to 3.5 per month, resulting in a difference in effect between feverfew and placebo of 0.6 attacks per month. For the secondary outcome measures intensity and duration of migraine attacks, incidence and severity of nausea and vomiting, and global assessment no statistically significant differences were reported. Results of previous trials are not convincing: three trials reporting positive effects of feverfew are all of small sample size (17 to 60 participants), while two rigorous trials (n = 50, 147) did not find significant differences between feverfew and placebo. Only mild and transient adverse events, most commonly gastrointestinal complaints and mouth ulcers, were reported in the included trials. Since the last version of this review, one larger rigorous study has been included, reporting a difference in effect between feverfew and placebo of 0.6 attacks per month. This adds some positive evidence to the mixed and inconclusive findings of the previous review. However, this constitutes low quality evidence, which needs to be confirmed in larger rigorous trials with stable feverfew extracts and clearly defined migraine populations before firm conclusions can be drawn. It appears from the data reviewed that feverfew is not associated with any major safety concerns.
We identified two RCTs meeting our inclusion criteria. The two trials tested different comparisons. One RCT included 35 participants and compared PCV with 'eight drugs in one day' multidrug chemotherapy, which is a combination of drugs with different mechanisms of action. Median survival was 6 months for the PCV group and 6.5 months for the 'eight drugs in one day' group. Adverse event outcomes were not graded or quantified. Progression-free survival (PFS) and quality of life (QoL) were not described in the methods and were not an outcome of interest. The sample size in this study was small, which lead to insufficient statistical power to detect clinical differences. According to the GRADE approach we judged the quality of evidence to be low for survival outcome and very low for chemotherapy toxicity The second multi-institutional RCT included 447 participants and compared PCV with Temozolomide (TMZ). Participants were randomised into three arms to receive PCV, and two different regimens of TMZ in a 2:1:1 ratio at first recurrence. The trial reported a median overall survival of 6.7 months and 7.2 months for the PCV and TMZ group respectively. It reported a PFS of 3.6 months for the PCV group and 4.7 months for the TMZ group. There was no observed difference of effect on overall survival (hazard ratio (HR) 0.91, 95% CI 0.74 to 1.11; P = 0.35) or PFS (HR 0.89, 95% CI 0.73 to 1.08; P = 0.23) in participants receiving PCV or TMZ chemotherapy. The proportion of people with at least one grade 3 or 4 adverse event was not clinically important at 9.2% versus 12.2% in PCV and TMZ arms respectively. Mean QoL scores calculated at baseline, 12 weeks and 24 weeks was 51.9 versus 59.8 favouring TMZ (P = 0.04) which is statistically but not clinically significant and was less than the pre-defined 10 point change for moderate improvement. We judged the GRADE quality of evidence to be moderate for overall survival, PFS, and chemotherapy toxicity and low for QoL. Evidence is based on a single large trial analysis as the other trial was small, with inadequate power to detect survival difference. Chemotherapy-naive patients with HGG at first recurrence when treated with PCV or TMZ have similar survival and time-to-progression outcomes. Adverse events are similar and QoL scores are statistically but not clinically significant between TMZ and PCV. Further RCTs should be conducted with adequate power following CONSORT guidelines with emphasis on QoL outcomes.
We included 28 trials (4438 participants) in the updated review. We considered most participants to be at low to moderate risk of death after surgery. We assessed two studies as having low risk of bias and 11 studies high risk of bias. Investigators reported no differences in risk of mortality within the first year after surgery between low-dose versus high-dose opioid-based general anaesthesia groups (OR 0.53, 95% CI 0.25 to 1.12; eight trials, 1994 participants, low level of evidence) and between a time-directed extubation protocol versus usual care (OR 0.80, 95% CI 0.45 to 1.45; 10 trials, 1802 participants, low level of evidence). Researchers noted no significant differences between low-dose and high-dose opioid-based anaesthesia groups in the following postoperative complications: myocardial infarction (RR 0.98, 95% CI 0.48 to 1.99; eight trials, 1683 participants, low level of evidence), stroke (RR 1.17, 95% CI 0.36 to 3.78; five trials, 562 participants, low level of evidence) and tracheal reintubation (RR 1.77, 95% CI 0.38 to 8.27; five trials, 594 participants, low level of evidence). Comparisons with usual care revealed no significant differences in the risk of postoperative complications associated with a time-directed extubation protocol: myocardial infarction (RR 0.59, 95% CI 0.27 to 1.31; eight trials, 1378 participants, low level of evidence), stroke (RR 0.85, 95% CI 0.33 to 2.16; 11 trials, 1646 participants, low level of evidence) and tracheal reintubation (RR 1.34, 95% CI 0.74 to 2.41; 12 trials, 1261 participants, low level of evidence). Although levels of heterogeneity were high, low-dose opioid anaesthesia was associated with reduced time to extubation (reduction of 4.3 to 10.5 hours, 14 trials, 2486 participants, low level of evidence) and length of stay in the intensive care unit (reduction of 0.4 to 7.0 hours, 12 trials, 1394 participants, low level of evidence). Use of a time-directed extubation protocol was associated with reduced time to extubation (reduction of 3.7 to 8.8 hours, 16 trials, 2024 participants, low level of evidence) and length of stay in the intensive care unit (reduction of 3.9 to 10.5 hours, 13 trials, 1888 participants, low level of evidence). However, these two fast-track care interventions were not associated with reduced total length of stay in the hospital (low level of evidence). Low-dose opioid-based general anaesthesia and time-directed extubation protocols for fast-track interventions have risks of mortality and major postoperative complications similar to those of conventional (not fast-track) care, and therefore appear to be safe for use in patients considered to be at low to moderate risk. These fast-track interventions reduced time to extubation and shortened length of stay in the intensive care unit but did not reduce length of stay in the hospital.
Our review included six RCTs (representing a total of 278 adult lung transplant recipients) that assessed the use of T-cell antibody induction. Evaluation of the included studies found all to be at high risk of bias. We conducted comparisons of polyclonal or monoclonal T-cell antibody induction versus no induction (3 studies, 140 participants); polyclonal T-cell antibody versus no induction (3 studies, 125 participants); interleukin-2 receptor antagonists (IL-2RA) versus no induction (1 study, 25 participants); polyclonal T-cell antibody versus muromonab-CD3 (1 study, 64 participants); and polyclonal T-cell antibody versus IL-2RA (3 studies, 100 participants). Overall we found no significant differences among interventions in terms of mortality, acute rejection, adverse effects, infection, pneumonia, cytomegalovirus infection, bronchiolitis obliterans syndrome, post-transplantation lymphoproliferative disease, or cancer. We found a significant outcome difference in one study that compared antithymocyte globulin versus muromonab-CD3 relating to adverse events (25/34 (74%) versus 12/30 (40%); RR 1.84, 95% CI 1.13 to 2.98). This suggested that antithymocyte globulin increased occurrence of adverse events. However, trial sequential analysis found that the required information size had not been reached, and the cumulative Z-curve did not cross the trial sequential alpha-spending monitoring boundaries. None of the studies reported quality of life or kidney injury. Trial sequential analyses indicated that none of the meta-analyses achieved required information sizes and the cumulative Z-curves did not cross the trial sequential alpha-spending monitoring boundaries, nor reached the area of futility. No clear benefits or harms associated with the use of T-cell antibody induction compared with no induction, or when different types of T-cell antibodies were compared were identified in this review. Few studies were identified that investigated use of antibodies against T-cells for induction after lung transplantation, and numbers of participants and outcomes were also limited. Assessment of the included studies found that all were at high risk of methodological bias. Further RCTs are needed to perform robust assessment of the benefits and harms of T-cell antibody induction for lung transplant recipients. Future studies should be designed and conducted according to methodologies to reduce risks of systematic error (bias) and random error (play of chance).
One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update. Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The second study with 10 participants examined the addition of intravenous ketamine bolus in two different doses to ongoing morphine therapy, compared with placebo. Both of these studies reported reduction in pain intensity and reduction in morphine requirements when ketamine was added to opioid for refractory cancer pain. The new study identified by the updated search had a parallel group design and 185 participants. This placebo-controlled study examined rapid titration of subcutaneous ketamine to high dose (500 mg) in participants who were using different opioids. There were no differences between groups for patient-reported pain intensity. Pooling of the data from the three included trials was not appropriate because of clinical heterogeneity. The study examining intrathecal drug administration reported no adverse events related to ketamine. In the study using intravenous bolus administration, ketamine caused hallucinations in four of 10 participants. In the rapid dose escalation/high-dose subcutaneous ketamine study, there was almost twice the incidence of adverse events in the ketamine group, compared to the placebo group, with the most common adverse events being needle site irritation and cognitive disturbance. Two serious adverse events (bradyarrhythmia and cardiac arrest) thought to be related to ketamine were also reported in this trial. For all three studies there was an unclear risk of bias overall. Using GRADE, we judged the quality of the evidence to be very low due to study limitations and imprecision due to the small number of participants in all comparisons. Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain. The evidence was of very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is high. Rapid dose escalation of ketamine to high dose (500 mg) does not appear to have clinical benefit and may be associated with serious adverse events. More randomised controlled trials (RCTs) examining specific low-dose ketamine clinical regimens in current use are needed.
Thirty-six studies (2838 participants) were included. Xanthine versus placebo (18 studies): The proportion of symptom free days was larger with xanthine compared with placebo (7.97% [95% CI 3.41, 12.53]). Rescue medication usage was lower with xanthine, with no significant difference in symptom scores or hospitalisations. FEV1, and PEF were better with xanthine. Xanthine was associated with non-specific side-effects. Data from behavioural scores were inconclusive. Xanthine versus ICS (four studies) : Exacerbations were less frequent with ICS, but no significant difference on lung function was observed. Individual studies reported significant improvements in symptom measures in favour of steroids, and one study reported a difference in growth rate in favour of xanthine. No difference was observed for study withdrawal or tremor. Xanthine was associated with more frequent headache and nausea. Xanthine versus regular SABA (10 studies): No significant difference in symptoms, rescue medication usage and spirometry. Individual studies reported improvement in PEF with beta-agonist. Beta-agonist treatment led to fewer hospitalisations and headaches. Xanthine was associated with less tremor. Xanthine versus SCG (six studies ): No significant difference in symptoms, exacerbations and rescue medication. Sodium cromoglycate was associated with fewer gastro-intestinal side-effects than xanthine. Xanthine versus KET (one study): No statistical tests of significance between xanthine and ketotifen were reported. : Xanthine + ICS versus placebo + same dose ICS (three studies) : Results were conflicting due to clinical/methodological differences, and could not be aggregated. Xanthine + ICS versus ICS + leukotriene (one study): Results from one trial One small parallel study did not measure the primary outcome of symptoms; differences between treatments in end of treatment values were not statistically significant. Xanthines as first-line preventer alleviate symptoms and reduce requirement for rescue medication in children with mild to moderate asthma. When compared with ICS they were less effective in preventing exacerbations. Xanthines had similar efficacy as single preventative agent compared with regular SABA and SCG. Evidence on AEs (adverse effects) was equivocal: there was evidence for increased AEs overall, but no evidence that any specific AE (including effects on behaviour and attention) occurred more frequently than with placebo. There is insufficient evidence from available studies to make firm conclusions about the effectiveness of xanthines as add-on preventative treatment to ICS, and there are no published paediatric studies comparing xanthines with alternatives in this role. Our data suggest that xanthines are only suitable as first-line preventative asthma therapy in children when ICS are not available. Pre-trial exposure to the agents assessed may have pre-disposed the trial populations to tolerate the drug, and may have threatened blinding. They may have a role as add-on therapy in more severe asthma not controlled by ICS, but further studies are needed to examine this, and to define the risk-benefit ratio compared with other agents.
We included 10 studies (165 participants) that examined the short- and medium-term effect of music therapy interventions (one week to seven months) for children with ASD. Music therapy was superior to 'placebo' therapy or standard care with respect to the primary outcomes social interaction within the therapy context (SMD 1.06, 95% CI 0.02 to 2.10, 1 RCT, n = 10); generalised social interaction outside of the therapy context (SMD 0.71, 95% CI 0.18 to 1.25, 3 RCTs, n = 57, moderate quality evidence), non-verbal communicative skills within the therapy context (SMD 0.57, 95% CI 0.29 to 0.85, 3 RCTs, n = 30), verbal communicative skills (SMD 0.33, 95% CI 0.16 to 0.49, 6 RCTs, n = 139), initiating behaviour (SMD 0.73, 95% CI 0.36 to 1.11, 3 RCTs, n = 22, moderate quality evidence), and social-emotional reciprocity (SMD 2.28, 95% CI 0.73 to 3.83, 1 RCT, n = 10, low quality evidence). There was no statistically significant difference in non-verbal communicative skills outside of the therapy context (SMD 0.48, 95% CI -0.02 to 0.98, 3 RCTs, n = 57, low quality evidence). Music therapy was also superior to 'placebo' therapy or standard care in secondary outcome areas, including social adaptation (SMD 0.41, 95% CI 0.21 to 0.60, 4 RCTs, n = 26), joy (SMD 0.96, 95% CI 0.04 to 1.88, 1 RCT, n = 10), and quality of parent-child relationships (SMD 0.82, 95% CI 0.13 to 1.52, 2 RCTs, n = 33, moderate quality evidence). None of the included studies reported any adverse effects. The small sample sizes of the studies limit the methodological strength of these findings. The findings of this updated review provide evidence that music therapy may help children with ASD to improve their skills in primary outcome areas that constitute the core of the condition including social interaction, verbal communication, initiating behaviour, and social-emotional reciprocity. Music therapy may also help to enhance non-verbal communication skills within the therapy context. Furthermore, in secondary outcome areas, music therapy may contribute to increasing social adaptation skills in children with ASD and to promoting the quality of parent-child relationships. In contrast to the studies included in an earlier version of this review published in 2006, the new studies included in this update enhanced the applicability of findings to clinical practice. More research using larger samples and generalised outcome measures is needed to corroborate these findings and to examine whether the effects of music therapy are enduring. When applying the results of this review to practice, it is important to note that the application of music therapy requires specialised academic and clinical training.
We included one United Kingdom (UK) study in the review. In this randomised controlled trial, a total of 80 participants, with a mean age of 58 years, were treated for 12 months by a specialist nurse or doctor, then were crossed over to the other clinician for the next 12 months. Two participants died during the study period. Six participants failed to cross over to nurse-led care because of unstable bronchiectasis. Overall, the level of study completion was high. Data show no difference in the numbers of exacerbations requiring treatment with antibiotics (rate ratio 1.09, 95% confidence interval (CI) 0.91 to 1.30, 80 participants, moderate-certainty evidence). Investigators reported more hospital admissions in the nurse-led care group (rate ratio 1.52, 95% CI 1.04 to 2.23, 80 participants, moderate-certainty evidence) and did not report emergency department attendance. For secondary outcomes, participants in the nurse-led care group used more healthcare resources during the first year of the trial. Increased admissions and greater use of resources made treatment costs for nurse-led groups' higher. Total costs for both years of the study were £8,464 and £5,228 for nurse-led care compared with doctor-led care. However, by the second year, treatment costs were almost equitable between the two groups, which may reflect the nurses' learning of how to better treat people with bronchiectasis. No statistically significant changes were observed in quality of life, exercise capacity, mortality, or lung function. Wide confidence intervals led to uncertainty regarding these results. Adverse events were not an outcome for this review. This update of the review shows that only one trial met review criteria. Review authors were unable to demonstrate effectiveness of nurse-led care compared with doctor-led care on the basis of findings of a single study. The included study reported no significant differences, but limited evidence means that differences in clinical outcomes between nurse-led care and usual care within the setting of a specialist clinic remain unclear. Further research is required to determine whether nurse-led care is cost-effective, if guidelines and protocols for bronchiectasis management are followed does this increases costs and how effective nurse-led management of bronchiectasis is in other clinical settings such as inpatient and outreach.
We included sixteen controlled trials involving 2318 adult participants. The studies measured diverse outcomes. Many of the participants found recordings or summaries of their consultations valuable, with between 60% and 100% of participants (across twelve studies) reading the summary or listening to the recording at least once. The recordings were used to help inform family and friends (range 41.5% to 94.4% of participants in nine studies). Five out of nine studies reported better recall of information for those receiving recordings or summaries. Three out of ten studies found that participants provided with a recording or summary were more satisfied. No studies (out of ten) found any statistically significant difference between groups in terms of anxiety or depression. Three studies evaluated the effects on quality of life, but found no main effects. No study evaluated the intervention's effects on survival. The provision of recordings or summaries of key consultations may benefit most adults with cancer. Although more research is needed to improve our understanding of these interventions, most patients find them very useful. Practitioners should consider offering people recordings or written summaries of their consultations
We included 10 randomised trials (836 participants) in this review. Four trials (40%) had low risk of bias, the remaining 60% of trials had a high risk of bias. The quality of the evidence for the effects of CBT on patients with chronic NP was from very low to moderate. There was low quality evidence that CBT was better than no treatment for improving pain (standard mean difference (SMD) -0.58, 95% confidence interval (CI) -1.01 to -0.16), disability (SMD -0.61, 95% CI -1.21 to -0.01), and quality of life (SMD -0.93, 95% CI -1.54 to -0.31) at short-term follow-up, while there was from very low to low quality evidence of no effect on various psychological indicators at short-term follow-up. Both at short- and intermediate-term follow-up, CBT did not affect pain (SMD -0.06, 95% CI -0.33 to 0.21, low quality, at short-term follow-up; MD -0.89, 95% CI -2.73 to 0.94, low quality, at intermediate-term follow-up) or disability (SMD -0.10, 95% CI -0.40 to 0.20, moderate quality, at short-term follow-up; SMD -0.24, 95% CI-0.54 to 0.07, moderate quality, at intermediate-term follow-up) compared to other types of interventions. There was moderate quality evidence that CBT was better than other interventions for improving kinesiophobia at intermediate-term follow-up (SMD -0.39, 95% CI -0.69 to -0.08, I2 = 0%). Finally, there was very low quality evidence that CBT in addition to another intervention did not differ from the other intervention alone in terms of effect on pain (SMD -0.36, 95% CI -0.73 to 0.02) and disability (SMD -0.10, 95% CI -0.56 to 0.36) at short-term follow-up. For patients with subacute NP, there was low quality evidence that CBT was better than other interventions at reducing pain at short-term follow-up (SMD -0.24, 95% CI -0.48 to 0.00), while no difference was found in terms of effect on disability (SMD -0.12, 95% CI -0.36 to 0.12) and kinesiophobia. None of the included studies reported on adverse effects. With regard to chronic neck pain, CBT was found to be statistically significantly more effective for short-term pain reduction only when compared to no treatment, but these effects could not be considered clinically meaningful. When comparing both CBT to other types of interventions and CBT in addition to another intervention to the other intervention alone, no differences were found. For patients with subacute NP, CBT was significantly better than other types of interventions at reducing pain at short-term follow-up, while no difference was found for disability and kinesiophobia. Further research is recommended to investigate the long-term benefits and risks of CBT including for the different subgroups of subjects with NP.
We included 10 studies with 709 participants in this review. Of the 10 studies, eight were conducted in high income countries (USA and Italy), seven were conducted prior to 2000 and seven had predominantly men. Seven studies assessed antidepressants versus placebo, two compared different antidepressant classes and one had three arms comparing two antidepressant classes with placebo. Antidepressant therapy may result in a greater improvement in depression compared to placebo. There was a moderate improvement in depression when assessed with the Hamilton Depression Rating Scale (HAM-D) score as a continuous outcome (SMD 0.59, 95% CI 0.21 to 0.96; participants = 357; studies = 6; I2 = 62%, low quality evidence). However, there was no evidence of improvement when this was assessed with HAM-D score as a dichotomized outcome (RR 1.10, 95% CI 0.89 to 1.35; participants = 434; studies = 5; I2 = 0%, low quality evidence) or Clinical Global Impression of Improvement (CGI-I) score (RR 1.28, 95% CI 0.93 to 1.77; participants = 346; studies = 4; I2 = 29%, low quality evidence). There was little to no difference in the proportion of study dropouts between study arms (RR 1.28, 95% CI 0.91 to 1.80; participants = 306; studies = 4; I2 = 0%, moderate quality evidence). The methods of reporting adverse events varied substantially between studies, this resulted in very low quality evidence contributing to a pooled estimate (RR 0.88, 95% CI 0.64 to 1.21; participants = 167; studies = 2; I2 = 34%; very low quality evidence). Based on this, we were unable to determine if there was a difference in the proportion of participants experiencing adverse events in the antidepressant versus placebo arms. However, sexual dysfunction was reported commonly in people receiving selective serotonin reuptake inhibitors (SSRIs). People receiving tricyclic antidepressants (TCAs) frequently reported anticholinergic adverse effects such as dry mouth and constipation. There were no reported grade 3 or 4 adverse events in any study group. There was no evidence of a difference in follow-up CD4 count at study termination (MD -6.31 cells/mm3, 95% CI -72.76 to 60.14; participants = 176; studies = 3; I2 = 0%; low quality evidence). Only one study evaluated quality of life score (MD 3.60, 95% CI -0.38 to 7.58; participants = 87; studies = 1; very low quality evidence), due to the poor quality evidence we could not draw conclusions for this outcome. There were few studies comparing different antidepressant classes. We are uncertain if SSRIs differ from TCAs with regard to improvement in depression as evaluated by HAM-D score (MD -3.20, 95% CI -10.87 to 4.47; participants = 14; studies = 1; very low quality evidence). There was some evidence that mirtazapine resulted in a greater improvement in depression compared to an SSRI (MD 9.00, 95% CI 3.61 to 14.39; participants = 70; studies = 1; low quality evidence); however, this finding was not consistent for all measures of improvement in depression for this comparison. No studies reported on virological suppression or any other HIV specific outcomes. The studies included in this review had an overall unclear or high risk of bias due to under-reporting of study methods, high risk of attrition bias and inadequate sequence generation methods. Heterogeneity between studies and the limited number of participants, and events lead to downgrading of the quality of the evidence for several outcomes. This review demonstrates that antidepressant therapy may be more beneficial than placebo for the treatment of depression in PLWH. The low quality of the evidence contributing to this assessment and the lack of studies representing PLWH from generalized epidemics in low- to middle-income countries make the relevance of these finding in today's context limited. Future studies that evaluate the effectiveness of antidepressant therapy should be designed and conducted rigorously. Such studies should incorporate evaluation of stepped care models and health system strengthening interventions in the study design. In addition, outcomes related to HIV care and antiretroviral therapy should be reported.
We included 12 trials in the original review (2009) and included no further trials in the first update (2011). An additional seven new trials met the inclusion criteria in this second update. In total, we included 19 RCTs involving 1346 participants at entry, with 11 trials awaiting classification either because the full text was unavailable or information in the full text failed to clarify eligibility. We excluded most trials because TENS was given in combination with another treatment as part of the formal study design or TENS was not delivered using appropriate TENS technique. The types of acute pain included in this Cochrane Review were procedural pain, e.g. cervical laser treatment, venepuncture, screening flexible sigmoidoscopy and non-procedural pain, e.g. postpartum uterine contractions and rib fractures. We pooled data for pain intensity for six trials (seven comparisons) comparing TENS with placebo but the I2 statistic suggested substantial heterogeneity. Mean difference (MD) with 95% confidence intervals (CIs) on a visual analogue scale (VAS, 100 mm) was -24.62 mm (95% CI -31.79 to -17.46) in favour of TENS. Data for the proportion of participants achieving ≥ 50% reduction in pain was pooled for four trials (seven comparisons) and relative risk was 3.91 (95% CI 2.42 to 6.32) in favour of TENS over placebo. We pooled data for pain intensity from five trials (seven comparisons) but the I2 statistic suggested considerable heterogeneity. MD was -19.05 mm (95% CI -27.30 to -10.79) in favour of TENS using a random-effects model. It was not possible to pool other data. There was a high risk of bias associated with inadequate sample sizes in treatment arms and unsuccessful blinding of treatment interventions. Seven trials reported minor adverse effects, such as mild erythema and itching underneath the electrodes and participants disliking TENS sensation. This Cochrane Review update includes seven new trials, in addition to the 12 trials reviewed in the first update in 2011. The analysis provides tentative evidence that TENS reduces pain intensity over and above that seen with placebo (no current) TENS when administered as a stand-alone treatment for acute pain in adults. The high risk of bias associated with inadequate sample sizes in treatment arms and unsuccessful blinding of treatment interventions makes definitive conclusions impossible. There was incomplete reporting of treatment in many reports making replication of trials impossible.
We included 18 RCTs involving 2952 participants; 15 compared rhCG with uhCG, and 3 compared rhLH with uhCG. The evidence for different comparisons ranged from very low to high quality: limitations were poor reporting of study methods and imprecision. Pharmaceutical companies funded 9 of the 18 studies, and 5 studies did not clearly report funding source. Ongoing pregnancy/live birth There was no conclusive evidence of a difference between rhCG and uhCG (OR 1.15, 95% CI 0.89 to 1.49; 7 RCTs, N = 1136, I2 = 0%, moderate quality evidence) or between rhLH and uhCG (OR 0.95, 95% CI 0.51 to 1.78, 2 RCTs, N = 289, I2 = 0%, very low quality evidence) for ongoing pregnancy/live birth rates. OHSS There was no evidence of a difference between rhCG and uhCG in the incidence of OHSS: moderate to severe OHSS (OR 1.76, 95% CI 0.37 to 8.45; 3 RCTs, N = 417, I2 = 0%, low quality evidence), moderate OHSS (OR 0.78, 95% CI 0.27 to 2.27; 1 RCT, N = 243, I2 = 0%, low quality evidence), mild to moderate OHSS (OR 1.00, 95% CI 0.42 to 2.38; 2 RCTs, N = 320, I2 = 0%, low quality evidence) or undefined OHSS (OR 1.18, 95% CI 0.50 to 2.78; 3 RCTs, N = 495, I2 = 0%, low quality evidence). Likewise, there was no evidence of a difference between rhLH and uhCG in OHSS rates for moderate OHSS (OR 0.82, 95% CI 0.39 to 1.69, 2 RCTs, N = 280, I2 = 5%, very low quality evidence). Other adverse events There was no evidence of a difference in miscarriage rates between rhCG and uhCG (OR 0.72, 95% CI 0.41 to 1.25; 8 RCTs, N = 1196, I2 = 0%, low quality evidence) or between rhLH and uhCG (OR 0.95, 95% CI 0.38 to 2.40; 2 RCTs, N = 289, I2 = 0%, very low quality evidence). For other adverse effects (most commonly injection-site reactions) rhCG was associated with a lower number of adverse events than uhCG (OR 0.52, 95% CI 0.35 to 0.76; 5 RCTS, N = 561; I2 = 67%, moderate quality evidence). However, when we used a random-effects model due to substantial statistical heterogeneity, there was no evidence of a difference between the groups (OR 0.56, 95% CI 0.27 to 1.13). Only one study comparing rLH and uhCG reported other adverse events, and it was impossible to draw conclusions. We conclude that there is no evidence of a difference between rhCG or rhLH and uhCG for live birth or ongoing pregnancy rates or rates of OHSS.
We included 22 studies with 1097 randomised participants. Twenty-one studies with 890 participants contributed data to meta-analyses. Participants in the studies had dementia of varying degrees of severity, and all were resident in institutions. Seven studies delivered an individual music intervention; the other studies delivered the intervention to groups of participants. Most interventions involved both active and receptive musical elements. The methodological quality of the studies varied. All were at high risk of performance bias and some were at high risk of detection or other bias. At the end of treatment, we found low-quality evidence that the interventions may improve emotional well-being and quality of life (standardised mean difference (SMD) 0.32, 95% confidence interval (CI) 0.02 to 0.62; 9 studies, 348 participants) and reduce anxiety (SMD –0.43, 95% CI –0.72 to –0.14; 13 studies, 478 participants). We found low-quality evidence that music-based therapeutic interventions may have little or no effect on cognition (SMD 0.15, 95% CI –0.06 to 0.36; 7 studies, 350 participants). There was moderate-quality evidence that the interventions reduce depressive symptoms (SMD –0.27, 95% CI –0.45 to –0.09; 11 studies, 503 participants) and overall behaviour problems (SMD –0.23, 95% CI –0.46 to –0.01; 10 studies, 442 participants), but do not decrease agitation or aggression (SMD –0.07, 95% CI –0.24 to 0.10; 14 studies, 626 participants). The quality of the evidence on social behaviour was very low, so effects were very uncertain. The evidence for long-term outcomes measured four or more weeks after the end of treatment was of very low quality for anxiety and social behaviour, and for the other outcomes, it was of low quality for little or no effect (with small SMDs, between 0.03 and 0.34). Providing people with dementia who are in institutional care with at least five sessions of a music-based therapeutic intervention probably reduces depressive symptoms and improves overall behavioural problems at the end of treatment. It may also improve emotional well-being and quality of life and reduce anxiety, but may have little or no effect on agitation or aggression or on cognition. We are uncertain about effects on social behaviour and about long-term effects. Future studies should examine the duration of effects in relation to the overall duration of treatment and the number of sessions.
We identified one randomized controlled trial (CCLG-ENSG-5) that included 262 patients with high-risk neuroblastoma who were randomized to receive either rapid COJEC (N = 130) or standard OPEC/COJEC (N = 132) induction chemotherapy. We graded the evidence as low quality; we downgraded for risk of bias and imprecision. There was no clear evidence of a difference between the treatment groups in complete response (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.71 to 1.38), treatment-related mortality (RR 1.21, 95% CI 0.33 to 4.39), overall survival (hazard ratio (HR) 0.83, 95% CI 0.63 to 1.10), and event-free survival (HR 0.86, 95% CI 0.65 to 1.13). We calculated the HRs using the complete follow-up period of the trial. Febrile neutropenia (two or more episodes), proven fungal infections, septicemia (one or more episodes), gastrointestinal toxicity (grade 3 or 4), renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m2), neurological toxicity (grade 3 or 4), and ototoxicity (Brock grade 2 to 4) were addressed as early toxicities (during pre-operative chemotherapy). For febrile neutropenia, septicemia, and renal toxicity, a statistically significant difference in favor of the standard treatment arm was identified; for all other early toxicities no clear evidence of a difference between treatment groups was identified. With regard to late non-hematological toxicities (median follow-up 12.7 years; range 6.9 to 16.5 years), the study provided data on any complication, renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73m2), ototoxicity (Brock grade 1 to 4), endocrine complications, neurocognitive complications (i.e. behavioral, speech, or learning difficulties), and second malignancies. For endocrine complications and neurocognitive complications, a statistically significant difference in favor of the rapid COJEC arm was found; for all other late non-hematological toxicities no clear evidence of a difference between treatment groups was identified. Data on progression-free survival and health-related quality of life were not reported. We identified one randomized controlled trial that evaluated rapid COJEC versus standard induction therapy in patients with high-risk neuroblastoma. No clear evidence of a difference in complete response, treatment-related mortality, overall survival, and event-free survival between the treatment alternatives was found. This could be the result of low power or too short a follow-up period. Results of both early and late toxicities were ambiguous. Information on progression-free survival and health-related quality of life were not available. This trial was performed in the 1990s. Since then, many changes in, for example, treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of rapid COJEC and standard induction therapy in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.
A total of 16 randomised controlled trials (n=2277) were included in the meta-analysis.Despite the size of this sample, the pooled 95% confidence intervals were rather wide and there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressive agents. However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95%CI 0.35 to 0.85). There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs. Currently, there is inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events (acceptability) and the rates of experiencing adverse events (tolerability). Information about other clinically meaningful outcomes such as cost-effectiveness and social functioning, including the ability to return to work, is lacking. Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression.
Two randomized controlled trials (331 participants) met the inclusion criteria. They were conducted in the 1970s and 1980s with follow-up reports available after 18 months, three years, and five years; one trial also reported 10 years follow up. Completeness of follow up varied at the different time points, with less than 80% of participants available for analysis at several time points. There was no statistically significant difference for any of the outcome measures: kyphosis angle, neurological deficit (none went on to develop this), bony fusion, absence of spinal tuberculosis, death from any cause, activity level regained, change of allocated treatment, or bone loss. Neither trial reported on pain. Of the 130 participants allocated to chemotherapy only, 12 had a neurological deficit and five needed a decompression operation. One trial suggested that an initial kyphosis angle greater than 30° is likely to deteriorate, especially in children. The two included trials had too few participants to be able to say whether routine surgery might help. Although current medication and operative techniques are now far more advanced, these results indicate that routine surgery cannot be recommended unless within the context of a large, well-conducted randomized controlled trial. Clinicians may judge that surgery may be clinically indicated in some groups of patients. Future studies need to address these topics as well as the patient's view of their disease and treatment.
Twenty-four studies were identified that involved acupuncture for endometriosis; however only one trial, enrolling 67 participants, met all the inclusion criteria. The single included trial defined pain scores and cure rates according to the Guideline for Clinical Research on New Chinese Medicine. Dysmenorrhoea scores were lower in the acupuncture group (mean difference -4.81 points, 95% confidence interval -6.25 to -3.37, P < 0.00001) using the 15-point Guideline for Clinical Research on New Chinese Medicine for Treatment of Pelvic Endometriosis scale. The total effective rate ('cured', 'significantly effective' or 'effective') for auricular acupuncture and Chinese herbal medicine was 91.9% and 60%, respectively (risk ratio 3.04, 95% confidence interval 1.65 to 5.62, P = 0.0004). The improvement rate did not differ significantly between auricular acupuncture and Chinese herbal medicine for cases of mild to moderate dysmenorrhoea, whereas auricular acupuncture did significantly reduce pain in cases of severe dysmenorrhoea. Data were not available for secondary outcomes measures. The evidence to support the effectiveness of acupuncture for pain in endometriosis is limited, based on the results of only a single study that was included in this review. This review highlights the necessity for developing future studies that are well-designed, double-blinded, randomised controlled trials that assess various types of acupuncture in comparison to conventional therapies.
The review contains four studies with a total of 149 participants. Two studies compared NPWT with dressings; one study compared NPWT with a series of gel treatments and one study compared NPWT with 'moist wound healing'. One study had a 24-week follow-up period, and two had a six-week follow-up period, the follow-up time was unclear for one study. Three of the four included studies were deemed to be at a high risk of bias from one or more 'Risk of bias' domains and all evidence was deemed to be of very low quality. Only one study reported usable primary outcome data (complete wound healing), but this had only 12 participants and there were very few events (only one participant healed in the study). There was little other useful data available from the included studies on positive outcomes such as wound healing or negative outcomes such as adverse events. There is currently no rigorous RCT evidence available regarding the effects of NPWT compared with alternatives for the treatment of pressure ulcers. High uncertainty remains about the potential benefits or harms, or both, of using this treatment for pressure ulcer management.
This review included 19 trials involving 2137 participants. Only five trials fulfilled the criteria of good methodological quality. One trial compared laser trabeculoplasty with topical beta-blocker to no intervention in early glaucoma. The risk of glaucoma progression was higher in the control group at six years of follow up (risk ratio (RR) 0.71 95% confidence interval (CI) 0.53 to 0.95). No difference in health-related quality of life was observed between the two groups. Three trials compared laser trabeculoplasty to medication (regimens used before the 1990s) in people with newly diagnosed OAG. The risk of uncontrolled intraocular pressure (IOP) was higher in the medication group compared to the trabeculoplasty group at six months and two years of follow up. Three trials compared laser trabeculoplasty with trabeculectomy. The risk of uncontrolled IOP was significantly higher in the trabeculoplasty group at six months but significant heterogeneity was observed at two years. Diode and selective laser are compared to argon laser trabeculoplasty in three trials and there is some evidence showing a comparable effect in controlling IOP at six months and one year of follow up. Evidence suggests that, in people with newly diagnosed OAG, the risk of uncontrolled IOP is higher in people treated with medication used before the 1990s when compared to laser trabeculoplasty at two years follow up. Trabeculoplasty is less effective than trabeculectomy in controlling IOP at six months and two years follow up. Different laser technology and protocol modalities were compared to the traditional laser trabeculoplasty and more evidence is necessary to determine if they are equivalent or not. There is no evidence to determine the effectiveness of laser trabeculoplasty compared to contemporary medication (prostaglandin analogues, topical anhydrase inhibitors and alpha2-agonists) and also with contemporary surgical techniques. Also there should be further investigation in to the effectiveness of laser trabeculoplasty in specific racial groups, specific diagnostic groups, such as pseudoexfoliation and pigmentary glaucoma and different stages of OAG. More research is also required determining cost-effectiveness of laser trabeculoplasty in the management of glaucoma.
A total of three studies involving 466 participants were included. There was no statistically significant difference between the asthma clinic group and the control group for most outcomes (primary outcomes: asthma exacerbations leading to hospitalisation or accident and emergency (A&E) visit, use of reliever and preventer medication, quality of life; secondary outcomes: symptoms, time lost from work and withdrawals from the intervention or usual care). However, the confidence intervals were wide for all outcomes and there was substantial heterogeneity between the studies for both A&E visits and time lost from work. One study (101 patients) looked at nocturnal awakenings due to asthma and found a statistically significant reduction in the number of patients reporting this symptom in the asthma clinic group compared to the usual care group (OR 0.31; 95% CI 0.12 to 0.77). There were no studies looking at the secondary outcome of exacerbations requiring oral steroids. There is limited evidence of efficacy for primary care based asthma clinics, and firm conclusions cannot be formed until more good quality trials have been carried out.
The review included seven studies, involving 380 adults. Of the 380 randomised participants, 348 completed the studies. Due to differences in outcomes reported among the seven studies, we could only perform limited meta-analysis for both the short-term ICS use (6 months or less) and the longer-term ICS use (> 6 months). During stable state in the short-term group (ICS for 6 months or less), based on the two studies from which data could be included, there were no significant differences from baseline values in the forced expiratory volume in the first second (FEV1) at the end of the study (mean difference (MD) -0.09, 95% confidence interval (CI) -0.26 to 0.09) and forced vital capacity (FVC) (MD 0.01 L, 95% CI -0.16 to 0.17) in adults on ICS (compared to no ICS). Similarly, we did not find any significant difference in the average exacerbation frequency (MD 0.09, 95% CI -0.61 to 0.79) or health-related quality of life (HRQoL) total scores in adults on ICS when compared with no ICS, though data available were limited. Based on a single non-placebo controlled study from which we could not extract clinical data, there was marginal, though statistically significant improvement in sputum volume and dyspnoea scores on ICS. The single study on long-term outcomes (over 6 months) that examined lung function and other clinical outcomes, showed no significant effect of ICS on any of the outcomes. We could not draw any conclusion on adverse effects due to limited available data. Despite the authors of all seven studies stating they were double-blind, we judged one study (in the short duration ICS) as having a high risk of bias based on blinding, attrition and reporting of outcomes. The GRADE quality of evidence was low for all outcomes (due to non-placebo controlled trial, indirectness and imprecision with small numbers of participants and studies). This updated review indicates that there is insufficient evidence to support the routine use of ICS in adults with stable state bronchiectasis. Further, we cannot draw any conclusion for the use of ICS in adults during an acute exacerbation or in children (for any state), as there were no studies.
We included 28 small, low quality studies (29 reports) involving 2564 participants. Of 20 studies (21 reports) comparing morphine with placebo, nine studies with adequate data were included in the meta-analysis. Overall, the risk of bias was unclear. Overall, the quality of the evidence assessed using GRADE was low to very low, downgraded primarily due to risk of bias, small study size, and imprecision. No statistical difference was found between 1 mg IA morphine and placebo in pain intensity (visual analogue scale (VAS)) at early phase (zero to two hours) (mean difference (MD) -0.50, 95% CI -1.15 to 0.14; participants = 297; studies = 7; low quality evidence), medium phase (two to six hours) (MD -0.47, 95% CI -1.09 to 0.14; participants = 297; studies = 7; low quality evidence) and late phase (six to 30 hours) (MD -0.88, 95% CI -1.81 to 0.04; participants = 297; studies = 7; low quality evidence). No significant difference was found between 1 mg and 2 mg morphine for pain intensity at early phase (MD -0.56, 95% CI -1.93 to 0.81; participants = 105; studies = 2; low quality evidence), while 4 mg/5 mg morphine provided better analgesia than 1 mg morphine at late phase (MD 0.67, 95% CI 0.08 to 1.25; participants = 97; studies = 3; low quality evidence). IA morphine was not better than local anaesthetic agents at early phase (MD 1.43, 95% CI 0.49 to 2.37; participants = 248; studies = 5; low quality evidence), NSAIDs at early phase (MD 0.95, 95% CI -0.95 to 2.85; participants = 80; studies = 2; very low quality evidence), sufentanil, fentanyl or pethidine for pain intensity. IA morphine was similar to intramuscular (IM) morphine for pain intensity at early phase (MD 0.21, 95% CI -0.48 to 0.90; participants = 72; studies = 2; very low quality evidence). Meta-analysis indicated that there was no difference between IA morphine and placebo or bupivacaine in time to first analgesic request. Eleven out of 20 studies comparing morphine with placebo reported adverse events and no statistical difference was obtained regarding the incidence of adverse events (risk ratio (RR) 1.09, 95% CI 0.51 to 2.36; participants = 314; studies = 8; low quality evidence). Seven of 28 studies reported participants' withdrawal. There were not enough data for withdrawals to be able to perform meta-analysis. We have not found high quality evidence that 1 mg IA morphine is better than placebo at reducing pain intensity at early, medium or late phases. No statistical difference was reported between IA morphine and placebo regarding the incidence of adverse events. The relative effects of 1 mg morphine when compared with IA bupivacaine, NSAIDs, sufentanil, fentanyl and pethidine are uncertain. The quality of the evidence is limited by high risk of bias and small size of the included studies, which might bias the results. More high quality studies are needed to get more conclusive results.
One randomised controlled trial has compared pramipexole with bromocriptine using a double-blind, parallel group, multicentre design. It was not powered to examine differences between active treatment arms. There was a larger reduction in off time with pramipexole therapy compared with bromocriptine (weighted mean difference 1.4 hours; 0, 2.8, 95% CI). No differences occurred in dyskinesia rating scale, dyskinesia as an adverse event or UPDRS complication score. The UPDRS ADL and motor scores showed similar improvements compared to placebo with both agonists. Levodopa dose reduction was similar with both agonists. Subscales of the Functional Status Questionnaire showed significant improvements compared to placebo with both agonists. The finding that the EuroQol improved significantly compared with placebo with pramipexole but not bromocriptine should be treated with caution. Dopaminergic adverse events were similar with each agonist, as was the all cause withdrawal rate. Although pramipexole and bromocriptine improved off time and reduced parkinsonian motor impairments and disability compared with placebo, no conclusions regarding their comparative effectiveness and safety can be drawn as this single trial did not have adequate power to assess such differences. Further larger trials are required to examine this issue in the future.
Seventeen studies (831 participants) met the inclusion criteria. All the studies had some shortcomings, such as small sample size, under-reporting of methods and data, and lack of blinding. OA versus control appliances (six studies): OA reduced daytime sleepiness in two crossover trials (ESS score -1.81; 95%CI -2.72 to -0.90), and improved apnoea-hypopnoea index (AHI) (-10.78 events/hr; 95% CI-15.53 to -6.03 parallel group data - five studies). OA versus CPAP (ten studies): There was no statistically significant difference in symptoms for either parallel or crossover studies, although OAs were less effective than CPAP in reducing apnoea-hypopnoea index in parallel and crossover studies. CPAP was more effective at improving minimum arterial oxygen saturation during sleep compared with OA. In two small crossover studies, participants preferred OA therapy to CPAP. OA versus corrective upper airway surgery (one study): Symptoms of daytime sleepiness were initially lower with surgery, but this difference disappeared at 12 months. AHI did not differ significantly initially, but did so after 12 months in favour of OA. There is increasing evidence suggesting that OA improves subjective sleepiness and sleep disordered breathing compared with a control. CPAP appears to be more effective in improving sleep disordered breathing than OA. The difference in symptomatic response between these two treatments is not significant, although it is not possible to exclude an effect in favour of either therapy. Until there is more definitive evidence on the effectiveness of OA in relation to CPAP, with regard to symptoms and long-term complications, it would appear to be appropriate to recommend OA therapy to patients with mild symptomatic OSAH, and those patients who are unwilling or unable to tolerate CPAP therapy. Future research should recruit patients with more severe symptoms of sleepiness, to establish whether the response to therapy differs between subgroups in terms of quality of life, symptoms and persistence with usage. Long-term data on cardiovascular health are required.
We included 39 parallel randomised controlled trials (RCTs) involving adults and children with asthma, 28 of which (n = 16,303) contributed data to at least one meta-analysis. Follow-up ranged from two months to two years (median six months), and trials were conducted mainly in high-income countries. Most studies reported some measure of adherence to ICS and a variety of other outcomes such as quality of life and asthma control. Studies generally were at low or unclear risk of selection bias and at high risk of biases associated with blinding. We considered around half the studies to be at high risk for attrition bias and selective outcome reporting. We classified studies into four comparisons: adherence education versus control (20 studies); electronic trackers or reminders versus control (11 studies); simplified drug regimens versus usual drug regimens (four studies); and school-based directly observed therapy (three studies). Two studies are described separately. All pooled results for adherence education, electronic trackers or reminders and simplified regimens showed better adherence than controls. Analyses limited to studies using objective measures revealed that adherence education showed a benefit of 20 percentage points over control (95% confidence interval (CI) 7.52 to 32.74; five studies; low-quality evidence); electronic trackers or reminders led to better adherence of 19 percentage points (95% CI 14.47 to 25.26; six studies; moderate-quality evidence); and simplified regimens led to better adherence of 4 percentage points (95% CI 1.88 to 6.16; three studies; moderate-quality evidence). Our confidence in the evidence was reduced by risk of bias and inconsistency. Improvements in adherence were not consistently translated into observable benefit for clinical outcomes in our pooled analyses. None of the intervention types showed clear benefit for our primary clinical outcomes - exacerbations requiring an oral corticosteroid (OCS) (evidence of very low to low quality) and asthma control (evidence of low to moderate quality); nor for our secondary outcomes - unscheduled visits (evidence of very low to moderate quality) and quality of life (evidence of low to moderate quality). However, some individual studies reported observed benefits for OCS and use of healthcare services. Most school or work absence data were skewed and were difficult to interpret (evidence of low quality, when graded), and most studies did not specifically measure or report adverse events. Studies investigating the possible benefit of administering ICS at school did not measure adherence, exacerbations requiring OCS, asthma control or adverse events. One study showed fewer unscheduled visits, and another found no differences; data could not be combined. Pooled results suggest that a variety of interventions can improve adherence. The clinical relevance of this improvement, highlighted by uncertain and inconsistent impact on clinical outcomes such as quality of life and asthma control, is less clear. We have low to moderate confidence in these findings owing to concerns about risk of bias and inconsistency. Future studies would benefit from predefining an evidence-based 'cut-off' for acceptable adherence and using objective adherence measures and validated tools and questionnaires. When possible, covert monitoring and some form of blinding or active control may help disentangle effects of the intervention from effects of inclusion in an adherence trial.
We included two studies, both from the United States. People offered health insurance information and application support by community-based case managers were probably more likely to enrol their children into health insurance programmes (risk ratio (RR) 1.68, 95% confidence interval (CI) 1.44 to 1.96, moderate quality evidence) and were probably more likely to continue insuring their children (RR 2.59, 95% CI 1.95 to 3.44, moderate quality evidence). Of all the children that were insured, those in the intervention group may have been insured quicker (47.3 fewer days, 95% CI 20.6 to 74.0 fewer days, low quality evidence) and parents may have been more satisfied on average (satisfaction score average difference 1.07, 95% CI 0.72 to 1.42, low quality evidence). In the second study applications were handed out in emergency departments at hospitals, compared to not handing out applications, and may have had an effect on enrolment (RR 1.5, 95% CI 1.03 to 2.18, low quality evidence). Community-based case managers who provide health insurance information, application support, and negotiate with the insurer probably increase enrolment of children in health insurance schemes. However, the transferability of this intervention to other populations or other settings is uncertain. Handing out insurance application materials in hospital emergency departments may help increase the enrolment of children in health insurance schemes. Further studies evaluating the effectiveness of different strategies for expanding health insurance coverage in vulnerable population are needed in different settings, with careful attention given to study design.
Six trials (1422 participants) were included in the review. There was a high rate of failure to complete treatment on all treatments which may have biased the estimates of relative efficacy. Olanzapine was superior to placebo at reducing manic symptoms as monotherapy (Young Mania Rating Scale (YMRS) - weighted mean difference (WMD): -5.94, 95% CI -9.09 to -2.80) and in combination with lithium/valproate (YMRS) (WMD -4.01, 95% confidence interval -6.06 to -1.96). Olanzapine monotherapy was superior at reducing psychotic symptoms (PANSS positive symptoms subscale WMD: -3.54, 95% CI -5.28 to -1.80). Olanzapine was superior to divalproex at reducing manic symptoms (standardised mean difference (SMD): -0.29, 95% CI -0.50 to -0.08). Olanzapine did not lead to a statistically higher rate of clinical response than haloperidol (RR: 1.03, 95% CI 0.77 to 1.38). Fewer patients discontinued treatment on olanzapine than placebo (RR: 0.62, 95% CI 0.48 to 0.80). Olanzapine caused greater weight gain than placebo (WMD 1.91Kg, 95% CI 1.29 to 2.53) and somnolence (RR: 2.13 95% CI 1.62 to 2.79) but not more depressive symptoms (RR: 0.95, 95% CI 0.65 to 1.40) or movement disorder (WMD: -0.33, 95% CI -0.74 to 0.09). Olanzapine caused more prolactin elevation than placebo (RR: 4.35 95%CI 1.77 to 10.70). Olanzapine caused greater weight gain (WMD: 1.54, 95% CI 1.02 to 2.05); somnolence (RR: 1.80 95% CI 1.32 to 2.46) and movement disorders (SAS - WMD: 0.72 95% CI 0.11 to 1.33) than divalproex but less nausea ( RR: 0.36 95% CI 0.20 to 0.65). Olanzapine caused more weight gain than haloperidol (RR: 3.59, 95% CI 1.49 to 8.64) but less movement disorder (EPS RR: 0.10, 95% CI 0.04 to 0.24). Olanzapine is an effective treatment for mania and may be more efficacious than divalproex, though leads to more weight gain. Clinicians should consider both the relative efficacy and the different incidence of specific adverse effects of available drugs.
We included ten papers reporting results from six intervention studies. Overall, design quality and analysis limited the risks of bias. Several CCT programmes provided strong evidence of a positive impact on the use of health services, nutritional status and health outcomes, respectively assessed by anthropometric measurements  and self-reported episodes of illness. It is hard to attribute these positive effects to the cash incentives specifically because other components may also contribute. Several studies provide evidence of positive impacts on the uptake of preventive services by children and pregnant women. We found no evidence about effects on health care expenditure. Conditional cash transfer programmes have been the subject of some well-designed evaluations, which strongly suggest that they could be an effective approach to improving access to preventive services. Their replicability under different conditions - particularly in more deprived settings - is still unclear because they depend on effective primary health care and mechanisms to disburse payments. Further rigorous evaluative research is needed, particularly where CCTs are being introduced in low income countries, for example in Sub-Saharan Africa or South Asia.
Five studies reported five comparisons of paraprofessionals versus professionals (n=106) and five comparisons of paraprofessionals versus control condition (n=220). No differences were found between paraprofessionals and professionals (SMD=0.09, 95% CI -0.23 to 0.40, p=0.58), and no significant heterogeneity. Studies comparing paraprofessionals versus control (mixed continuous and dichotomous data) showed a significant effect in favour of paraprofessionals (OR=0.34, 95% CI 0.13 to 0.88, p=0.03), but heterogeneity was indicated (I²=60.9%, Chi²= 10.24, df=4, p=0.04). After correction for heterogeneity and removing one study of low quality, the pooling of data from three studies (n=128; mixed gender; women) indicated no significant difference in effect between paraprofessionals and professionals (SMD=0.13, 95% CI -0.39 to 0.64; p=0.63) and a strongly significant pooled effect for three studies (n=188; women) favouring paraprofessionals over the control condition (OR=0.30, 95% CI 0.18 to 0.48, p<0.00001), and homogeneity indicated between studies (I²=0%, Chi²=0.47, df=2, p=0.79). The few studies included in the review did not allow conclusions about the effect of paraprofessionals compared to professionals, but three studies (women only) indicated a significant effect for paraprofessionals (all volunteers) compared to no treatment. The evidence to date may justify the development and evaluation of programs incorporating paraprofessionals in treatment programs for anxiety and depressive disorders.
The only point-of-care biomarker of infection currently available to primary care identified in this review was C-reactive protein. We included six trials (3284 participants; 139 children) that evaluated a C-reactive protein point-of-care test. The available information was from trials with a low to moderate risk of bias that address the main objectives of this review. Overall a reduction in the use of antibiotic treatments was found in the C-reactive protein group (631/1685) versus standard of care (785/1599). However, the high level of heterogeneity and the statistically significant test for subgroup differences between the three RCTs and three cluster-RCTs suggest that the results of the meta-analysis on antibiotic use should be interpreted with caution and the pooled effect estimate (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92; I2 statistic = 68%) may not be meaningful. The observed heterogeneity disappeared in our preplanned subgroup analysis based on study design: RR 0.90, 95% CI 0.80 to 1.02; I2 statistic = 5% for RCTs and RR 0.68, 95% CI 0.61 to 0.75; I2 statistic = 0% for cluster-RCTs, suggesting that this was the cause of the observed heterogeneity. There was no difference between using a C-reactive protein point-of-care test and standard care in clinical recovery (defined as at least substantial improvement at day 7 and 28 or need for re-consultations day 28). However, we noted an increase in hospitalisations in the C-reactive protein group in one study, but this was based on few events and may be a chance finding. No deaths were reported in any of the included studies. We classified the quality of the evidence as moderate according to GRADE due to imprecision of the main effect estimate. A point-of-care biomarker (e.g. C-reactive protein) to guide antibiotic treatment of ARIs in primary care can reduce antibiotic use, although the degree of reduction remains uncertain. Used as an adjunct to a doctor's clinical examination this reduction in antibiotic use did not affect patient-reported outcomes, including recovery from and duration of illness. However, a possible increase in hospitalisations is of concern. A more precise effect estimate is needed to assess the costs of the intervention and compare the use of a point-of-care biomarker to other antibiotic-saving strategies.
We included 83 trials in this review. The majority of trials (67) were carried out in school settings with eight in colleges or universities, four in clinical settings, three in the community and four in mixed settings. Twenty-nine trials were carried out in unselected populations and 53 in targeted populations. For the primary outcome of depression diagnosis at medium-term follow-up (up to 12 months), there were 32 trials with 5965 participants and the risk of having a diagnosis of depression was reduced for participants receiving an intervention compared to those receiving no intervention (risk difference (RD) -0.03, 95% confidence interval (CI) -0.05 to -0.01; P value = 0.01). We rated this evidence as moderate quality according to the GRADE criteria. There were 70 trials (73 trial arms) with 13,829 participants that contributed to the analysis for the primary outcome of depression symptoms (self-rated) at the post-intervention time point, with results showing a small but statistically significant effect (standardised mean difference (SMD) -0.21, 95% CI -0.27 to -0.15; P value < 0.0001). This effect persisted to the short-term assessment point (up to three months) (SMD -0.31, 95% CI -0.45 to -0.17; P value < 0.0001; 16 studies; 1558 participants) and medium-term (4 to 12 months) assessment point (SMD -0.12, 95% CI -0.18 to -0.05; P value = 0.0002; 53 studies; 11,913 participants); however, the effect was no longer evident at the long-term follow-up. We rated this evidence as low to moderate quality according to the GRADE criteria. The evidence from this review is unclear with regard to whether the type of population modified the overall effects; there was statistically significant moderation of the overall effect for depression symptoms (P value = 0.0002), but not for depressive disorder (P value = 0.08). For trials implemented in universal populations there was no effect for depression diagnosis (RD -0.01, 95% CI -0.03 to 0.01) and a small effect for depression symptoms (SMD -0.11, 95% CI -0.17 to -0.05). For trials implemented in targeted populations there was a statistically significantly beneficial effect of intervention (depression diagnosis RD -0.04, 95% CI -0.07 to -0.01; depression symptoms SMD -0.32, 95% CI -0.42 to -0.23). Of note were the lack of attention placebo-controlled trials in targeted populations (none for depression diagnosis and four for depression symptoms). Among trials implemented in universal populations a number used an attention placebo comparison in which the intervention consistently showed no effect. Overall the results show small positive benefits of depression prevention, for both the primary outcomes of self-rated depressive symptoms post-intervention and depression diagnosis up to 12 months (but not beyond). Estimates of numbers needed to treat to benefit (NNTB = 11) compare well with other public health interventions. However, the evidence was of moderate to low quality using the GRADE framework and the results were heterogeneous. Prevention programmes delivered to universal populations showed a sobering lack of effect when compared with an attention placebo control. Interventions delivered to targeted populations, particularly those selected on the basis of depression symptoms, had larger effect sizes, but these seldom used an attention placebo comparison and there are practical difficulties inherent in the implementation of targeted programmes. We conclude that there is still not enough evidence to support the implementation of depression prevention programmes. Future research should focus on current gaps in our knowledge. Given the relative lack of evidence for universal interventions compared with attention placebo controls and the poor results from well-conducted effectiveness trials of universal interventions, in our opinion any future such trials should test a depression prevention programme in an indicated targeted population using a credible attention placebo comparison group. Depressive disorder as the primary outcome should be measured over the longer term, as well as clinician-rated depression. Such a trial should consider scalability as well as the potential for the intervention to do harm.
We included three studies (179 participants) comparing LESS-DN with laparoscopic donor nephrectomy. There were no significant differences between LESS-DN and laparoscopic donor nephrectomy for mean operative time (2 studies, 79 participants: MD 6.36 min, 95% CI -11.85 to 24.57), intra-operative blood loss (2 studies, 79 participants: MD -8.31 mL, 95% CI -23.70 to 7.09), or complication rates (3 studies, 179 participants: RD 0.05, 95% CI -0.04 to 0.14). Pain scores at discharge were significantly less in the LESS-DN group (2 studies, 79 participants: MD -1.19, 95% CI -2.17 to -0.21). For all other outcomes (length of hospital stay; length of time to return to normal activities; blood transfusions; conversion to another form of surgery; warm ischaemia time; total analgesic requirement; graft loss) there were no significant differences observed. Although risk of bias was assessed as low overall, one study was assessed at high risk of attrition bias. Given the small number and size of included studies it is uncertain whether LESS-DN is better than laparoscopic donor nephrectomy. Well designed and adequately powered RCTs are needed to better define the role of LESS-DN as a minimally invasive option for kidney donor surgery.
Thirteen trials were included. None measured an injury outcome. Two trials measured error, and the remaining trials used neuropsychological tests to assess cognitive performance. The trials assessing the impact on errors found that caffeine significantly reduced the number of errors compared to placebo. The pooled effect estimates on performance by cognitive domain suggest that, when compared to placebo, caffeine improved concept formation and reasoning (SMD -0.41; 95% CI -1.04 to 0.23), memory (SMD -1.08; 95% CI -2.07 to -0.09), orientation and attention (SMD -0.55; 95% CI -0.83 to -0.27) and perception (SMD -0.77; 95% CI -1.73 to 0.20); although there was no beneficial effect on verbal functioning and language skills (SMD 0.18; 95% CI -0.50 to 0.87). One trial comparing the effects of caffeine with a nap found that there were significantly less errors made in the caffeine group. Other trials comparing caffeine with other active interventions (for example nap, bright light, modafinil) found no significant differences. There is a high risk of bias for the adequacy of allocation concealment and presence of selective outcome reporting amongst the trials. Caffeine may be an effective intervention for improving performance in shift workers however, there are no trials from which we can assess its effect on injuries. The results largely originate from studies involving young participants under simulated conditions, and the extent to which the findings are generalisable to older workers and real world shift work is unclear. Based on the current evidence, there is no reason for healthy individuals who already use caffeine within recommended levels to improve their alertness to stop doing so. The assessment of the relative effects of caffeine to other potential countermeasures should be a focus of future research.
We identified 182 studies with a total of 16,855 included participants investigating outcomes of surgery for epilepsy. Nine studies were RCTs (including two that randomised participants to surgery or medical treatment (99 participants included in the two trials received medical treatment)). Risk of bias in these RCTs was unclear or high. Most of the remaining 173 non-randomised studies followed a retrospective design. We assessed study quality using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses, we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across domains. In terms of freedom from seizures, two RCTs found surgery (n = 97) to be superior to medical treatment (n = 99); four found no statistically significant differences between anterior temporal lobectomy (ATL) with or without corpus callosotomy (n = 60), between subtemporal or transsylvian approach to selective amygdalohippocampectomy (SAH) (n = 47); between ATL, SAH and parahippocampectomy (n = 43) or between 2.5 cm and 3.5 cm ATL resection (n = 207). One RCT found total hippocampectomy to be superior to partial hippocampectomy (n = 70) and one found ATL to be superior to stereotactic radiosurgery (n = 58); and another provided data to show that for Lennox-Gastaut syndrome, no significant differences in seizure outcomes were evident between those treated with resection of the epileptogenic zone and those treated with resection of the epileptogenic zone plus corpus callosotomy (n = 43). We judged evidence from the nine RCTs to be of moderate to very low quality due to lack of information reported about the randomised trial design and the restricted study populations. Of the 16,756 participants included in this review who underwent a surgical procedure, 10,696 (64%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to recording of adverse events to be very poor. In total, 120 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography, history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection, and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation, and presence of postoperative discharges were prognostic factors of outcome.Twenty-nine studies reported multi-variable models of prognostic factors, and showed that the direction of association of factors with outcomes was generally the same as that found in univariate analyses. We observed variability in many of our analyses, likely due to small study sizes with unbalanced group sizes and variation in the definition of seizure outcome, the definition of prognostic factors, and the influence of the site of surgery Study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcomes. Future research should be of high quality, follow a prospective design, be appropriately powered, and focus on specific issues related to diagnostic tools, the site-specific surgical approach, and other issues such as extent of resection. Researchers should investigate prognostic factors related to the outcome of surgery via multi-variable statistical regression modelling, where variables are selected for modelling according to clinical relevance, and all numerical results of the prognostic models are fully reported. Journal editors should not accept papers for which study authors did not record adverse events from a medical intervention. Researchers have achieved improvements in cancer care over the past three to four decades by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.
There are no new trials to include in this review update. Previously, four studies with a total of 224 participants were included; one was performed exclusively in children and three in adolescents or adults. One using an antitussive had no extractable pneumonia-specific data. Three different mucolytics (bromhexine, ambroxol, neltenexine) were used in the remaining studies, of which only two had extractable data. They demonstrated no significant difference for the primary outcome of 'not cured or not improved' for mucolytics. A secondary outcome of 'not cured' was reduced (odds ratio (OR) for children 0.36, 95% confidence interval (CI) 0.16 to 0.77; number needed to treat to benefit (NNTB) at day 10 = 5 (95% CI 3 to 16) and OR 0.32 for adults (95% CI 0.13 to 0.75); NNTB at day 10 = 5 (95% CI 3 to 19)). In a post hoc analysis combining data for children and adults, again there was no difference in the primary outcome of 'not cured or not improved' (OR 0.85, 95% CI 0.40 to 1.80) although mucolytics reduced the secondary outcome 'not cured' (OR 0.34, 95% CI 0.19 to 0.60; NNTB 4, 95% CI 3 to 8). The risk of bias was low or unclear. There is insufficient evidence to decide whether OTC medications for cough associated with acute pneumonia are beneficial. Mucolytics may be beneficial but there is insufficient evidence to recommend them as an adjunctive treatment for acute pneumonia. This leaves only theoretical recommendations that OTC medications containing codeine and antihistamines should not be used in young children.
In this Cochrane review we identified 19 relevant studies including a total of 1421 patients that examined 16 different intervention comparisons. Of the studies that compared buprenorphine to another drug, 11 studies performed comparative analyses between the randomised groups, and five studies found that buprenorphine was superior to the comparison treatment. Three studies found no differences between buprenorphine and the comparison drug, while another three studies found treatment with buprenorphine to be inferior to the alternative treatment in terms of the side effects profile or patients preference/acceptability. Of the studies that compared different doses or formulations/routes of administration of buprenorphine, pain intensity ratings did not differ significantly between intramuscular buprenorphine and buprenorphine suppository. However, the average severity of dizziness, nausea, vomiting and adverse events as a total were all significantly higher in the intramuscular group relatively to the suppository group (one study). Sublingual buprenorphine was associated with faster onset of pain relief compared to subdermal buprenorphine, with similar duration analgesia and no significant differences in adverse event rates reported between the treatments (one study). In terms of transdermal buprenorphine, two studies found it superior to placebo, whereas a third study found no difference between placebo and different doses of transdermal buprenorphine. The studies that examined different doses of transdermal buprenorphine did not report a clear dose-response relationship. The quality of this evidence base was limited by under-reporting of most bias assessment items (e.g., the patient selection items), by small sample sizes in several included studies, by attrition (with data missing from 8.2% of the enrolled/randomised patients for efficacy and from 14.6% for safety) and by limited or no reporting of the expected outcomes in a number of cases. The evidence for all the outcomes was very low quality. Based on the available evidence, it is difficult to say where buprenorphine fits in the treatment of cancer pain with strong opioids. However, it might be considered to rank as a fourth-line option compared to the more standard therapies of morphine, oxycodone and fentanyl, and even there it would only be suitable for some patients. However, palliative care patients are often heterogeneous and complex, so having a number of analgesics available that can be given differently increases patient and prescriber choice. In particular, the sublingual and injectable routes seemed to have a more definable analgesic effect, whereas the transdermal route studies left more questions.
We included in this review a total of 17 studies with 1988 participants (evidence current until November 2017). Three studies limited their inclusion to people with intermittent claudication, 12 limited inclusion to people with varying levels of critical limb ischaemia, and two included people with either condition. Study investigators evaluated many different types of gene therapies, using different protocols. Most studies evaluated growth factor-encoding gene therapy, with six studies using vascular endothelial growth factor (VEGF)-encoding genes, four using hepatocyte growth factor (HGF)-encoding genes, and three using fibroblast growth factor (FGF)-encoded genes. Two studies evaluated hypoxia-inducible factor 1-alpha (HIF-1α) gene therapy, one study used a developmental endothelial locus-1 gene therapy, and the final study evaluated a stromal cell-derived factor-1 (SDF-1) gene therapy. Most studies reported outcomes after 12 months of follow-up, but follow-up ranged from three months to two years. Overall risk of bias varied between studies, with many studies not providing sufficient detail for adequate determination of low risk of bias for many domains. Two studies did not utilise a placebo control, leading to risk of performance bias. Several studies reported in previous protocols or in their Methods sections that they would report on certain outcomes for which no data were then reported, increasing risk of reporting bias. All included studies reported sponsorships from corporate entities that led to unclear risk of other bias. The overall quality of evidence ranged from moderate to very low, generally as the result of heterogeneity and imprecision, with few or no studies reporting on outcomes. Evidence suggests no clear differences for the outcomes of amputation-free survival, major amputation, and all-cause mortality between those treated with gene therapy and those not receiving this treatment (all moderate-quality evidence). Low-quality evidence suggests improvement in complete ulcer healing with gene therapy (odds ratio (OR) 2.16, 95% confidence interval (CI) 1.02 to 4.59; P = 0.04). We could not combine data on quality of life and can draw no conclusions at this time regarding this outcome (very low-quality evidence). We included one study in the meta-analysis for ankle brachial index, which showed no clear differences between treatments, but we can draw no overall association (low-quality evidence). We combined in a meta-analysis pain symptom scores as assessed by visual analogue scales from two studies and found no clear differences between treatment groups (very low-quality evidence). We carried out extensive subgroup analyses by PAD classification, dosage schedule, vector type, and gene used but identified no substantial differences. Moderate-quality evidence shows no clear differences in amputation-free survival, major amputation, and all-cause mortality between those treated with gene therapy and those not receiving gene therapy. Some evidence suggests that gene therapy may lead to improved complete ulcer healing, but this outcome needs to be explored with improved reporting of the measure, such as decreased ulcer area in cm², and better description of ulcer types and healing. Further standardised data that are amenable to meta-analysis are needed to evaluate other outcomes such as quality of life, ankle brachial index, symptom scores, and claudication distance.
The results of nine randomised controlled trials (N = 482 women) showed that laparoscopic surgery was associated with fewer adverse events of surgery (surgical injury or postoperative complications including fever or infection) (OR 0.3, 95% CI 0.2 to 0.5), less postoperative pain (VAS score WMD -2.4, 95% CI -2.7 to -2.0), greater likelihood of being pain free after two days (OR 7.42, 95% CI 4.86 to 11.33), and fewer days in hospital (WMD -2.88, 95% CI -3.1 to -2.7) than with laparotomy. In one study that reported costs, laparoscopy was associated with a significant reduction in costs compared to laparotomy (WMD - USD 1045, 95% CI -1348 to -742) in 1993. Very high levels of heterogeneity made it inappropriate to pool data on duration of surgery. Three RCTs compared laparoscopy versus minilaparotomy and found that laparoscopy was associated with reduced odds of any adverse event (surgical injury or postoperative complications) (OR 0.10, 95% CI 0 to 0.8) and lower VAS scores for pain (WMD -1.0, 95% CI -1.6 to -0.45). Duration of hospital stay ranged between 1 and 2.2 days, with substantial heterogeneity. In women undergoing surgery for benign ovarian tumours, laparoscopy was associated with a reduction in fever, urinary tract infection, postoperative complications, postoperative pain, number of days in hospital, and total cost. These findings should be interpreted with caution since only a small number of studies were identified. These included a total of only 769 women and not all of the important outcomes were reported in each study.
Six RCTs that investigated PUFAs emerged from the search strategy, accounting for 794 randomised patients. PUFAs did not have a significant effect on disease progression at 24 months. Omega-6 fatty acids (11 to 23 g/day linoleic acid) didn't show any benefit in 144 MS patients (RR 1.04, 95% CI 0.66 to 1.63). Linoleic acid (2.9 to 3.4 g/day) had no benefit in 65 chronic progressive MS patients (RR 0.78, 95% CI 0.43 to 1.42). Omega-3 fatty acids had no benefit in 292 relapsing remitting MS patients (RR 0.82, 95% CI 0.65 to 1.03, P = 0.08). Slight potential benefits in relapse outcomes were associated with omega-6 fatty acids in some studies, however these findings were limited by the reduced validity of the endpoints. No judgements about safety or patient-reported outcomes were possible. In general, trial quality was poor. No studies on vitamin supplementation and allergen-free diets were analysed as none met the eligibility criteria, mainly due to lack of clinical outcomes. PUFAs seem to have no major effect on the main clinical outcome in MS (disease progression), but they may tend to reduce the frequency of relapses over two years. However, the data that are available are insufficient to assess a real benefit or harm from PUFA supplementation because of their uncertain quality. Evidence on the possible benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking. More research is required to assess the effectiveness of dietary interventions in MS.
Nine randomised trials, including 936 patients, met the inclusion criteria. Methodological quality was considered adequate in only one trial. There was a significant funnel plot asymmetry (regression coefficient=3.37, standard error 1.40, P=0.047). Ten different medicinal herbs were tested in the nine trials. Compared to non-specific treatment or placebo, Fuzheng Jiedu Tang (compound of herbs) showed significantly positive effects on clearance of serum HBsAg, HBeAg, and HBV DNA; Polyporus umbellatus polysaccharide on serum HBeAg and HBV DNA; Phyllanthus amarus on serum HBeAg. Phyllanthus compound and kurorinone showed no significant effect on clearance of serum HBeAg and HBV DNA and on alanine aminotransferase normalisation compared to interferon treatment. There were no significant effects of the other examined herbs. Some Chinese medicinal herbs may work in chronic hepatitis B. However, the evidence is too weak to recommend any single herb. Rigorously designed, randomised, double-blind, placebo-controlled trials are required.
We included 10 trials, of which six focused on Parkinson's disease and four on multiple sclerosis. None of the studies reported data on the primary outcome (functional performance). In Parkinson's disease, after pooling two studies, a single session of WBV caused a significant improvement of gait measured using the Timed Up and Go test (TUG) in comparison to standing exercises (mean difference -3.09, 95% confidence interval -5.60 to -0.59; P = 0.02; I2 = 0%). Nevertheless, longer duration of WBV did not show significant results in comparison with physical therapy in body balance or signs and symptoms measured with the Unified Parkinson's Disease Rating Scale (UPDRS). In multiple sclerosis there was no evidence of a short-term or long-term effect of WBV on body balance, gait, muscle performance or quality of life. Adverse events were reported in few trials. In those trials that reported them, the intervention appeared to be safe. There is insufficient evidence of the effect of WBV training on functional performance of neurodegenerative disease patients. Also, there is insufficient evidence regarding its beneficial effects on signs and symptoms of the disease, body balance, gait, muscle strength and quality of life compared to other active physical therapy or passive interventions in Parkinson's disease or multiple sclerosis. More studies assessing other functional tests and accurately assessing safety are needed before a definitive recommendation is established.
Two trials with 49 participants were included. One trial had low risk of bias. The other trial had high risk of bias. Hormone replacement had no effect on all-cause mortality (RD 0.00; 95% CI -0.11 to 0.11, I² = 0%) and fractures (RD -0.08; 95% CI -0.24 to 0.07, I² = 0%). Hormone replacement significantly increased adverse events and number of patients having hormone replacement withdrawn due to adverse events (RR 5.26; 95% CI 1.26 to 22.04, I² = 0%). Hormone replacement had no significant effect on lumbar spine bone mineral density (MD 1.25 g/cm² yearֿ¹; 95% CI -0.91 to 3.42, I² = 0%). On the other hand, a significant increase in proximal femur bone mineral density was observed in the control group (MD 2.24 g/cm² yearֿ¹; 95% CI 0.74 to 3.74, I² = 0%). Hormone replacement had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity. Hormone replacement had no significant effect on serum bilirubin concentration (MD 4.60 µmol/L; 95% CI -3.42 to 12.62, I² = 0%). We did not find evidence to support the use of hormone replacement for women with primary biliary cirrhosis. It seems that hormone replacement is connected with a significant increase in the occurrence of adverse events.
Five randomised controlled trials (RCTs) with 11,565 participants and three interrupted time series studies (ITSs) with 26.3 data points on average met the criteria. For educational interventions aiming at reducing injury rates among adults the pooled rate ratio after recalculation from effect sizes in three RCTs was 1.02 (95% CI 0.87 to 1.20). For educational interventions aiming at children the pooled rate ratio for injury rates in two RCTs was 1.27 (95% CI 0.51 to 3.16).   One ITS study that evaluated the effect of an intervention that included financial incentives decreased the injury level immediately after the intervention with an effect size of -2.68 (95% CI -3.80 to -1.56) but did not have a significant effect on the injury trend over time with an effect size of -0.22 (95% CI -0.47 to 0.03).   One ITS study that evaluated the effect of legislation to ban Endosulfan pesticide on fatal pesticide poisonings increased the level of poisonings immediately after the introduction with an effect size of 2.20 (95% CI 0.97 to 3.43) but led to decrease in the trend of poisonings over time with an effect size of -2.15 (95% CI -2.64 to -1.66).   One ITS study documented four different regulations aiming to increase the use of rollover protective structures (ROPS) on tractors and their effect on injuries and fatal injuries. The introduction of two different pieces of legislation requiring ROPS on new tractors sold after a certain date was associated with a decrease of fatal injuries over the long term (effect size -0.93 95% CI -1.82 to -0.03). Otherwise the introduction of legislation was associated with an increase of injury rates. Introduction of legislation requiring ROPS on all tractors, old tractors included, was not associated with a decrease but with an increase of injuries and fatal injuries over the long term. The selected studies provided no evidence that educational interventions are effective in decreasing injury rates among agricultural workers. Financial incentives could reduce injury rates. Legislation to ban pesticides could be effective. Legislation expanding the use of safety devices (ROPS) on new tractors was associated with a decrease in fatal injuries.
Three trials involving 126 patients were included, with complete data available for 93 patients. The participants were heterogeneous, none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to RBC transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study fewer than half the participants were included in the final analysis. One RCT of restrictive versus liberal RBC transfusion aims to recruit 860 patients but has yet to be completed. There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed RCTs of sufficient power are urgently needed.
One study with 85 participants met the selection criteria. This trial studied all the absorbent product designs included in this review. Data were presented on all included outcomes. For preventing leakage, for preference and for overall acceptability disposable insert pads are better than disposable menstrual pads which are better than washable pants with integral pad which are better than washable insert pads. There is no strong evidence that either disposables or washables are better for skin health. The disposable insert is the most expensive design and there is no dominant design for cost-effectiveness. There is evidence that some women will prefer alternative designs which are all cheaper than disposable inserts. Although data were available from only one eligible trial the data were sufficiently robust to make recommendations for practice. Disposable insert pads are typically more effective than the other designs considered. However, because they are the most expensive, providing choice of designs (or combinations of designs for different circumstances) is likely to be cost-effective.
From 109 potentially relevant studies only three (104 patients) met our inclusion criteria: Bogie 2007 (46 children), Browne 1997 (29 children) and Nowak 2010 (29 adults). Bogie 2007 investigated the addition of intravenous terbutaline to high dose nebulised albuterol in children with acute severe asthma, requiring intensive care unit (ICU) admission. Browne 1997 investigated the benefit of adding intravenous salbutamol to inhaled salbutamol in children with acute severe asthma in the emergency department. Nowak 2010 investigated addition of IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids) among adults, and was reported as a conference abstract only. There was no significant advantage (OR 0.29; 95%CI 0.06 to 1.38, one trial, 29 adults) for adding IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids) with regard to hospitalisation rates. Various outcome indicators for the length of stay were reported among the trials. Browne 1997 reported a significantly shorter recovery time (in terms of cessation of 30 minute salbutamol) for children in the IV salbutamol with inhaled salbutamol group (four hours) versus the 11.1 hours for the inhaled salbutamol group (P = 0.03). Time to cessation of hourly nebuliser was also significantly shorter (P = 0.02) for the IV plus inhaled salbutamol group (11.5 hours versus 21.2 hours), and they were ready for emergency patient discharge on average 9.7 hours earlier than the inhaled salbutamol group (P < 0.05). In a paediatric ICU study Bogie 2007 reported no significant advantage in length of paediatric ICU admission (hours) for adding IV terbutaline to nebulised albuterol (MD -12.95, 95% CI: -38.74, 12.84). Browne 1997 reported there were only six out of 14 children with a pulmonary index score above six in the IV plus inhaled salbutamol group at two hours compared with 14 of the 15 in the inhaled salbutamol group (P = 0.02) In Browne 1997 there was a higher proportion of tremor in the IV plus inhaled salbutamol group than in the inhaled salbutamol group (P < 0.02). Nowak 2010 did not report any statistically significant adverse effects associated with adding IV bedoradrine to standard care (nebulised albuterol, ipratropium and oral corticosteroids). Troponin levels were elevated in three children in the IV terbutaline + nebulised albuterol group at 12 and 24 hours in Bogie 2007 There is very limited evidence from one study (Browne 1997) to support the use of IV beta2-agonists in children with severe acute asthma with respect to shorter recovery time, and similarly there is limited evidence (again from one study Browne 1997) suggesting benefit with regard to pulmonary index scores; however this advantage needs to be considered carefully in relation to the increased side effects associated with IV beta2-agonists. We identified no significant benefits for adults with severe acute asthma. Until more, adequately powered, high quality clinical trials in this area are conducted it is not possible to form a robust evaluation of the addition of IV beta2-agonists in children or adults with severe acute asthma.
We included 105 studies involving 31,043 participants. This update added 18 studies and removed 28 previously included studies comparing detailed versus simple decision aids. During the 'Risk of bias' assessment, we rated two items (selective reporting and blinding of participants/personnel) as mostly unclear due to inadequate reporting. Twelve of 105 studies were at high risk of bias. With regard to the attributes of the choice made, decision aids increased participants' knowledge (MD 13.27/100; 95% confidence interval (CI) 11.32 to 15.23; 52 studies; N = 13,316; high-quality evidence), accuracy of risk perceptions (RR 2.10; 95% CI 1.66 to 2.66; 17 studies; N = 5096; moderate-quality evidence), and congruency between informed values and care choices (RR 2.06; 95% CI 1.46 to 2.91; 10 studies; N = 4626; low-quality evidence) compared to usual care. Regarding attributes related to the decision-making process and compared to usual care, decision aids decreased decisional conflict related to feeling uninformed (MD −9.28/100; 95% CI −12.20 to −6.36; 27 studies; N = 5707; high-quality evidence), indecision about personal values (MD −8.81/100; 95% CI −11.99 to −5.63; 23 studies; N = 5068; high-quality evidence), and the proportion of people who were passive in decision making (RR 0.68; 95% CI 0.55 to 0.83; 16 studies; N = 3180; moderate-quality evidence). Decision aids reduced the proportion of undecided participants and appeared to have a positive effect on patient-clinician communication. Moreover, those exposed to a decision aid were either equally or more satisfied with their decision, the decision-making process, and/or the preparation for decision making compared to usual care. Decision aids also reduced the number of people choosing major elective invasive surgery in favour of more conservative options (RR 0.86; 95% CI 0.75 to 1.00; 18 studies; N = 3844), but this reduction reached statistical significance only after removing the study on prophylactic mastectomy for breast cancer gene carriers (RR 0.84; 95% CI 0.73 to 0.97; 17 studies; N = 3108). Compared to usual care, decision aids reduced the number of people choosing prostate-specific antigen screening (RR 0.88; 95% CI 0.80 to 0.98; 10 studies; N = 3996) and increased those choosing to start new medications for diabetes (RR 1.65; 95% CI 1.06 to 2.56; 4 studies; N = 447). For other testing and screening choices, mostly there were no differences between decision aids and usual care. The median effect of decision aids on length of consultation was 2.6 minutes longer (24 versus 21; 7.5% increase). The costs of the decision aid group were lower in two studies and similar to usual care in four studies. People receiving decision aids do not appear to differ from those receiving usual care in terms of anxiety, general health outcomes, and condition-specific health outcomes. Studies did not report adverse events associated with the use of decision aids. In subgroup analysis, we compared results for decision aids used in preparation for the consultation versus during the consultation, finding similar improvements in pooled analysis for knowledge and accurate risk perception. For other outcomes, we could not conduct formal subgroup analyses because there were too few studies in each subgroup. Compared to usual care across a wide variety of decision contexts, people exposed to decision aids feel more knowledgeable, better informed, and clearer about their values, and they probably have a more active role in decision making and more accurate risk perceptions. There is growing evidence that decision aids may improve values-congruent choices. There are no adverse effects on health outcomes or satisfaction. New for this updated is evidence indicating improved knowledge and accurate risk perceptions when decision aids are used either within or in preparation for the consultation. Further research is needed on the effects on adherence with the chosen option, cost-effectiveness, and use with lower literacy populations.
We included 11 RCTs with 6750 participants, but only six of these included people with COPD (2469 participants). The others were conducted on elderly and high-risk individuals, some of whom had chronic lung disease. Interventions compared with placebo were inactivated virus injections and live attenuated intranasal virus vaccines. Some studies compared intra-muscular inactivated vaccine and intranasal live attenuated vaccine with intra-muscular inactivated vaccine and intranasal placebo. Studies were conducted in the UK, USA and Thailand. Inactivated vaccine reduced the total number of exacerbations per vaccinated participant compared with those who received placebo (mean difference (MD) –0.37, 95% confidence interval (CI) –0.64 to –0.11; P = 0.006; two RCTs, 180 participants; low quality evidence). This was due to the reduction in 'late' exacerbations, occurring after three or four weeks (MD –0.39, 95% CI –0.61 to –0.18; P = 0.0004; two RCTs, 180 participants; low quality evidence). Both in people with COPD, and in older people (only a minority of whom had COPD), there were significantly more local adverse reactions in people who had received the vaccine, but the effects were generally mild and transient. There was no evidence of an effect of intranasal live attenuated virus when this was added to inactivated intramuscular vaccination. Two studies evaluating mortality for influenza vaccine versus placebo were too small to have detected any effect on mortality. However, a large study (N=2215) noted that there was no difference in mortality when adding live attenuated virus to inactivated virus vaccination, It appeared, from the limited number of RCTs we were able to include, all of which were more than a decade old, that inactivated vaccine reduced exacerbations in people with COPD. The size of effect was similar to that seen in large observational studies, and was due to a reduction in exacerbations occurring three or more weeks after vaccination, and due to influenza. There was a mild increase in transient local adverse effects with vaccination, but no evidence of an increase in early exacerbations. Addition of live attenuated virus to the inactivated vaccine was not shown to confer additional benefit.
We included two studies, involving 319 women. There was no statistically significant difference between the two groups in either of the primary outcomes of caesarean section (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.42 to 2.12) or instrumental delivery (RR 0.88, 95% CI 0.72 to 1.08). Similarly, there were no statistically significant differences between the two groups in any of the secondary outcomes for which data were available. This included Apgar score less than seven at five minutes (RR 3.06, 0.13 to 73.33), admission to neonatal intensive care unit (RR 1.07, 95% CI 0.29 to 3.93), uterine hyperstimulation (RR 1.32, 95% CI 0.97 to 1.80) and postpartum haemorrhage (RR 0.96, 95% CI 0.58, 1.59). There was no statistically significant difference identified between women in spontaneous labour with epidural analgesia who were augmented with oxytocin, compared with those who received placebo. However, due to the limited number of women included in the studies, further research in the form of randomised controlled trials are required.
Nine trials were identified in the searches and five trials, with a total of 547 participants, met the inclusion criteria. Only one trial reported incidence of pneumococcal infection, and this demonstrated that the polysaccharide pneumococcal vaccine used (PPV14) failed to reduce significantly the risk of infection in children under three years of age, but was associated with only minor adverse events. Three trials of conjugate pneumococcal vaccines found that antibody responses were increased compared to control groups, including those in infants, although clinical outcomes were not measured in these trials. Previous trials have shown that conjugate pneumococcal vaccines are safe and effective in normal healthy individuals, including those under the age of two years. The controlled trials included in this review have demonstrated immunogenicity (the ability to induce the body's immune response, without which there is no protection) of these vaccines, and observational studies in people with sickle cell disease support these findings. We therefore recommend that conjugate pneumococcal vaccines are used in people with sickle cell disease. Randomised trials in people with sickle cell disease will be needed to determine the optimal vaccination regimen when further, potentially more effective vaccines become available. Such trials should measure clinical outcomes of effectiveness. The trials included in this review were published between 1983 and 2003. We have not identified any further relevant trials up to December 2011. We therefore do not plan to update this review until new trials are published.
From the 12,966 citations screened, we assessed 26 full-text articles and included five RCTs (643 participants). Low-quality evidence from the meta-analysis performed on two trials using the Oswestry Disability Index (pain-related disability) to compare direct decompression with or without fusion versus multi-modal non-operative care showed no significant differences at six months (mean difference (MD) -3.66, 95% confidence interval (CI) -10.12 to 2.80) and at one year (MD -6.18, 95% CI -15.03 to 2.66). At 24 months, significant differences favoured decompression (MD -4.43, 95% CI -7.91 to -0.96). Low-quality evidence from one small study revealed no difference in pain outcomes between decompression and usual conservative care (bracing and exercise) at three months (risk ratio (RR) 1.38, 95% CI 0.22 to 8.59), four years (RR 7.50, 95% CI 1.00 to 56.48) and 10 years (RR 4.09, 95% CI 0.95 to 17.58). Low-quality evidence from one small study suggested no differences at six weeks in the Oswestry Disability Index for patients treated with minimally invasive mild decompression versus those treated with epidural steroid injections (MD 5.70, 95% CI 0.57 to 10.83; 38 participants). Zurich Claudication Questionnaire (ZCQ) results were better for epidural injection at six weeks (MD -0.60, 95% CI -0.92 to -0.28), and visual analogue scale (VAS) improvements were better in the mild decompression group (MD 2.40, 95% CI 1.92 to 2.88). At 12 weeks, many cross-overs prevented further analysis. Low-quality evidence from a single study including 191 participants favoured the interspinous spacer versus usual conservative treatment at six weeks, six months and one year for symptom severity and physical function. All remaining studies reported complications associated with surgery and conservative side effects of treatment: Two studies reported no major complications in the surgical group, and the other study reported complications in 10% and 24% of participants, including spinous process fracture, coronary ischaemia, respiratory distress, haematoma, stroke, risk of reoperation and death due to pulmonary oedema. We have very little confidence to conclude whether surgical treatment or a conservative approach is better for lumbar spinal stenosis, and we can provide no new recommendations to guide clinical practice. However, it should be noted that the rate of side effects ranged from 10% to 24% in surgical cases, and no side effects were reported for any conservative treatment. No clear benefits were observed with surgery versus non-surgical treatment. These findings suggest that clinicians should be very careful in informing patients about possible treatment options, especially given that conservative treatment options have resulted in no reported side effects. High-quality research is needed to compare surgical versus conservative care for individuals with lumbar spinal stenosis.
We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.
We included in this review nine studies involving a total of 421 participants, 411 of whom were included in the meta-analysis examining short-term effects of music therapy for depression. Concerning primary outcomes, we found moderate-quality evidence of large effects favouring music therapy and TAU over TAU alone for both clinician-rated depressive symptoms (SMD -0.98, 95% CI -1.69 to -0.27, 3 RCTs, 1 CCT, n = 219) and patient-reported depressive symptoms (SMD -0.85, 95% CI -1.37 to -0.34, 3 RCTs, 1 CCT, n = 142). Music therapy was not associated with more or fewer adverse events than TAU. Regarding secondary outcomes, music therapy plus TAU was superior to TAU alone for anxiety and functioning. Music therapy and TAU was not more effective than TAU alone for improved quality of life (SMD 0.32, 95% CI -0.17 to 0.80, P = 0.20, n = 67, low-quality evidence). We found no significant discrepancies in the numbers of participants who left the study early (OR 0.49, 95% CI 0.14 to 1.70, P = 0.26, 5 RCTs, 1 CCT, n = 293, moderate-quality evidence). Findings of the present meta-analysis indicate that music therapy added to TAU provides short-term beneficial effects for people with depression if compared to TAU alone. Additionally, we are uncertain about the effects of music therapy versus psychological therapies on clinician-rated depression (SMD -0.78, 95% CI -2.36 to 0.81, 1 RCT, n = 11, very low-quality evidence), patient-reported depressive symptoms (SMD -1.28, 95% CI -3.75 to 1.02, 4 RCTs, n = 131, low-quality evidence), quality of life (SMD -1.31, 95% CI - 0.36 to 2.99, 1 RCT, n = 11, very low-quality evidence), and leaving the study early (OR 0.17, 95% CI 0.02 to 1.49, 4 RCTs, n = 157, moderate-quality evidence). We found no eligible evidence addressing adverse events, functioning, and anxiety. We do not know whether one form of music therapy is better than another for clinician-rated depressive symptoms (SMD -0.52, 95% CI -1.87 to 0.83, 1 RCT, n = 9, very low-quality evidence), patient-reported depressive symptoms (SMD -0.01, 95% CI -1.33 to 1.30, 1 RCT, n = 9, very low-quality evidence), quality of life (SMD -0.24, 95% CI -1.57 to 1.08, 1 RCT, n = 9, very low-quality evidence), or leaving the study early (OR 0.27, 95% CI 0.01 to 8.46, 1 RCT, n = 10). We found no eligible evidence addressing adverse events, functioning, or anxiety. Findings of the present meta-analysis indicate that music therapy provides short-term beneficial effects for people with depression. Music therapy added to treatment as usual (TAU) seems to improve depressive symptoms compared with TAU alone. Additionally, music therapy plus TAU is not associated with more or fewer adverse events than TAU alone. Music therapy also shows efficacy in decreasing anxiety levels and improving functioning of depressed individuals. Future trials based on adequate design and larger samples of children and adolescents are needed to consolidate our findings. Researchers should consider investigating mechanisms of music therapy for depression. It is important to clearly describe music therapy, TAU, the comparator condition, and the profession of the person who delivers the intervention, for reproducibility and comparison purposes.
We included one randomised cross-over study, enrolling 87 participants, which compared TPD with continuous equilibrating PD (CEPD) for patients with AKI. Sequence generation was adequate while allocation concealment was not reported. Our primary outcomes of mortality and recovery of renal function (complete or partial) were not reported (high risk of selective reporting bias). The results from this one study showed TPD resulted in higher creatinine clearance (CrCl) (MD 1.88 mL/min, 95% CI 0.91 to 2.85) and blood urea nitrogen (BUN) clearance (MD 14.71 mL/min, 95% CI 8.24 to 21.18) than CEPD; was superior to CEPD in the removal of potassium, phosphates and in generating ultrafiltrate; was better tolerated; consumed less time and was less expensive than CEPD. There was greater protein loss with TPD. No adverse events were reported. At present, there is insufficient RCT evidence to enable evaluation of the effect of TPD in patients with AKI. Well-designed and larger RCTs are required to better understand the risks and benefits of TPD for AKI.
We included two trials with 851 patients that evaluated the efficacy and safety of daclizumab versus placebo for RRMS. We judged them to be at low risk of bias. Due to different time point evaluations and available data on primary studies, we were unable to undertake a meta-analysis. At 24 weeks, the median change was 0 (range -2 to 3) in the interferon beta and placebo group, 0 (-2 to 4) in the interferon beta and low-dose daclizumab group and 0 (-2 to 2) in the interferon beta and high-dose daclizumab group in 230 participants. The proportion of patients who had new clinical relapses were the following: 16 patients (21%) in the interferon beta and high-dose daclizumab group, 19 (24%) in the interferon beta and low-dose daclizumab group and 19 (25%) in the interferon beta and placebo group had relapses (P value = 0.87). At 52 weeks, the changes in Expanded Disability Status Scale (EDSS) from baseline was 0.09 ± 0.71 in placebo group, -0.08 ± 0.52 in low-dose daclizumab group and 0.05 ± 0.61 in high-dose daclizumab group in 621 participants. There was a significant difference between placebo and low-dose daclizumab groups (P value = 0.01), but no significant difference between placebo and high-dose daclizumab groups (P value = 0.49). The proportion of patients with new relapsing MS was significantly reduced in both daclizumab groups (19% in low-dose daclizumab group, 20% in high-dose daclizumab group) compared with placebo group (36%) (P value < 0.0001 and P value = 0.00032, respectively). There was no increased number of patients in any adverse events (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07) or serious adverse events in daclizumab groups compared with placebo (RR 1.15, 95% CI 0.29 to 4.54). Infections were the most frequent adverse events in treated participants and were resolved with standard therapies. One trial was still ongoing. There was insufficient evidence to determine whether daclizumab was more effective than placebo in patients affected by RRMS in terms of clinical and MRI measures of outcomes. Daclizumab appeared to be relatively well tolerated. Infections were the most frequent adverse events, and were resolved with standard therapies.
Two studies, comparing reablement with usual home-care services with 811 participants, met our eligibility criteria for inclusion; we also identified three potentially eligible studies, but findings were not yet available. One included study was conducted in Western Australia with 750 participants (mean age 82.29 years). The second study was conducted in Norway (61 participants; mean age 79 years). We are very uncertain as to the effects of reablement compared with usual care as the evidence was of very low quality for all of the outcomes reported. The main findings were as follows. Functional status: very low quality evidence suggested that reablement may be slightly more effective than usual care in improving function at nine to 12 months (lower scores reflect greater independence; standardised mean difference (SMD) -0.30; 95% confidence interval (CI) -0.53 to -0.06; 2 studies with 249 participants). Adverse events: reablement may make little or no difference to mortality at 12 months' follow-up (RR 0.97; 95% CI 0.74 to 1.29; 2 studies with 811 participants) or rates of unplanned hospital admission at 24 months (RR 0.94; 95% CI 0.85 to 1.03; 1 study with 750 participants). The very low quality evidence also means we are uncertain whether reablement may influence quality of life (SMD -0.23; 95% CI -0.48 to 0.02; 2 trials with 249 participants) or living arrangements (RR 0.92, 95% CI 0.62 to 1.34; 1 study with 750 participants) at time points up to 12 months. People receiving reablement may be slightly less likely to have been approved for a higher level of personal care than people receiving usual care over the 24 months' follow-up (RR 0.87; 95% CI 0.77 to 0.98; 1 trial, 750 participants). Similarly, although there may be a small reduction in total aggregated home and healthcare costs over the 24-month follow-up (reablement: AUD 19,888; usual care: AUD 22,757; 1 trial with 750 participants), we are uncertain about the size and importance of these effects as the results were based on very low quality evidence. Neither study reported user satisfaction with the service. There is considerable uncertainty regarding the effects of reablement as the evidence was of very low quality according to our GRADE ratings. Therefore, the effectiveness of reablement services cannot be supported or refuted until more robust evidence becomes available. There is an urgent need for high quality trials across different health and social care systems due to the increasingly high profile of reablement services in policy and practice in several countries.
Four studies were included in this review enrolling a total of 123 babies. In one study, persistent hypotension was more common in hydrocortisone treated infants as compared to those who received dopamine as primary treatment for hypotension (RR 8.2, 95% CI 0.47 to 142.6; RD 0.19, 95% CI 0.01 to 0.37). In two studies comparing steroid versus placebo, persistent hypotension (defined as a continuing need for inotrope infusion) was less common in steroid treated infants as compared to controls who received placebo for refractory hypotension (RR 0.35, 95% CI 0.19 to 0.65; RD -0.47, 95% CI - 0.68 to - 0.26; NNT = 2.1, 95% CI 1.47, 3.8). There were no statistically significant effects on any other short or long-term outcome. A further two studies that have only been published in abstract form to date, may be eligible for inclusion in a future update of this review. Hydrocortisone may be as effective as dopamine when used as a primary treatment for hypotension. But the long term safety data on the use of hydrocortisone in this manner is unknown.Steroids are effective in treatment of refractory hypotension in preterm infants without an increase in short term adverse consequences. However, long term safety or benefit data is lacking. With long term benefit or safety data lacking steroids cannot be recommended routinely for the treatment of hypotension in preterm infants.
We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.
Ten studies randomised individuals and trial sizes varied from n=31 to n=549. One study randomised 392 households and enrolled a total of 509 persons with HIV and 1,521 HIV-negative household members. Two ongoing studies were identified. Intensive home-based nursing significantly improved self-reported knowledge of HIV and medications, self-reported adherence and difference in pharmacy drug refill (1 study). Another study, comparing proportion of participants with greater than 90% adherence, found statistically significant differences over time but no significant change in CD4 counts and viral loads. A third study found significant differences in HIV stigma, worry and physical functioning but no differences in depressive symptoms, mood, general health, and overall functioning. Comprehensive case management by trans-professional teams compared to usual care by primary care nurses had no significant difference in quality-of-life after 6-months of follow-up (n=57) and average length of time on service (n=549). Home total parenteral nutrition had no significant impact on overall survival and rate of re-hospitalisation. Two trials comparing computers with brochures/nothing/standard medical care found no significant effect on health status, and decision-making confidence and skill, but a reduction in social isolation after controlling for depression. Two trials evaluating home exercise programmes found opposing results. Home-based safe water systems reduced diarrhea frequency and severity among persons with HIV in Africa. Studies were generally small and very few studies were done in developing countries. There was a lack of studies truly looking at the effect of home based care itself or looking at significant end points (death and progression to AIDS). However, the range of interventions and HBC models evaluated can assist in making evidence-based decisions about HIV care and support.
For the 2013 update, we identified and excluded one new clinical trial. This updated review includes 14 trials, randomizing a total of 8033 women. The unstratified analysis found early intervention with amniotomy and oxytocin to be associated with a modest reduction in the risk of caesarean section; however, the confidence interval (CI) included the null effect (risk ratio (RR) 0.89; 95% CI 0.79 to 1.01; 14 trials; 8033 women). In prevention trials, early augmentation was associated with a modest reduction in the number of caesarean births (RR 0.87; 95% CI 0.77 to 0.99; 11 trials; 7753). A policy of early amniotomy and early oxytocin was associated with a shortened duration of labour (average mean difference (MD) - 1.28 hours; 95% CI -1.97 to -0.59; eight trials; 4816 women). Sensitivity analyses excluding four trials with a full package of active management did not substantially affect the point estimate for risk of caesarean section (RR 0.87; 95% CI 0.73 to 1.05; 10 trials; 5165 women). We found no other significant effects for the other indicators of maternal or neonatal morbidity. In prevention trials, early intervention with amniotomy and oxytocin appears to be associated with a modest reduction in the rate of caesarean section over standard care.
Three studies provided data on the comparison between vitrectomy and observation in eyes with macular hole and visual acuity less than 20/50. Two studies, conducted in the USA and published in 1996 and 1997, used a similar protocol and included participants with stage II macular hole (42 eyes randomised, 36 analysed, number of participants not reported) or participants with stage III/IV hole (129 eyes of 120 participants, 115 eyes in analyses). The third study, conducted in the UK and published in 2004, included 185 eyes of 174 participants with full-thickness macular hole (41 eyes with stage II holes and 74 eyes with stage III/IV holes in analyses). Studies were of good quality for randomisation and allocation concealment, whereas visual acuity measurement was unmasked. At 6 to 12 months, visual acuity was improved by about 1.5 Snellen lines (-0.16 logMAR, 95% confidence intervals -0.23 to -0.09 logMAR, 270 eyes, moderate-quality evidence). The chances of macular hole closure at 6 to 12 months were greatly increased using vitrectomy, yielding an odds ratio of 31.4 (95% confidence intervals 14.9 to 66.3, 265 eyes, high-quality evidence; raw sum data: 76% vitrectomy, 11% observation). Vitrectomy was beneficial both in smaller (stage II) and in larger (stage III/IV) macular holes. The largest study reported that cataract surgery was needed in about half of cases at two years after operation and that retinal detachment occurred in about 5% of operated eyes. Vitrectomy is effective in improving visual acuity, resulting in a moderate visual gain, and in achieving hole closure in people with macular hole. However, these results may not apply to modern surgery due to technological improvements in vitrectomy techniques.
We located two studies (291 participants) for inclusion in this review. The trials were clinically heterogeneous with differences in duration of follow-up, and nasal decontamination regimens. One study compared mupirocin (2% contained in a base of polyethylene glycol 400 and polyethylene glycol 3350) with a placebo in elective cardiac surgery patients; and one study compared Anerdian (iodine 0.45% to 0.57% (W/V), chlorhexidine acetate 0.09% to 0.11% (W/V)) with no treatment also in cardiac surgery patients. The trials reported limited outcome data on SSI, adverse events and secondary outcomes (e.g. S aureus SSI, mortality). Mupirocin compared with placebo This study found no clear difference in SSI risk following use of mupirocin compared with placebo (1 trial, 257 participants); risk ratio (RR) 1.60, 95% confidence interval (CI) 0.79 to 3.25 based on 18/130 events in the mupirocin group and 11/127 in the control group; low-certainty evidence (downgraded twice due to imprecision). Anerdian compared with no treatment It is uncertain whether there is a difference in SSI risk following treatment with Anerdian compared with no treatment (1 trial, 34 participants); RR 0.89, 95% CI 0.06 to 13.08 based on 1/18 events in the Anerdian group and 1/16 in the control group; very low certainty evidence (downgraded twice due to imprecision and once due to risk of bias). There is currently limited rigorous RCT evidence available regarding the clinical effectiveness of nasal decontamination in the prevention of SSI. This limitation is specific to the focused question our review addresses, looking at nasal decontamination as a single intervention in participants undergoing surgery who are known S aureus carriers. We were only able to identify two studies that met the inclusion criteria for this review and one of these was very small and poorly reported. The potential benefits and harms of using decontamination for the prevention of SSI in this group of people remain uncertain.
Forty-five cluster-RCTs, two quasi-RCTs, and eight CBA studies, including over 84,000 participants, met the inclusion criteria. Most included studies were conducted in low- or middle-income countries (LMICs) (50 studies) with unimproved water sources (30 studies) and unimproved or unclear sanitation (34 studies). The primary outcome in most studies was self-reported diarrhoea, which is at high risk of bias due to the lack of blinding in over 80% of the included studies. Source-based water quality improvements There is currently insufficient evidence to know if source-based improvements such as protected wells, communal tap stands, or chlorination/filtration of community sources consistently reduce diarrhoea (one cluster-RCT, five CBA studies, very low quality evidence). We found no studies evaluating reliable piped-in water supplies delivered to households. Point-of-use water quality interventions On average, distributing water disinfection products for use at the household level may reduce diarrhoea by around one quarter (Home chlorination products: RR 0.77, 95% CI 0.65 to 0.91; 14 trials, 30,746 participants, low quality evidence; flocculation and disinfection sachets: RR 0.69, 95% CI 0.58 to 0.82, four trials, 11,788 participants, moderate quality evidence). However, there was substantial heterogeneity in the size of the effect estimates between individual studies. Point-of-use filtration systems probably reduce diarrhoea by around a half (RR 0.48, 95% CI 0.38 to 0.59, 18 trials, 15,582 participants, moderate quality evidence). Important reductions in diarrhoea episodes were shown with ceramic filters, biosand systems and LifeStraw® filters; (Ceramic: RR 0.39, 95% CI 0.28 to 0.53; eight trials, 5763 participants, moderate quality evidence; Biosand: RR 0.47, 95% CI 0.39 to 0.57; four trials, 5504 participants, moderate quality evidence; LifeStraw®: RR 0.69, 95% CI 0.51 to 0.93; three trials, 3259 participants, low quality evidence). Plumbed in filters have only been evaluated in high-income settings (RR 0.81, 95% CI 0.71 to 0.94, three trials, 1056 participants, fixed effects model). In low-income settings, solar water disinfection (SODIS) by distribution of plastic bottles with instructions to leave filled bottles in direct sunlight for at least six hours before drinking probably reduces diarrhoea by around a third (RR 0.62, 95% CI 0.42 to 0.94; four trials, 3460 participants, moderate quality evidence). In subgroup analyses, larger effects were seen in trials with higher adherence, and trials that provided a safe storage container. In most cases, the reduction in diarrhoea shown in the studies was evident in settings with improved and unimproved water sources and sanitation. Interventions that address the microbial contamination of water at the point-of-use may be important interim measures to improve drinking water quality until homes can be reached with safe, reliable, piped-in water connections. The average estimates of effect for each individual point-of-use intervention generally show important effects. Comparisons between these estimates do not provide evidence of superiority of one intervention over another, as such comparisons are confounded by the study setting, design, and population. Further studies assessing the effects of household connections and chlorination at the point of delivery will help improve our knowledge base. As evidence suggests effectiveness improves with adherence, studies assessing programmatic approaches to optimising coverage and long-term utilization of these interventions among vulnerable populations could also help strategies to improve health outcomes.
Three studies met the inclusion criteria. These included one placebo-controlled trial (942 patients) and two add-on placebo-controlled trials, i.e. one plus glatiramer acetate (110 patients) and the second plus interferon beta-1a (1171 patients). This review assessed the efficacy, tolerability and safety of NTZ in patients with RRMS. Data was conclusive with respect to efficacy and tolerability, but not safety. As far as efficacy is concerned, the results showed statistically significant evidence in favour of NTZ for all the primary outcomes and for the secondary ones where data was available. NTZ reduced the risk of experiencing at least one new exacerbation at 2 years by about 40% and of experiencing progression at 2 years by about 25% as compared to a control group. MRI parameters showed statistical evidence in favour of participants receiving NTZ. Infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis and menstrual disorders were reported as adverse events (AEs) more frequently after NTZ treatment. In this review NTZ was found to be well tolerated over a follow-up period of two years: the number of patients experiencing at least one AE (including severe and serious AEs) during this period did not differ between NTZ-treated patients and controls. Safety concerns have been raised about Progressive Multifocal Leukoencephalopathy (PML). In the trials included in this review, two cases of PML were encountered: one in a patient who had received 29 doses of NTZ and a second fatal case of PML in another patient after 37 doses of NTZ. Our protocol was insufficient to evaluate PML risk as well as other rare and long-term adverse events such as cancers and other opportunistic infections, which are very important issues in considering the risk/benefit ratio of NTZ. Although one trial did not contribute to efficacy results due to its duration, we found robust evidence in favour of a reduction in relapses and disability at 2 years in RRMS patients treated with NTZ. The drug was well tolerated. There are current significant safety concerns due to reporting of an increasing number of PML cases in patients treated with NTZ. This review was unable to provide an up-to-date systematic assessment of the risk due to the maximum 2 year-duration of the trials included. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs. All the data in this review came from trials supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.
We included three studies with 1853 participants who had undergone surgical removal of impacted wisdom teeth, hip replacement, or hysterectomy. The overall risk of bias across the three included studies was low, with unclear risk of bias in relation to the size of the three studies. Two studies did not report all our prespecified outcomes, which limited the analyses we could do. The proportion of participants achieving at least 50% pain relief over six hours with dexketoprofen 25 mg plus tramadol 75 mg was 66%, compared to 32% with placebo, giving an NNT of 3.0 (95% CI 2.5 to 3.7) (RR 2.1 (95% CI 1.7 to 2.4); 748 participants; 3 studies) (moderate quality evidence). The response rate with dexketoprofen 25 mg alone was 53% (RR 1.3 (95% CI 1.1 to 1.4); 744 participants; 3 studies) and with tramadol alone was 45% (RR 1.5 (95% CI 1.3 to 1.7); 741 participants; 3 studies) (moderate quality evidence). We downgraded the evidence because of some inconsistency in the results. The median time to use of rescue medication could not be estimated exactly, but was probably eight hours or more, indicating a long duration of effect (moderate quality evidence). We downgraded the evidence because it was not possible to estimate the effect exactly in the two multiple dose studies, resulting in imprecision. Fewer participants used rescue medication with higher doses of active treatment (summary statistic not calculated; 123 participants; 1 study) (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events. Adverse events and serious adverse events were not reported consistently for the single dose phase of the studies. In the single dose study, 11% of participants experienced adverse events with dexketoprofen 25 mg plus tramadol 75 mg, which were mostly mild or moderate nausea, vomiting, or dizziness, and typical with these medicines. Rates were lower with placebo and lower doses (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events. Information on multiple dosing over three and five days supported a low event rate with the combination. Overall, rates were generally low in all treatment arms, as they were for withdrawals for adverse events or other reasons. A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than placebo or the same dose of dexketoprofen or tramadol alone. The magnitude of the effect was similar to other good analgesics. Adverse event rates were low. There is modest uncertainty about the precision of the point estimate for efficacy, but the NNT of 3 is consistent with other analgesics considered effective and commonly used.
No new studies were included for this update. Seven studies with a combined total of 802 participants were included in this review. No significant difference was observed between heparin treatment and control groups for pain-free walking distance or maximum walking distance at the end of treatment. There were no data to indicate that LMWHs benefit walking distance. Revascularisation or amputation-free survival rates were reported in one study only with a five year follow-up. No study reported a significant effect on overall mortality or cardiovascular events and the pooled odds ratios were not significant for these outcomes either. Major and minor bleeding events were significantly more frequent in the group treated with oral anticoagulants compared to control, with a non-significant increase in fatal bleeding events. No major bleeding events were reported in the study evaluating heparin, while a non-significant increase in minor bleeding events was reported. The benefit of heparin, LMWHs and oral anticoagulants for treatment of intermittent claudication has not been established while an increased risk of major bleeding events has been observed, especially with oral anticoagulants. There is no clear evidence to support the use of anticoagulants for intermittent claudication at this stage.
Twenty small trials (1239 people with neck pain) containing 38 comparisons were included. Analysis was limited by trials of varied quality, heterogeneous treatment subtypes and conflicting results. The main findings for reduction of neck pain by treatment with electrotherapeutic modalities were as follows. Very low quality evidence determined that pulsed electromagnetic field therapy (PEMF) and repetitive magnetic stimulation (rMS) were more effective than placebo, while transcutaneous electrical nerve stimulation (TENS) showed inconsistent results. Very low quality evidence determined that PEMF, rMS and TENS were more effective than placebo. Low quality evidence (1 trial, 52 participants) determined that permanent magnets (necklace) were no more effective than placebo (standardized mean difference (SMD) 0.27, 95% CI -0.27 to 0.82, random-effects model). Very low quality evidence showed that modulated galvanic current, iontophoresis and electric muscle stimulation (EMS) were not more effective than placebo. There were four trials that reported on other outcomes such as function and global perceived effects, but none of the effects were of clinical importance. When TENS, iontophoresis and PEMF were compared to another treatment, very low quality evidence prevented us from suggesting any recommendations. No adverse side effects were reported in any of the included studies. We cannot make any definite statements on the efficacy and clinical usefulness of electrotherapy modalities for neck pain. Since the evidence is of low or very low quality, we are uncertain about the estimate of the effect. Further research is very likely to change both the estimate of effect and our confidence in the results. Current evidence for PEMF, rMS, and TENS shows that these modalities might be more effective than placebo. When compared to other interventions the quality of evidence was very low thus preventing further recommendations. Funding bias should be considered, especially in PEMF studies. Galvanic current, iontophoresis, EMS, and a static magnetic field did not reduce pain or disability. Future trials on these interventions should have larger patient samples, include more precise standardization, and detail treatment characteristics.
Four cross-over studies, published between 1968 and 1982, involving 121 patients, and four different NSAIDs were included. The generation of the allocation sequence and the use of methods to conceal the allocation were not described in any of the studies. The studies were double-blind but it was not clear whether the blinding was effective. Methods for collecting adverse effects were not described. The NSAIDs were preferred more often than paracetamol by the patients or the investigator. In the largest trial, 20 out of 54 patients (37%) preferred ibuprofen and 7 out of 54 (13%) paracetamol. Investigators preference (as established by joint tenderness, grip strength and joint circumference) was 17 out of 35 for diclofenac versus 5 out of 35 for paracetamol in another trial. However, because of the weaknesses in the trials, no firm conclusion can be drawn. When considering the trade off between the benefits and harms of non-steroidal anti-inflammatory drugs and paracetamol/acetaminophen, it is not known whether one is better than the other for rheumatoid arthritis. But people with rheumatoid arthritis and the researchers in the study did prefer non-steroidal anti-inflammatory drugs more than acetaminophen/paracetamol. There is a need for a large trial, with appropriate randomisation, double-blinding, test of the success of the blinding, and with explicit methods to measure and analyse pain and adverse effects.
The review included 27 RCTs involving 1803 children. Of these, six were multi-arm and one was also a cross-over study. Most studies were small, with numbers randomised ranging from 16 to 202. A total of 19 studies were at high risk of bias for at least one domain. Few studies reported data suitable for pooling due to heterogeneity in interventions, outcomes and measurements. Individual conservative interventions (lifestyle, behavioural or physical) versus no treatment Transcutaneous electrical nerve stimulation (TENS) versus sham (placebo) TENS. More children receiving active TENS may achieve continence (risk ratio (RR) 4.89, 95% confidence interval (CI) 1.68 to 14.21; 3 studies; n = 93; low-certainty evidence). One individual conservative intervention versus another individual or combined conservative intervention Pelvic floor muscle training (PFMT) with urotherapy versus urotherapy alone. We are uncertain whether more children receiving PFMT with urotherapy achieve continence (RR 2.36, 95% CI 0.65 to 8.53, 95% CI 25 to 100; 3 studies; n = 91; very low-certainty evidence). Voiding education with uroflowmetry feedback and urotherapy versus urotherapy alone. Slightly more children receiving voiding education with uroflow feedback and urotherapy may achieve continence (RR 1.13, 95% CI 0.87 to 1.45; 3 studies; n = 151; low-certainty evidence). Urotherapy with timer watch versus urotherapy alone. We are uncertain whether urotherapy plus timer watch increases the number of children achieving continence compared to urotherapy alone (RR 1.42, 95% CI 1.12 to 1.80; 1 study; n = 58; very low-certainty evidence). Combined conservative interventions versus other combined conservative interventions TENS and standard urotherapy versus PFMT with electromyographic biofeedback and standard urotherapy. We are uncertain whether there is any evidence of a difference between treatment groups in the proportions of children achieving continence (RR 1.11, 95% CI 0.73 to 1.68; 1 study; n = 78; very low-certainty evidence). PFMT with electromyography biofeedback and standard urotherapy versus PFMT without feedback but with standard urotherapy. We are uncertain whether there is any evidence of a difference between treatment groups in the proportions of children achieving continence (RR 1.05, 95% CI 0.72 to 1.52; 1 study; n = 41; very low-certainty evidence). Individual conservative interventions versus non-conservative interventions (pharmacological or invasive, combined or not with any conservative interventions) PFMT versus anticholinergics. We are uncertain whether more children receiving PFMT than anticholinergics achieve continence (RR 1.92, 95% CI 1.17 to 3.15; equivalent to an increase from 33 to 64 per 100 children; 2 studies; n = 86; very low-certainty evidence). TENS versus anticholinergics. We are uncertain whether there was any evidence of a difference between treatment groups in the proportions of children achieving continence (RR 0.81, 95% CI 0.05 to 12.50; 2 studies; n = 72; very low-certainty evidence). Combined conservative interventions versus non-conservative interventions (pharmacological or invasive, combined or not with any conservative interventions) Voiding education with uroflowmetry feedback versus anticholinergics. We are uncertain whether there was any evidence of a difference between treatment groups in the proportion of children achieving continence (RR 1.02, 95% CI 0.58 to 1.78; 1 study; n = 64; very low-certainty evidence). The review found little reliable evidence that can help affected children, their carers and the clinicians working with them to make evidence-based treatment decisions. In this scenario, the clinical experience of individual clinicians and the support of carers may be the most valuable resources. More well-designed research, with well-defined interventions and consistent outcome measurement, is needed.
The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196). Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin. All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL. Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported. The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome. Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). All agents were generally effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional desirable effects compared with the current standard oxytocin. The two combination regimens, however, are associated with significant side effects. Carbetocin may be more effective than oxytocin for some outcomes without an increase in side effects.
We included 31 trials (1760 participants; 897 randomized to peripheral nerve blocks and 863 to no regional blockade). Results of eight trials with 373 participants show that peripheral nerve blocks reduced pain on movement within 30 minutes of block placement (standardized mean difference (SMD) -1.41, 95% confidence interval (CI) -2.14 to -0.67; equivalent to -3.4 on a scale from 0 to 10; I2 = 90%; high quality of evidence). Effect size was proportionate to the concentration of local anaesthetic used (P < 0.00001). Based on seven trials with 676 participants, we did not find a difference in the risk of acute confusional state (risk ratio (RR) 0.69, 95% CI 0.38 to 1.27; I2 = 48%; very low quality of evidence). Three trials with 131 participants reported decreased risk for pneumonia (RR 0.41, 95% CI 0.19 to 0.89; I2 = 3%; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 5 to 72; moderate quality of evidence). We did not find a difference in risk of myocardial ischaemia or death within six months, but the number of participants included was well below the optimal information size for these two outcomes. Two trials with 155 participants reported that peripheral nerve blocks also reduced time to first mobilization after surgery (mean difference -11.25 hours, 95% CI -14.34 to -8.15 hours; I2 = 52%; moderate quality of evidence). One trial with 75 participants indicated that the cost of analgesic drugs was lower when they were given as a single shot block (SMD -3.48, 95% CI -4.23 to -2.74; moderate quality of evidence). High-quality evidence shows that regional blockade reduces pain on movement within 30 minutes after block placement. Moderate-quality evidence shows reduced risk for pneumonia, decreased time to first mobilization and cost reduction of the analgesic regimen (single shot blocks).
Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn’s disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children.
We included three trials (283 participants in the analyses) that ran for two to three years. All participants were ex- or never-smokers and had genetic variants that carried a high risk of developing COPD. Only one trial reported mortality data (one person of 93 died in the treatment group and three of 87 died in the placebo group). There was no information on harms in the oldest trial. Another trial reported serious adverse events in 10 participants in the treatment group and 18 participants in the placebo group. In the most recent trial, serious adverse events occurred in 28 participants in each group. None of the trials reported mean number of lung infections or hospital admissions. In the two trials that reported exacerbations, there were more exacerbations in the treatment group than in the placebo group, but the results of both trials included the possibility of no difference. Quality of life was similar in the two groups. Forced expiratory volume in one second (FEV1) deteriorated more in participants in the treatment group than in the placebo group but the confidence interval (CI) included no difference (standardised mean difference -0.19, 95% CI -0.42 to 0.05; P = 0.12). For carbon monoxide diffusion, the difference was -0.11 mmol/minute/kPa (95% CI -0.35 to 0.12; P = 0.34). Lung density measured by computer tomography (CT) scan deteriorated significantly less in the treatment group than in the placebo group (mean difference (MD) 0.86 g/L, 95% CI 0.31 to 1.42; P = 0.002). Several secondary outcomes were unreported in the largest and most recent trial whose authors had numerous financial conflicts of interest. This review update added one new study and 143 new participants, but the conclusions remain unchanged. Due to sparse data, we could not arrive at a conclusion about the impact of augmentation therapy on mortality, exacerbations, lung infections, hospital admission and quality of life, and there was uncertainty about possible harms. Therefore, it is our opinion that augmentation therapy with alpha-1 antitrypsin cannot be recommended.
The search identified two studies (a multicenter study from Japan and the United Kingdom) with 361 participants. Primary outcomes Our results indicate that single-dose intravesical chemotherapy instillation may reduce the risk of bladder cancer recurrence over time compared to no instillation (hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.32 to 0.82, low-certainty evidence). After 12 months follow-up, this would result in 127 fewer bladder cancer recurrences (95% CI: 182 to 44 fewer bladder cancer recurrences) per 1000 participants. We downgraded the certainty of evidence by two levels due to study limitations and imprecision. We found no trials that reported on the outcomes of time to death from upper tract urothelial carcinoma. The effect of single-dose intravesical chemotherapy instillation on serious adverse events is uncertain (risk ratio [RR]: not estimable, 95% CI: not estimable, there were no events, very low-certainty evidence). We downgraded the certainty of evidence by one level due to study limitations and by two levels due to imprecision. Secondary outcomes We found no trials that reported on the outcomes of time to death from any cause and participants’ disease-specific quality of life. The effect of single-dose intravesical chemotherapy instillation on minor adverse events is uncertain (risk ratio [RR]: not estimable, 95% CI: not estimable, there were no events, very low-certainty evidence). We downgraded the certainty of evidence by one level due to study limitations and by two levels due to imprecision. For patients who have undergone nephroureterectomy for upper tract urothelial carcinoma, single-dose intravesical chemotherapy instillation may reduce bladder cancer recurrence after nephroureterectomy. However, we are uncertain as to the risk of serious (and minor) adverse events. We found no evidence for the outcome of time to death from upper tract urothelial carcinoma. We were unable to conduct any of the preplanned subgroup analyses, particularly those based on operative approach, pathologic stage, and method of bladder cuff excision.
We identified 16 trials, predominantly of moderate to good quality, involving 994 participants, most with chronic obstructive pulmonary disease (COPD). Compared with IPPV weaning, NPPV weaning significantly decreased mortality. The benefits for mortality were significantly greater in trials enrolling exclusively participants with COPD (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.56) versus mixed populations (RR 0.81, 95% CI 0.47 to 1.40). NPPV significantly reduced weaning failure (RR 0.63, 95% CI 0.42 to 0.96) and ventilator-associated pneumonia (RR 0.25, 95% CI 0.15 to 0.43); shortened length of stay in an intensive care unit (mean difference (MD) -5.59 days, 95% CI -7.90 to -3.28) and in hospital (MD -6.04 days, 95% CI -9.22 to -2.87); and decreased the total duration of ventilation (MD -5.64 days, 95% CI -9.50 to -1.77) and the duration of endotracheal mechanical ventilation (MD - 7.44 days, 95% CI -10.34 to -4.55) amidst significant heterogeneity. Noninvasive weaning also significantly reduced tracheostomy (RR 0.19, 95% CI 0.08 to 0.47) and reintubation (RR 0.65, 95% CI 0.44 to 0.97) rates. Noninvasive weaning had no effect on the duration of ventilation related to weaning. Exclusion of a single quasi-randomized trial did not alter these results. Subgroup analyses suggest that the benefits for mortality were significantly greater in trials enrolling exclusively participants with COPD versus mixed populations. Summary estimates from 16 trials of moderate to good quality that included predominantly participants with COPD suggest that a weaning strategy that includes NPPV may reduce rates of mortality and ventilator-associated pneumonia without increasing the risk of weaning failure or reintubation.
48 studies (n = 3054 participants) were included. The review supported the efficacy of CBT and particularly CBT-BN in the treatment of people with bulimia nervosa and also (but less strongly due to the small number of trials) related eating disorder syndromes. Other psychotherapies were also efficacious, particularly interpersonal psychotherapy in the longer-term. Self-help approaches that used highly structured CBT treatment manuals were promising. Exposure and Response Prevention did not enhance the efficacy of CBT. Psychotherapy alone is unlikely to reduce or change body weight in people with bulimia nervosa or similar eating disorders. There is a small body of evidence for the efficacy of CBT in bulimia nervosa and similar syndromes, but the quality of trials is very variable and sample sizes are often small. More and larger trials are needed, particularly for binge eating disorder and other EDNOS syndromes. There is a need to develop more efficacious therapies for those with both a weight and an eating disorder.
We included 12 studies (n = 1837), of which, three compared PCT to a wait-list/minimal attention (WL/MA) group and 11 compared PCT to TF-CBT. PCT was more effective than WL/MA in reducing PTSD symptom severity (SMD -0.84, 95% CI -1.10 to -0.59; participants = 290; studies = 3; I² = 0%). We assessed the quality of this evidence as moderate. The results of the non-inferiority analysis comparing PCT to TF-CBT did not support PCT non-inferiority, with the 95% confidence interval surpassing the clinically meaningful cut-off (MD 6.83, 95% CI 1.90 to 11.76; 6 studies, n = 607; I² = 42%). We assessed this quality of evidence as low. CAPS differences between PCT and TF-CBT attenuated at 6-month (MD 1.59, 95% CI -0.46 to 3.63; participants = 906; studies = 6; I² = 0%) and 12-month (MD 1.22, 95% CI -2.17 to 4.61; participants = 485; studies = 3; I² = 0%) follow-up periods. To confirm the direction of the treatment effect using all eligible trials, we also evaluated PTSD SMD differences. These results were consistent with the primary MD outcomes, with meaningful effect size differences between PCT and TF-CBT at post-treatment (SMD 0.32, 95% CI 0.08 to 0.56; participants = 1129; studies = 9), but smaller effect size differences at six months (SMD 0.17, 95% CI 0.05 to 0.29; participants = 1339; studies = 9) and 12 months (SMD 0.17, 95% CI 0.03 to 0.31; participants = 728; studies = 5). PCT had approximately 14% lower treatment dropout rates compared to TF-CBT (RD -0.14, 95% CI -0.18 to -0.10; participants = 1542; studies = 10). We assessed the quality of this evidence as moderate. There was no evidence of meaningful differences on self-reported PTSD (MD 4.50, 95% CI 3.09 to 5.90; participants = 983; studies = 7) or depression symptoms (MD 1.78, 95% CI -0.23 to 3.78; participants = 705; studies = 5) post-treatment. Moderate-quality evidence indicates that PCT is more effective in reducing PTSD severity compared to control conditions. Low quality of evidence did not support PCT as a non-inferior treatment compared to TF-CBT on clinician-rated post-treatment PTSD severity. The treatment effect differences between PCT and TF-CBT may attenuate over time. PCT participants drop out of treatment at lower rates relative to TF-CBT participants. Of note, all of the included studies were primarily designed to test the effectiveness of TF-CBT which may bias results away from PCT non-inferiority.The current systematic review provides the most rigorous evaluation to date to determine whether PCT is comparably as effective as TF-CBT. Findings are generally consistent with current clinical practice guidelines that suggest that PCT may be offered as a treatment for PTSD when TF-CBT is not available.
We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.94 to 1.19, I2 = 0%; moderate-certainty evidence) or progression-free survival in four trials where we were able to pool data (1631 women; HR 1.02; 95% CI 0.92 to 1.13, I2 = 0%; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were poorly and incompletely reported across studies. There may be clinically meaningful differences in favour of NACT compared to PDS with regard to serious adverse effects (SAE grade 3+). These data suggest that NACT may reduce the risk of need for blood transfusion (risk ratio (RR) 0.80; 95% CI 0.64 to 0.99; four studies,1085 women; low-certainty evidence), venous thromboembolism (RR 0.28; 95% CI 0.09 to 0.90; four studies, 1490 women; low-certainty evidence), infection (RR 0.30; 95% CI 0.16 to 0.56; four studies, 1490 women; moderate-certainty evidence), compared to PDS. NACT probably reduces the need for stoma formation (RR 0.43, 95% CI 0.26 to 0.72; two studies, 581 women; moderate-certainty evidence) and bowel resection (RR 0.49, 95% CI 0.26 to 0.92; three studies, 1213 women; moderate-certainty evidence), as well as reducing postoperative mortality (RR 0.18; 95% CI 0.06 to 0.54:five studies, 1571 women; moderate-certainty evidence). QoL on the EORTC QLQ-C30 scale produced inconsistent and imprecise results in two studies (MD -1.34, 95% CI -2.36 to -0.32; participants = 307; very low-certainty evidence) and use of the QLQC-30 and QLQC-Ov28 in another study (MD 7.60, 95% CI 1.89 to 13.31; participants = 217; very low-certainty evidence) meant that little could be inferred. The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.
Five studies met our inclusion criteria; all were retrospective observational studies and therefore at high risk of bias. Meta-analysis of three studies assessing over 9000 women suggested that institutions with gynaecologic oncologists on site may prolong survival in women with ovarian cancer, compared to community or general hospitals: hazard ratio (HR) of death was 0.90 (95% confidence interval (CI) 0.82 to 0.99). Similarly, another meta-analysis of three studies assessing over 50,000 women, found that teaching centres or regional cancer centres may prolong survival in women with any gynaecological cancer compared to community or general hospitals (HR 0.91; 95% CI 0.84 to 0.99). The largest of these studies included all gynaecological malignancies and assessed 48,981 women, so the findings extend beyond ovarian cancer. One study compared community hospitals with semi-specialised gynaecologists versus general hospitals and reported non-significantly better disease-specific survival in women with ovarian cancer (HR 0.89; 95% CI 0.78 to 1.01). The findings of included studies were highly consistent. Adverse event data were not reported in any of the studies. We found low quality, but consistent evidence to suggest that women with gynaecological cancer who received treatment in specialised centres had longer survival than those managed elsewhere. The evidence was stronger for ovarian cancer than for other gynaecological cancers. Further studies of survival are needed, with more robust designs than retrospective observational studies. Research should also assess the quality of life associated with centralisation of gynaecological cancer care. Most of the available evidence addresses ovarian cancer in developed countries; future studies should be extended to other gynaecological cancers within different healthcare systems.
All 36 included trials originated from China and were at overall high risk of bias. The trials included 6044 pregnant women who were HBsAg, HBeAg, or hepatitis B virus DNA (HBV-DNA) positive. Only seven trials reported inclusion of HBeAg-positive mothers. All 36 trials compared HBIG versus no intervention. None of the trials used placebo. Most of the trials assessed HBIG 100 IU (two trials) and HBIG 200 IU (31 trials). The timing of administration of HBIG varied; 30 trials administered three doses of HBIG 200 IU at 28, 32, and 36 weeks of pregnancy. None of the trials reported all-cause mortality or other serious adverse events in the mothers or babies. Serological signs of hepatitis B infection of the newborns were reported as HBsAg, HBeAg, and HBV-DNA positive results at end of follow-up. Twenty-nine trials reported HBsAg status in newborns (median 1.2 months of follow-up after birth; range 0 to 12 months); seven trials reported HBeAg status (median 1.1 months of follow-up after birth; range 0 to 12 months); and 16 trials reported HBV-DNA status (median 1.2 months of follow-up; range 0 to 12 months). HBIG reduced mother-to-child transmission (MTCT) of HBsAg when compared with no intervention (179/2769 (6%) with HBIG versus 537/2541 (21%) with no intervention; RR 0.30, TSA-adjusted CI 0.20 to 0.52; I2 = 36%; 29 trials; 5310 participants; very low quality evidence). HBV-DNA reduced MTCT of HBsAg (104/1112 (9%) with HBV-DNA versus 382/1018 (38%) with no intervention; RR 0.25, TSA-adjusted CI 0.22 to 0.27; I2 = 84%; 16 trials; 2130 participants; low quality evidence). TSA supported both results. Meta-analysis showed that maternal HBIG did not decrease HBeAg in newborns compared with no intervention (184/889 (21%) with HBIG versus 232/875 (27%) with no intervention; RR 0.68, TSA-adjusted CI 0.04 to 6.37; I2 = 90%; 7 trials; 1764 participants; very low quality evidence). TSA could neither support nor refute this observation as data were too sparse. None of the trials reported adverse events of the immunoglobulins on the newborns, presence of local and systemic adverse events on the mothers, or cost-effectiveness of treatment. Due to very low to low quality evidence found in this review, we are uncertain of the effect of benefit of antenatal HBIG administration to the HBV-infected mothers on newborn outcomes, such as HBsAg, HBV-DNA, and HBeAg compared with no intervention. The results of the effects of HBIG on HBsAg and HBeAg are surrogate outcomes (raising risk of indirectness), and we need to be critical while interpreting the findings. We found no data on newborn mortality or maternal mortality or both, or other serious adverse events. Well-designed randomised clinical trials are needed to determine the benefits and harms of HBIG versus placebo in prevention of MTCT of HBV.
We included 33 trials, involving 13,114 children (˜49% females) from 20 countries in Latin America, Africa and Asia. The methodological quality of the trials was mixed. Nineteen trials evaluated intermittent iron supplementation versus no intervention or a placebo and 21 studies evaluated intermittent versus daily iron supplementation. Some of these trials contributed data to both comparisons. Iron alone was provided in most of the trials. Fifteen studies included children younger than 60 months; 11 trials included children 60 months and older, and seven studies included children in both age categories. One trial included exclusively females. Seven trials included only anaemic children; three studies assessed only non-anaemic children, and in the rest the baseline prevalence of anaemia ranged from 15% to 90%. In comparison with receiving no intervention or a placebo, children receiving iron supplements intermittently have a lower risk of anaemia (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72, ten studies) and iron deficiency (RR 0.24, 95% CI 0.06 to 0.91, three studies) and have higher haemoglobin (mean difference (MD) 5.20 g/L, 95% CI 2.51 to 7.88, 19 studies) and ferritin concentrations (MD 14.17 µg/L, 95% CI 3.53 to 24.81, five studies). Intermittent supplementation was as effective as daily supplementation in improving haemoglobin (MD –0.60 g/L, 95% CI –1.54 to 0.35, 19 studies) and ferritin concentrations (MD –4.19 µg/L, 95% CI –9.42 to 1.05, 10 studies), but increased the risk of anaemia in comparison with daily iron supplementation (RR 1.23, 95% CI 1.04 to1.47, six studies). Data on adherence were scarce and it tended to be higher among those children receiving intermittent supplementation, although this result was not statistically significant. We did not identify any differential effect of the type of intermittent supplementation regimen (one, two or three times a week), the total weekly dose of elemental iron, the nutrient composition, whether recipients were male or female or the length of the intervention. Intermittent iron supplementation is efficacious to improve haemoglobin concentrations and reduce the risk of having anaemia or iron deficiency in children younger than 12 years of age when compared with a placebo or no intervention, but it is less effective than daily supplementation to prevent or control anaemia. Intermittent supplementation may be a viable public health intervention in settings where daily supplementation has failed or has not been implemented. Information on mortality, morbidity, developmental outcomes and side effects, however, is still lacking.
Two randomised controlled trials with a total of 141 preterm infants met the inclusion criteria for the comparison of routine monitoring versus no monitoring of gastric residual in preterm infants. Both trials were done in infants with birth weight < 1500 g. Routine monitoring of gastric residual may have little or no effect on the incidence of necrotising enterocolitis (risk ratio (RR) 3.07, 95% confidence interval (CI) 0.50 to 18.77; participants = 141; studies = 2; low-quality evidence). Routine monitoring may increase the risk of feed interruption episodes (RR 2.07, 95% CI 1.39 to 3.07; participants = 141; studies = 2; low-quality evidence); the number needed to treat for an additional harmful outcome (NNTH) was 3 (95% CI 2 to 6). Routine monitoring of gastric residual may increase time taken to establish full enteral feeds (mean difference (MD) 3.92, 95% CI 2.06 to 5.77 days; participants = 141; studies = 2; low-quality evidence), time taken to regain birth weight (MD 1.70, 95% CI 0.01 to 3.39 days; participants = 80; studies = 1; low-quality evidence), and number of total parenteral nutrition days (MD 3.29, 95% CI 1.66 to 4.92 days; participants = 141; studies = 2; low-quality evidence). We are uncertain as to the effect of routine monitoring of gastric residual on other outcomes such as incidence of surgical necrotising enterocolitis, extrauterine growth restriction at discharge, parenteral nutrition-associated liver disease, duration of central venous line (CVL) usage, incidence of invasive infection, mortality before discharge, and duration of hospital stay. We found no data for outcomes such as aspiration pneumonia, gastroesophageal reflux, growth measures following discharge, and neurodevelopmental outcome. Only one trial with 87 preterm infants met the inclusion criteria for the comparison of using two different criteria of gastric residual to interrupt feeds while monitoring gastric residual. The trial was done in infants with birth weight of 1500 to 2000 g. We are uncertain as to the effect of using two different criteria of gastric residual on outcomes such as incidence of necrotising enterocolitis or surgical necrotising enterocolitis, time to establish full enteral feeds, time to regain birth weight, number of total parenteral nutrition days, number of infants experiencing feed interruption episodes, extrauterine growth restriction at discharge, parenteral nutrition-associated liver disease, incidence of invasive infection, and mortality before discharge (very low quality evidence). We found no data on duration of CVL usage, aspiration pneumonia, gastroesophageal reflux, duration of hospital stay, growth measures following discharge, and neurodevelopmental outcome. Review authors found insufficient evidence as to whether routine monitoring of gastric residual reduces the incidence of necrotising enterocolitis because trial results are imprecise. Low-quality evidence suggests that routine monitoring of gastric residual increases the risk of feed interruption episodes, increases the time taken to reach full enteral feeds and to regain birth weight, and increases the number of total parenteral nutrition (TPN) days. Available data are insufficient to comment on other major outcomes such as incidence of invasive infection, parenteral nutrition-associated liver disease, mortality before discharge, extrauterine growth restriction at discharge, number of CVL days, and duration of hospital stay. Further randomised controlled trials are warranted to provide more precise estimates of the effects of routine monitoring of gastric residual on important outcomes, especially necrotising enterocolitis, in preterm infants.
There were 15 included studies (6008 enrolled participants); 13 studies contributed data. Women using home uterine monitoring were less likely to experience preterm birth at less than 34 weeks (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.99; three studies, 1596 women; fixed-effect analysis) (GRADE high). This difference was not evident when we carried out a sensitivity analysis, restricting the analysis to studies at low risk of bias based on study quality (RR 0.75, 95% CI 0.57 to 1.00; one study, 1292 women). There was no difference in the rate of perinatal mortality (RR 1.22, 95% CI 0.86 to 1.72; two studies, 2589 babies) (GRADE low). There was no difference in the number of preterm births at less than 37 weeks (average RR 0.85, CI 0.72 to 1.01; eight studies, 4834 women; random-effects, Tau2 = 0.03, I2 = 68%) (GRADE very low). Infants born to women using home uterine monitoring were less likely to be admitted to neonatal intensive care unit (average RR 0.77, 95% CI 0.62 to 0.96; five studies, 2367 babies; random-effects, Tau2 = 0.02, I2 = 32%) (GRADE moderate). This difference was not maintained when we restricted the analysis to studies at low risk of bias (RR 0.86, 95% CI 0.74 to 1.01; one study, 1292 babies). Women using home uterine monitoring made more unscheduled antenatal visits (mean difference (MD) 0.48, 95% CI 0.31 to 0.64; two studies, 1994 women) (GRADE moderate). Women using home uterine monitoring were also more likely to have prophylactic tocolytic drug therapy (average RR 1.21, 95% CI 1.01 to 1.45; seven studies, 4316 women; random-effects, Tau2 = 0.03, I2 = 62%), but this difference was no longer evident when we restricted the analysis to studies at low risk of bias (average RR 1.22, 95% CI 0.90 to 1.65; three studies, 3749 women; random-effects, Tau2 = 0.05, I2 = 76%) (GRADE low). The number of antenatal hospital admissions did not differ between home groups (RR 0.91, 95% CI 0.74 to 1.11; three studies, 1494 women (GRADE low)). We found no data on maternal anxiety or acceptability. Home uterine monitoring may result in fewer admissions to a neonatal intensive care unit but in more unscheduled antenatal visits and tocolytic treatment; the level of evidence is generally low to moderate. Important group differences were not evident when we undertook sensitivity analysis using only trials at low risk of bias. There is no impact on maternal and perinatal outcomes such as perinatal mortality or incidence of preterm birth.
We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin. We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention. In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo. In children, exacerbation frequency was reduced more with macrolides than with placebo (IRR 0.50, 95% CI 0.35 to 0.71; 89 children; one study; low-quality evidence). However there was no significant difference in this age group with regard to: hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children. Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.
Twelve trials were included in the review. There were seven crossover trials and five parallel group studies. For the comparisons between anticholinergic drugs with tricyclic antidepressants, alpha adrenergic agonists, afferent nerve inhibitors, and calcium channel blocker a single trial was identified for each. Nine trials compared flavoxate with anticholinergics. There was no evidence of a difference in cure rates between anticholinergics and flavoxate. Adverse effects were more frequent in anticholinergic groups versus flavoxate groups (RR 2.28 95% CI 1.45 to 3.56). There was no strong evidence to favour either anticholinergic drugs or the comparators. Many of the drugs considered in trials in this review are no longer used in clinical practice (and this includes the most commonly tested - flavoxate). There is inadequate evidence as to determine whether any of the available druge are better or worse than anticholinergic medications. Larger randomised controlled trials in clinical settings are required to further establish the role of these medications in the management of overactive bladder syndrome.
We included ten studies, with a total of 928 women. All included studies reported outcomes per woman randomised. We assessed no studies as being at low risk of bias across all domains and found that the main limitation was lack of blinding. Using the GRADE method, we determined that the quality of the evidence ranged from moderate to very low, and we identified issues arising from risk of bias, imprecision, and inconsistency. Comparing follicular flushing to aspiration alone revealed probably little or no difference in the live birth rate (OR 0.95, 95% CI 0.58 to 1.56; three RCTs; n = 303; I2 = 30%; moderate-quality evidence). This suggests that with a live birth rate of approximately 41% with aspiration alone, the equivalent live birth rate with follicular flushing is likely to lie between 29% and 52%. None of the included studies reported on the primary outcome of miscarriage rate. Data show probably little or no difference in oocyte yield (MD -0.28 oocytes, 95% CI -0.64 to 0.09; six RCTs; n = 708; I2 = 0%; moderate-quality evidence). Very low-quality evidence suggests that the duration of oocyte retrieval was longer in the follicular flushing group than in the aspiration only group (MD 166.01 seconds, 95% CI 141.96 to 190.06; six RCTs; n = 714; I2 = 88%). We found no evidence of a difference in the total number of embryos per woman randomised (MD -0.10 embryos, 95% CI -0.34 to 0.15; two RCTs; n = 160; I2 = 58%; low-quality evidence) and no evidence of a difference in the number of embryos cryopreserved (meta-analysis not possible). Data show probably little or no difference in the clinical pregnancy rate (OR 1.07, 95% CI 0.78 to 1.46; five RCTs; n = 704; I2 = 49%; moderate-quality evidence). Only two studies reported on adverse outcomes: One reported no differences in patient-reported adverse outcomes (depression, anxiety, and stress), and the other reported no differences in needle blockage, vomiting, and hypotension. No studies reported on safety. This review suggests that follicular flushing probably has little or no effect on live birth rates compared with aspiration alone. None of the included trials reported on effects of follicular aspiration and flushing on the miscarriage rate. Data suggest little or no difference between follicular flushing and aspiration alone with respect to oocyte yield, total embryo number, or number of cryopreserved embryos. In addition, follicular flushing probably makes little or no difference in the clinical pregnancy rate. Evidence was insufficient to allow any firm conclusions with respect to adverse events or safety.
We included six studies (916 participants with 988 teeth) reported in English. All the studies had high risk of bias. The six studies examined five different comparisons, including MTA versus intermediate restorative material (IRM), MTA versus super ethoxybenzoic acid cement (Super-EBA), Super-EBA versus IRM, dentine-bonded resin composite versus glass ionomer cement and glass ionomer cement versus amalgam. There was therefore little pooling of data and very little evidence for each comparison. There is weak evidence of little or no difference between MTA and IRM at the first year of follow-up (risk ratio (RR) 1.09; 95% confidence interval (CI): 0.97 to 1.22; 222 teeth; quality of evidence: low). Insufficient evidence of a difference between MTA and IRM on success rate at the second year of follow-up (RR 1.06; 95% CI: 0.89 to 1.25; 86 teeth, 86 participants; quality of evidence: very low). All the other outcomes were based on a single study. There is insufficient evidence of any difference between MTA and Super-EBA at the one-year follow-up (RR 1.03; 95% CI: 0.96 to 1.10; 192 teeth, 192 participants; quality of evidence: very low), and only weak evidence indicating there might be a small increase in success rate at the one-year follow-up in favour of IRM compared to Super-EBA (RR 0.90; 95% CI: 0.80 to 1.01; 194 teeth; quality of evidence: very low). There was also insufficient and weak evidence to show that dentine-bonded resin composite might be a better choice for increasing retrograde filling success rate compared to glass ionomer cement at the one-year follow-up (RR 2.39; 95% CI: 1.60 to 3.59; 122 teeth, 122 participants; quality of evidence: very low). And there was insufficient evidence of a difference between glass ionomer cement and amalgam at both the one-year (RR 0.98; 95% CI: 0.86 to 1.12; 105 teeth; quality of evidence: very low) and five-year follow-ups (RR 1.00; 95% CI: 0.84 to 1.20; 82 teeth; quality of evidence: very low). None of these studies reported an adverse event. Based on the present limited evidence, there is insufficient evidence to draw any conclusion as to the benefits of any one material over another. We conclude that more high-quality RCTs are required.
We included 14 studies (421 participants) in the analysis. The sensitivities for conversion from MCI to Alzheimer's disease dementia were between 25% and 100% while the specificities were between 15% and 100%. From the summary ROC curve we fitted we estimated that the sensitivity was 76% (95% confidence interval (CI): 53.8 to 89.7) at the included study median specificity of 82%. This equates to a positive likelihood ratio of 4.03 (95% CI: 2.97 to 5.47), and a negative likelihood ratio of 0.34 (95% CI: 0.15 to 0.75). Three studies recruited participants from the same Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort but only the largest ADNI study (Herholz 2011) is included in the meta-analysis. In order to demonstrate whether the choice of ADNI study or discriminating brain region (Chételat 2003) or reader assessment (Pardo 2010) make a difference to the pooled estimate, we performed five additional analyses. At the median specificity of 82%, the estimated sensitivity was between 74% and 76%. There was no impact on our findings. In addition to evaluating Alzheimer's disease dementia, five studies evaluated the accuracy of ¹⁸F-FDG PET for all types of dementia. The sensitivities were between 46% and 95% while the specificities were between 29% and 100%; however, we did not conduct a meta-analysis because of too few studies, and those studies which we had found recruited small numbers of participants. Our findings are based on studies with poor reporting, and the majority of included studies had an unclear risk of bias, mainly for the reference standard and participant selection domains. According to the assessment of Index test domain, more than 50% of studies were of poor methodological quality. It is difficult to determine to what extent the findings from the meta-analysis can be applied to clinical practice. Given the considerable variability of specificity values and lack of defined thresholds for determination of test positivity in the included studies, the current evidence does not support the routine use of ¹⁸F-FDG PET scans in clinical practice in people with MCI. The ¹⁸F-FDG PET scan is a high-cost investigation, and it is therefore important to clearly demonstrate its accuracy and to standardise the process of ¹⁸F-FDG PET diagnostic modality prior to its being widely used. Future studies with more uniform approaches to thresholds, analysis and study conduct may provide a more homogeneous estimate than the one available from the included studies we have identified.
Two small studies (enrolling a total of 105 participants) met the inclusion criteria. One was a standard cognitive behavioural treatment (CBT) programme for 61 people with pain from spinal cord injury, followed up for three months, and compared with a waiting list. The other was weekly group psychotherapy for 44 people with burning mouth syndrome, compared with a daily placebo tablet. The overall risk of bias was high in both trials. The CBT study assessed participants for pain, disability, mood, and quality of life, with improvement in treatment and control groups. However, there was no more improvement in the treatment group than in the control for any outcome, either post-treatment or at follow-up. The group psychotherapy study only assessed pain, classifying participants by pain severity. There is a lack of evidence on the efficacy and safety of psychological interventions for people with neuropathic pain. There is insufficient evidence of the efficacy and safety of psychological interventions for chronic neuropathic pain. The two available studies show no benefit of treatment over either waiting list or placebo control groups.
One study, including 28 participants was included in the review; the results were described, primarily, in a narrative manner. This study assessed the feasibility of splenectomy using a laparoscopic approach versus open surgery. Given the lack of detail regarding the study methods beyond randomisation, the overall risk of bias for this study was unclear. The study was carried out over a period of 3.5 years, with each participant followed up only until discharge (less than one week after the intervention); it did not assess the majority of the outcomes outlined in this review (including two of the three primary outcomes, frequency of transfusion and quality of life). A total of three serious post-operative adverse events (the review's third primary outcome) were reported in the laparoscopic splenectomy group (one case of atelectasis and two cases of bleeding), compared to two events of atelectasis in the open surgery group; however, there were no significant differences between the groups for either atelectasis, risk ratio (RR) 0.50 (95% confidence interval (CI) 0.05 to 4.90) or for bleeding, RR 5.00 (95% CI 0.26 to 95.61) (very low-quality evidence). In addition, the study also reported three serious cases of intra-operative bleeding in the laparoscopic group which mandated conversion to open surgery, although the difference between groups was not statistically significant, RR 7.00 (95% CI 0.39 to 124.14) (very low-quality evidence). These effect estimates are based on very small numbers and hence are unreliable and imprecise. From this small study, there appeared to be an advantage for the laparoscopic approach, in terms of post-operative hospital stay, although the group difference was not large (median difference of 1.5 days, P = 0.03). The review was unable to find good quality evidence, in the form of randomised controlled studies, regarding the efficacy of splenectomy for treating thalassaemia major or intermedia. The single included study provided little information about the efficacy of splenectomy, and compared open surgery and laparoscopic methods. Further studies need to evaluate the long-term effectiveness of splenectomy and the comparative advantages of surgical methods. Due to a lack of high quality evidence from randomised controlled studies, well-conducted observational studies may be used to answer this question.
We identified five studies involving the laxatives lactulose, senna, co-danthramer, misrakasneham, docusate and magnesium hydroxide with liquid paraffin. Overall, the study findings were at an unclear risk of bias. As all five studies compared different laxatives or combinations of laxatives, it was not possible to perform a meta-analysis. There was no evidence on whether individual laxatives were more effective than others or caused fewer adverse effects. This second update found that laxatives were of similar effectiveness but the evidence remains limited due to insufficient data from a few small RCTs. None of the studies evaluated polyethylene glycol or any intervention given rectally. There is a need for more trials to evaluate the effectiveness of laxatives in palliative care populations. Extrapolating findings on the effectiveness of laxatives evaluated in other populations should proceed with caution. This is because of the differences inherent in people receiving palliative care that may impact, in a likely negative way, on the effect of a laxative.
With this update, four new studies were identified resulting in a total of six trials including 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment. None of the six studies reported our primary outcome of live birth rate. Pooled data showed no evidence of a difference in clinical pregnancy rate per woman between monitoring with TVUS only and combined monitoring (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests that compared with women with a 34% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate in women using TVUS only was between 29% and 44%. There was no evidence of a difference between the groups in the reported cases of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that compared with women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate in women monitored by TVUSS only was between 2% and 8%. There was no evidence of a difference between the groups in the mean number of oocytes retrieved pre woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence). The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. This review update found no evidence from randomised trials to suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. A combined monitoring protocol including both TVUS and serum estradiol may need to be retained as precautionary good clinical practice and as a confirmatory test in a subset of women to identify those at high risk of OHSS. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.
Nineteen trials (1249 participants) were included in the review. Four trials reported using an adequate method of allocation concealment and six trials blinded participants and personnel. Only two electrotherapy modalities (low-level laser therapy (LLLT) and pulsed electromagnetic field therapy (PEMF)) have been compared to placebo. No trial has compared an electrotherapy modality plus manual therapy and exercise to manual therapy and exercise alone. The two main questions of the review were investigated in nine trials. Low quality evidence from one trial (40 participants) indicated that LLLT for six days may result in improvement at six days. Eighty per cent (16/20) of participants reported treatment success with LLLT compared with 10% (2/20) of participants receiving placebo (risk ratio (RR) 8.00, 95% confidence interval (CI) 2.11 to 30.34; absolute risk difference 70%, 95% CI 48% to 92%). No participants in either group reported adverse events. We were uncertain whether PEMF for two weeks improved pain or function more than placebo at two weeks because of the very low quality evidence from one trial (32 participants). Seventy-five per cent (15/20) of participants reported pain relief of 30% or more with PEMF compared with 0% (0/12) of participants receiving placebo (RR 19.19, 95% CI 1.25 to 294.21; absolute risk difference 75%, 95% CI 53% to 97%). Fifty-five per cent (11/20) of participants reported total recovery of joint function with PEMF compared with 0% (0/12) of participants receiving placebo (RR 14.24, 95% CI 0.91 to 221.75; absolute risk difference 55%, 95% CI 31 to 79). Moderate quality evidence from one trial (63 participants) indicated that LLLT plus exercise for eight weeks probably results in greater improvement when measured at the fourth week of treatment, but a similar number of adverse events, compared with placebo plus exercise. The mean pain score at four weeks was 51 points with placebo plus exercise, while with LLLT plus exercise the mean pain score was 32 points on a 100 point scale (mean difference (MD) 19 points, 95% CI 15 to 23; absolute risk difference 19%, 95% CI 15% to 23%). The mean function impairment score was 48 points with placebo plus exercise, while with LLLT plus exercise the mean function impairment score was 36 points on a 100 point scale (MD 12 points, 95% CI 6 to 18; absolute risk difference 12%, 95% CI 6 to 18). Mean active abduction was 70 degrees with placebo plus exercise, while with LLLT plus exercise mean active abduction was 79 degrees (MD 9 degrees, 95% CI 2 to 16; absolute risk difference 5%, 95% CI 1% to 9%). No participants in either group reported adverse events. LLLT's benefits on function were maintained at four months. Based on very low quality evidence from six trials, we were uncertain whether therapeutic ultrasound, PEMF, continuous short wave diathermy, Iodex phonophoresis, a combination of Iodex iontophoresis with continuous short wave diathermy, or a combination of therapeutic ultrasound with transcutaneous electrical nerve stimulation (TENS) were effective adjuncts to exercise. Based on low or very low quality evidence from 12 trials, we were uncertain whether a diverse range of electrotherapy modalities (delivered alone or in combination with manual therapy, exercise, or other active interventions) were more or less effective than other active interventions (for example glucocorticoid injection). Based upon low quality evidence from one trial, LLLT for six days may be more effective than placebo in terms of global treatment success at six days. Based upon moderate quality evidence from one trial, LLLT plus exercise for eight weeks may be more effective than exercise alone in terms of pain up to four weeks, and function up to four months. It is unclear whether PEMF is more or less effective than placebo, or whether other electrotherapy modalities are an effective adjunct to exercise. Further high quality randomised controlled trials are needed to establish the benefits and harms of physical therapy interventions (that comprise electrotherapy modalities, manual therapy and exercise, and are reflective of clinical practice) compared to interventions with evidence of benefit (for example glucocorticoid injection or arthrographic joint distension).
We identified two studies that met our selection criteria: a controlled interrupted time series study evaluating a regulatory policy involving the monitoring of prescribing of benzodiazepines; and a controlled before‒after study of an educational policing involving mailed educational materials on prescribing for physicians and Health Maintenance Organization (HMO) members as well as an intervention to regulate drug reimbursement. We are uncertain about the effects on medicine use of a regulatory policy involving the monitoring of prescribing with triplicate prescriptions, compared with no regulatory intervention (very low certainty evidence). We are also uncertain about the effects on medicine use, assessed through doctors' prescribing, and costs of an educational policy involving mailed educational materials on prescribing for physicians and HMO members, compared to no educational intervention or an intervention to regulate drug reimbursement (very low certainty evidence). Neither of the included studies measured healthcare utilization, health outcomes, or additional costs, if any, to patients. We are uncertain of the effects of educational or regulatory policies targeting prescribers due to very limited evidence of very low certainty. The impacts of these policies therefore need to be evaluated rigorously using appropriate study designs. Evaluations are needed across a range of settings, including low- and middle-income countries, and across different types of prescribers and medicines.
We included in the analysis four trials with 495 participants (most with systemic sclerosis). We formed two separate comparisons: cyclophosphamide versus placebo (two trials, 195 participants) and cyclophosphamide versus mycophenolate (two trials, 300 participants). We found evidence to be of low quality, as dropout rates were high in the intervention groups, and as we noted a wide confidence interval around the effect with small differences, which affected the precision of results. The data demonstrates significant improvement in lung function with cyclophosphamide compared with placebo (post-treatment FVC % mean difference (MD) 2.83, 95% confidence interval (CI) 0.80 to 4.87; P = 0.006) but no significant difference in post-treatment DLCO (% MD -1.68, 95% CI -4.37 to 1.02; P = 0.22; two trials, 182 participants). Risk of adverse effects was increased in the cyclophosphamide treatment groups compared with the placebo groups, in particular, haematuria, leukopenia, and nausea, leading to a higher rate of withdrawal from cyclophosphamide treatment. The data demonstrates statistically significant improvement in one-measure of quality of life in one trial favouring cyclophosphamide over placebo and clinically and statistically significant improvement in breathlessness in one trial favouring cyclophosphamide compared with placebo, with no significant impact on mortality. Trialists reported no significant impact on lung function when cyclophosphamide was used compared with mycophenolate at 12 months (FVC % MD -0.82, 95% CI -3.95 to 2.31; P = 0.61; two trials, 149 participants; DLCO % MD -1.41, 95% CI -10.40 to 7.58; P = 0.76; two trials, 149 participants). Risk of side effects was increased with cyclophosphamide versus mycophenolate, in particular, leukopenia and thrombocytopenia. The data demonstrates no significant impact on health-related quality of life, all-cause mortality, dyspnoea, or cough severity in the cyclophosphamide group compared with the mycophenolate group. No trials reported outcomes associated with functional exercise tests. We performed subgroup analysis to determine whether severity of lung function, connective tissue disease diagnosis, or radiological pattern had any impact on outcomes. One trial reported that cyclophosphamide protected against decreased FVC in individuals with worse fibrosis scores, and also showed that cyclophosphamide may be more effective in those with worse lung function. No association could be made between connective tissue disease diagnosis and outcomes. This review, which is based on studies of varying methodological quality, demonstrates that overall, in this population, small benefit may be derived from the use of cyclophosphamide in terms of mean difference in % FVC when compared with placebo, but not of the difference in % DLCO, or when compared with mycophenolate. Modest clinical improvement in dyspnoea may be noted with the use of cyclophosphamide. Clinical practice guidelines should advise clinicians to consider individual patient characteristics and to expect only modest benefit at best in preserving FVC. Clinicians should carefully monitor for adverse effects during treatment and in the years thereafter. Further studies are required to examine the use of cyclophosphamide; they should be adequately powered to compare outcomes within different subgroups, specifically, stratified for extent of pulmonary infiltrates on high-resolution computed tomography (HRCT) and skin involvement in SSc. Studies on other forms of connective tissue disease are needed. Researchers may consider comparing cyclophosphamide (a potent immunosuppressant) versus antifibrotic agents, or comparing both versus placebo, in particular, for those with evidence of rapidly progressive fibrotic disease, who may benefit the most.
Seventeen studies were included. Ten were conducted in a school setting, two in universities, and five in workplaces. One study directly measured health outcomes, and all included studies measured travel outcomes. Two cluster randomised controlled trials in the school setting showed either no change in travel mode or mixed results. A randomised controlled trial in the workplace setting, conducted in a pre-selected group who were already contemplating or preparing for active travel, found improved health-related quality of life on some sub scales, and increased walking. Two controlled before-after studies found that school travel interventions increased walking. Other studies were judged to be at high risk of bias. No included studies were conducted in low- or middle-income countries, and no studies measured the social distribution of effects or adverse effects, such as injury. There is insufficient evidence to determine whether organisational travel plans are effective for improving health or changing travel mode. Organisational travel plans should be considered as complex health promotion interventions, with considerable potential to influence community health outcomes depending on the environmental context in which they are introduced. Given the current lack of evidence, organisational travel plans should be implemented in the context of robustly-designed research studies, such as well-designed cluster randomised trials.
Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group. There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment.
We included a total of six trials (four randomized and two quasi-randomized) with 102 eyes in 61 children. Two trials were conducted in the USA and one trial each in Egypt, Israel, Lebanon and Saudi Arabia. All trials included children aged younger than one year when diagnosed with PCG, and followed them for periods ranging from six months to five years. No two trials compared the same pair of surgical interventions, so we did not perform any meta-analysis. One trial compared trabeculotomy versus goniotomy; a second trial compared combined trabeculectomy-trabeculotomy with mitomycin C versus trabeculectomy-trabeculotomy with mitomycin C and deep sclerectomy; a third trial compared combined trabeculotomy-trabeculectomy versus trabeculotomy; a fourth trial compared one goniotomy versus two goniotomies; a fifth trial compared trabeculotomy versus viscocanalostomy; and the sixth trial compared surgical goniotomy versus neodymium-YAG laser goniotomy. For IOP change and surgical success (defined by IOP achieved), none of the trials reported a difference between pairs of surgical techniques. However, due to the limited sample sizes for all trials (average of 10 children per trial), the evidence as to whether a particular surgical technique is effective and which surgical technique is better still remains uncertain. Adverse events, such as choroidal detachment, shallow anterior chamber and hyphema, were reported from four trials. None of the trials reported quality of life or economic data. These trials were neither designed nor reported well overall. Two trials were quasi-randomized trials and judged to have high risk of selection bias; four trials were at unclear or high risk for performance bias and detection bias; and we judged one trial to have high risk of attrition bias due to high proportions of losses to follow-up. Due to poor study design and reporting, the reliability and applicability of evidence remain unclear. No conclusions could be drawn from the trials included in this review due to paucity of data. More research is needed to determine which of the many surgeries performed for PCG are effective.
We included six trials in the review, with a total of 429 adult participants, the majority of whom were male (63%). Three trials evaluated different types of fixation and three analysed different types of bone graft substitutes. All six trials were small and at substantial risk of bias. We judged the quality of most of the available evidence to be very low, meaning that we are very uncertain about these results. One trial compared the use of a circular fixator combined with insertion of percutaneous screws (hybrid fixation) versus standard open reduction and internal fixation (ORIF) in people with open or closed Schatzker types V or VI tibial plateau fractures. Results (66 participants) for quality of life scores using the 36-item Short Form Health Survey (SF-36)), Hospital for Special Surgery (HSS) scores and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores tended to favour hybrid fixation, but a benefit of ORIF could not be ruled out. Participants in the hybrid fixation group had a lower risk for an unplanned reoperation (351 per 1000 people compared with 450 in the ORIF group; 95% CI 197 fewer to 144 more) and were more likely to have returned to their pre-injury activity level (303 per 1000 people, compared with 121 in the ORIF group; 95% CI 15 fewer to 748 more). Results of the two groups were comparable for the WOMAC pain subscale and stiffness scores, but mean knee range of motion values were higher in the hybrid group. Another trial compared the use of a minimally invasive plate (LISS system) versus double-plating ORIF in 84 people who had open or closed bicondylar tibial plateau fractures. Nearly twice as many participants (22 versus 12) in the ORIF group had a bone graft. Quality of life, pain, knee range of motion and return to pre-injury activity were not reported. The trial provided no evidence of differences in HSS knee scores, complications or reoperation entailing implant removal or revision fixation. A quasi-randomised trial comparing arthroscopically-assisted percutaneous reduction and internal fixation versus standard ORIF reported results at 14 months in 58 people with closed Schatzker types II or III tibial plateau fracture. Quality of life, pain and return to pre-injury activity were not reported. There was very low quality evidence of higher HSS knee scores and higher knee range of motion values in the arthroscopically assisted group. No reoperations were reported. Three trials compared different types of bone substitute versus autologous bone graft (autograft) for managing bone defects. Quality of life, pain and return to pre-injury activity were not reported. Only one trial (25 participants) reported on lower limb function, finding good or excellent results in both groups for walking, climbing stairs, squatting and jumping at 12 months. The incidences of individual complications were similar between groups in all three trials. One trial found no cases of inflammatory response in the 20 participants receiving bone substitute, and two found no complications associated with the donor site in the autograft group (58 participants). However, all 38 participants in the autologous iliac bone graft group of one trial reported prolonged pain from the harvest site. Two trials reported similar range of motion results in the two groups, whereas the third trial favoured the bone substitute group. Currently, there is insufficient evidence to ascertain the best method of fixation or the best method of addressing bone defects during surgery. However, the evidence does not contradict approaches aiming to limit soft-tissue dissection and damage or to avoid autograft donor site complications through using bone substitutes. Further well-designed, larger randomised trials are warranted.
Four studies (involving 206 participants) met the inclusion criteria for this review. Three studies, involving 194 participants, assessed the effects of online interventions to target executive functioning (that is monitoring and changing behaviour, problem solving, planning, etc.). These studies, which were all conducted by the same research team, compared online interventions against a 'placebo' (participants were given internet resources on brain injury). The interventions were delivered in the family home with additional support or training, or both, from a psychologist or doctoral student. The fourth study investigated the use of a computer program to target memory in addition to components of executive functioning (that is attention, organisation, and problem solving). No information on the study setting was provided, however a speech-language pathologist, teacher, or occupational therapist accompanied participants. Two studies assessed adolescents and young adults with mild to severe traumatic brain injury (TBI), while the remaining two studies assessed children and adolescents with moderate to severe TBI. Risk of bias We assessed the risk of selection bias as low for three studies and unclear for one study. Allocation bias was high in two studies, unclear in one study, and low in one study. Only one study (n = 120) was able to conceal allocation from participants, therefore overall selection bias was assessed as high. One study took steps to conceal assessors from allocation (low risk of detection bias), while the other three did not do so (high risk of detection bias). Primary outcome 1: Executive functioning: Technology-based intervention versus placebo Results from meta-analysis of three studies (n = 194) comparing online interventions with a placebo for children and adolescents with TBI, favoured the intervention immediately post-treatment (standardised mean difference (SMD) -0.37, 95% confidence interval (CI) -0.66 to -0.09; P = 0.62; I2 = 0%). (As there is no 'gold standard' measure in the field, we have not translated the SMD back to any particular scale.) This result is thought to represent only a small to medium effect size (using Cohen’s rule of thumb, where 0.2 is a small effect, 0.5 a medium one, and 0.8 or above is a large effect); this is unlikely to have a clinically important effect on the participant. The fourth study (n = 12) reported differences between the intervention and control groups on problem solving (an important component of executive functioning). No means or standard deviations were presented for this outcome, therefore an effect size could not be calculated. The quality of evidence for this outcome according to GRADE was very low. This means future research is highly likely to change the estimate of effect. Primary outcome 2: Memory One small study (n = 12) reported a statistically significant difference in improvement in sentence recall between the intervention and control group following an eight-week remediation programme. No means or standard deviations were presented for this outcome, therefore an effect size could not be calculated. Secondary outcomes Two studies (n = 158) reported on anxiety/depression as measured by the Child Behavior Checklist (CBCL) and were included in a meta-analysis. We found no evidence of an effect with the intervention (mean difference -5.59, 95% CI -11.46 to 0.28; I2 = 53%). The GRADE quality of evidence for this outcome was very low, meaning future research is likely to change the estimate of effect. A single study sought to record adverse events and reported none. Two studies reported on use of the intervention (range 0 to 13 and 1 to 24 sessions). One study reported on social functioning/social competence and found no effect. The included studies reported no data for other secondary outcomes (that is quality of life and academic achievement). This review provides low-quality evidence for the use of technology-based interventions in the rehabilitation of executive functions and memory for children and adolescents with TBI. As all of the included studies contained relatively small numbers of participants (12 to 120), our findings should be interpreted with caution. The involvement of a clinician or therapist, rather than use of the technology, may have led to the success of these interventions. Future research should seek to replicate these findings with larger samples, in other regions, using ecologically valid outcome measures, and reduced clinician involvement.
We identified one randomized controlled study recruiting 97 low birthweight infants that met the inclusion criteria. The study was conducted in the UK in 1987 and 1988. Randomized infants received ETT suctioning every six or 12 hours during the first three days of life. The quality of reporting was limited and we rated the trial at high risk of bias. Furthermore, the trial lacked adequate power. There were no statistically significant differences in any of reported outcomes: bronchopulmonary dysplasia (defined as oxygen at more than 30 days; risk ratio (RR) 0.49, 95% confidence interval (CI) 0.20 to 1.20); incidence of pneumothorax (RR 0.70, 95% CI 0.24 to 2.05); intraventricular hemorrhage (RR 1.12, 95% CI 0.44 to 2.85); neonatal death (RR 1.40, 95% CI 0.58 to 3.37); and time on ventilation (median time 39 hours in the 12-hourly group and 28 hours in the six-hourly group; RD not applicable for this outcome as mean and standard deviation were not reported). Tests for heterogeneity were not applicable as only one study was included. There was insufficient evidence to identify the ideal frequency of ETT suctioning in ventilated neonates. Future research should focus on the effects in the very preterm newborns, that is, the most vulnerable population as concerns the risk of both lung and brain damage. Assessment should include the cases of prolonged ventilation, when more abundant, dense secretions are common. Clinical trials might include comparisons between 'as-scheduled' versus 'as-needed' endotracheal suctioning, that is, based on specific indications, as well frequent versus less frequent suctioning schedules.
We included four studies (188 participants). Two studies were double-blind RCTs, one was a non-randomised controlled trial, and one was an observational retrospective case-matched study. The age of participants ranged from 27 to 37.8 years. In three studies participants had quiescent IBD and in one study participants had active or quiescent IBD. Participants in one study had co-morbid anxiety or depression. One study used duloxetine (60 mg daily), one study used fluoxetine (20 mg daily), one study used tianeptine (36 mg daily), and one study used various antidepressants in clinical ranges. Three studies had placebo controls and one study had a no treatment control group. One RCT was rated as low risk of bias and the other was rated as high risk of bias (incomplete outcome data). The non-randomised controlled trial was rated as high risk of bias (random sequence generation, allocation concealment, blinding). The observational study was rated as high methodological quality, but is still considered to be at high risk of bias given its observational design. The effect of antidepressants on anxiety and depression is uncertain. At 12 weeks, the mean anxiety score in antidepressant participants was 6.11 + 3 compared to 8.5 + 3.45 in placebo participants (MD -2.39, 95% -4.30 to -0.48, 44 participants, low certainty evidence). At 12 months, the mean anxiety score in antidepressant participants was 3.8 + 2.5 compared to 4.2 + 4.9 in placebo participants (MD -0.40, 95% -3.47 to 2.67, 26 participants; low certainty evidence). At 12 weeks, the mean depression score in antidepressant participants was 7.47 + 2.42 compared to 10.5 + 3.57 in placebo participants (MD -3.03, 95% CI -4.83 to -1.23, 44 participants; low certainty evidence). At 12 months, the mean depression score in antidepressant participants was 2.9 + 2.8 compared to 3.1 + 3.4 in placebo participants (MD -0.20, 95% -2.62 to 2.22, 26 participants; low certainty evidence). The effect of antidepressants on AEs is uncertain. Fifty-seven per cent (8/14) of antidepressant participants group reported AEs versus 25% (3/12) of placebo participants (RR 2.29, 95% CI 0.78 to 6.73, low certainty evidence). Commonly reported AEs include nausea, headache, dizziness, drowsiness, sexual problems, insomnia, fatigue, low mood/anxiety, dry mouth, muscle spasms and hot flushes. None of the included studies reported any serious AEs. None of the included studies reported on pain. One study (44 participants) reported on QoL at 12 weeks and another study (26 participants) reported on QoL at 12 months. Physical, Psychological, Social and Environmental QoL were improved at 12 weeks compared to placebo (all low certainty evidence). There were no group differences in QoL at 12 months (all low certainty evidence). The effect of antidepressants on maintenance of clinical remission and endoscopic relapse is uncertain. At 12 months, 64% (9/14) of participants in the antidepressant group maintained clinical remission compared to 67% (8/12) of placebo participants (RR 0.96, 95% CI 0.55 to 1.69; low certainty evidence). At 12 months, none (0/30) of participants in the antidepressant group had endoscopic relapse compared to 10% (3/30) of placebo participants (RR 0.14, 95% CI 0.01 to 2.65; very low certainty evidence). The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of antidepressants in IBD can be drawn. Future studies should employ RCT designs, with a longer follow-up and develop solutions to address attrition. Inclusion of objective markers of disease activity is strongly recommended as is testing antidepressants from different classes, as at present it is unclear if any antidepressant (or class thereof) has differential efficacy.
We included four trials involving 1365 participants. Three trials compared the intravenous GP IIb-IIIa inhibitor Abciximab with intravenous placebo (1215 participants) and one trial compared the intravenous GP IIb-IIIa inhibitor Tirofiban with intravenous aspirin (150 participants). Treatment with either of these GP IIb-IIIa inhibitors did not significantly reduce long-term death or dependency (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.77 to 1.22, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.52 to 1.92, for the comparison between Tirofiban and aspirin) and had no effect on deaths from all causes (OR 1.08, 95% CI 0.77 to 1.53, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.35 to 2.82, for the comparison between Tirofiban and aspirin). Abciximab was associated with a significant increase in symptomatic intracranial haemorrhage (OR 4.6, 95% CI 2.01 to 10.54) and with a non-significant increase in major extracranial haemorrhage (OR 1.81, 95% CI 0.96 to 3.41), whereas the only small trial comparing Tirofiban with aspirin showed no increased risk of bleeding complications with Tirofiban (OR 0.32, 95% CI 0.03 to 3.19, for symptomatic intracranial haemorrhage; OR 3.04, 95% CI 0.12 to 75.83, for major extracranial haemorrhages). There was no significant inconsistency across the studies. The available trial evidence showed that, for individuals with acute ischaemic stroke, GP IIb-IIIa inhibitors are associated with a significant risk of intracranial haemorrhage with no evidence of any reduction in death or disability in survivors. These data do not support their routine use in clinical practice. The conclusion is driven by trials of Abciximab, which contributed 89% of the total number of study participants considered.
Nine trials were used in the analysis (n = 1282 patients). These trials were found to be predominantly at low risk of bias. We did not find strong evidence of an effect of DSI on the total duration of ventilation. Pooled data from nine trials demonstrated a 13% reduction in the geometric mean, with relatively wide confidence intervals (CI) indicating imprecision (95% CI 26% reduction to 2% increase, moderate quality evidence). Similarly, we did not find strong evidence of an effect on ICU length of stay (-10%, 95% CI -20% to 3%, n = 9 trials, moderate quality evidence) or hospital length of stay (-6%, 95% CI -18% to 8%, n = 8 trials, moderate quality evidence). Heterogeneity for these three outcomes was moderate and statistically significant. The risk ratio for ICU mortality was 0.96 (95% CI 0.77 to 1.21, n = 7 trials, moderate quality evidence), for rate of accidental endotracheal tube removal 1.07 (95% CI 0.55 to 2.12, n = 6 trials, moderate quality evidence), for catheter removal 1.48 (95% CI 0.76 to 2.90, n = 4 trials), and for incidence of new onset delirium 1.02 (95% CI 0.91 to 1.13, n = 3 trials, moderate quality evidence). Differences in the doses of any drug used or quality of life score (Short Form (SF)-36) did not reach statistical significance. Tracheostomy was performed less frequently in the DSI group (RR 0.73, 95% CI 0.57 to 0.92, n = 6 trials, moderate quality evidence). Sensitivity analysis of unlogged data resulted in similar findings. Post hoc analysis to further explain heterogeneity, based on study country of origin, showed that studies conducted in North America resulted in a reduction in the duration of mechanical ventilation (-21%, 95% CI -33% to -5%, n = 5 trials). We have not found strong evidence that DSI alters the duration of mechanical ventilation, mortality, length of ICU or hospital stay, adverse event rates, drug consumption, or quality of life for critically ill adults receiving mechanical ventilation compared to sedation strategies that do not include DSI. We advise that caution should be applied when interpreting and applying the findings as the overall effect of treatment is always < 1 and the upper limit of the CI is only marginally higher than the no-effect line. These results should be considered unstable rather than negative for DSI given the statistical and clinical heterogeneity identified in the included trials.
We included two RCTs with 81 participants. One RCT involved 14 critically ill children with ARDS (very low quality of evidence), and one RCT involved 67 critically ill adults (very low quality evidence). Only one RCT (paediatric trial) provided data on mortality and found no difference between intervention and control. However, this trial was eligible for meta-analysis due to a cross-over design. We assessed the benefits and harms of aerosolized prostacyclin. One RCT found no difference in improvement of partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio (mean difference (MD) -25.35, 95% confidence interval (CI) -60.48 to 9.78; P = 0.16; 67 participants, very low quality evidence). There were no adverse events such as bleeding or organ dysfunction in any of the included trials. Due to the limited number of RCTs, we were unable to perform the prespecified subgroup and sensitivity analyses or trial sequential analysis. We are unable to tell from our results whether the intervention has an important effect on mortality because the results were too imprecise to rule out a small or no effect. Therefore, no current evidence supports or refutes the routine use of aerosolized prostacyclin for people with ARDS. There is an urgent need for more RCTs.
We included 11 trials reporting results for 3403 women evaluating the effects of vaginal cleansing (eight using povidone-iodine, two chlorhexidine, one benzalkonium chloride) on post-cesarean infectious morbidity. Additionally, some trials used vaginal preparations using sponge sticks, douches, or soaked gauze wipes. The control groups were typically no vaginal preparation (eight trials) or the use of a saline vaginal preparation (three trials). The risk of bias in the studies reduced our confidence in the results for endometritis outcomes. Vaginal preparation with antiseptic solution immediately before cesarean delivery probably reduces the incidence of post-cesarean endometritis from 8.7% in control groups to 3.8% in vaginal cleansing groups (average risk ratio (RR) 0.36, 95% confidence interval (CI) 0.20 to 0.63, 10 trials, 3283 women, moderate quality of evidence). Subgroup analysis could not rule out larger reductions in endometritis with antiseptics in women who were in labor or in women whose membranes had ruptured when antiseptics were used. Risks of postoperative fever and postoperative wound infection may be slightly lowered by antiseptic preparation, but the confidence intervals around the effects for both outcomes are consistent with a large reduction in risk and no difference between groups (fever: RR 0.87 (0.72 to 1.05; wound infection: RR 0.74 (95% CI 0.49 to 1.11), both moderate-quality evidence). Two trials reported a lower risk of a composite outcome of wound complication or endometritis in women receiving preoperative vaginal preparation (RR 0.46, 95% CI 0.26 to 0.82, two trials, 499 women, moderate-quality evidence). No adverse effects were reported with either the povidone-iodine or chlorhexidine vaginal cleansing. Vaginal preparation with povidone-iodine or chlorhexidine solution compared to saline or not cleansing immediately before cesarean delivery probably reduces the risk of post-cesarean endometritis. Subgroup analysis could not rule out larger reductions in endometritis with antiseptics in women who were in labor or in women whose membranes had ruptured when antiseptics were used. The quality of the evidence using GRADE was moderate for all reported outcomes. We downgraded the outcome of post-cesarean endometritis and composite of wound complications or endometritis for risk of bias and postoperative fever and postoperative wound infections for wide CIs. As a simple, generally inexpensive intervention, providers may consider implementing preoperative vaginal cleansing with povidone-iodine or chlorhexidine before performing cesarean deliveries.
Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat. We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.
We included six studies treating 310 participants (mean or median age 49 to 64 years) with various neuropathic pain conditions. Five studies used a cross-over design, and one used a parallel-group design; 272 participants were randomised to treatment with nortriptyline, 145 to placebo, 94 to gabapentin, 56 to gabapentin plus nortriptyline, 55 to morphine, 55 to morphine plus nortriptyline, 39 to chlorimipramine, and 33 to amitriptyline. Treatment periods lasted from three to eight weeks. All studies had one or more sources of potential major bias. No study provided first or second tier evidence for any outcome. Only one study reported our primary outcome of people with at least 50% reduction in pain. There was no indication that either nortriptyline or gabapentin was more effective in postherpetic neuralgia (very low quality evidence). Two studies reported the number of people with at least moderate pain relief, and one reported the number who were satisfied with their pain relief and had tolerable adverse effects. We considered these outcomes to be equivalent to our other primary outcome of Patient Global Impression of Change (PGIC) much or very much improved. We could not pool data, but third tier evidence in individual studies indicated similar efficacy to other active interventions (gabapentin, morphine, chlorimipramine, and amitriptyline), and to placebo in the conditions studied (very low quality evidence). Adverse event reporting was inconsistent and fragmented. More participants reported adverse events with nortriptyline than with placebo, similar numbers with nortriptyline and other antidepressants (amitriptyline and chlorimipramine) and gabapentin, and slightly more with morphine (very low quality evidence). No study reported any serious adverse events or deaths. We found little evidence to support the use of nortriptyline to treat the neuropathic pain conditions included in this review. There were no studies in the treatment of trigeminal neuralgia. The studies were methodologically flawed, largely due to small size, and potentially subject to major bias. The results of this review do not support the use of nortriptyline as a first line treatment. Effective medicines with much greater supportive evidence are available, such as duloxetine and pregabalin.
We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler. Deaths Eleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths). No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group. Non-fatal serious adverse events A total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27). Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22). Asthma-related serious adverse events Eighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8). Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12). We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS. Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment. However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.
We included a total of four studies with 296 participants. Three studies with 206 participants compared quetiapine, an atypical (second-generation) antipsychotic, with placebo. One study used a cross-over design and two studies a parallel-group design. Study duration was eight or 12 weeks. Quetiapine was used in all studies with a bedtime dosage between 50 and 300 mg/day. All studies had one or more sources of potential major bias and we judged them to be at moderate risk of bias overall. The primary outcomes in this review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Second tier evidence indicated that quetiapine was not statistically superior to placebo in the number of participants with a 50% or more pain reduction (very low quality evidence). No study reported data on PGIC. A greater proportion of participants on quetiapine reported a 30% or more pain reduction (risk difference (RD) 0.12, 95% confidence interval (CI) 0.00 to 0.23; number needed to treat for an additional benefit (NNTB) 8, 95% CI 5 to 100) (very low quality evidence). A greater proportion of participants on quetiapine reported a clinically relevant improvement of health-related quality of life compared to placebo ( RD 0.18, 95% CI 0.05 to 0.31; NNTB 5, 95% CI 3 to 20) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing sleep problems (standardised mean difference (SMD) -0.67, 95% CI -1.10 to -0.23), depression (SMD -0.39, 95% CI -0.74 to -0.04) and anxiety (SMD -0.40, 95% CI -0.69 to -0.11) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing the risk of withdrawing from the study due to a lack of efficacy (RD -0.14, 95% CI -0.23 to -0.05) (very low quality evidence). There was no statistically significant difference between quetiapine and placebo in the proportion of participants withdrawing due to adverse events (tolerability) (very low quality evidence), in the frequency of serious adverse events (safety) (very low quality evidence) and in the proportion of participants reporting dizziness and somnolence as an adverse event (very low quality evidence). In more participants in the quetiapine group a substantial weight gain was noted (RD 0.08, 95% CI 0.02 to 0.15; number needed to treat for an additional harm (NNTH) 12, 95% CI 6 to 50) (very low quality evidence). We downgraded the quality of evidence by three levels to a very low quality rating because of limitations of study design, indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed). One parallel design study with 90 participants compared quetiapine (50 to 300 mg/day flexible at bedtime) to amitriptyline (10 to 75 mg/day flexible at bedtime). The study had three major risks of bias and we judged it to be at moderate risk of bias overall. We downgraded the quality of evidence by two levels to a low quality rating because of indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed). Third tier evidence indicated no statistically significant differences between the two drugs. Both drugs did not statistically significantly differ in the reduction of average scores for pain, fatigue, sleep problems, depression, anxiety and for limitations of health-related quality of life and in the proportion of participants reporting dizziness, somnolence and weight gain as a side effect (low quality evidence). Compared to amitriptyline, more participants left the study due to adverse events (low quality evidence). No serious adverse events were reported (low quality evidence). We found no relevant study with other antipsychotics than quetiapine in fibromyalgia. Very low quality evidence suggests that quetiapine may be considered for a time-limited trial (4 to 12 weeks) to reduce pain, sleep problems, depression and anxiety in fibromyalgia patients with major depression. Potential side effects such as weight gain should be balanced against the potential benefits in shared decision making with the patient.
We included 85 trials involving a total of 8815 randomised participants (26 new studies were included in this update). There was a wide range of different treatments and a variety of trial designs. Many of the studies were judged to be at high risk of bias in one or more areas of trial design. Trials of salicylic acid (SA) versus placebo showed that the former significantly increased the chance of clearance of warts at all sites (RR (risk ratio) 1.56, 95% CI (confidence interval) 1.20 to 2.03). Subgroup analysis for different sites, hands (RR 2.67, 95% CI 1.43 to 5.01) and feet (RR 1.29, 95% CI 1.07 to 1.55), suggested it might be more effective for hands than feet. A meta-analysis of cryotherapy versus placebo for warts at all sites favoured neither intervention nor control (RR 1.45, 95% CI 0.65 to 3.23). Subgroup analysis for different sites, hands (RR 2.63, 95% CI 0.43 to 15.94) and feet (RR 0.90, 95% CI 0.26 to 3.07), again suggested better outcomes for hands than feet. One trial showed cryotherapy to be better than both placebo and SA, but only for hand warts. There was no significant difference in cure rates between cryotherapy at 2-, 3-, and 4-weekly intervals. Aggressive cryotherapy appeared more effective than gentle cryotherapy (RR 1.90, 95% CI 1.15 to 3.15), but with increased adverse effects. Meta-analysis did not demonstrate a significant difference in effectiveness between cryotherapy and SA at all sites (RR 1.23, 95% CI 0.88 to 1.71) or in subgroup analyses for hands and feet. Two trials with 328 participants showed that SA and cryotherapy combined appeared more effective than SA alone (RR 1.24, 95% CI 1.07 to 1.43). The benefit of intralesional bleomycin remains uncertain as the evidence was inconsistent. The most informative trial with 31 participants showed no significant difference in cure rate between bleomycin and saline injections (RR 1.28, 95% CI 0.92 to 1.78). Dinitrochlorobenzene was more than twice as effective as placebo in 2 trials with 80 participants (RR 2.12, 95% CI 1.38 to 3.26). Two trials of clear duct tape with 193 participants demonstrated no advantage over placebo (RR 1.43, 95% CI 0.51 to 4.05). We could not combine data from trials of the following treatments: intralesional 5-fluorouracil, topical zinc, silver nitrate (which demonstrated possible beneficial effects), topical 5-fluorouracil, pulsed dye laser, photodynamic therapy, 80% phenol, 5% imiquimod cream, intralesional antigen, and topical alpha-lactalbumin-oleic acid (which showed no advantage over placebo). We did not identify any RCTs that evaluated surgery (curettage, excision), formaldehyde, podophyllotoxin, cantharidin, diphencyprone, or squaric acid dibutylester. Data from two new trials comparing SA and cryotherapy have allowed a better appraisal of their effectiveness. The evidence remains more consistent for SA, but only shows a modest therapeutic effect. Overall, trials comparing cryotherapy with placebo showed no significant difference in effectiveness, but the same was also true for trials comparing cryotherapy with SA. Only one trial showed cryotherapy to be better than both SA and placebo, and this was only for hand warts. Adverse effects, such as pain, blistering, and scarring, were not consistently reported but are probably more common with cryotherapy. None of the other reviewed treatments appeared safer or more effective than SA and cryotherapy. Two trials of clear duct tape demonstrated no advantage over placebo. Dinitrochlorobenzene (and possibly other similar contact sensitisers) may be useful for the treatment of refractory warts.
The search identified two randomized controlled trials for inclusion. One trial included 47 hypertensive patients and showed that garlic significantly reduces mean supine systolic blood pressure by 12 mmHg (95% CI 0.56 to 23.44 mmHg, p=0.04) and mean supine diastolic blood pressure by 9 mmHg (95% CI 2.49 to 15.51 mmHg, p=0.007) versus placebo. The authors state that garlic was "free from side effects" and that no serious side effects were reported. There were 3 cases "where a slight smell of garlic was noted." The second trial could not be meta-analysed as they did not report the number of people randomized to each treatment group. They did report that 200 mg of garlic powder given three times daily, in addition to hydrochlorothiazide-triamterene baseline therapy, produced a mean reduction of systolic blood pressure by 10-11 mmHg and of diastolic blood pressure by 6-8 mmHg versus placebo. Neither trial reported clinical outcomes and insufficient data was provided on adverse events. There is insufficient evidence to determine if garlic provides a therapeutic advantage versus placebo in terms of reducing the risk of mortality and cardiovascular morbidity in patients diagnosed with hypertension. There is also insufficient evidence to determine the difference in withdrawals due to adverse events between patients treated with garlic or placebo. Based on 2 trials in 87 hypertensive patients, it appears that garlic reduces mean supine systolic and diastolic blood pressure by approximately 10-12 mmHg and 6-9 mmHg, respectively, over and above the effect of placebo but the confidence intervals for these effect estimates are not precise and this difference in blood pressure reduction falls within the known variability in blood pressure measurements. This makes it difficult to determine the true impact of garlic on lowering blood pressure.
Seventy-eight randomised trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I2- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002). We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.
Nine studies were identified, five of which met the inclusion criteria. A meta-analysis of two trials in which 71 patients were randomized to nicotine and 70 to placebo showed a statistically significant benefit for nicotine treatment. After four to six weeks of treatment 19 of 71 patients treated with transdermal nicotine were in clinical remission compared to 9 of 70 treated with placebo (OR=2.56, 95% CI 1.02-6.45). In the same group of patients improvement or remission was noted in 29 of the 71 patients assigned to nicotine compared to 14 of 70 patients assigned to placebo (OR=2.72, 95% CI 1.28 - 5.81). For patients with left sided colitis the odds ratio was 2.31 (95% CI 1.05-5.10). When transdermal nicotine was compared to standard medical therapy no significant benefit for nicotine was observed. After four to six weeks of standard therapy (oral prednisone or mesalamine), 34 of 63 patients were in clinical or sigmoidoscopic remission compared to 33 of 66 patients treated with transdermal nicotine (OR=0.77, 95% CI 0.37-1.60). A meta-analysis of all five studies which included 137 patients treated with transdermal nicotine and 133 patients treated with a placebo or standard therapy demonstrated no statistically significant benefit of nicotine therapy (OR=1.23; 95% CI 0.71-2.14). Patients treated with transdermal nicotine were significantly more likely to withdrawal due to adverse events than patients treated with placebo or standard medical therapy (OR=5.82, 95% CI, 1.66 - 20.47) and were significantly more likely to suffer from an adverse event than patients treated with placebo or standard medical therapy (OR=3.54, 95% CI, 2.07 - 6.08). The results of this review provide evidence that transdermal nicotine is superior to placebo for the induction of remission in patient's with ulcerative colitis. The review did not identify any significant advantage for transdermal nicotine therapy compared to standard medical therapy. Adverse events associated with transdermal nicotine are significant and limit its use in some patients.
One trial, which included 49 infants, met the inclusion criteria. The trial compared the use of inhaled corticosteroids (budesonide) with placebo. We found no differences between groups in terms of need for nasal continuous positive airway pressure (risk ratio (RR) 1.27, 95% confidence interval (CI) 0.65 to 2.51; 1 study, 49 participants) and need for mechanical ventilation (RR 0.52, 95% CI 0.05 to 5.38; 1 study, 49 participants). The type of mechanical ventilation used in the included study was high-frequency oscillation. Tests for heterogeneity were not applicable for any of the analyses as only one study was included. Out of the secondary outcomes we deemed to be of greatest importance to patients, the study only reported on duration of hospital stay, which was no different between groups. The quality of the evidence is very low, due to the imprecision of the estimates and indirectness. We identified no ongoing trials. Given the paucity and very low quality of the available evidence, we are unable to determine the benefits and harms of postnatal administration of either inhaled or systemic corticosteroids for the management of TTN.
We included 29 studies involving 5392 participants (mean age = 64 years, age range 23 to 86 years, 82% male). However, few studies contributed data to meta-analyses due to inconsistency in outcome definition and reporting. In general, risk of bias varied from low to high risk of bias across included studies, and insufficient detail was provided to inform judgement in several cases. The quality of the evidence of key outcomes ranged from moderate to low quality due to the presence of moderate or high statistical heterogeneity, imprecision of results or due to limitations in the design of individual studies. Compared with no RIPC, we found that RIPC has no treatment effect on the rate of the composite endpoint with RR 0.99 (95% confidence interval (CI) 0.78 to 1.25); 2 studies; 2463 participants; moderate-quality evidence. Participants randomised to RIPC showed an equivalent or better effect regarding the amount of cTnT release measured at 72 hours after surgery with SMD -0.32 (95% CI -0.65 to 0.00); 3 studies; 1120 participants; moderate-quality evidence; and expressed as AUC 72 hours with SMD -0.49 (95% CI -0.96 to -0.02); 3 studies; 830 participants; moderate-quality evidence. We found the same result in favour of RIPC for the cTnI release measured at 48 hours with SMD -0.21 (95% CI -0.40 to -0.02); 5 studies; 745 participants; moderate-quality evidence; and measured at 72 hours after surgery with SMD -0.37 (95% CI -0.59 to -0.15); 2 studies; 459 participants; moderate-quality evidence. All other primary outcomes showed no differences between groups (cTnT release measured at 48 hours with SMD -0.14, 95% CI -0.33 to 0.06; 4 studies; 1792 participants; low-quality evidence and cTnI release measured as AUC 72 hours with SMD -0.17, 95% CI -0.48 to 0.14; 2 studies; 159 participants; moderate-quality evidence). We also found no differences between groups for all-cause mortality after 30 days, non-fatal myocardial infarction after 30 days, any new stroke after 30 days, acute renal failure after 30 days, length of stay on the intensive care unit (days), any complications and adverse effects related to ischaemic preconditioning. We did not assess many patient-centred/salutogenic-focused outcomes. We found no evidence that RIPC has a treatment effect on clinical outcomes (measured as a composite endpoint including all-cause mortality, non-fatal myocardial infarction or any new stroke, or both, assessed at 30 days after surgery). There is moderate-quality evidence that RIPC has no treatment effect on the rate of the composite endpoint including all-cause mortality, non-fatal myocardial infarction or any new stroke assessed at 30 days after surgery, or both. We found moderate-quality evidence that RIPC reduces the cTnT release measured at 72 hours after surgery and expressed as AUC (72 hours). There is moderate-quality evidence that RIPC reduces the amount of cTnI release measured at 48 hours, and measured 72 hours after surgery. Adequately-designed studies, especially focusing on influencing factors, e.g. with regard to anaesthetic management, are encouraged and should systematically analyse the commonly used medications of people with cardiovascular diseases.
In the first version of this review there were six eligible trials concerning 649 participants comparing plasma exchange with supportive treatment. No new eligible trials have been identified in subsequent updates. Two other studies compared different numbers of plasma exchanges. Overall the included trials had a moderate risk of bias (in general, the studies were at low risk but all had a high risk of bias from lack of blinding). In one trial with 220 severely affected participants, the median time to recover walking with aid was significantly shorter with plasma exchange (30 days) than without plasma exchange (44 days). In another trial with 91 mildly affected participants, the median time to onset of motor recovery was significantly shorter with plasma exchange (six days) than without plasma exchange (10 days). After four weeks, moderate-quality evidence from the combined data of three trials accounting for a total of 349 patients showed that plasma exchange significantly increased the proportion of patients who recovered the ability to walk with assistance (risk ratio (RR) 1.60, 95% confidence interval (CI) 1.19 to 2.15). In five trials with 623 participants in total, moderate-quality evidence showed that the RR for improvement by one or more disability grades after four weeks was 1.64 (95% CI 1.37 to 1.96) times greater with plasma exchange. Participants treated with plasma exchange also fared better, according to moderate-quality evidence, in time to recover walking without aid (three trials with 349 participants; RR 1.72, 95% CI 1.06 to 2.79) and requirement for artificial ventilation (five trials with 623 participants; RR 0.53, 95% CI 0.39 to 0.74). More participants had relapses by the end of follow-up in the plasma exchange group than in the control group (six trials with 649 participants; RR 2.89, 95% CI 1.05 to 7.93; moderate-quality evidence). Despite this, according to moderate-quality evidence, the likelihood of full muscle strength recovery at one year was greater with plasma exchange than without plasma exchange (five trials with 404 participants; RR 1.24, 95% CI 1.07 to 1.45), and the likelihood of severe motor sequelae was less (six trials with 649 participants; RR 0.65, 95% CI 0.44 to 0.96). High-quality evidence from six trials with 649 participants could not confirm or refute a lower risk of death following plasma exchange compared to control (RR 0.86, 95% CI 0.45 to 1.65). Three trials (N = 556) provided details of serious adverse events during the hospital stay; combined analyses found no increase in serious infectious events compared to the control group (RR 0.91, 95% CI 0.73 to 1.13), nor were there clear differences in blood pressure instability, cardiac arrhythmias or pulmonary emboli. Moderate-quality evidence shows significantly more improvement with plasma exchange than with supportive care alone in adults with Guillain-Barré syndrome, without a significant increase in serious adverse events. According to moderate-quality evidence, there was a small but significant increase in the risk of relapse during the first six to 12 months after onset in people treated with plasma exchange compared with those who were not treated. Despite this, after one year, full recovery of muscle strength was more likely and severe residual weakness less likely with plasma exchange.
Four trials were included. These involved a total of 278, mainly adult, participants with 283 mallet finger injuries. All four trials were methodologically flawed, including inadequate outcome assessment. Three trials compared different types of finger splints versus a standard Stack splint. One trial found a lower incidence of treatment failure in participants treated with a perforated custom-made splint. One trial found there were fewer complications in participants treated with a padded aluminium-alloy malleable finger splint; however, the incidence of treatment failure was similar in the two treatment groups. One trial evaluating the Abouna splint found a similar incidence of treatment failure in the two groups. However, the Abouna splint often needed replacing due to disintegration of its rubber cover and rusting of the exposed wires and was also less popular with participants. The fourth trial found no statistically significant differences between participants whose mallet finger was treated with Kirschner wire fixation and those with a Pryor and Howard splint. Similar numbers had complications in the two groups. There was insufficient evidence from comparisons tested within randomised controlled trials to establish the relative effectiveness of different, either custom-made or off-the-shelf, finger splints used for treating mallet finger injury. There was a useful reminder that splints used for prolonged immobilisation should be robust enough for everyday use, and of the central importance of patient adherence to instructions for splint use. There was insufficient evidence to determine when surgery is indicated.
Routine/revealed ultrasound versus selective ultrasound/concealed: 11 trials including 37,505 women. Ultrasound for fetal assessment in early pregnancy reduces the failure to detect multiple pregnancy by 24 weeks' gestation (risk ratio (RR) 0.07, 95% confidence interval (CI) 0.03 to 0.17; participants = 295; studies = 7), moderate quality of evidence). Routine scans improve the detection of major fetal abnormality before 24 weeks' gestation (RR 3.46, 95% CI 1.67 to 7.14; participants = 387; studies = 2,moderate quality of evidence). Routine scan is associated with a reduction in inductions of labour for 'post term' pregnancy (RR 0.59, 95% CI 0.42 to 0.83; participants = 25,516; studies = 8), but the evidence related to this outcome is of low quality, because most of the pooled effect was provided by studies with design limitation with presence of heterogeneity (I² = 68%). Ultrasound for fetal assessment in early pregnancy does not impact on perinatal death (defined as stillbirth after trial entry, or death of a liveborn infant up to 28 days of age) (RR 0.89, 95% CI 0.70 to 1.12; participants = 35,735; studies = 10, low quality evidence). Routine scans do not seem to be associated with reductions in adverse outcomes for babies or in health service use by mothers and babies. Long-term follow-up of children exposed to scan in utero does not indicate that scans have a detrimental effect on children's physical or cognitive development. The review includes several large, well-designed trials but lack of blinding was a problem common to all studies and this may have an effect on some outcomes. The quality of evidence was assessed for all review primary outcomes and was judged as moderate or low. Downgrading of evidence was based on including studies with design limitations, imprecision of results and presence of heterogeneity. Early ultrasound improves the early detection of multiple pregnancies and improved gestational dating may result in fewer inductions for post maturity. Caution needs to be exercised in interpreting the results of aspects of this review in view of the fact that there is considerable variability in both the timing and the number of scans women received.
We included two randomised trials with 615 participants. Both studies delivered real-time video counselling for smoking cessation individually, compared with telephone counselling. We judged one study at unclear risk of bias and one study at high risk of bias. There was no statistically significant treatment effect for smoking cessation (using the strictest definition and longest follow-up) across the two included studies when real-time video counselling was compared to telephone counselling (risk ratio (RR) 2.15, 95% confidence interval (CI) 0.38 to 12.04; 2 studies, 608 participants; I2 = 66%). We judged the overall certainty of the evidence for smoking cessation as very low due to methodological limitations, imprecision in the effect estimate reflected by the wide 95% CIs and inconsistency of cessation rates. There were no significant differences between real-time video counselling and telephone counselling reported for number of quit attempts among people who continued to smoke (mean difference (MD) 0.50, 95% CI –0.60 to 1.60; 1 study, 499 participants), mean number of counselling sessions completed (MD –0.20, 95% CI –0.45 to 0.05; 1 study, 566 participants), completion of all sessions (RR 1.13, 95% CI 0.71 to 1.79; 1 study, 43 participants) or therapeutic alliance (MD 1.13, 95% CI –0.24 to 2.50; 1 study, 398 participants). Participants in the video counselling arm were more likely than their telephone counselling counterparts to recommend the programme to a friend or family member (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 398 participants); however, there were no between-group differences on satisfaction score (MD 0.70, 95% CI –1.16 to 2.56; 1 study, 29 participants). There is very little evidence about the effectiveness of real-time video counselling for smoking cessation. The existing research does not suggest a difference between video counselling and telephone counselling for assisting people to quit smoking. However, given the very low GRADE rating due to methodological limitations in the design, imprecision of the effect estimate and inconsistency of cessation rates, the smoking cessation results should be interpreted cautiously. High-quality randomised trials comparing real-time video counselling to telephone counselling are needed to increase the confidence of the effect estimate. Furthermore, there is currently no evidence comparing real-time video counselling to a control group. Such research is needed to determine whether video counselling increases smoking cessation.
We included 26 RCTs randomising 23,499 participants. All included studies assessed effects of ezetimibe plus other lipid-modifying drugs compared with other lipid-modifying drugs alone or plus placebo. Our findings were driven by the largest study (IMPROVE-IT), which had weights ranging from 41.5% to 98.4% in the different meta-analyses. Ezetimibe with statins probably reduces the risk of major adverse cardiovascular events compared with statins alone (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.90 to 0.98; a decrease from 284/1000 to 267/1000, 95% CI 256 to 278; 21,727 participants; 10 studies; moderate-quality evidence). Trials reporting all-cause mortality used ezetimibe with statin or fenofibrate and found they have little or no effect on this outcome (RR 0.98, 95% CI 0.91 to 1.05; 21,222 participants; 8 studies; high-quality evidence). Adding ezetimibe to statins probably reduces the risk of non-fatal myocardial infarction (MI) (RR 0.88, 95% CI 0.81 to 0.95; a decrease from 105/1000 to 92/1000, 95% CI 85 to 100; 21,145 participants; 6 studies; moderate-quality evidence) and non-fatal stroke (RR 0.83, 95% CI 0.71 to 0.97; a decrease 32/1000 to 27/1000, 95% CI 23 to 31; 21,205 participants; 6 studies; moderate-quality evidence). Trials reporting cardiovascular mortality added ezetimibe to statin or fenofibrate, probably having little or no effect on this outcome (RR 1.00, 95% CI 0.89 to 1.12; 19457 participants; 6 studies; moderate-quality evidence). The need for coronary revascularisation might be reduced by adding ezetimibe to statin (RR 0.94, 95% CI 0.89 to 0.99; a decrease from 196/1000 to 184/1000, 95% 175 to 194; 21,323 participants; 7 studies); however, no difference in coronary revascularisation rate was observed when a sensitivity analysis was limited to studies with a low risk of bias. In terms of safety, adding ezetimibe to statins may make little or no difference in the risk of hepatopathy (RR 1.14, 95% CI 0.96 to 1.35; 20,687 participants; 4 studies; low-quality evidence). It is uncertain whether ezetimibe increase or decrease the risk of myopathy (RR 1.31, 95% CI 0.72 to 2.38; 20,581 participants; 3 studies; very low-quality evidence) and rhabdomyolysis, given the wide CIs and low event rate. Little or no difference in the risk of cancer, gallbladder-related disease and discontinuation due to adverse events were observed between treatment groups. For serum lipids, adding ezetimibe to statin or fenofibrate might further reduce the low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglyceride levels and likely increase the high-density lipoprotein cholesterol levels; however, substantial heterogeneity was detected in most analyses. None of the included studies reported on health-related quality of life. Moderate- to high-quality evidence suggests that ezetimibe has modest beneficial effects on the risk of CVD endpoints, primarily driven by a reduction in non-fatal MI and non-fatal stroke, but it has little or no effect on clinical fatal endpoints. The cardiovascular benefit of ezetimibe might involve the reduction of LDL-C, total cholesterol and triglycerides. There is insufficient evidence to determine whether ezetimibe increases the risk of adverse events due to the low and very low quality of the evidence. The evidence for beneficial effects was mainly obtained from individuals with established atherosclerotic cardiovascular disease (ASCVD, predominantly with acute coronary syndrome) administered ezetimibe plus statins. However, there is limited evidence regarding the role of ezetimibe in primary prevention and the effects of ezetimibe monotherapy in the prevention of CVD, and these topics thus requires further investigation.
We included three RCTs (327 children) which were assessed at low to moderate risk of bias. One RCT included 219 children with AOM, and used a three-arm, parallel group, double-blind design to compare paracetamol versus ibuprofen versus placebo. All children also received antibiotics and those with fever > 39 °C could have received paracetamol (30 mg to 60 mg) additionally to the studied treatments. Another RCT involved 156 febrile children (26 of whom had AOM). The study design was a three-arm, parallel group, double-blind design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol. The third RCT included 889 children with respiratory tract infections (82 of whom had AOM). This study applied a 3 x 2 x 2 factorial, open-label design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol. Study participants were randomised to one of the three treatment groups as well as two dosing groups (regular versus as required) and two steam inhalation groups (steam versus no steam). Authors of two RCTs provided crude subgroup data on children with AOM. We used data from the remaining trial to inform comparison of paracetamol versus placebo (148 children) and ibuprofen versus placebo (146 children) assessments. Data from all included RCTs informed comparison of ibuprofen versus paracetamol (183 children); data from the two RCTs informed comparison of ibuprofen plus paracetamol versus paracetamol alone (71 children). We found evidence, albeit of low quality, that both paracetamol and ibuprofen as monotherapies were more effective than placebo in relieving pain at 48 hours (paracetamol versus placebo: proportion of children with pain 10% versus 25%, RR 0.38, 95% CI 0.17 to 0.85; number needed to treat to benefit (NNTB) 7; ibuprofen versus placebo: proportion of children with pain 7% versus 25%, RR 0.28, 95% CI 0.11 to 0.70; NNTB 6). Very low quality evidence suggested that adverse events did not significantly differ between children treated with either paracetamol, ibuprofen or placebo. We found insufficient evidence of a difference between ibuprofen and paracetamol in relieving ear pain at 24 hours (2 RCTs, 39 children; RR 0.83, 95% CI 0.59 to 1.18; very low quality evidence), 48 to 72 hours (3 RCTs, 183 children; RR 0.91, 95% CI 0.54 to 1.54; low quality evidence) and four to seven days (2 RCTs, 38 children; RR 0.74, 95% CI 0.17 to 3.23; very low quality evidence). Data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone came from two RCTs that provided crude subgroup data for 71 children with AOM. The small sample provided imprecise effect estimates and we were consequently unable to draw any firm conclusions (very low quality evidence). Despite explicit guideline recommendations on its use, current evidence on the effectiveness of paracetamol or NSAIDs, alone or combined, in relieving pain in children with AOM is limited. Low quality evidence indicates that both paracetamol and ibuprofen as monotherapies are more effective than placebo in relieving short-term ear pain in children with AOM. There is insufficient evidence of a difference between ibuprofen and paracetamol in relieving short-term ear pain in children with AOM, whereas data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone were insufficient to draw any firm conclusions. Further research is needed to provide insights into the role of ibuprofen as adjunct to paracetamol, and other analgesics such as anaesthetic eardrops, for children with AOM.
We included a total of 13 randomised trials with 790 patients. Loss of hepatitis B 'e' antigen (OR 1.41, 95% confidence interval 1.03 to 1.92, P = 0.03) and hepatitis B virus DNA (OR = 1.51, 95% confidence interval 1.12 to 2.05, P = 0.008) were significantly more frequent among patients treated with the sequential combination of glucocorticosteroids and alfa interferon than among patients treated with alfa interferon alone. Glucocorticosteroid pretreatment did not significantly influence seroconversion from hepatitis B 'e' antigen to antibodies to hepatitis B 'e' antigen, loss of hepatitis B surface antigen, normalisation of alanine aminotransferase/aspartate aminotransferase activities, and severity of adverse events. Glucocorticosteroid pretreatment did not significantly affect mortality and adverse events. The effect of glucocorticosteroid pretreatment on liver histology and quality of life could not be assessed due to insufficient data. Pretreatment with glucocorticosteroids before treatment with alfa interferon in patients with hepatitis B 'e' antigen positive chronic hepatitis B may be more effective than treatment with alfa interferon alone with regard to loss of hepatitis B 'e' antigen and hepatitis B virus DNA, but evidence for effect on clinical outcomes is lacking.
The search retrieved 62 reports in total. Of these, we assessed 12 reports in full, corresponding to six trials. We included three trials and excluded one; two trials are ongoing. The included trials were conducted in hospital settings. Two trials were conducted in India; the third trial was a large cluster-randomised trial, which took place in 13 European countries. Overall, we judged the included trials to be at a low risk of bias. One study evaluated the use of calibrated drapes versus visual estimation, another evaluated the use of calibrated drapes versus the gravimetric technique (weight of blood-soaked materials), therefore, we were unable to pool the data from the two studies. The third study did not measure any of the outcomes of interest, so did not contribute data to the analyses. Direct measurement using calibrated drapes versus visual estimation One cluster-randomised controlled trial in 13 western European countries, with over 25,000 women, examined this comparison. The trial did not report on postpartum anaemia (defined as Hb lower than 9 mg/dL), blood loss greater than 500 mL, or maternal infection. Moderate-quality evidence suggests there is probably little or no difference between groups in: severe morbidity (coagulopathy, organ failure, intensive care unit admission; adjusted risk ratio (RR) 0.82, 95% confidence interval (CI) 0.48 to 1.39); the risk of blood transfusion (adjusted RR 0.82, 95% CI 0.46 to 1.46); the use of plasma expanders (adjusted RR 0.77, 95% CI 0.42 to 1.42); and the use of therapeutic uterotonics (adjusted RR 0.87, 95% CI 0.42 to 1.76). Direct measurement using calibrated drapes (Excellent BRASSS-V Drape™) versus gravimetric technique One randomised controlled trial in India, with 900 women, examined this comparison. The trial did not report on postpartum anaemia (defined as Hb lower than 9 mg/dL), severe morbidity, or maternal infection. High-quality evidence showed that using calibrated drapes improved the detection of blood loss greater than 500 mL when compared with the gravimetric technique (RR 1.86, 95% CI 1.11 to 3.11). Low-quality evidence suggests there may be little or no difference in the risk of blood transfusion between the two groups (RR 1.00, 95% CI 0.06 to 15.94), or in the use of plasma expanders, reported as intravenous fluids given for PPH treatment (RR 0.67; 95% CI 0.19 to 2.35). High-quality evidence showed little or no difference in the use of therapeutic uterotonics (RR 1.01, 95% CI 0.90 to 1.13), but the use of therapeutic uterotonics was extremely high in both arms of the study (57% and 56%). Overall, the evidence in this review is insufficient to support the use of one method over another for blood loss estimation after vaginal birth. In general, the quality of evidence for our predefined outcomes ranged from low to high quality, with downgrading decisions due to imprecision. The included trials did not report on many of our primary and secondary outcomes. In trials that evaluate methods for estimating blood loss during vaginal birth, we believe it is important to measure their impact on clinical maternal and neonatal outcomes, along with their diagnostic accuracy. This body of knowledge needs further, well designed, appropriately powered, randomised controlled trials that correlate blood loss with relevant clinical outcomes, such as those listed in this review.
Six studies found since 2004 were originally viewed as possible inclusions, but when the family-centred score assessment was tested, only one met the minimum score of family-centredness and was included in this review. This was an unpublished RCT involving 288 children post-tonsillectomy in a care-by-parent unit (CBPU) compared with standard inpatient care.The study used a range of behavioural, economic and physical measures. It showed that children in the CBPU were significantly less likely to receive inadequate care compared with standard inpatient admission, and there were no significant differences for their behavioural outcomes or other physical outcomes. Parents were significantly more satisfied with CBPU care than standard care, assessed both before discharge and at 7 days after discharge. Costs were lower for CPBU care compared with standard inpatient care. No other outcomes were reported. The study was rated as being at low to unclear risk of bias. This update of a review has found limited, moderate-quality evidence that suggests some benefit of a family-centred care intervention for children's clinical care, parental satisfaction, and costs, but this is based on a small dataset and needs confirmation in larger RCTs. There is no evidence of harms. Overall, there continues to be little high-quality quantitative research available about the effects of family-centred care. Further rigorous research on the use of family-centred care as a model for care delivery to children and families in hospitals is needed. This research should implement well-developed family-centred care interventions, ideally in randomised trials. It should investigate diverse participant groups and clinical settings, and should assess a wide range of outcomes for children, parents, staff and health services.
We included nine RCTs involving 725 women. However, five trials did not contribute data. Four trials involving 358 women contributed data. Trials were generally at mixed risk of bias. We only identified data for three comparisons: pharmaceutical treatment versus placebo or no treatment; acupuncture versus no treatment and pharmacological intervention versus advice on dietary and lifestyle changes. Pharmaceutical treatment compared with placebo or no treatment Two trials evaluated any pharmaceutical treatment compared with placebo or no treatment. One trial examined a treatment rarely used nowadays (intramuscular prostigmine 0.5 mg versus placebo). One trial evaluated the effect of magnesium and aluminium hydroxide plus simethicone liquid and tablet compared with placebo. For the primary outcome of this review (relief of heartburn), women who received pharmaceutical treatment reported complete heartburn relief more often than women receiving no treatment or placebo (risk ratio (RR) 1.85, 95% confidence interval (CI) 1.36 to 2.50 in two RCTs of 256 women, I2 = 0%, moderate-quality evidence). Data on partial relief of heartburn were heterogenous and showed no clear difference (average RR 1.35, 95% CI 0.38 to 4.76 in two RCTs of 256 women, very low-quality evidence). In terms of secondary outcomes, there was no clear difference in the rate of side effects between the pharmaceutical treatment group and the placebo/no treatment group (RR 0.63, 95% CI 0.21 to 1.89 in two RCTs of 256 women, very low-quality evidence). Pharmacological intervention versus advice on dietary and lifestyle choices One study compared 1 g of sucralfate with advice on dietary and lifestyle choices in treating heartburn. More women in the sucralfate group experienced complete relief of heartburn compared to women who received advice on diet and lifestyle choices (RR 2.41, 95% CI 1.42 to 4.07; participants = 65; studies = one). The only secondary outcome of interest addressed by this trial was side effects. The evidence was not clear on intervention side effects rate between the two groups (RR 1.74, 95% CI 0.07 to 41.21; participants = 66; studies = one). There was only one instance of side effects in the pharmacological group. Acupuncture compared with no treatment One trial evaluated acupuncture compared with no treatment but did not report data relating to this review's primary outcome (relief of heartburn). In terms of secondary outcomes, there was no difference in the rate of side effects between women who had acupuncture and women who had no treatment (RR 2.43, 95% CI 0.11 to 55.89 in one RCT of 36 women). With regard to quality of life, women who had acupuncture reported improved ability to sleep (RR 2.80, 95% CI 1.14 to 6.86) and eat (RR 2.40, 95% CI 1.11 to 5.18 in one RCT of 36 women). The following secondary outcomes were not reported upon in any of the trials included in the review: miscarriage, preterm labour, maternal satisfaction, fetal anomalies, intrauterine growth restriction, low birthweight. There are no large-scale RCTs to assess heartburn relief in pregnancy. This review of nine small studies (which involved data from only four small studies) indicates that there are limited data suggesting that heartburn in pregnancy could be completely relieved by pharmaceutical treatment. Three outcomes were assessed and assigned a quality rating using the GRADE methods. Evidence from two trials for the outcome of complete relief of heartburn was assessed as of moderate quality. Evidence for the outcomes of partial heartburn relief and side effects was graded to be of very low quality. Downgrading decisions were based in part on the small size of the trials and on heterogenous and imprecise results. There are insufficient data to assess acupuncture versus no treatment and no data to assess other comparisons (miscarriage, preterm labour, maternal satisfaction, fetal anomalies, intrauterine growth restriction, low birthweight). Further RCTs are needed to fully evaluate the effectiveness of interventions for heartburn in pregnancy. Future research should also address other medications such as histamine 2-receptor antagonists, promotility drugs, proton pump inhibitors, and a raft-forming alginate reflux suppressant in treatment of heartburn in pregnancy. More research is needed on acupuncture and other complimentary therapies as treatments for heartburn in pregnancy. Future research should also evaluate any adverse outcomes, maternal satisfaction with treatment and measure pregnant women's quality of life in relation to the intervention.
Only one study met the inclusion criteria, an RCT conducted in Tanzania between May 2003 and October 2004. Women in the intervention group (n=760) received a letter for their male partners, which invited them to return together to receive Couple Voluntary Counselling and Testing (CVCT) for HIV. Women in the control group (n=761) received individual HIV VCT during their first ANC visit and then usual care. The percentages of women who received HIV VCT and collected their results were 48%, 45% and 39% in the intervention group and 93%, 78% and 71% in the control group (p <0,001). Only 33% of women in the intervention group returned with their male partners and only 47% of them went through the whole CVCT process. The proportion of women who received HIV prophylaxis at delivery was not different between the two arms (27% in the intervention and 22% in the control group). The study had a high risk of bias. We found only one eligible study that assessed the effectiveness of male involvement in improving women’s uptake of PMTCT services, which only focused on one part of the perinatal PMTCT cascade. We urgently need more rigorously designed studies assessing the impact of male engagement interventions on women’s uptake of PMTCT services to know if this intervention can contribute to improve uptake of PMTCT services and reduce vertical transmission of HIV in children.
Four studies, involving a total of 414 participants, met the inclusion criteria. Three studies were conducted in adult participants and one in adolescents. The average age of participants ranged from 14 to 43 years. The trials lasted between two months and 12 months. The interventions were based on Pennebaker's method. The risk of bias across most domains of the studies was generally considered to be low, however three of four studies were considered at high risk of bias due to lack of assessor blinding and one study was at high risk of bias for selective reporting. The interpretation of these studies was limited by diverse outcome measurements, measurement tools, control group techniques, and number and/or times of follow-up. A pooled result from the four studies, including a total of 146 intervention and 135 control participants, indicated uncertain effect in forced expiratory volume in one second (FEV1) % predicted between the disclosure group and the control group (mean difference (MD) 3.43%, 95% confidence interval (CI) -0.61% to 7.47%; very low-quality evidence) at ≤ three months' follow-up. Similarly, evidence from two studies indicated that written emotional disclosure found uncertain effect on forced vital capacity (FVC) (standardised mean difference (SMD) -0.02, 95% CI -0.30 to 0.26; low-quality evidence) and asthma symptoms (SMD -0.22, 95% CI -0.52 to 0.09; low-quality evidence) but may result in improved asthma control at ≤ three months' follow-up (SMD 0.29, 95% CI 0.01 to 0.58; low-quality evidence). We were unable to pool the data for other outcomes. Results from individual trials did not reveal a significant benefit of written emotional disclosure for quality of life, medication use, healthcare utilisation or psychological well-being. Evidence from one trial suggests a significant reduction in beta agonist use (MD -1.62, 95% CI -2.62 to -0.62; low-quality evidence) at ≤ three months' follow-up in the disclosure group compared with controls. The review did not address any adverse effects of emotional writing. Evidence was insufficient to show whether written emotional disclosure compared with writing about non-emotional topics had an effect on the outcomes included in this review. Evidence is insufficient to allow any conclusions as to the role of disclosure in quality of life, psychological well-being, medication use and healthcare utilisation. The evidence presented in this review is generally of low quality. Better designed studies with standardised reporting of outcome measurement instruments are required to determine the effectiveness of written emotional disclosure in the management of asthma.
We included 22 randomized trials (2130 participants). The mean treatment duration was 2.3 ± 1.3 months (ranging from one to six months). Twenty trials were conducted in China and 18 trials were published in Chinese. Overall, the risk of bias of included trials was high or unclear. Five different herbal medicines were evaluated in the included trials, which compared herbs with conventional medicine in six comparisons (20 trials), or placebo (two trials). There were no outcome data in any of the trials on cardiovascular events and death from any cause. One trial each reported well-being (no significant differences) and economic costs. No serious adverse events were observed. Xuezhikang was the most commonly used herbal formula investigated. A significant effect on total cholesterol (two trial, 254 participants) was shown in favor of Xuezhikang when compared with inositol nicotinate (mean difference (MD) -0.90 mmol/L, 95% confidence interval (CI) -1.13 to -0.68) . Some herbal medicines may have cholesterol-lowering effects. Our findings have to be interpreted with caution due to high or unclear risk of bias of the included trials.
We included three randomised controlled trials (RCTs) involving 1358 participants. None of the studies provided useable data for the key outcomes of not having seen a dentist in the past year, not brushing teeth twice a day, chronic pain, clinically important adverse events, and service use. Data for leaving the study early and change in plaque index scores were provided. Oral health education compared with standard care When 'oral health education' was compared with 'standard care', there was no clear difference between the groups for numbers leaving the study early (1 RCT, n = 50, RR 1.67, 95% CI 0.45 to 6.24, moderate-quality evidence), while for dental state: no clinically important change in plaque index, an effect was found. Although this was statistically significant and favoured the intervention group, it is unclear if it was clinically important (1 RCT, n = 40, MD - 0.50 95% CI - 0.62 to - 0.38, very low quality evidence).These limited data may have implications regarding improvement in oral hygiene. Motivational interview + oral health education compared with oral health education Similarly, when 'motivational interview + oral health education' was compared with 'oral health education', there was no clear difference for the outcome of leaving the study early (1 RCT, n = 60 RR 3.00, 95% CI 0.33 to 27.23, moderate-quality evidence), while for dental state: no clinically important change in plaque index, an effect favouring the intervention group was found (1 RCT, n = 56, MD - 0.60 95% CI - 1.02 to - 0.18 very low-quality evidence). These limited, clinically opaque data may or may not have implications regarding improvement in oral hygiene. Monitoring compared with no monitoring For this comparison, only data for leaving the study early were available. We found a difference in numbers leaving early, favouring the 'no monitoring' group (1 RCT, n = 1682, RR 1.07, 95% CI 1.00 to 1.14, moderate-quality evidence). However, these data are problematic. The control denominator is implied and not clear, and follow-up did not depend only on individual participants, but also on professional caregivers and organisations - the latter changing frequently resulting in poor follow-up, but not a good reflection of the acceptability of the monitoring to patients. For this comparison, no data were available for 'no clinically important change in plaque index'. We found no evidence from trials that oral health advice helps people with serious mental illness in terms of clinically meaningful outcomes. It makes sense to follow guidelines and recommendations such as those put forward by the British Society for Disability and Oral Health working group until better evidence is generated. Pioneering trialists have shown that evaluative studies relevant to oral health advice for people with serious mental illness are possible.
Eleven studies met the inclusion criteria. Ten studies reported data on patient level: the scan was positive or negative. One study reported on all single lesions (lesion level). The sensitivity of ¹²³I-MIBG (SPECT-CT) scintigraphy (objective 1.1), determined in 608 of 621 eligible patients included in the 11 studies, varied from 67% to 100%. One study, that reported on a lesion level, provided data to calculate the specificity: 68% in 115 lesions in 22 patients. The sensitivity of ¹²³I-MIBG scintigraphy for detecting metastases separately from the primary tumour in patients with all neuroblastoma stages ranged from 79% to 100% in three studies and the specificity ranged from 33% to 89% for two of these studies. One study reported on the diagnostic accuracy of 18F-FDG-PET(-CT) imaging (add-on test) in patients with negative ¹²³I-MIBG scintigraphy (objective 1.2). Two of the 24 eligible patients with proven neuroblastoma had a negative ¹²³I-MIBG scan and a positive 18F-FDG-PET(-CT) scan. The sensitivity of 18F-FDG-PET(-CT) imaging as a single diagnostic test (objective 2.1) and compared to ¹²³I-MIBG (SPECT-CT) (objective 2.2) was only reported in one study. The sensitivity of 18F-FDG-PET(-CT) imaging was 100% versus 92% of ¹²³I-MIBG (SPECT-CT) scintigraphy. We could not calculate the specificity for both modalities. The reported sensitivities of ¹²³-I MIBG scintigraphy for the detection of neuroblastoma and its metastases ranged from 67 to 100% in patients with histologically proven neuroblastoma. Only one study in this review reported on false positive findings. It is important to keep in mind that false positive findings can occur. For example, physiological uptake should be ruled out, by using SPECT-CT scans, although more research is needed before definitive conclusions can be made. As described both in the literature and in this review, in about 10% of the patients with histologically proven neuroblastoma the tumour does not accumulate ¹²³I-MIBG (false negative results). For these patients, it is advisable to perform an additional test for staging and assess response to therapy. Additional tests might for example be 18F-FDG-PET(-CT), but to be certain of its clinical value, more evidence is needed. The diagnostic accuracy of 18F-FDG-PET(-CT) imaging in case of a negative ¹²³I-MIBG scintigraphy could not be calculated, because only very limited data were available. Also the detection of the diagnostic accuracy of index test 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma tumour and its metastases, and to compare this to comparator test ¹²³I-MIBG (SPECT-CT) scintigraphy, could not be calculated because of the limited available data at time of this search. At the start of this project, we did not expect to find only very limited data on specificity. We now consider it would have been more appropriate to use the term "the sensitivity to assess the presence of neuroblastoma" instead of "diagnostic accuracy" for the objectives.
The previous update (2008) had identified 53 potential studies and included 37 combined for meta-analysis. In this latest update we identified a further 13 studies and included 11, summarizing the results of 50 trials including 4151 participants. Overall, succinylcholine was superior to rocuronium for achieving excellent intubating conditions: RR 0.86 (95% confidence interval (CI) 0.81 to 0.92; n = 4151) and clinically acceptable intubation conditions (RR 0.97, 95% CI 0.95 to 0.99; n = 3992, 48 trials). A high incidence of detection bias amongst the trials coupled with significant heterogeneity provides moderate-quality evidence for these conclusions, which are unchanged from the previous update. Succinylcholine was more likely to produce excellent intubating conditions when using thiopental as the induction agent: RR 0.81 (95% CI: 0.73 to 0.88; n = 2302, 28 trials). In the previous update, we had concluded that propofol was the superior induction agent with succinylcholine. There were no reported incidences of severe adverse outcomes. We found no statistical difference in intubation conditions when succinylcholine was compared to 1.2 mg/kg rocuronium; however, succinylcholine was clinically superior as it has a shorter duration of action. Succinylcholine created superior intubation conditions to rocuronium in achieving excellent and clinically acceptable intubating conditions.
Eleven trials are included in this update; 10 of these we judged to be at an unclear or high risk of bias. The trials were clinically heterogeneous with differences in duration of follow-up, and ultrasound regimens. Nine trials evaluated high frequency ultrasound; seven studies provided data for ulcers healed and two provided data on change in ulcer size only. Two trials evaluated low frequency ultrasound and both reported ulcers healed data. It is uncertain whether high frequency ultrasound affects the proportion of ulcers healed compared with no ultrasound at any of the time points evaluated: at seven to eight weeks (RR 1.21, 95% CI 0.86 to 1.71; 6 trials, 678 participants; low quality evidence - downgraded once for risk of bias and once for imprecision); at 12 weeks (RR 1.26, 95% CI 0.92 to 1.73; 3 trials, 489 participants; moderate quality evidence - downgraded once for imprecision); and at 12 months (RR 0.93, 95% CI 0.73 to 1.18; 1 trial, 337 participants; low quality evidence - downgraded once for unclear risk of bias and once for imprecision). One trial (92 participants) reported that a greater percentage reduction in ulcer area was achieved at four weeks with high-frequency ultrasound, while another (73 participants) reported no clear difference in change in ulcer size at seven weeks. We downgraded the level of this evidence to very low, mainly for risk of bias (typically lack of blinded outcome assessment and attrition) and imprecision. Data from one trial (337 participants) suggest that high frequency ultrasound may increase the risk of non-serious adverse events (RR 1.29, 95% CI 1.02 to 1.64; moderate quality evidence - downgraded once for imprecision) and serious adverse events (RR 1.21, 95% CI 0.78 to 1.89; moderate quality evidence downgraded once for imprecision). It is uncertain whether low frequency ultrasound affects venous ulcer healing at eight and 12 weeks (RR 3.91, 95% CI 0.47 to 32.85; 2 trials, 61 participants; very low quality evidence (downgraded for risk of bias and imprecision)). High-frequency ultrasound probably makes little or no difference to quality of life (moderate quality evidence, downgraded for imprecision). The outcomes of adverse effects, quality of life and cost were not reported for low-frequency ultrasound treatment. It is uncertain whether therapeutic ultrasound (either high or low frequency) improves the healing of venous leg ulcers. We rated most of the evidence as low or very low quality due to risk of bias and imprecision.
Two studies (n of 80), where n is the number of participants, met the inclusion criteria. Ultrasound to the palmar and dorsal aspects of the hand significantly increased grip strength, measured as weighted mean difference (WMD) from control [WMD 28.07 (95 CI: 13.37 to 42.77)]. Ultrasound to the palmar and dorsal aspects of the hand also appeared to have beneficial effects on the following outcome measures: wrist dorsal flexion [WMD 1.90 (95%CI: 0.64 to 3.16)], duration of morning stiffness [WMD 28.54 (95%CI: 0.18 to 56.90)], number of swollen joints [WMD 1.02 (95%CI: 0.45 to 1.59)], and the number of painful joints [WMD 1.20 (95%CI: 0.45 to 1.95)]. There was no significant difference between a) exercises and wax baths, b) exercises with ultrasound, c) exercises with ultrasound and faradic hand baths on the outcome measures: pain score, grip strength, circumference of proximal interphalangeal (PIP) joints, articular index, and range of motion or level of activity. The reviewers concluded that ultrasound in combination with exercises, faradic current and wax bath treatment modalities is not supported and cannot be recommended. Ultrasound alone can, however, be used on the hand to increase grip strength, and to a lesser extent and based on borderline results, increase wrist dorsal flexion, decrease morning stiffness, reduce the number of swollen joints, and reduce the number of painful joints. It is important to note that these conclusions are limited by methodological considerations such as poor quality of the included trials, the low number of clinical trials, and the small number of study participants.
We included 21 RCTs (2082 women). The included trials mostly assessed the levonorgestrel-releasing intrauterine device (LNG IUS) (no conclusions could be reached from one small study assessing Progestasert which was discontinued in 2001) and so conclusions are based only on LNG IUS. Comparisons were made with placebo, oral medical treatment, endometrial destruction techniques and hysterectomy. Ratings for the overall quality of the evidence for each comparison ranged from very low to high. Limitations in the evidence included inadequate reporting of study methods and inconsistency. Seven studies compared the LNG IUS with oral medical therapy: either norethisterone acetate (NET) administered over most of the menstrual cycle, medroxyprogesterone acetate (MPA) (administered for 10 days), the oral contraceptive pill, mefenamic acid or usual medical treatment where participants could choose the oral treatment that was most suitable. The LNG IUS was more effective at reducing HMB as measured by the alkaline haematin method (MD 66.91 mL, 95% CI 42.61 to 91.20; two studies, 170 women; I2 = 81%, low quality evidence) or by Pictorial Bleeding Assessment Chart (PBAC) scores (MD 55.05, 95% CI 27.83 to 82.28; three studies, 335 women; I2 = 79%, low quality evidence), improving quality of life and a greater number of women continued with their treatment at two years when compared with oral treatment. Although substantial heterogeneity was identified for the bleeding outcomes, the direction of effect consistently favoured the LNG IUS. There was insufficient evidence to reach conclusions on satisfaction. Minor adverse effects (such as pelvic pain, breast tenderness and ovarian cysts) were more common with the LNG IUS. Ten studies compared the LNG IUS with endometrial destruction techniques: three with transcervical resection, one with rollerball ablation and six with thermal balloon ablation. Evidence was inconsistent and very low quality with respect to reduction in bleeding outcomes and satisfaction was comparable between treatments (low and moderate quality evidence). Improvements in quality of life were experienced with both types of treatment. Minor adverse events were more common with the LNG IUS overall, but it appeared more cost effective compared to thermal ablation within a two-year time frame in one study. Three studies compared the LNG IUS with hysterectomy. The LNG IUS was not as successful at reducing HMB as hysterectomy (high quality evidence). The women in these studies reported improved quality of life, regardless of treatment. In spite of the high rate of surgical treatment in those having LNG IUS within 10 years, the LNG IUS was more cost effective than hysterectomy. The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than oral medication as a treatment for heavy menstrual bleeding (HMB). It is associated with a greater reduction in HMB, improved quality of life and appears to be more acceptable long term but is associated with more minor adverse effects than oral therapy. When compared to endometrial ablation, it is not clear whether the LNG IUS offers any benefits with regard to reduced HMB and satisfaction rates and quality of life measures were similar. Some minor adverse effects were more common with the LNG IUS but it appeared to be more cost effective than endometrial ablation techniques. The LNG IUS was less effective than hysterectomy in reducing HMB. Both treatments improved quality of life but the LNG IUS appeared more cost effective than hysterectomy for up to 10 years after treatment.
In the original 2010 review, we identified no relevant studies. This updated review included one RCT involving 245 participants that compared abdominal paracentesis and intraperitoneal infusion of catumaxomab versus abdominal paracentesis alone. The study was at high risk of bias in almost all domains. The data were not suitable for analysis. The median time to the first deterioration of QoL ranged from 19 to 26 days in participants receiving paracentesis alone compared to 47 to 49 days among participants receiving paracentesis with catumaxomab infusion (very low-certainty evidence). Adverse events were only reported among participants receiving catumaxomab infusion. The most common severe adverse events were abdominal pain and lymphopenia (157 participants; very low-certainty evidence). There were no data on the improvement of symptoms, satisfaction of participants and caregivers, and cost-effectiveness. Currently, there is insufficient evidence to recommend the most appropriate management of drainage for malignant ascites among women with gynaecological cancer, as there was only very low-certainty evidence from one small RCT at overall high risk of bias.
We included 22 trials involving 9753 participants. In participants with symptomatic carotid stenosis, compared with endarterectomy stenting was associated with a higher risk of periprocedural death or stroke (the primary safety outcome; OR 1.70, 95% CI 1.31 to 2.19; P < 0.0001, I² = 5%; 10 trials, 5396 participants; high-certainty evidence); and periprocedural death, stroke, or myocardial infarction (OR 1.43, 95% CI 1.14 to 1.80; P = 0.002, I² = 0%; 6 trials, 4861 participants; high-certainty evidence). The OR for the primary safety outcome was 1.11 (95% CI 0.74 to 1.64) in participants under 70 years old and 2.23 (95% CI 1.61 to 3.08) in participants 70 years old or more (interaction P = 0.007). There was a non-significant increase in periprocedural death or major or disabling stroke with stenting (OR 1.36, 95% CI 0.97 to 1.91; P = 0.08, I² = 0%; 7 trials, 4983 participants; high-certainty evidence). Compared with endarterectomy, stenting was associated with lower risks of myocardial infarction (OR 0.47, 95% CI 0.24 to 0.94; P = 0.03, I² = 0%), cranial nerve palsy (OR 0.09, 95% CI 0.06 to 0.16; P < 0.00001, I² = 0%), and access site haematoma (OR 0.32, 95% CI 0.15 to 0.68; P = 0.003, I² = 27%). The combination of periprocedural death or stroke or ipsilateral stroke during follow-up (the primary combined safety and efficacy outcome) favoured endarterectomy (OR 1.51, 95% CI 1.24 to 1.85; P < 0.0001, I² = 0%; 8 trials, 5080 participants; high-certainty evidence). The rate of ipsilateral stroke after the periprocedural period did not differ between treatments (OR 1.05, 95% CI 0.75 to 1.47; P = 0.77, I² = 0%). In participants with asymptomatic carotid stenosis, there was a non-significant increase in periprocedural death or stroke with stenting compared with endarterectomy (OR 1.72, 95% CI 1.00 to 2.97; P = 0.05, I² = 0%; 7 trials, 3378 participants; moderate-certainty evidence). The risk of periprocedural death or stroke or ipsilateral stroke during follow-up did not differ significantly between treatments (OR 1.27, 95% CI 0.87 to 1.84; P = 0.22, I² = 0%; 6 trials, 3315 participants; moderate-certainty evidence). Moderate or higher carotid artery restenosis (50% or greater) or occlusion during follow-up was more common after stenting (OR 2.00, 95% CI 1.12 to 3.60; P = 0.02, I² = 44%), but the difference in risk of severe restenosis was not significant (70% or greater; OR 1.26, 95% CI 0.79 to 2.00; P = 0.33, I² = 58%; low-certainty evidence). Stenting for symptomatic carotid stenosis is associated with a higher risk of periprocedural stroke or death than endarterectomy. This extra risk is mostly attributed to an increase in minor, non-disabling strokes occurring in people older than 70 years. Beyond the periprocedural period, carotid stenting is as effective in preventing recurrent stroke as endarterectomy. However, combining procedural safety and long-term efficacy in preventing recurrent stroke still favours endarterectomy. In people with asymptomatic carotid stenosis, there may be a small increase in the risk of periprocedural stroke or death with stenting compared with endarterectomy. However, CIs of treatment effects were wide and further data from randomised trials in people with asymptomatic stenosis are needed.
We included two RCTs and four CRCTs involving 352 physicians, 48 residents, and 135 allied health practitioners. Overall risk of bias was low as was quality of the evidence. One comparison was supported by three studies and three comparisons were supported by single studies, but outcomes across the three studies were highly heterogeneous. We found no studies to support EHI versus no alternative. Given these factors, it was not possible to determine the relative effectiveness of interventions. All studies reported practitioner use of EHI, two reported on compliance with electronic practice guidelines, and none reported on patient outcomes. One trial (139 participants) measured guideline adherence for an electronic versus printed guideline, but reported no difference between groups (median OR 0.85, IQR 0.74 to 1.08). One small cross-over trial (10 participants) reported increased use of clinical guidelines when provided with a mobile versus stationary, desktop computer (mean use per shift: intervention group (IG) 3.6, standard deviation (SD) 1.7 vs. control group (CG) 2.0 (SD 1.9), P value = 0.033). One cross-over trial (203 participants) reported that using a customized versus a generic interface had little impact on practitioners' use of EHI (mean difference in adjusted end-of-study rate: 0.77 logins/month/user, 95% confidence interval (CI) CI 0.43 to 1.11). Three trials included education or training and reported increased use of EHI by practitioners following training. This review provided no evidence that the use of EHI translates into improved clinical practice or patient outcomes, though it does suggest that when practitioners are provided with EHI and education or training, the use of EHI increases. We have defined use as the activity of logging into an EHI resource, but based on our findings use does not automatically translate to the application of EHI in practice. While using EHI may be an important component of evidence-based medicine, alone it is insufficient to improve patient care or clinical practices. For EHI to be applied in patient care, it will be necessary to understand why practitioners' are reluctant to apply EHI when treating people, and to determine the most effective way(s) to reduce this reluctance.
We included six RCTs (one with a cross-over design) randomising 310 children and reporting outcomes for 297 children. Most participants were aged under seven months with only two participants aged over one year (seven and 12 years old); where specified, 60% were boys. In two studies, condition severity was mild to moderate; one study included two participants with severe ISD; the other studies did not describe baseline severity or described it as body surface area affected. The study setting was not always clear but likely a paediatric outpatient clinic in the following countries: Thailand, Israel, USA, France, and Australia. Two studies compared oral biotin (a B group vitamin) against placebo, two studies compared proprietary products against placebo cream or a control shampoo, and two studies compared topical corticosteroids against other products. The studies were generally short-term, between 10 and 42 days' duration; only one study followed the participants until resolution of the rash or eight months of age. We assessed the risk of bias as unclear for most aspects due to lack of reporting, but two of the studies were at high risk of performance and detection bias due to the appearance of the intervention, the trial design (open-label), or use of overlabelled tubes. Two trials had a high risk of attrition bias. All the results given below were based on very low-quality evidence. Treatment duration ranged from one week to three weeks. For the two trials comparing biotin versus placebo (n = 35), one did not report a measure of change in severity (only change in duration of rash) while the other did not report raw data (only 'no statistically significant difference'), measured at three weeks. Neither trial reported on adverse events. Two trials compared proprietary products against placebo (n = 160). One trial assessed change in severity via percentage success (96% of participants in non-steroidal cream Promiseb versus 92% in placebo), and reported no adverse events (both assessed at day 14). The other trial assessed change in severity via reduction in lesional score (surface area covered), finding better results for lactamide MEA gel (a moisturising agent) plus shampoo (81.4%) compared with shampoo only (70.2%; P = 0.0092). No adverse events were described, but signs of discomfort were similar in both groups (both assessed at day 21). In the comparison of topical steroids versus another product, change in severity was measured through evaluation of cure and body surface (n = 102). In one trial comparing hydrocortisone 1% lotion with licochalcone 0.025% lotion, there was no significant difference in participants cured (95.8% with hydrocortisone compared to 97.1% with licochalcone). One person in the licochalcone group developed more erythema, but there were no other adverse events (both outcomes assessed at day 14). In the trial comparing flumethasone pivalate 0.02% ointment versus eosin 2% aqueous solution, a reduction in body surface area affected was seen in both groups at day 10 (9% with corticosteroid versus 7% with aqueous solution), with all infants showing less than 10% involvement. There were no adverse events (both outcomes assessed at day 10). No studies measured QoL. We found no trials testing commonly used treatments such as mineral oils, salicylic acid, or antifungals. Our review identified only a limited number of studies investigating the effects of interventions for ISD in infants and young children. Unlike the reviews investigating the effects of treatments in adults, our results showed that there is uncertainty regarding the effectiveness and safety of studied treatments due to the very low-certainty evidence for all comparisons and outcomes. We assessed most bias domains as at unclear risk, but there was a high risk of bias for (mainly) performance, attrition, and detection bias. Evidence was limited further by imprecision (small studies, low number of events), indirectness (mainly with the outcomes assessed), and poor trial reporting. In most studies, the prognosis for the condition was favourable regardless of intervention but interpretation is limited by the very low-certainty evidence. Further research is needed with large, well-conducted, and well-reported intervention trials, particularly of interventions commonly recommended or used, such as emollients or shampoos and brushing, antifungals, or steroids. All studies should report standardised and validated relevant outcome measures, including adverse events, severity, and QoL, and they should be conducted in primary care settings where the majority of ISD is managed. Future trials should compare against placebo, no treatment, or standard care.
We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in the reporting of methods and results. The mean difference (MD) in glycosylated haemoglobin A1c (HbA1c) was -0.15% (95% CI -0.2% to -0.1%; P value < 0.00001; 2608 participants; 9 trials; low quality evidence) in favour of insulin analogues. The comparison of the risk of severe hypoglycaemia between the two treatment groups showed an OR of 0.89 (95% CI 0.71 to 1.12; P value = 0.31; 2459 participants; 7 trials; very low quality evidence). For overall hypoglycaemia, also taking into account mild forms of hypoglycaemia, the data were generally of low quality, but also did not indicate substantial group differences. Regarding nocturnal severe hypoglycaemic episodes, two trials reported statistically significant effects in favour of the insulin analogue, insulin aspart. However, due to inconsistent reporting in publications and trial reports, the validity of the result remains questionable. We also found no clear evidence for a substantial effect of insulin analogues on health-related quality of life. However, there were few results only based on subgroups of the trial populations. None of the trials reported substantial effects regarding weight gain or any other adverse events. No trial was designed to investigate possible long-term effects (such as all-cause mortality, diabetic complications), in particular in people with diabetes related complications. Our analysis suggests only a minor benefit of short-acting insulin analogues on blood glucose control in people with type 1 diabetes. To make conclusions about the effect of short acting insulin analogues on long-term patient-relevant outcomes, long-term efficacy and safety data are needed.
We included six trials, with a total of 748 women in this review. All trials included women in whom there was no overriding indication for immediate delivery in the fetal or maternal interest. Half of the trials were at low risk of bias for methods of randomisation and allocation concealment; and four trials were at low risk for selective reporting. For most other domains, risk of bias was unclear. There were insufficient data for reliable conclusions about the comparative effects on most outcomes for the mother. Two studies reported on maternal deaths; neither study reported any deaths (two studies; 320 women; low-quality evidence). It was uncertain whether interventionist care reduced eclampsia (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.06 to 15.58; two studies; 359 women) or pulmonary oedema (RR 0.45, 95% CI 0.07 to 3.00; two studies; 415 women), because the quality of the evidence for these outcomes was very low. Evidence from two studies suggested little or no clear difference between the interventionist and expectant care groups for HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome (RR 1.09, 95% CI 0.62 to 1.91; two studies; 359 women; low-quality evidence). No study reported on stroke. With the addition of data from two studies for this update, there was now evidence to suggest that interventionist care probably made little or no difference to the incidence of caesarean section (average RR 1.01, 95% CI 0.91 to 1.12; six studies; 745 women; Heterogeneity: Tau² = 0.01; I² = 63%). For the baby, there was insufficient evidence to draw reliable conclusions about the effects on perinatal deaths (RR 1.11, 95% CI 0.62 to 1.99; three studies; 343 women; low-quality evidence). Babies whose mothers had been allocated to the interventionist group had more intraventricular haemorrhage (RR 1.94, 95% CI 1.15 to 3.29; two studies; 537 women; moderate-quality evidence), more respiratory distress caused by hyaline membrane disease (RR 2.30, 95% CI 1.39 to 3.81; two studies; 133 women), required more ventilation (RR 1.50, 95% CI 1.11 to 2.02; two studies; 300 women), and were more likely to have a lower gestation at birth (mean difference (MD) -9.91 days, 95% CI -16.37 to -3.45 days; four studies; 425 women; Heterogeneity: Tau² = 31.74; I² = 76%). However, babies whose mothers had been allocated to the interventionist group were no more likely to be admitted to neonatal intensive care (average RR 1.19, 95% CI 0.89 to 1.60; three studies; 400 infants; Heterogeneity: Tau² = 0.05; I² = 84%). Babies born to mothers in the interventionist groups were more likely to have a longer stay in the neonatal intensive care unit (MD 7.38 days, 95% CI -0.45 to 15.20 days; three studies; 400 women; Heterogeneity: Tau² = 40.93, I² = 85%) and were less likely to be small-for-gestational age (RR 0.38, 95% CI 0.24 to 0.61; three studies; 400 women). There were no clear differences between the two strategies for any other outcomes. This review suggested that an expectant approach to the management of women with severe early onset pre-eclampsia may be associated with decreased morbidity for the baby. However, this evidence was based on data from only six trials. Further large, high-quality trials are needed to confirm or refute these findings, and establish if this approach is safe for the mother.
We identified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73 to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site, performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality. Perioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for elderly patients.
We included 68 systematic reviews published in the Cochrane Library up to May 2018. All were of high quality. These reviews identified 38 interventions that were effective (n = 23) or promising (n = 15), and they identified 19 interventions that were ineffective (n = 2) or possibly ineffective (n = 17). For 15 interventions, review authors were unable to draw conclusions owing to lack of evidence. We identified an additional 11 protocols and four titles for future inclusion in this overview. This overview provides the most up-to-date evidence on ART cycles from systematic reviews of randomised controlled trials. Fertility treatments are costly, and the stakes are high. Using the best available evidence to optimise outcomes is best practice. Evidence from this overview could be used to develop clinical practice guidelines and protocols that can be applied in daily clinical practice to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation, and ovarian hyperstimulation syndrome.
We included 34 trials (16 trials of cessation; nine trials of reduction; one trial of relapse prevention; eight trials that reported smoking outcomes for interventions aimed at other purposes). Seven trials compared bupropion with placebo; meta-analysis showed that cessation rates after bupropion were significantly higher than placebo at the end of treatment (seven trials, N = 340; risk ratio [RR] 3.03; 95% confidence interval [CI] 1.69 to 5.42) and after six months (five trials, N = 214, RR 2.78; 95% CI 1.02 to 7.58). There were no significant differences in positive, negative and depressive symptoms between bupropion and placebo groups. There were no reports of major adverse events such as seizures with bupropion. Smoking cessation rates after varenicline were significantly higher than placebo, at the end of treatment (2 trials, N = 137; RR 4.74, 95% CI 1.34 to 16.71). Only one trial reported follow-up at six months and the CIs were too wide to provide evidence of a sustained effect (one trial, N = 128, RR 5.06, 95% CI 0.67 to 38.24). There were no significant differences in psychiatric symptoms between the varenicline and placebo groups. Nevertheless, there were reports of suicidal ideation and behaviours from two people on varenicline. Two studies reported that contingent reinforcement (CR) with money may increase smoking abstinence rates and reduce the level of smoking in patients with schizophrenia. However, it is uncertain whether these benefits can be maintained in the longer term. There was no evidence of benefit for the few trials of other pharmacological therapies (including nicotine replacement therapy (NRT)) and psychosocial interventions in helping smokers with schizophrenia to quit or reduce smoking. Bupropion increases smoking abstinence rates in smokers with schizophrenia, without jeopardizing their mental state. Varenicline may also improve smoking cessation rates in schizophrenia, but its possible psychiatric adverse effects cannot be ruled out. CR may help this group of patients to quit and reduce smoking in the short term. We failed to find convincing evidence that other interventions have a beneficial effect on smoking in schizophrenia.
A systematic search of all available databases and other sources failed to identify any completed randomized, double-blind and placebo-controlled trials, assessing the efficacy of ibuprofen in AD eligible for inclusion in the review. One double-blind placebo-controlled trial investigating ibuprofen treatment for age-associated memory impairment has been identified, but is yet unfinished and no data are yet available. Other trials assessing the effect of ibuprofen on CSF beta amyloid in cognitively unimpaired individuals and the effect of other NSAIDs such as naproxen and rofecoxib for people with AD are currently underway. No evidence yet exists from randomized double-blind and placebo-controlled trials on whether ibuprofen is efficacious for patients diagnosed as having Alzheimer's disease. Ibuprofen, like other NSAIDs, has an identifiable and in some instances a significant side-effect profile which may include gastrointestinal bleeding. Therefore, it needs to be shown that the benefits of such a treatment outweighs the risk of side effects before ibuprofen can be recommended for people with Alzheimer's disease.
Six studies were identified that randomised 596 live kidney donors to either LDN or ODN arms. All studies were assessed as having low or unclear risk of bias for selection bias, allocation bias, incomplete outcome data and selective reporting bias. Four of six studies had high risk of bias for blinding. Various different combinations of techniques were used in each study, resulting in heterogeneity in the results. The conversion rate from LDN to ODN ranged from 1% to 1.8%. LDN was generally found to be associated with reduced analgesia use, shorter hospital stay, and faster return to normal physical functioning. The extracted kidney was exposed to longer warm ischaemia periods (2 to 17 minutes) with no associated short-term consequences. ODN was associated with shorter duration of procedure. For those outcomes that could be meta-analysed there were no significant differences between LDN or ODN for perioperative complications (RR 0.87, 95% CI 0.47 to 4.59), reoperations (RR 0.57, 95% CI 0.09 to 3.64), early graft loss (RR 0.31, 95% CI 0.06 to 1.48), delayed graft function (RR 1.09, 95% CI 0.52 to 2.30), acute rejection (RR 1.41, 95 % CI 0.87 to 2.27), ureteric complications (RR 1.51, 95% CI 0.69 to 3.31), kidney function at one year (SMD 0.15, 95% CI -0.11 to 0.41) or graft loss at one year (RR 0.76, 95% CI 0.15 to 3.85). LDN is associated with less pain compared with open surgery; however, there are equivalent numbers of complications and occurrences of perioperative events that require further intervention. Kidneys obtained using LDN procedures were exposed to longer warm ischaemia periods than ODN-acquired grafts, although this has not been reported as being associated with short-term consequences.
We included six trials involving 497 participants to study efficacy. They showed some benefit (e.g. reduction of cough at day seven) from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because data were unavailable. Thirty-four studies, including the previous six trials involving 2064 children, were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 59 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system. The results have to be interpreted with caution because they are based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self limiting diseases (for example, acute cough, bronchitis). Given strong concerns about safety, these drugs should only be used for acute upper and lower RTIs in the context of a RCT with regards to children younger than two years.
We identified 60 studies, enrolling 3802 recipients. Twenty-nine studies (2262 participants) compared calcium channel blockers (CCB) to placebo/no treatment, 10 studies (445 participants) compared angiotensin converting enzyme inhibitors (ACEi) to placebo/no treatment and seven studies (405 participants) compared CCB to ACEi. CCB compared to placebo/no treatment (plus additional agents in either arm as required) reduced graft loss (RR 0.75, 95% CI 0.57 to 0.99) and improved glomerular filtration rate (GFR), (MD, 4.45 mL/min, 95% CI 2.22 to 6.68). Data on ACEi versus placebo/no treatment were inconclusive for GFR (MD -8.07 mL/min, 95% CI -18.57 to 2.43), and variable for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD -11.48 mL/min, 95% CI -5.75 to -7.21), proteinuria (MD -0.28 g/24 h, 95% CI -0.47 to -0.10), haemoglobin (MD -12.96 g/L, 95% CI -5.72 to -10.21) and increased hyperkalaemia (RR 3.74, 95% CI 1.89 to 7.43). Graft loss data were inconclusive (RR 7.37, 95% CI 0.39 to 140.35). Other drug comparisons were compared in small numbers of participants and studies. These data suggest that CCB may be preferred as first line agents for hypertensive kidney transplant recipients. ACEi have some detrimental effects in kidney transplant recipients. More high quality studies reporting patient centred outcomes are required.
Searches identified seven publications relating to four studies. We excluded three studies. One post hoc (secondary) analysis of a study published in four reports assessed the efficacy of hydromorphone in neuropathic pain, satisfied our inclusion criteria, and was included in the review. The single included study had an enriched enrolment, randomised withdrawal design with 94 participants who were successfully switched from oral morphine to oral hydromorphone extended release (about 60% of those enrolled). These participants were then randomised to continuing hydromorphone for 12 weeks or tapering down the hydromorphone dose to placebo. The methodological quality of the study was generally good, but we judged the risk of bias for incomplete outcome data as unclear, and for study size as high. Since we identified only one study for inclusion, we were unable to carry out any analyses. The included study did not report any of our prespecified primary outcomes, which relate to the number of participants achieving moderate or substantial levels of pain relief. It did report a slightly larger increase in average pain intensity for placebo in the randomised withdrawal phase than for continuing with hydromorphone. It also reported the number of participants who withdrew due to lack of efficacy in the randomised withdrawal phase, which may be an indicator of efficacy. However, in addition to using an enriched enrolment, randomised withdrawal study design, there was an unusual choice of imputation methods for withdrawals (about 50% of participants); the evidence was of very low quality and inadequate to make a judgement on efficacy. Adverse events occurred in about half of participants with hydromorphone, the most common being constipation and nausea. A similar proportion of participants experienced adverse events with placebo, the most common being opioid withdrawal syndrome (very low quality evidence). Most adverse events were mild or moderate in intensity. One in eight participants withdrew while taking hydromorphone during the conversion and titration phase, despite participants being opioid-tolerant (very low quality evidence). We downgraded the quality of the evidence to very low because there was only one study with few participants, it did not report clinically useful efficacy outcomes, and it was a post hoc analysis. There was insufficient evidence to support or refute the suggestion that hydromorphone has any efficacy in any neuropathic pain condition.
A total of 155 studies met the inclusion criteria; 107 studies provided sufficient data for quantitative synthesis. The results from the caries severity data indicate that the initiation of water fluoridation results in reductions in dmft of 1.81 (95% CI 1.31 to 2.31; 9 studies at high risk of bias, 44,268 participants) and in DMFT of 1.16 (95% CI 0.72 to 1.61; 10 studies at high risk of bias, 78,764 participants). This translates to a 35% reduction in dmft and a 26% reduction in DMFT compared to the median control group mean values. There were also increases in the percentage of caries free children of 15% (95% CI 11% to 19%; 10 studies, 39,966 participants) in deciduous dentition and 14% (95% CI 5% to 23%; 8 studies, 53,538 participants) in permanent dentition. The majority of studies (71%) were conducted prior to 1975 and the widespread introduction of the use of fluoride toothpaste. There is insufficient information to determine whether initiation of a water fluoridation programme results in a change in disparities in caries across socioeconomic status (SES) levels. There is insufficient information to determine the effect of stopping water fluoridation programmes on caries levels. No studies that aimed to determine the effectiveness of water fluoridation for preventing caries in adults met the review's inclusion criteria. With regard to dental fluorosis, we estimated that for a fluoride level of 0.7 ppm the percentage of participants with fluorosis of aesthetic concern was approximately 12% (95% CI 8% to 17%; 40 studies, 59,630 participants). This increases to 40% (95% CI 35% to 44%) when considering fluorosis of any level (detected under highly controlled, clinical conditions; 90 studies, 180,530 participants). Over 97% of the studies were at high risk of bias and there was substantial between-study variation. There is very little contemporary evidence, meeting the review's inclusion criteria, that has evaluated the effectiveness of water fluoridation for the prevention of caries. The available data come predominantly from studies conducted prior to 1975, and indicate that water fluoridation is effective at reducing caries levels in both deciduous and permanent dentition in children. Our confidence in the size of the effect estimates is limited by the observational nature of the study designs, the high risk of bias within the studies and, importantly, the applicability of the evidence to current lifestyles. The decision to implement a water fluoridation programme relies upon an understanding of the population's oral health behaviour (e.g. use of fluoride toothpaste), the availability and uptake of other caries prevention strategies, their diet and consumption of tap water and the movement/migration of the population. There is insufficient evidence to determine whether water fluoridation results in a change in disparities in caries levels across SES. We did not identify any evidence, meeting the review's inclusion criteria, to determine the effectiveness of water fluoridation for preventing caries in adults. There is insufficient information to determine the effect on caries levels of stopping water fluoridation programmes. There is a significant association between dental fluorosis (of aesthetic concern or all levels of dental fluorosis) and fluoride level. The evidence is limited due to high risk of bias within the studies and substantial between-study variation.
Nine trials involving a total of 448 participants were included. We judged two trials to be at unclear risk of bias and seven to be at high risk of bias. The majority of items of risk of bias were evaluated to be at unclear or high risk level in more than 50% of the included trials. Each trial except two was addressing a different type of intervention. All evidence was rated as being of very low quality due to problems with risk of bias and imprecision of results, the latter being due to very small sample sizes, low event rates, 95% confidence intervals including the possibility of benefit for both the test and control groups, or combinations of these problems. This means that we are very uncertain about all of the results presented in this review. One trial compared metal-free single crowns (full contour zirconia) to cast gold single crowns in 224 participants and found insufficient evidence of a difference in failure rate after one year, but after five years there was some evidence of a benefit for the gold crowns. There was insufficient evidence of a difference for crown complications at either time of assessment. One trial compared three-unit metal-free FDPs (lithium disilicate) to three-unit metal-ceramic FDPs in 37 participants. There was insufficient evidence of a difference in bridge failure at one and six years, but some evidence of a benefit for the lithium disilicate group in terms of bridge complications at six years. One trial compared zirconia-ceramic FDPs to metal-ceramic FDPs in 34 participants but found insufficient evidence of a difference in bridge failures (i.e. no failures in either treatment group), bridge complications or patients' aesthetic evaluation at any time of assessment up to three years. One trial compared metal-free cantilevered FDPs to metal-ceramic cantilevered FDPs in 21 participants. There was insufficient evidence of a difference for any primary outcome: bridge failures (i.e. no failures in either treatment group), bridge complications, or patients' aesthetic evaluation at any time of assessment up to three years. One trial compared metal-free implant-supported screw retained single crowns (zirconia veneered with feldspathic ceramic) to metal-ceramic implant-supported screw-retained single crowns in 20 participants. There was insufficient evidence of a difference for any primary outcome: crown failures (i.e. no failures in either treatment group), crown complications, or satisfaction/aesthetic evaluation at any time of assessment up to two years. Two trials compared metal-free implant abutments (zirconia) to metal implant abutments both supporting single crowns in 50 participants. There was insufficient evidence of a difference in abutment failure at one year. One trial compared metal-free implant-supported FDPs made of two different types of zirconia ceramic in 18 participants. There was insufficient evidence of a difference in failures at any time of assessment up to 10 years (i.e. no failures in either treatment group). There was some evidence of a benefit for the zirconia-toughened alumina group in terms of complications (chipping). One trial compared metal-free tooth-supported FDPs made with two different veneering techniques (pressed versus layered) in 40 participants. There was insufficient evidence of a difference for failures (i.e. no failures in either treatment group) or complications at any time of assessment up to three years. There is insufficient evidence to support or refute the effectiveness of metal-free materials for fixed prosthodontic treatment over metal-ceramic or other type of standard restorations. The overall quality of existing evidence was very low, therefore great caution should be exercised when generalising the results of the included trials. Until more evidence becomes available clinicians should continue to base decisions on which material to use for fixed prosthodontic treatment on their own clinical experience, whilst taking into consideration the individual circumstances and preferences of their patients. There is urgent need of properly designed RCTs.
A total of 17 trials involving 1061 participants (range 13 to 213 participants per trial) were included. Of these, 16 trials compared either deferiprone alone with desferrioxamine alone, or a combined therapy of deferiprone and desferrioxamine with either deferiprone alone or desferrioxamine alone; one compared different schedules of deferiprone. There was little consistency between outcomes and limited information to fully assess the risk of bias of most of the included trials. Four trials reported mortality; each reported the death of one individual receiving deferiprone with or without desferrioxamine. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage. Earlier trials measuring the cardiac iron load indirectly by magnetic resonance imaging (MRI) T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, a meta-analysis of two trials suggested that left ventricular ejection fraction was significantly reduced in patients who received desferrioxamine alone compared with combination therapy. One trial, which planned five years of follow up, was stopped early due to the beneficial effects of combined treatment compared with deferiprone alone in terms of serum ferritin levels reduction. The results of this and three other trials suggest an advantage of combined therapy over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no conclusive or consistent evidence for the improved efficacy of combined deferiprone and desferrioxamine therapy over monotherapy from direct or indirect measures of liver iron. Both deferiprone and desferrioxamine produce a significant reduction in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised controlled trials to suggest that either has a greater reduction of clinically significant end organ damage. Evidence of adverse events were observed in all treatment groups. Occurrence of any adverse event was significantly more likely with deferiprone than desferrioxamine in one trial, RR 2.24 (95% CI 1.19 to 4.23). Meta-analysis of a further two trials showed a significant increased risk of adverse events associated with combined deferiprone and desferrioxamine compared with desferrioxamine alone, RR 3.04 (95% CI 1.18 to 7.83). The most commonly reported adverse event was joint pain, which occurred significantly more frequently in patients receiving deferiprone than desferrioxamine, RR 2.64 (95% CI 1.21 to 5.77). Other common adverse events included gastrointestinal disturbances as well as neutropenia or leucopenia, or both. In the absence of data from randomised controlled trials, there is no evidence to suggest the need for a change in current treatment recommendations; namely that deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. Intensified desferrioxamine treatment (by either subcutaneous or intravenous route) or use of other oral iron chelators, or both, remains the established treatment to reverse cardiac dysfunction due to iron overload. Indeed, the US Food and Drug Administration (FDA) recently only gave support for deferiprone to be used as a last resort for treating iron overload in thalassaemia, myelodysplasia and sickle cell disease. However, there is evidence that adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.
We identified 14 studies that met our inclusion criteria, with a total of 6641 randomised participants, of whom 5638 completed the study. All studies lasted between two and 78 weeks and showed good methodological quality overall. We included 10 comparisons in this review, seven for which the dose of VI and FF was 100/25 mcg (VI/FF 100/25 mcg vs placebo; VI/FF 100/25 mcg vs same dose of FF; VI/FF 100/25 mcg vs same dose of VI; VI/FF 100/25 mcg vs fluticasone propionate (FP) 500 mcg twice-daily; VI/FF 100/25 mcg vs fluticasone propionate/salmeterol (FP/SAL) 250/50 mcg twice-daily; VI/FF 100/25 mcg vs FP/SAL 250/25 mcg twice-daily; FF/VI 100/25 vs FP/SAL500/50) and three for which the dose of VI and FF was 200/25 mcg (VI/FF 200/25 mcg vs placebo; VI/FF 200/25 mcg vs FP 500 mcg; VI/FF 200/25 mcg vs same dose of FF). We found very few opportunities to combine results from the 14 included studies in meta-analyses. We tabulated the data for our pre-specified primary outcomes. In particular, we found insufficient information to assess whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety. Only one of the 14 studies looked at health-related quality of life when comparing VI and FF 100/25 mcg versus placebo and identified a significant advantage of VI/FF 100/25 mcg (mean difference (MD) 0.30, 95% confidence interval (CI) 0.14 to 0.46; 329 participants); we recognised this as moderate-quality evidence. Only two studies compared VI/FF 100/25 mcg versus placebo with respect to exacerbations; both studies reported no exacerbations in either treatment arm. Five studies (VI/FF 100/25 mcg vs placebo) sought information on serious adverse events; all five studies reported no serious adverse events in the VI/FF 100/25 mcg or placebo arms. We found no comparison relevant to our primary outcomes for VI/FF at a higher dose (200/25 mcg) versus placebo. The small number of studies contributing to each comparison precludes the opportunity to draw robust conclusions for clinical practice. These studies were not of sufficient duration to allow conclusions about long-term side effects. Some evidence suggests clear advantages for VI/FF, in combination, compared with placebo, particularly for forced expiratory volume in one second (FEV1) and peak expiratory flow; however, the variety of questions addressed in the included studies did not allow review authors to draw firm conclusions. Information was insufficient for assessment of whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety. It is clear that more research is required to reduce the uncertainties that surround interpretation of these studies. It will be necessary for these findings to be replicated in other work before more robust conclusions are revealed. Only five of the 13 included studies provided data on health-related quality of life, and only six recorded asthma exacerbations. Only one study focused on paediatric patients, so no conclusions can be drawn for the paediatric population. More research is needed, particularly in the primary outcome areas selected for this review, so that we can draw firmer conclusions in the next update of this review.
We included 96 studies published between 1955 and 2014 in this updated review. Seven studies with 11,356 randomised participants (7047 evaluated) reported the effects of fluoride toothpaste up to 1500 ppm on the primary dentition; one study with 2500 randomised participants (2008 evaluated) reported the effects of 1450 ppm fluoride toothpaste on the primary and permanent dentition; 85 studies with 48,804 randomised participants (40,066 evaluated) reported the effects of toothpaste up to 2400 ppm on the immature permanent dentition; and three studies with 2675 randomised participants (2162 evaluated) reported the effects of up to 1100 ppm fluoride toothpaste on the mature permanent dentition. Follow-up in most studies was 36 months. In the primary dentition of young children, 1500 ppm fluoride toothpaste reduces caries increment when compared with non-fluoride toothpaste (MD -1.86 dfs, 95% confidence interval (CI) -2.51 to -1.21; 998 participants, one study, moderate-certainty evidence); the caries-preventive effects for the head-to-head comparison of 1055 ppm versus 550 ppm fluoride toothpaste are similar (MD -0.05, dmfs, 95% CI -0.38 to 0.28; 1958 participants, two studies, moderate-certainty evidence), but toothbrushing with 1450 ppm fluoride toothpaste slightly reduces decayed, missing, filled teeth (dmft) increment when compared with 440 ppm fluoride toothpaste (MD -0.34, dmft, 95%CI -0.59 to -0.09; 2362 participants, one study, moderate-certainty evidence). The certainty of the remaining evidence for this comparison was judged to be low. We included 81 studies in the network meta-analysis of D(M)FS increment in the permanent dentition of children and adolescents. The network included 21 different comparisons of seven fluoride concentrations. The certainty of the evidence was judged to be low with the following exceptions: there was high- and moderate-certainty evidence that 1000 to 1250 ppm or 1450 to 1500 ppm fluoride toothpaste reduces caries increments when compared with non-fluoride toothpaste (SMD -0.28, 95% CI -0.32 to -0.25, 55 studies; and SMD -0.36, 95% CI -0.43 to -0.29, four studies); there was moderate-certainty evidence that 1450 to 1500 ppm fluoride toothpaste slightly reduces caries increments when compared to 1000 to 1250 ppm (SMD -0.08, 95% CI -0.14 to -0.01, 10 studies); and moderate-certainty evidence that the caries increments are similar for 1700 to 2200 ppm and 2400 to 2800 ppm fluoride toothpaste when compared to 1450 to 1500 ppm (SMD 0.04, 95% CI -0.07 to 0.15, indirect evidence only; SMD -0.05, 95% CI -0.14 to 0.05, two studies). In the adult permanent dentition, 1000 or 1100 ppm fluoride toothpaste reduces DMFS increment when compared with non-fluoride toothpaste in adults of all ages (MD -0.53, 95% CI -1.02 to -0.04; 2162 participants, three studies, moderate-certainty evidence). The evidence for DMFT was low certainty. Only a minority of studies assessed adverse effects of toothpaste. When reported, effects such as soft tissue damage and tooth staining were minimal. This Cochrane Review supports the benefits of using fluoride toothpaste in preventing caries when compared to non-fluoride toothpaste. Evidence for the effects of different fluoride concentrations is more limited, but a dose-response effect was observed for D(M)FS in children and adolescents. For many comparisons of different concentrations the caries-preventive effects and our confidence in these effect estimates are uncertain and could be challenged by further research. The choice of fluoride toothpaste concentration for young children should be balanced against the risk of fluorosis.
We included six RCTs with 527 participants. Only one RCT was judged to be at low risk of bias. The remaining five RCTs were at unclear or high risk of bias. No trial mentioned the primary outcomes of longest follow-up mortality, Glasgow Outcome Scale score at three months or any adverse events related to mannitol or hypertonic saline. Three trials mentioned the secondary outcomes of intraoperative brain relaxation, hospital stay and ICU stay; quality of life was not reported in any of the trials. Brain relaxation was inadequate in 42 of 197 participants in the hypertonic saline group and in 68 of 190 participants in the mannitol group. The risk ratio for brain bulge or tense brain in the hypertonic saline group was 0.60 (95% confidence interval (CI) 0.44 to 0.83, low-quality evidence). One trial reported ICU and hospital stay. The mean (standard deviation (SD)) duration of ICU stay in the mannitol and hypertonic saline groups was 1.28 (0.5) and 1.25 (0.5) days (P value 0.64), respectively; the mean (SD) duration of hospital stay in the mannitol and hypertonic saline groups was 5.7 (0.7) and 5.7 (0.8) days (P value 1.00), respectively From the limited data available on the use of mannitol and hypertonic saline for brain relaxation during craniotomy, it is suggested that hypertonic saline significantly reduces the risk of tense brain during craniotomy. A single trial suggests that ICU stay and hospital stay are comparable with the use of mannitol or hypertonic saline. However, focus on other related important issues such as long-term mortality, long-term outcome, adverse events and quality of life is needed.
We included 25 randomised clinical trials described in 45 reports. The trials included a total of 2690 participants aged between five and 17 years. In 17 trials, participants were also diagnosed with various comorbidities. The social skills interventions were described as: 1) social skills training, 2) cognitive behavioural therapy, 3) multimodal behavioural/psychosocial therapy, 4) child life and attention skills treatment, 5) life skills training, 6) the "challenging horizon programme", 7) verbal self-instruction, 8) meta-cognitive training, 9) behavioural therapy, 10) behavioural and social skills treatment, and 11) psychosocial treatment. The control interventions were no intervention or waiting list. The duration of the interventions ranged from five weeks to two years. We considered the content of the social skills interventions to be comparable and based on a cognitive-behavioural model. Most of the trials compared child social skills training or parent training combined with medication versus medication alone. Some of the experimental interventions also included teacher consultations. More than half of the trials were at high risk of bias for generation of the allocation sequence and allocation concealment. No trial reported on blinding of participants and personnel. Most of the trials did not report on differences between groups in medication for comorbid disorders. We used all eligible trials in the meta-analyses, but downgraded the certainty of the evidence to low or very low. We found no clinically relevant treatment effect of social skills interventions on the primary outcome measures: teacher-rated social skills at end of treatment (standardised mean difference (SMD) 0.11, 95% confidence interval (CI) 0.00 to 0.22; 11 trials, 1271 participants; I2 = 0%; P = 0.05); teacher-rated emotional competencies at end of treatment (SMD −0.02, 95% CI −0.72 to 0.68; two trials, 129 participants; I2 = 74%; P = 0.96); or on teacher-rated general behaviour (SMD −0.06 (negative value better), 95% CI −0.19 to 0.06; eight trials, 1002 participants; I2 = 0%; P = 0.33). The effect on the primary outcome, teacher-rated social skills at end of treatment, corresponds to a MD of 1.22 points on the social skills rating system (SSRS) scale (95% CI 0.09 to 2.36). The minimal clinical relevant difference (10%) on the SSRS is 10.0 points (range 0 to 102 points on SSRS). We found evidence in favour of social skills training on teacher-rated core ADHD symptoms at end of treatment for all eligible trials (SMD −0.26, 95% CI −0.47 to −0.05; 14 trials, 1379 participants; I2= 69%; P = 0.02), but the finding is questionable due to lack of support from sensitivity analyses, high risk of bias, lack of clinical significance, high heterogeneity, and low certainty. The studies did not report any serious or non-serious adverse events. The review suggests that there is little evidence to support or refute social skills training for children and adolescents with ADHD. We may need more trials that are at low risk of bias and a sufficient number of participants to determine the efficacy of social skills training versus no training for ADHD. The evidence base regarding adolescents is especially weak.
We included 35 studies of which 31 provided data on 7697 women. For the main comparison between cephalosporins versus penicillins, there were 30 studies of which 27 provided data on 7299 women. There was a lack of good quality data and important outcomes often included only small numbers of women. For the comparison of a single cephalosporin versus a single penicillin (Comparison 1 subgroup 1), we found no significant difference between these classes of antibiotics for our chosen most important seven outcomes namely: maternal sepsis - there were no women with sepsis in the two studies involving 346 women; maternal endometritis (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.81 to 1.52, nine studies, 3130 women, random effects, moderate quality of the evidence); maternal wound infection (RR 0.83, 95% CI 0.38 to 1.81, nine studies, 1497 women, random effects, low quality of the evidence), maternal urinary tract infection (RR 1.48, 95% CI 0.89 to 2.48, seven studies, 1120 women, low quality of the evidence) and maternal composite adverse effects (RR 2.02, 95% CI 0.18 to 21.96, three studies, 1902 women, very low quality of the evidence). None of the included studies looked for infant sepsis nor infant oral thrush. This meant we could only conclude that the current evidence shows no overall difference between the different classes of antibiotics in terms of reducing maternal infections after caesarean sections. However, none of the studies reported on infections diagnosed after the initial postoperative hospital stay. We were unable to assess what impact, if any, the use of different classes of antibiotics might have on bacterial resistance. Based on the best currently available evidence, cephalosporins and penicillins have similar efficacy at caesarean section when considering immediate postoperative infections. We have no data for outcomes on the baby, nor on late infections (up to 30 days) in the mother. Clinicians need to consider bacterial resistance and women's individual circumstances.
We included 14 trials (854 participants). Eleven studies reported on gender (men: 472, women: 157). Participant age varied from 18 to 74 years. Most participants had a single, mainly non-infected, wound on one foot, which had been there for less than a year. Only seven studies reported whole study duration (there was no follow-up post-treatment), which was on average six months (range: 1 to 12 months). The studies were conducted in Brazil, Ethiopia, Egypt, Indonesia, Mexico, South Korea, and India. Many 'Risk of bias' assessments were rated as unclear risk due to limited information. Six studies had high risk of bias in at least one domain, including selection and attrition bias. Thirteen studies evaluated different interventions for treating existing ulcers, one of them also evaluated prevention of new ulcers. One study aimed to prevent skin changes, such as cracking and fissures. Investigated interventions included: laser therapy, light-emitting diode (LED), zinc tape, intralesional pentoxifylline, pulsed magnetic fields, wax therapy, ketanserin, human amniotic membrane gel, phenytoin, plaster shoes, and footwear. We are uncertain about the following key results, as the certainty of evidence is very low. All time points were measured from baseline. Three studies compared zinc tape versus other interventions and reported results in favour of zinc tape. One study compared zinc tape versus magnesium sulphate: at one month the number of healed ulcers and reduction in mean ulcer area was higher with zinc tape (risk ratio (RR) 2.00, 95% confidence interval (CI) 0.43 to 9.21, and mean difference (MD) -14.30 mm², 95% CI -26.51 to -2.09, respectively, 28 participants). Another study compared zinc tape and povidone iodine and found that even though there was a greater reduction in ulcer area after six weeks of treatment with zinc tape, there was no clear difference due to the wide 95% CI (MD 128.00 mm², 95% CI -110.01 to 366.01; 38 participants). The third study (90 participants) compared adhesive zinc tape with gauze soaked in Eusol, and found the healing time for deep ulcers was less compared to zinc tape: 17 days (95% CI 12 to 20) versus 30 days (95% CI 21 to 63). Adverse events were only collected in the study comparing zinc tape with gauze soaked in Eusol: there were no signs of skin sensitisation in either group at two months. Two studies compared topical phenytoin versus saline dressing and reported results in favour of phenytoin. One study reported a greater mean percentage reduction of ulcer area after four weeks with phenytoin 2% (MD 39.30%, 95% CI 25.82 to 52.78; 23 participants), and the other study reported a greater mean percentage reduction of ulcer volume (16.60%) after four weeks with phenytoin (95% CI 8.46 to 24.74; 100 participants). No adverse events were observed with either treatment during the four-month treatment period (2 studies, 123 participants). Prevention of ulcers was not evaluated in these nor the zinc studies, as the interventions were not for preventative use. Two studies compared protective footwear (with or without self-care) with either 1) polyvinyl chloride (PVC) boots, or 2) pulsed magnetic fields plus self-care and protective footwear. In the study comparing canvas shoes versus PVC boots, none of the 72 participants with scars at the start of the study developed new ulcers over one-year follow-up. Healing of ulcers was assessed in 38 participants from this study, but we are unclear if there is a difference between groups. In the study comparing pulsed magnetic fields (in addition to self-care and protective footwear) to only self-care and footwear in 33 participants, we are uncertain if the mean volume of ulcers at four to five weeks' follow-up was different between groups; this study did not evaluate the prevention of ulcers. Information for adverse events was only reported in the study comparing canvas shoes with PVC boots; the authors stated that the PVC boots could become hot in strong sunlight and possibly burn the feet. Based on the available evidence, we could not draw firm conclusions about the effects of the included interventions. The main evidence limitations were high or unclear risk of bias, including selection, performance, detection, and attrition bias; imprecision due to few participants in the studies; and indirectness from poor outcome measurement and inapplicable interventions. Future research should clearly report important outcomes, such as adverse events, and assess widely available interventions, which should include treatments aimed at prevention. These trials should ensure allocation concealment, blinding, and an adequate sample size.
No completed studies met the inclusion criteria for the review. Two ongoing trials fulfilled the selection criteria, however neither are complete. 'Early-stage squamous cell carcinoma of the oropharynx: radiotherapy versus trans-oral robotic surgery (ORATOR)' is a phase II randomised controlled trial comparing primary radiation therapy with primary transoral robotic surgery for small-volume primary (T1-2, N0-2) OPSCC. It is currently in progress with an estimated completion date of June 2021. 'European Organisation for Research and Treatment of Cancer 1420 (EORTC 1420-HNCG-ROG)' is a phase III, randomised study assessing the "best of" radiotherapy compared to transoral robotic surgery/transoral laser microsurgery in patients with T1-T2, N0 squamous cell carcinoma of the oropharynx and base of tongue. It was due to start accrual mid-2016. The role of endoscopic head and neck surgery in the management of OPSCC is clearly expanding as evidenced by its more overt incorporation into the current National Comprehensive Cancer Network guidelines. Data are mounting regarding its outcomes both in terms of survival and lower morbidity. As confidence increases, it is being used in the management of more advanced OPSCC. Based on this review, there is currently no high-quality evidence from randomised controlled trials regarding clinical outcomes for patients with oropharyngeal cancer receiving endoscopic head and neck surgery compared with primary chemoradiotherapy.
We included 26 trials (2051 participants). All studies used listening to pre-recorded music. The results suggested that music listening may have a beneficial effect on preoperative anxiety. Specifically, music listening resulted, on average, in an anxiety reduction that was 5.72 units greater (95% CI -7.27 to -4.17, P < 0.00001) than that in the standard care group as measured by the Stait-Trait Anxiety Inventory (STAI-S), and -0.60 standardized units (95% CI -0.90 to -0.31, P < 0.0001) on other anxiety scales. The results also suggested a small effect on heart rate and diastolic blood pressure, but no support was found for reductions in systolic blood pressure, respiratory rate, and skin temperature. Most trials were assessed to be at high risk of bias because of lack of blinding. Blinding of outcome assessors is often impossible in music therapy and music medicine studies that use subjective outcomes, unless in studies in which the music intervention is compared to another treatment intervention. Because of the high risk of bias, these results need to be interpreted with caution. None of the studies included wound healing, infection rate, time to discharge, or patient satisfaction as outcome variables. One large study found that music listening was more effective than the sedative midazolam in reducing preoperative anxiety and equally effective in reducing physiological responses. No adverse effects were identified. This systematic review indicates that music listening may have a beneficial effect on preoperative anxiety. These findings are consistent with the findings of three other Cochrane systematic reviews on the use of music interventions for anxiety reduction in medical patients. Therefore, we conclude that music interventions may provide a viable alternative to sedatives and anti-anxiety drugs for reducing preoperative anxiety.
We included eight studies with 513 participants, providing a total of 47 comparisons of outcome between intervention and control conditions. Nineteen comparisons were statistically significant, all favouring the intervention group. We conducted nine meta-analyses using data from four studies in total (each meta-analysis included data from two studies). Four meta-analyses showed statistically significant findings favouring the intervention group for the following outcomes: parent responsiveness to the child post-intervention (SMD -0.91, 95% CI -1.52 to -0.30, P = 0.04); infant responsiveness to mother at follow-up (SMD -0.65, 95% CI -1.25 to -0.06, P = 0.03); and an overall measure of parent-child interactions post-intervention (SMD -0.71, 95% CI -1.31 to -0.11, P = 0.02), and at follow-up (SMD -0.90, 95% CI -1.51 to -0.30, P = 0.004). The results of the remaining five meta-analyses were inconclusive. Variation in the measures used, the included populations and interventions, and the risk of bias within the included studies limit the conclusions that can be reached. The findings provide some evidence to suggest that parenting programmes may be effective in improving a number of aspects of parent-child interaction both in the short- and long-term, but further research is now needed.
We included in this updated review one new study (70 participants), resulting in a total of three RCTs (140 participants who drank 3 to 40 AU/d). All three studies were of moderate to good quality. All studies evaluated the effects of intensive alcohol cessation interventions, including pharmacological strategies for alcohol withdrawal symptoms, patient education, and relapse prophylaxis. We identified one ongoing study. Overall, 53 of the 122 participants from three studies who underwent surgery developed any type of postoperative complication that required treatment. Of 61 participants in the intervention groups, 20 had complications, compared with 33 of 61 participants in the control groups (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.40 to 0.96). Results show differences between the three clinical studies regarding outcome measurement and intensity of the interventions. However, all alcohol cessation programmes were intensive and included pharmacological therapy. The overall quality of evidence for this outcome is moderate. In-hospital and 30-day postoperative mortality rates were low in the three studies. Researchers reported one death among 61 participants in the intervention groups, and three deaths among 61 participants in the control groups (RR 0.47, 95% CI 0.07 to 2.96). The quality of evidence for this outcome is low. Investigators describe more successful quitters at the end of the intervention programme than among controls. Forty-one out of 70 participants in the intervention groups successfully quit drinking compared with only five out of 70 participants in the control groups (RR 8.22, 95% CI 1.67 to 40.44). The quality of evidence for this outcome is moderate. All three studies reported postoperative alcohol consumption (grams of alcohol/week) at the end of the programme as median and range values; therefore it was not possible to estimate the mean and the standard deviation (SD). We performed no meta-analysis. All three studies reported length of stay, and none of these studies described a significant difference in length of stay. Data were insufficient for review authors to perform a meta-analysis. No studies reported on the prevalence of participants without risky drinking in the longer term. This systematic review assessed the efficacy of perioperative alcohol cessation interventions for postoperative complications and alcohol consumption. All three studies showed a significant reduction in the number of participants who quit drinking alcohol during the intervention period. Intensive alcohol cessation interventions offered for four to eight weeks to participants undergoing all types of surgical procedures to achieve complete alcohol cessation before surgery probably reduced the number of postoperative complications. Data were insufficient for review authors to assess their effects on postoperative mortality. No studies reported an effect on length of stay, and no studies addressed the prevalence of risky drinking in the longer term. Included studies were few and reported small sample sizes; therefore one should be careful about drawing firm conclusions based on these study results. All three studies were conducted in Denmark, and most participants were men. The included participants may represent a selective group, as they could have been more motivated and/or more interested in participating in clinical research or otherwise different, and effects may have been overestimated for both intervention and control groups in these studies. Trial results indicate that these studies are difficult to perform, that strong research competencies are necessary for future studies, and that further evaluation of perioperative alcohol cessation interventions in high-quality randomized controlled trials is needed. Once published and assessed, the one 'ongoing' study identified may alter the conclusions of this review.
Five cluster-RCTs of 111 schools met the review eligibility criteria. Investigators measured outcomes in participating staff and often in children or parents, most often at between 1 and 12 months. All interventions were educational programmes but duration, content and delivery varied; some involved elements of training for pupils or primary care providers. We noted risk of selection, performance, detection and attrition biases, although to a differing extent across studies and outcomes. Quanitative and qualitative analyses were limited. Only one study reported visits to the ED or hospital and provided data that were too skewed for analysis. No studies reported any deaths or adverse events. Studies did not report asthma control consistently, but results showed no difference between groups on the paediatric asthma quality of life questionnaire (mean difference (MD) 0.14, 95% confidence interval (CI) -0.03 to 0.31; 1005 participants; we downgraded the quality of evidence to low for risk of bias and indirectness). Data for symptom days, night-time awakenings, restricted activities of daily living and school absences were skewed or could not be analysed; some mean scores were better in the trained group, but most differences between groups were small and did not persist to 24 months. Schools that received asthma education were more adherent to asthma policies, and staff were better prepared; more schools that had received staff asthma training had written asthma policies compared with control schools, more intervention schools showed improvement in measures taken to prevent or manage exercise-induced asthma attacks and more staff at intervention schools reported that they felt able to administer salbutamol via a spacer. However, the quality of the evidence was low; results show imbalances at baseline, and confidence in the evidence was limited by risk of bias and imprecision. Staff knowledge was higher in groups that had received asthma education, although results were inconsistent and difficult to interpret owing to differences between scales (low quality). Available information about the interventions was insufficient for review authors to conduct a meaningful qualitative synthesis of the content that led to a successful intervention, or of the resources required to replicate results accurately. Asthma education for school staff increases asthma knowledge and preparedness, but studies vary and all available evidence is of low quality. Studies have not yet captured whether this improvement in knowledge has led to appreciable benefits over the short term or the longer term for the safety and health of children with asthma in school. Randomised evidence does not contribute to our knowledge of content or attributes of interventions that lead to the best outcomes, or of resources required for successful implementation. Complete reporting of the content and resources of educational interventions is essential for assessment of their effectiveness and feasibility for implementation. This applies to both randomised and non-randomised studies, although the latter may be better placed to observe important clinical outcomes such as exacerbations and mortality in the longer term.
We identified 15 Cochrane reviews (255 included trials) and three non-Cochrane reviews (55 included trials) for inclusion within this overview. For all interventions, with available data, results are presented as comparisons of: 1. Intervention versus placebo or standard care; 2. Different forms of the same intervention (e.g. one opioid versus another opioid); 3. One type of intervention versus a different type of intervention (e.g. TENS versus opioid). Not all reviews included results for all comparisons. Most reviews compared the intervention with placebo or standard care, but with the exception of opioids and epidural analgesia, there were few direct comparisons between different forms of the same intervention, and even fewer comparisons between different interventions. Based on these three comparisons, we have categorised interventions into: " What works" ,“What may work”, and “Insufficient evidence to make a judgement”. WHAT WORKS Evidence suggests that epidural, combined spinal epidural (CSE) and inhaled analgesia effectively manage pain in labour, but may give rise to adverse effects. Epidural, and inhaled analgesia effectively relieve pain when compared with placebo or a different type of intervention (epidural versus opioids). Combined-spinal epidurals relieve pain more quickly than traditional or low dose epidurals. Women receiving inhaled analgesia were more likely to experience vomiting, nausea and dizziness. When compared with placebo or opioids, women receiving epidural analgesia had more instrumental vaginal births and caesarean sections for fetal distress, although there was no difference in the rates of caesarean section overall. Women receiving epidural analgesia were more likely to experience hypotension, motor blockade, fever or urinary retention. Less urinary retention was observed in women receiving CSE than in women receiving traditional epidurals. More women receiving CSE than low-dose epidural experienced pruritus. WHAT MAY WORK There is some evidence to suggest that immersion in water, relaxation, acupuncture, massage and local anaesthetic nerve blocks or non-opioid drugs may improve management of labour pain, with few adverse effects.  Evidence was mainly limited to single trials. These interventions relieved pain and improved satisfaction with pain relief (immersion, relaxation, acupuncture, local anaesthetic nerve blocks, non-opioids) and childbirth experience (immersion, relaxation, non-opioids) when compared with placebo or standard care. Relaxation was associated with fewer assisted vaginal births and acupuncture was associated with fewer assisted vaginal births and caesarean sections. INSUFFICIENT EVIDENCE There is insufficient evidence to make judgements on whether or not hypnosis, biofeedback, sterile water injection, aromatherapy, TENS, or parenteral opioids are more effective than placebo or other interventions for pain management in labour. In comparison with other opioids more women receiving pethidine experienced adverse effects including drowsiness and nausea. Most methods of non-pharmacological pain management are non-invasive and appear to be safe for mother and baby, however, their efficacy is unclear, due to limited high quality evidence. In many reviews, only one or two trials provided outcome data for analysis and the overall methodological quality of the trials was low. High quality trials are needed. There is more evidence to support the efficacy of pharmacological methods, but these have more adverse effects. Thus, epidural analgesia provides effective pain relief but at the cost of increased instrumental vaginal birth. It remains important to tailor methods used to each woman’s wishes, needs and circumstances, such as anticipated duration of labour, the infant's condition, and any augmentation or induction of labour. A major challenge in compiling this overview, and the individual systematic reviews on which it is based, has been the variation in use of different process and outcome measures in different trials, particularly assessment of pain and its relief, and effects on the neonate after birth. This made it difficult to pool results from otherwise similar studies, and to derive conclusions from the totality of evidence. Other important outcomes have simply not been assessed in trials; thus, despite concerns for 30 years or more about the effects of maternal opioid administration during labour on subsequent neonatal behaviour and its influence on breastfeeding, only two out of 57 trials of opioids reported breastfeeding as an outcome. We therefore strongly recommend that the outcome measures, agreed through wide consultation for this project, are used in all future trials of methods of pain management.
We included 10 pharmacological (modafinil, intravenous immunoglobulin (IVIg), pyridostigmine, lamotrigine, amantadine, prednisone) and three non-pharmacological (muscle strengthening, rehabilitation in a warm climate (that is temperature ± 25°C, dry and sunny) and a cold climate (that is temperature ± 0°C, rainy or snowy), static magnetic fields) studies with a total of 675 participants with PPS in this review. None of the included studies were completely free from any risk of bias, the most prevalent risk of bias being lack of blinding. There was moderate- and low-quality evidence that IVIg has no beneficial effect on activity limitations in the short term and long term, respectively, and inconsistency in the evidence for effectiveness on muscle strength. IVIg caused minor adverse events in a substantial proportion of the participants. Results of one trial provided very low-quality evidence that lamotrigine might be effective in reducing pain and fatigue, resulting in fewer activity limitations without generating adverse events. Data from two single trials suggested that muscle strengthening of thumb muscles (very low-quality evidence) and static magnetic fields (moderate-quality evidence) are safe and beneficial for improving muscle strength and pain, respectively, with unknown effects on activity limitations. Finally, there was evidence varying from very low quality to high quality that modafinil, pyridostigmine, amantadine, prednisone and rehabilitation in a warm or cold climate are not beneficial in PPS. Due to insufficient good-quality data and lack of randomised studies, it was impossible to draw definite conclusions about the effectiveness of interventions for PPS. Results indicated that IVIg, lamotrigine, muscle strengthening exercises and static magnetic fields may be beneficial but need further investigation to clarify whether any real and meaningful effect exists.
In this update, we identified one new trial. Therefore, this version includes three trials (108 participants). Two trials compared carvedilol against placebo and another assessed rosuvastatin versus placebo. All trials had a high risk of bias. Meta-analysis of two trials showed a lower proportion of all-cause mortality in the carvedilol groups compared with the placebo groups (RR 0.69; 95% CI 0.12 to 3.88, I² = 0%; 69 participants; very low-quality evidence). Neither of the trials reported on cardiovascular mortality, time-to-heart decompensation, or disease-free periods. One trial (30 participants) found no difference in hospital readmissions (RR 1.00; 95% CI 0.31 to 3.28; very low-quality of evidence) or reported adverse events (RR 0.92; 95% CI 0.67 to 1.27; very low-quality of evidence) between the carvedilol and placebo groups. There was very low-quality evidence from two trials of inconclusive effects on quality of life (QoL) between the carvedilol and placebo groups. One trial (30 participants) assessed QoL with the Minnesota Living With Heart Failure Questionnaire (21 items; item scores range from 0 to 5; a lower MLHFQ score is better). The MD was -14.74; 95% CI -24.75 to -4.73. The other trial (39 participants) measured QoL with the Medical Outcomes Study 36-item short-form health survey (SF-36; item scores range from 0 to 100; higher SF-36 score is better). Data were not provided. One trial (39 participants) assessed the effect of rosuvastatin versus placebo. The trial did not report on any primary outcomes or adverse events. There was very low-quality evidence of uncertain effects on QoL (no data were provided). This first update of our review found very low-quality evidence for the effects of either carvedilol or rosuvastatin, compared with placebo, for treating heart failure in people with Chagas disease. The three included trials were underpowered and had a high risk of bias. There were no conclusive data to support or reject the use of either carvedilol or rosuvastatin for treating Chagas cardiomyopathy. Unless randomised clinical trials provide evidence of a treatment effect, and the trade-off between potential benefits and harms is established, policy-makers, clinicians, and academics should be cautious when recommending or administering either carvedilol or rosuvastatin to treat heart failure in people with Chagas disease. The efficacy and safety of other pharmacological interventions for treating heart failure in people with Chagas disease remains unknown.
Only one study from developing countries met the inclusion criteria and was included in the review. The study, a cluster randomised trial (10 clusters, n=849) compared VCT uptake between an optional location (including home-based) and a local clinic location in a population-based HIV survey. The study showed a higher uptake of VCT among participants in the optional-location group. Uptake was significantly greater in the optional-location group in those who were pre-test counselled only (RR=4.6; 95% CI 3.58 to 5.91); pretest counselled and tested (RR=4.6; 95% CI 3.51 to 5.92); and post-test counselled and received the test result (RR=4.8; 95% CI 3.62 to 6.21). This study, however, had significant methodological problems limiting further analysis and interpretation. Although home-based HIV VCT has the potential to enhance VCT uptake in developing countries, insufficient data exist to recommend large-scale implementation of home-based HIV testing. Further studies are needed to determine if home-based VCT is better than facility-based VCT in improving VCT uptake.
12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias. Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes. Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue. Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.
Three cross-over and two parallel trials were included with a total of 246 participants. The methodological quality of all studies was unclear. As the trials tested different comparisons, or had a different design or dealt with different outcome measures, meta-analysis was not performed. In one cross-over trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS but significantly reduced cataplexy. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In a second cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. In a third cross-over trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug. Two more trials with parallel design tested ritanserin versus placebo without finding differences of effectiveness in reducing EDS or cataplexy. Since the last version of this review no new studies were found. There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.
Only two small studies, with a combined total of 57 participants, met our inclusion criteria and were finally included. They were classified as having a moderate risk of bias with unclear issues regarding their methods, and according to the GRADE approach, the overall quality of the evidence would be considered as moderate. In one study the effects of intramuscular injections of BMMNCs in the ischaemic lower limbs of patients with CLI were compared with control (standard conservative treatment). No deaths were reported and no significant difference was observed between the two groups for either pain (P = 0.37) or the ankle brachial index (ABI) parameter. However, the treatment group showed a significantly smaller proportion of participants undergoing amputation compared with the control group (P = 0.026). In the other study, following subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) for five days, peripheral blood derived mononuclear cells were collected and then transplanted by intramuscular injections into ischaemic lower limbs. The effects were compared with daily intravenous prostaglandin E1 injections (control group). No deaths were reported. Pain reduction was greater in the treatment group than in the control group (P < 0.001) as was increase in ABI (mean increase 0.13 versus 0.02, P < 0.01). The treatment group experienced a statistically significant increase in pain-free walking distance (PFWD) compared with the control group (mean increase 306.4 m versus 78.6 m, P = 0.007). A smaller proportion of participants underwent amputation in the treatment group compared with the control group (0% versus 36%, P = 0.007). The data from the published trials suggest that there is insufficient evidence to support this treatment. These results were based on only two trials which had a very small number of participants. Therefore evidence from larger randomised controlled trials is needed in order to provide adequate statistical power to assess the role of intramuscular mononuclear cell implantation in patients with CLI.
Twelve studies (1187 participants) were included in the review. Risk of bias was unclear for the majority of domains in each study. Uric acid lowering therapy may make little or no difference in death at six months (2 studies, 498 participants: RR 1.66, 95% CI 0.61 to 4.48) or two years (2 studies, 220 participants): RR 0.13, 95% CI 0.02 to 1.06) (low certainty evidence). Uric acid lowering therapy may make little of no difference (low certainty evidence) in the incidence of ESKD at one or two years. Kidney function may be improved by uric acid lowering therapy at one year with a reduction in serum creatinine (2 studies, 83 participants: MD -73.35 µmol/L, 95% CI -107.28 to -39.41) and a rise in eGFR (1 study, 113 participants: MD 5.50 mL/min/1.73 m2, 95% CI 0.59 to 10.41). However it probably makes little or no difference to eGFR at two years (2 studies, 164 participants: MD 4.00 mL/min, 95% CI -3.28 to 11.28). Uric acid lowering therapy reduced uric acid levels at all time points (3, 4, 6, 12 and 24 months) (high certainty evidence). There is insufficient evidence to support an effect on blood pressure, proteinuria or other cardiovascular markers by uric acid lowering therapy. It should be noted that the apparent benefits of treatment were not apparent at all time points, introducing the potential for bias. There is limited data which suggests uric acid lowering therapy may prevent progression of chronic kidney disease but the conclusion is very uncertain. Benefits were not observed at all time points and study quality was generally low. Larger studies are required to study the effect of uric acid lowering therapy on CKD progression. Three ongoing studies will hopefully provide much needed high quality data.
The update search September 2014 found no further new studies for inclusion, the number of studies included in this review remains eight with a total of 1144 participants. Our main outcomes of interest are hospital use, global state, mental state, quality of life, participant satisfaction and family burden. With the exception of mental state, it was not possible to pool data for these outcomes. Crisis intervention may reduce repeat admissions to hospital (excluding index admissions) at six months (1 RCT, n = 369, RR 0.75 CI 0.50 to 1.13, high quality evidence), but does appear to reduce family burden (at six months: 1 RCT, n = 120, RR 0.34 CI 0.20 to 0.59, low quality evidence), improve mental state (Brief Psychiatric Rating Scale (BPRS) three months: 2 RCTs, n = 248, MD -4.03 CI -8.18 to 0.12, low quality evidence), and improve global state (Global Assessment Scale (GAS) 20 months; 1 RCT, n = 142, MD 5.70, -0.26 to 11.66, moderate quality evidence). Participants in the crisis-intervention group were more satisfied with their care 20 months after crisis (Client Satisfaction Questionnaire (CSQ-8): 1 RCT, n = 137, MD 5.40 CI 3.91 to 6.89, moderate quality evidence). However, quality of life scores at six months were similar between treatment groups (Manchester Short Assessment of quality of life (MANSA); 1 RCT, n = 226, MD -1.50 CI -5.15 to 2.15, low quality evidence). Favourable results for crisis intervention were also found for leaving the study early and family satisfaction. No differences in death rates were found. Some studies suggested crisis intervention to be more cost-effective than hospital care but all numerical data were either skewed or unusable. We identified no data on staff satisfaction, carer input, complications with medication or number of relapses. Care based on crisis-intervention principles, with or without an ongoing homecare package, appears to be a viable and acceptable way of treating people with serious mental illnesses. However only eight small studies with unclear blinding, reporting and attrition bias could be included and evidence for the main outcomes of interest is low to moderate quality. If this approach is to be widely implemented it would seem that more evaluative studies are still needed.
The overview included 39 separate Cochrane Reviews with 41 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 50,000 participants in approximately 460 individual studies. The individual reviews included only high-quality trials of standardised design, methods, and efficacy outcome reporting. No statistical comparison was undertaken. Reliable results (high quality information) were obtained for 53 pairs of drug and dose in painful postsurgical conditions; these included various fixed dose combinations, and fast acting formulations of some analgesics. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours. Good (low) NNTs were obtained with ibuprofen 200 mg plus paracetamol (acetaminophen) 500 mg (NNT compared with placebo 1.6; 95% confidence interval 1.5 to 1.8), ibuprofen fast acting 200 mg (2.1; 1.9 to 2.3); ibuprofen 200 mg plus caffeine 100 mg (2.1; 1.9 to 3.1), diclofenac potassium 50 mg (2.1; 1.9 to 2.5), and etoricoxib 120 mg (1.8; 1.7 to 2.0). For comparison, ibuprofen acid 400 mg had an NNT of 2.5 (2.4 to 2.6). Not all participants had good pain relief and, for many pairs of drug and dose, 50% or more did not achieve at least 50% maximum pain relief over four to six hours. Long duration of action (eight hours or greater) was found for etoricoxib 120 mg, diflunisal 500 mg, paracetamol 650 mg plus oxycodone 10 mg, naproxen 500/550 mg, celecoxib 400 mg, and ibuprofen 400 mg plus paracetamol 1000 mg. There was no evidence of analgesic effect for aceclofenac 150 mg, aspirin 500 mg, and oxycodone 5 mg (low quality evidence). No trial data were available in reviews of acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for nine drugs and doses, and data potentially susceptible to publication bias for 13 drugs and doses (very low quality evidence). There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.
Eight primary studies, including 570 participants, were included. The overall methodological quality of studies was good. Significant clinical heterogeneity resulting from differences in participants and interventions, as well as variation in outcome measures, limited the validity of comparisons between studies for most outcomes. Data for the primary outcome of clinical cure or significant (> 70%) improvement were available for only three studies, which were too heterogeneous to pool. Similarly, heterogeneity in study characteristics limited the validity of meta-analysis for the secondary outcomes of proportion of participants with clinical cure or over 50% reduction in cough severity measure and clinical cure. One parallel group trial of chronic cough which identified a significant treatment effect contributed the majority of statistical heterogeneity for these outcomes. While ICS treatment resulted in a mean decrease in cough score of 0.34 standard deviations (SMD -0.34; 95% CI -0.56 to -0.13; 346 participants), the quality of evidence was low. Heterogeneity also prevented meta-analysis for the outcome of mean change in visual analogue scale score. Meta-analysis was not possible for the outcomes of pulmonary function, complications of cough or biomarkers of inflammation due to insufficient data. There was moderate quality evidence that treatment with ICS did not significantly increase the odds of experiencing an adverse event (OR 1.67; 95% CI 0.92 to 3.04). The studies were highly heterogeneous and results were inconsistent. Heterogeneity in study design needs to be addressed in future research in order to test the efficacy of this intervention. International cough guidelines recommend that a trial of ICS should only be considered in patients after thorough evaluation including chest X-ray and consideration of spirometry and other appropriate investigations.
We included 33 studies enrolling 2056 participants. Twenty-six new studies were added to this 2019 update. Seven studies originally excluded from the 2005 review were included as they met the updated review eligibility criteria, which have been expanded to include RCTs in which participants did not meet criteria for depression as an inclusion criterion. Psychosocial interventions included acupressure, cognitive-behavioural therapy, counselling, education, exercise, meditation, motivational interviewing, relaxation techniques, social activity, spiritual practices, support groups, telephone support, visualisation, and voice-recording of a psychological intervention. The duration of study follow-up ranged between three weeks and one year. Studies included between nine and 235 participants. The mean study age ranged between 36.1 and 73.9 years. Random sequence generation and allocation concealment were at low risk of bias in eight and one studies respectively. One study reported low risk methods for blinding of participants and investigators, and outcome assessment was blinded in seven studies. Twelve studies were at low risk of attrition bias, eight studies were at low risk of selective reporting bias, and 21 studies were at low risk of other potential sources of bias. Cognitive behavioural therapy probably improves depressive symptoms measured using the Beck Depression Inventory (4 studies, 230 participants: MD -6.10, 95% CI -8.63 to -3.57), based on moderate certainty evidence. Cognitive behavioural therapy compared to usual care probably improves HRQoL measured either with the Kidney Disease Quality of Life Instrument Short Form or the Quality of Life Scale, with a 0.5 standardised mean difference representing a moderate effect size (4 studies, 230 participants: SMD 0.51, 95% CI 0.19 to 0.83) , based on moderate certainty evidence. Cognitive behavioural therapy may reduce major depression symptoms (one study) and anxiety, and increase self-efficacy (one study). Cognitive behavioural therapy studies did not report hospitalisation. We found low-certainty evidence that counselling may slightly reduce depressive symptoms measured with the Beck Depression Inventory (3 studies, 99 participants: MD -3.84, 95% CI -6.14 to -1.53) compared to usual care. Counselling reported no difference in HRQoL (one study). Counselling studies did not measure risk of major depression, suicide, or hospitalisation. Exercise may reduce or prevent major depression (3 studies, 108 participants: RR 0.47, 95% CI 0.27 to 0.81), depression of any severity (3 studies, 108 participants: RR 0.69, 95% CI 0.54 to 0.87) and improve HRQoL measured with Quality of Life Index score (2 studies, 64 participants: MD 3.06, 95% CI 2.29 to 3.83) compared to usual care with low certainty. With moderate certainty, exercise probably improves depression symptoms measured with the Beck Depression Inventory (3 studies, 108 participants: MD -7.61, 95% CI -9.59 to -5.63). Exercise may reduce anxiety (one study). No exercise studies measured suicide risk or withdrawal from dialysis. We found moderate-certainty evidence that relaxation techniques probably reduce depressive symptoms measured with the Beck Depression Inventory (2 studies, 122 participants: MD -5.77, 95% CI -8.76 to -2.78). Relaxation techniques reported no difference in HRQoL (one study). Relaxation studies did not measure risk of major depression or suicide. Spiritual practices have uncertain effects on depressive symptoms measured either with the Beck Depression Inventory or the Brief Symptom Inventory (2 studies, 116 participants: SMD -1.00, 95% CI -3.52 to 1.53; very low certainty evidence). No differences between spiritual practices and usual care were reported on anxiety (one study), and HRQoL (one study). No study of spiritual practices evaluated effects on suicide risk, withdrawal from dialysis or hospitalisation. There were few or no data on acupressure, telephone support, meditation and adverse events related to psychosocial interventions. Cognitive behavioural therapy, exercise or relaxation techniques probably reduce depressive symptoms (moderate-certainty evidence) for adults with ESKD treated with dialysis. Cognitive behavioural therapy probably increases health-related quality of life. Evidence for spiritual practices, acupressure, telephone support, and meditation is of low certainty . Similarly, evidence for effects of psychosocial interventions on suicide risk, major depression, hospitalisation, withdrawal from dialysis, and adverse events is of low or very low certainty.
The five randomised trials included in the review involved only 428 elderly patients. One small and potentially biased trial of 23 patients with undisplaced intracapsular fracture showed a reduced risk of non-union for those fractures treated operatively. The four trials on extracapsular fractures tested a variety of surgical techniques and implant devices and only one trial involving 106 patients can be considered to test current practice. In this trial, no differences were found in medical complications, mortality and long-term pain. However, operative treatment was more likely to result in the fracture healing without leg shortening, a shorter hospital stay and a statistically non-significant increase in the return of patients back to their original residence. Although there is a lack of available evidence to inform practice for undisplaced intracapsular fractures, variation in practice has reduced and most fractures are treated surgically. The limited available evidence from randomised trials does not suggest major differences in outcome between conservative and operative management programmes for extracapsular femoral fractures, but operative treatment is associated with a reduced length of hospital stay and improved rehabilitation. Conservative treatment will be acceptable where modern surgical facilities are unavailable, and will result in a reduction in complications associated with surgery, but rehabilitation is likely to be slower and limb deformity more common. Currently, it is difficult to conceive circumstances in which future trials would be practical or viable.
We included 38 trials involving 2728 participants. Results are based on individual studies or limited pooled analyses. There was good evidence in: Leishmania braziliensis and L. panamensis infections: Intramuscular (IM) meglumine antimoniate (MA) was better than oral allopurinol for 28 days (1RCT n=127, RR 0.39; 95% CI 0.26, 0.58). Intravenous (IV)MA for 20-days was better than 3-day and 7-day IVMA plus 15% paromomycin plus 12% methylbenzethonium chloride (PR-MBCL) or 7-day IVMA (1RCT n= 150, RR 0.24; 95% CI 0.11, 0.50; RR 0.69; 95% CI 0.53, 0.90; RR 0.64; 95% CI 0.44, 0.92 respectively). Oral allopurinol plus antimonials was better than IV antimonials (2RCT n= 168, RR 1.90; 95% CI 1.40, 2.59; I2=0%). L. braziliensis infections: Oral pentoxifylline plus IV sodium stibogluconate (SSG) was better than IVSSG (1RCT n= 23, RR 1.66; 95% CI 1.03, 2.69); IVMA was better than IM aminosidine sulphate (1RCT n= 38, RR 0.05; 95% CI 0.00, 0.78) and better than IV pentamidine isethionate (1RCT n= 80, RR 0.45; 95% CI 0.29, 0.71). Intramuscular MA was better than Bacillus Calmette-Guérin (1RCT n= 93, RR 0.46; 95% CI 0.32, 0.65). L .panamensis infections: Oral allopurinol was better than IVMA (1RCT n= 58, RR 2.20; 95% CI 1.34, 3.60). Aminosidine sulphate at doses of 12mg/kg/day and 18mg/kg/day for 14 days were better than aminosidine sulphate 12mg/kg/day for 7 days (1RCT n= 60, RR 0.23; 95% CI 0.07, 0.73; RR 0.23; 95% CI 0.07, 0.73 respectively). Oral ketoconazole for 28 days, oral miltefosine and topical PR-MBCL were better than placebo. Most trials have been designed and reported so poorly that they are inconclusive. There is a need for large well conducted studies that evaluate long-term effects of current therapies to improve quality and standardization of methods.
In all, 25 trials were included in the review, including 11 new studies since the last update, for a total of 19 that considered the efficacy of subcutaneous anti-IgE treatment as an adjunct to treatment with corticosteroids. For participants with moderate or severe asthma who were receiving background inhaled corticosteroid steroid (ICS) therapy, a significant advantage favoured subcutaneous omalizumab with regard to experiencing an asthma exacerbation (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.42 to 0.60; ten studies, 3261 participants). This represents an absolute reduction from 26% for participants suffering an exacerbation on placebo to 16% on omalizumab, over 16 to 60 weeks. A significant benefit was noted for subcutaneous omalizumab versus placebo with regard to reducing hospitalisations (OR 0.16, 95% CI 0.06 to 0.42; four studies, 1824 participants), representing an absolute reduction in risk from 3% with placebo to 0.5% with omalizumab over 28 to 60 weeks. No separate data on hospitalisations were available for the severe asthma subgroup, and all of these data were reported for participants with the diagnosis of moderate to severe asthma. Participants treated with subcutaneous omalizumab were also significantly more likely to be able to withdraw their ICS completely than those treated with placebo (OR 2.50, 95% CI 2.00 to 3.13), and a small but statistically significant reduction in daily inhaled steroid dose was reported for omalizumab-treated participants compared with those given placebo (weighted mean difference (WMD) -118 mcg beclomethasone dipropionate (BDP) equivalent per day, 95% CI -154 to -84). However, no significant difference between omalizumab and placebo treatment groups was seen in the number of participants who were able to withdraw from oral corticosteroid (OCS) therapy (OR 1.18, 95% CI 0.53 to 2.63). Participants treated with subcutaneous omalizumab as an adjunct to treatment with corticosteroids required a small but significant reduction in rescue beta2-agonist medication compared with placebo (mean difference (MD) -0.39 puffs per day, 95% CI -0.55 to -0.24; nine studies, 3524 participants). This benefit was observed in both the moderate to severe (MD -0.58, 95% CI -0.84 to -0.31) and severe (MD -0.30, 95% CI -0.49 to -0.10) asthma subgroups on a background therapy of inhaled corticosteroids; however, no significant difference between subcutaneous omalizumab and placebo was noted for this outcome in participants with severe asthma who were receiving a background therapy of inhaled plus oral corticosteroids. Significantly fewer serious adverse events were reported in participants assigned to subcutaneous omalizumab than in those receiving placebo (OR 0.72, 95% CI 0.57 to 0.91; 15 studies, 5713 participants), but more injection site reactions were observed (from 5.6% with placebo to 9.1% with omalizumab). To reflect current clinical practice, discussion of the results is limited to subcutaneous use, and trials involving intravenous and inhaled routes have been archived. Omalizumab was effective in reducing asthma exacerbations and hospitalisations as an adjunctive therapy to inhaled steroids and during steroid tapering phases of clinical trials. Omalizumab was significantly more effective than placebo in increasing the numbers of participants who were able to reduce or withdraw their inhaled steroids. Omalizumab was generally well tolerated, although more injection site reactions were seen with omalizumab. Further assessment in paediatric populations is necessary, as is direct double-dummy comparison with ICS. Although subgroup analyses suggest that participants receiving prednisolone had better asthma control when they received omalizumab, it remains to be tested prospectively whether the addition of omalizumab has a prednisolone-sparing effect. It is also not clear whether there is a threshold level of baseline serum IgE for optimum efficacy of omalizumab. Given the high cost of the drug, identification of biomarkers predictive of response is of major importance for future research.
Twelve studies, assessed as high (six) and unclear (six) risk of bias, comprising 689 participants (830 fractures), were included. Interventions examined different plate materials and morphology; use of one or two lag screws; microplate versus miniplate; early and delayed mobilization; eyelet wires versus Rapid IMF™ and the management of angle fractures with intraoral access alone or combined with a transbuccal approach. Patient-oriented outcomes were largely ignored and post-operative pain scores were inadequately reported. Unfortunately, only one or two trials with small sample sizes were conducted for each comparison and outcome. Our results and conclusions should therefore be interpreted with caution. We were able to pool the results for two comparisons assessing one outcome. Pooled data from two studies comparing two miniplates versus one miniplate revealed no significant difference in the risk of post-operative infection of surgical site (risk ratio (RR) 1.32, 95% CI 0.41 to 4.22, P = 0.64, I2 = 0%). Similarly, no difference in post-operative infection between the use of two 3-dimensional (3D) and standard (2D) miniplates was determined (RR 1.26, 95% CI 0.19 to 8.13, P = 0.81, I2 = 27%). The included studies involved a small number of participants with a low number of events. This review illustrates that there is currently inadequate evidence to support the effectiveness of a single approach in the management of mandibular fractures without condylar involvement. The lack of high quality evidence may be explained by clinical diversity, variability in assessment tools used and difficulty in grading outcomes with existing measurement tools. Until high level evidence is available, treatment decisions should continue to be based on the clinician's prior experience and the individual circumstances.
Seven studies, 492 participants, met the inclusion criteria Disulfiram versus placebo: no statistically significant results for dropouts but a trend favouring disulfiram, two studies, 87 participants, RR 0.82 (95% CI 0.66 to 1.03). One more study, 107 participants, favouring disulfiram, was excluded from meta-analysis due high heterogeneity, RR 0.34 (95% CI 0.20 to 0.58). For cocaine use, it was not possible to pool together primary studies, results from single studies showed that, one, out of four comparisons, was in favour of disulfiram (number of weeks abstinence, 20 participants, WMD 4.50 (95% CI 2.93 to 6.07). Disulfiram versus naltrexone: no statistically significant results for dropouts but a trend favouring disulfiram, three studies, 131 participants, RR 0.67 (95% CI 0.45 to 1.01). No significant difference for cocaine use was seen in the only study that considered this outcome. Disulfiram versus no pharmacological treatment: for cocaine use: a statistically significant difference in favour of disulfiram, one study, two comparisons, 90 participants: maximum weeks of consecutive abstinence, WMD 2.10 (95% CI 0.69 to 3.51); number of subjects achieving 3 or more weeks of consecutive abstinence, RR 1.88 (95% CI 1.09 to 3.23). There is low evidence, at the present, supporting the clinical use of disulfiram for the treatment of cocaine dependence. Larger randomised investigations are needed investigating relevant outcomes and reporting data to allow comparisons of results between studies. Results from ongoing studies will be added as soon as their results will be available.
We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision. We performed a meta-analysis of two trials with 59 participants. When metformin was compared with megestrol acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low-quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low-quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low-quality evidence). We found no data for recurrence of endometrial hyperplasia or health-related quality of life. Both studies (n = 59) provided data on progression of endometrial hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others. Another trial including 16 participants compared metformin plus megestrol acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low-quality evidence), recurrence of endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometrial hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low-quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37, one RCT, n = 16, very low-quality evidence). Investigators provided no data on abnormal uterine bleeding or health-related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetate study arm reported nausea. At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy - specifically, megestrol acetate - versus megestrol acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question.
This updated review includes two additional studies (and 976 additional participants), for a total of seven parallel-group RCTs and 1550 participants, 66% of whom were male. Participants' mean age was 68 years and was similar among studies. Airflow obstruction was moderately severe in three studies and severe in four studies; mean post bronchodilator forced expiratory volume in one second (FEV1) was 54% predicted, and 27% of participants were current smokers. Four studies prepared individualised action plans, one study an oral plan and two studies standard written action plans. All studies provided short educational input on COPD, and two studies supplied ongoing support for action plan use. Follow-up was 12 months in four studies and six months in three studies. When compared with usual care, an action plan with phone call follow-up significantly reduced the combined rate of hospitalisations and emergency department (ED) visits for COPD over 12 months in one study with 743 participants (rate ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.79; high-quality evidence), but the rate of hospitalisations alone in this study failed to achieve statistical significance (RR 0.69, 95% CI 0.47 to 1.01; moderate-quality evidence). Over 12 months, action plans significantly decreased the likelihood of hospital admission (odds ratio (OR) 0.69, 95% CI 0.49 to 0.97; n = 897; two RCTs; moderate-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) 19 (11 to 201)) and the likelihood of an ED visit (OR 0.55, 95% CI 0.38 to 0.78; n = 897; two RCTs; moderate-quality evidence; NNTB over 12 months 12 (9 to 26)) compared with usual care. Results showed no significant difference in all-cause mortality during 12 months (OR 0.88, 95% CI 0.59 to 1.31; n = 1134; four RCTs; moderate-quality evidence due to wide confidence interval). Over 12 months, use of oral corticosteroids was increased with action plans compared with usual care (mean difference (MD) 0.74 courses, 95% CI 0.12 to 1.35; n = 200; two RCTs; moderate-quality evidence), and the cumulative prednisolone dose was significantly higher (MD 779.0 mg, 95% CI 533.2 to 10248; n = 743; one RCT; high-quality evidence). Use of antibiotics was greater in the intervention group than in the usual care group (subgrouped by phone call follow-up) over 12 months (MD 2.3 courses, 95% CI 1.8 to 2.7; n = 943; three RCTs; moderate-quality evidence). Subgroup analysis by ongoing support for action plan use was limited; review authors noted no subgroup differences in the likelihood of hospital admission or ED visits or all-cause mortality over 12 months. Antibiotic use over 12 months showed a significant difference between subgroups in studies without and with ongoing support. Overall quality of life score on St George’s Respiratory Questionnaire (SGRQ) showed a small improvement with action plans compared with usual care over 12 months (MD -2.8, 95% CI -0.8 to -4.8; n = 1009; three RCTs; moderate-quality evidence). Low-quality evidence showed no benefit for psychological morbidity as measured with the Hospital Anxiety and Depression Scale (HADS). Use of COPD exacerbation action plans with a single short educational component along with ongoing support directed at use of the action plan, but without a comprehensive self-management programme, reduces in-hospital healthcare utilisation and increases treatment of COPD exacerbations with corticosteroids and antibiotics. Use of COPD action plans in this context is unlikely to increase or decrease mortality. Whether additional benefit is derived from periodic ongoing support directed at use of an action plan cannot be determined from the results of this review.
Twelve trials with a total of 1879 infants fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and eight compared nutrient-enriched preterm formula versus donor breast milk. Only the five most recent trials used nutrient-fortified donor breast milk. The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in four trials and lack of blinding in most of the trials. Most of the included trials were funded by companies that made the study formula. Formula-fed infants had higher in-hospital rates of weight gain (mean difference (MD) 2.51, 95% confidence interval (CI) 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). These meta-analyses contained high levels of heterogeneity. We did not find evidence of an effect on long-term growth or neurodevelopment. Formula feeding increased the risk of necrotising enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.05; number needed to treat for an additional harmful outcome (NNTH) 33, 95% CI 20 to 100; 9 studies, 1675 infants). The GRADE certainty of evidence was moderate for rates of weight gain, linear growth, and head growth (downgraded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotising enterocolitis (downgraded for imprecision). In preterm and LBW infants, moderate-certainty evidence indicates that feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotising enterocolitis. The trial data do not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.
Two randomised controlled trials including a total of 148 people aged 70 years or over with unstable extracapsular hip fractures in the trochanteric region were identified and included in this review. Both had methodological limitations, including inadequate assessment of longer-term outcome. One trial compared a cemented arthroplasty with a sliding hip screw. This found no significant differences between the two methods of treatment for operating time, local wound complications, mechanical complications, reoperation, mortality or loss of independence of previously independent patients at one year. There was, however, a higher blood transfusion need in the arthroplasty group. The other trial compared a cementless arthroplasty versus a proximal femoral nail. It also found a higher blood transfusion need in the arthroplasty group, together with a greater operative blood loss, and a longer length of surgery. There were no significant differences between the two interventions for mechanical complications, local wound complications, reoperation, general complications, mortality at one year or long-term function. None of the pooled outcome data yielded statistically significant differences between the arthroplasty and internal fixation, with the exception of the significantly higher numbers of participants in the arthroplasty group requiring blood transfusion (relative risk 1.71, 95% confidence interval 1.05 to 2.77). There is insufficient evidence from randomised trials to determine whether replacement arthroplasty has any advantage over internal fixation for extracapsular hip fractures. Further larger well-designed randomised trials comparing arthroplasty versus internal fixation for the treatment of unstable fractures are required.
Seven trials recruiting 3123 babies were included in the meta-analysis. Four trials recruiting 765 babies compared CPAP with supportive care and three trials (2364 infants) compared CPAP with mechanical ventilation. Apart from a lack of blinding of the intervention all studies were of low risk of bias. In the comparison of CPAP with supportive care there was a reduction in failed treatment (typical risk ratio (RR) 0.66, 95% confidence interval (CI) 0.45 to 0.98; typical risk difference (RD) −0.16, 95% CI −0.34 to 0.02; 4 studies, 765 infants, very low quality evidence). There was no reduction in bronchopulmonary dysplasia (BPD) or mortality. In trials comparing CPAP with assisted ventilation with or without surfactant, CPAP resulted in a small but clinically significant reduction in the incidence of BPD at 36 weeks, (typical RR 0.89, 95% CI 0.79 to 0.99; typical RD −0.04, 95% CI −0.08 to 0.00; 3 studies, 772 infants, moderate-quality evidence); and death or BPD (typical RR 0.89, 95% CI 0.81 to 0.97; typical RD −0.05, 95% CI −0.09 to 0.01; 3 studies, 1042 infants, moderate-quality evidence). There was also a clinically important reduction in the need for mechanical ventilation (typical RR 0.50, 95% CI 0.42 to 0.59; typical RD −0.49, 95% CI −0.59 to −0.39; 2 studies, 760 infants, moderate-quality evidence); and the use of surfactant in the CPAP group (typical RR 0.54, 95% CI 0.40 to 0.73; typical RD −0.41, 95% CI −0.54 to −0.28; 3 studies, 1744 infants, moderate-quality evidence). There is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. However when compared to mechanical ventilation prophylactic nasal CPAP in very preterm infants reduces the need for mechanical ventilation and surfactant and also reduces the incidence of BPD and death or BPD.
Four studies with 273 participants were included. All included studies reported clinical outcomes following valvuloplasty. We found no studies investigating other surgical procedures for the treatment of patients with DVI. All included studies investigated primary valve incompetence. We found no trials that investigated the results of surgery for secondary valvular incompetence or the obstructive form of DVI. Because different outcome measures were used, it was not possible to pool the results of included studies. The methodological quality of the included studies was low, mainly because information regarding randomisation and blinding was missing, or because data were incomplete or were presented poorly. Ulcer healing and ulcer recurrence were not reported in one study, and the remaining three studies did not include participants with ulcers or with active ulceration. Three studies reported no significant complications of surgery and no incidence of DVT during follow-up. One study did not report on the occurrence of complications. Clinical changes were assessed by subjective and objective measurements, as specified in the clinical, aetiological, anatomical, and pathophysiological (CEAP) classification score. This requires vascular laboratory measurements of lower limb haemodynamics before and after surgery. Tests include an overall evaluation of venous function with venous refilling time (VRT) or ambulatory venous pressure (AVP). Two small trials comparing external valvuloplasty using limited anterior plication in combination with ligation of incompetent superficial veins against ligation alone (L) showed that ligation plus limited anterior plication produced significant improvement in AVP: The mean difference was -15 mm Hg (95% confidence interval (CI) -20.9 to -9.0) at one year and -15 mm Hg (95% CI -21 to -8.9) at two years. Sustainable statistically significant improvement in AVP and VRT was achieved by ligation and limited anterior plication at 10 years in one study. However, AVP values after surgery remained relatively high, causing its benefit to be questioned. Similarly, another study including participants who were deteriorating preoperatively showed sustained mild clinical improvement for seven years in those subjected to valvuloplasty compared with participants undergoing superficial venous surgery alone. However, this benefit was lost when the condition of participants was stable preoperatively. One small study (n = 40) with grade 3 reflux and no participants with ulcers reported that external valvuloplasty of the femoral vein combined with surgical repair of the superficial venous system improved the haemodynamic status of the lower limbs, restored valvular function more effectively and achieved better outcomes than surgical repair of the superficial venous system alone. No evidence was found for benefit or harm of valvuloplasty in the treatment of patients with DVI secondary to primary valvular incompetence. The individual trials included in this review were small; they used different methods of assessment and overall were of poor quality. They did not include participants with severe DVI. Trials investigating the effects of other surgical procedures on deep veins are needed. Until the findings of such trials become available, the benefit of valvuloplasty remains uncertain.
The literature search yielded 359 reports of which only one study was identified that met our inclusion criteria and reported relevant clinical endpoints. This study randomised 4110 adult participants with a functioning kidney transplant and elevated homocysteine levels to folic acid plus high dose B multivitamins or low dose multivitamins who were followed for a mean 4.0 years. Despite effectively lowering homocysteine levels) in homocysteine levels at follow-up (MD -4.40 μmol/L, 95% CI -5.98 to -2.82) there was no evidence the intervention impacted on any of the outcomes reported including cardiovascular mortality (RR 0.91, 95% CI 0.69 to 1.20), all-cause mortality (RR 1.04, 95% CI 0.88 to 1.22), myocardial infarction (RR 1.02, 95% CI 0.77 to 1.35), stroke (RR 1.08, 95% CI 0.69 to 1.71), commencement of renal replacement therapy (RR 1.12, 95% CI 0.91 to 1.37) or all reported adverse events (RR 1.02, 95% CI 0.87 to 1.20). There was no evidence the intervention impacted on the primary endpoint of the study, a cardiovascular event composite (RR 0.99, 95% CI 0.85 to 1.15). The study was of high quality. There is no current evidence to support the use of homocysteine lowering therapy for cardiovascular disease prevention in kidney transplant recipients.
Two new studies incorporating 96 participants were identified in this update and were added to the six previously included studies. A total of eight studies incorporating 399 participants are included in the updated review. The participants were primarily men aged in their mid-thirties who had sustained a severe TBI. No studies included children. The studies were clinically diverse with regard to the interventions, time postinjury and the outcome measures used. At the end of intervention, the mean difference in peak power output was 35.47 watts (W) in favour of fitness training (MD 35.47 W, 95% CI 2.53 to 68.41 W; 3 studies, 67 participants; low-quality evidence). The CIs include both a possible clinically important effect and a possible negligible effect, and there was moderate heterogeneity among the studies. Five of the secondary outcomes had sufficient data at the end of intervention to enable meta-analysis: body composition (SMD 0.29 standard deviations (favouring control), 95% CI -0.22 to 0.79; 2 studies, 61 participants; low-quality evidence), strength (SMD -0.02 (favouring control), 95% CI -0.86 to 0.83; 2 studies, 23 participants; very low-quality evidence), fatigue (SMD -0.32 (favouring fitness training), 95% CI -0.90 to 0.26; 3 studies, 130 participants; very low-quality evidence), depression (SMD -0.43 (favouring fitness training), 95% CI -0.92 to 0.06; 4 studies, 220 participants; very low-quality evidence), and neuromotor function (MD 0.01 m (favouring fitness training), 95% CI -0.25 to 0.27; 2 studies, 109 participants; moderate-quality evidence). It was uncertain whether fitness training was more or less effective at improving these secondary outcomes compared to the control interventions. Quality of life was assessed in three trials, but we did not pool the data because of substantial heterogeneity. Five of the eight included studies had no dropouts from their intervention group and no adverse events were reported in any study. There is low-quality evidence that fitness training is effective at improving cardiorespiratory deconditioning after TBI; there is insufficient evidence to draw any definitive conclusions about the other outcomes. Whilst the intervention appears to be accepted by people with TBI, and there is no evidence of harm, more adequately powered and well-designed studies are required to determine a more precise estimate of the effect on cardiorespiratory fitness, as well as the effects across a range of important outcome measures and in people with different characteristics (e.g. children). In the absence of high quality evidence, clinicians may be guided by pre-exercise screening checklists to ensure the person with traumatic brain injury is safe to exercise, and set training parameters using guidelines established by the American College of Sports Medicine for people who have suffered a brain injury.
We included in this updated review five RCTs with a total of 403 participants, and we added two new trials identified during the 2015 search. One of the included studies was found to have a high risk of bias; no trial featured all pre-specified outcomes. We found two trials for which data are awaited for classification and one ongoing trial. Three studies compared advanced haemodynamic monitoring with a protocol using standard measures; three compared advanced haemodynamic monitoring with usual care; and one compared a protocol using standard measures with usual care. Meta-analyses for the two advanced haemodynamic monitoring comparisons are consistent with both increased and decreased risk of mortality (RR Mantel-Haenszel (M-H) random-effects 0.41, 95% confidence interval (CI) 0.14 to 1.20; 280 participants; RR M-H random-effects 0.45, 95% CI 0.07 to 2.95; 213 participants, respectively). The study comparing a protocol with usual care found no difference between groups for this outcome. Three studies comparing advanced haemodynamic monitoring with usual care reported data for length of stay and time to medical fitness. There was no statistically significant difference between groups for these outcomes in the two studies that we were able to combine (MD IV fixed 0.63, 95% CI -1.70 to 2.96); MD IV fixed 0.01, 95% CI -1.74 to 1.71, respectively) and no statistically significant difference in the third study. One study reported reduced time to medical fitness when comparing advanced haemodynamic monitoring with a protocol, and when comparing protocol monitoring with usual care. The number of participants with one or more complications showed no statistically significant differences in each of the two advanced haemodynamic monitoring comparisons (RR M-H random-effects 0.83, 95% CI 0.59 to 1.17; 280 participants; RR M-H random-effects 0.72, 95% CI 0.40 to 1.31; 173 participants, respectively), nor any differences in the protocol and usual care comparison. Only one study reported the number of participants able to return to normal accommodation after discharge with no statistically significant difference between groups. There were few studies with a small number of participants, and by using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach, we judged the quality of the outcome evidence as low. We had included one study with a high risk of bias, but upon applying GRADE, we downgraded the quality of this outcome evidence to very low. Five studies including a total of 403 participants provided no evidence that fluid optimization strategies improve outcomes for participants undergoing surgery for PFF. Further research powered to test some of these outcomes is ongoing.
Six studies met the inclusion criteria. The data obtained were unsuitable for the conduct of a meta-analysis; we have completed a qualitative summary. All studies were found to have high or unclear risk of bias in some aspects of their methodology. Five of the six studies reported data collected in the randomised controlled phase of the study. A sixth study did not report sufficient results to determine the effect of intrathecal baclofen versus placebo. Of these five studies, four were conducted using lumbar puncture or other short-term means of delivering intrathecal baclofen. One study assessed the effectiveness of implantable intrathecal baclofen pumps over six months. The four short-term studies demonstrated that intrathecal baclofen therapy reduces spasticity in children with cerebral palsy. However, two of these studies utilised inappropriate techniques for statistical analysis of results. The single longer-term study demonstrated minimal reduction in spasticity with the use of intrathecal baclofen therapy. One of the short-term studies and the longer term study showed improvement in comfort and ease of care. The longer term study found a small improvement in gross motor function and also in some domains of health-related quality of life. Some caution is required in interpreting the findings of the all the studies in the review due to methodological issues. In particular, there was a high risk of bias in the methodology of the longer term study due to the lack of placebo use in the control group and the absence of blinding to the intervention after randomisation for both participants and investigators. There is some limited short-term evidence that intrathecal baclofen is an effective therapy for reducing spasticity in children with cerebral palsy. The effect of intrathecal baclofen on long-term spasticity outcomes is less certain. The validity of the evidence for the effectiveness of intrathecal baclofen in treating spasticity in children with cerebral palsy from the studies in the review is constrained by the small sample sizes of the studies and methodological issues in some studies. Spasticity is a impairment in the domain of body structure and function. Consideration must also be given to the broader context in determining whether intrathecal baclofen therapy is effective. The aim of therapy may be, for example, to improve gross motor function, to increase participation at a social role level, to improve comfort, to improve the ease of care by others or to improve the overall quality of life of the individual. Intrathecal baclofen may improve gross motor function in children with cerebral palsy, but more reliable evidence is needed to determine this.There is some evidence that intrathecal baclofen improves ease of care and the comfort and quality of life of the individuals receiving it, but again small sample sizes and methodological issues in the studies mean that these results should be interpreted with caution. Further evidence of the effectiveness of intrathecal baclofen for treating spasticity, increasing gross motor function and improving comfort, ease of care and quality of life is needed from other investigators in order to validate these results. The short duration of the controlled studies included in this review did not allow for the exploration of questions regarding whether the subsequent need for orthopaedic surgery in children receiving intrathecal baclofen therapy is altered, or the safety and the economic implications of intrathecal baclofen treatment when long-term therapy is administered via an implanted device. Controlled studies are not the most appropriate study design to address these questions, cohort studies may be more appropriate.
Twenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified. Longest duration of therapy was 34.5 months. Published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised. The results of the single trial with relevant clinical endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events - PROactive study) have to be regarded as hypothesis-generating and need confirmation. Until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.
Sixty-five RCTs (N=166,206) were included, evaluating four classes of anti-hypertensive drugs: ACE inhibitors (12 trials), beta-blockers (20), calcium channel blockers (18) and nitrates (18). Acute stroke was studied in 6 trials (all involving CCBs). Acute myocardial infarction was studied in 59 trials. In the latter setting immediate nitrate treatment (within 24 hours) reduced all-cause mortality during the first 2 days (RR 0.81, 95%CI [0.74,0.89], p<0.0001). No further benefit was observed with nitrate therapy beyond this point. ACE inhibitors did not reduce mortality at 2 days (RR 0.91,95%CI [0.82, 1.00]), but did after 10 days (RR 0.93, 95%CI [0.87,0.98] p=0.01). No other blood pressure lowering drug administered as an immediate treatment or short-term treatment produced a statistical significant mortality reduction at 2, 10 or ≥30 days. There was not enough data studying acute stroke, and there were no RCTs evaluating other acute cardiovascular events. Nitrates reduce mortality (4-8 deaths prevented per 1000) at 2 days when administered within 24 hours of symptom onset of an acute myocardial infarction. No mortality benefit was seen when treatment continued beyond 48 hours. Mortality benefit of immediate treatment with ACE inhibitors post MI at 2 days did not reach statistical significance but the effect was significant at 10 days (3-5 deaths prevented per 1000). There is good evidence for lack of a mortality benefit with immediate or short-term treatment with beta-blockers and calcium channel blockers for acute myocardial infarction.
Information was available from 39 Cochrane reviews for 41 different analgesics or analgesic combinations (51 drug/dose/formulations) tested in single oral doses in participants with moderate or severe postoperative pain. This involved around 350 unique studies involving about 35,000 participants. Most studies involved younger participants with pain following removal of molar teeth. For most nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and combinations not containing opioids, there were few examples where participants experienced significantly more or fewer adverse events than with placebo. For aspirin 1000 mg and diflunisal 1000 mg, opioids, or fixed-dose combination drugs containing opioids, participants typically experienced significantly more adverse events than with placebo. Studies of combinations of ibuprofen and paracetamol reported significantly fewer adverse events. Serious adverse events were rare, occurring a rate of about 1 in 3200 participants. Most reviews did not report specific adverse events. Despite ongoing problems with the measurement, recording, and reporting of adverse events in clinical trials and in systematic reviews, the large amount of information available for single oral doses of analgesics provides evidence that adverse events rates are generally similar with active drug and placebo in these circumstances, except at higher doses of some drugs, and in combinations including opioids.
Nineteen trials providing outcome data for 1597 young to middle-aged adults were included. Many trials were at high risk of bias reflecting inadequate methods of randomization, lack of blinding and incomplete assessment of outcome. Pooled data for primary outcomes, reported in a minority of trials, showed no statistically significant differences between the two graft choices for functional assessment (single leg hop test), return to activity, Tegner and Lysholm scores, and subjective measures of outcome. There were also no differences found between the two interventions for re-rupture or International Knee Documentation Committee scores. There were inadequate long-term results, such as to assess the development of osteoarthritis. All tests (instrumental, Lachman, pivot shift) for static stability consistently showed that PT reconstruction resulted in a more statically stable knee compared with HT reconstruction. Conversely, patients experienced more anterior knee problems, especially with kneeling, after PT reconstruction. PT reconstructions resulted in a statistically significant loss of extension range of motion and a trend towards loss of knee extension strength. HT reconstructions demonstrated a trend towards loss of flexion range of motion and a statistically significant loss of knee flexion strength. The clinical importance of the above range of motion losses is unclear. There is insufficient evidence to draw conclusions on differences between the two grafts for long-term functional outcome. While PT reconstructions are more likely to result in statically stable knees, they are also associated with more anterior knee problems.
Only one randomised placebo-controlled, double-blind cross-over study met our selection criteria. In this study, 20 participants with motor tics were enrolled over a three-year recruitment period; 18 (14 of whom had a diagnosis of Tourette’s syndrome) completed the study; in total, 21 focal motor tics were treated. Although we considered most bias domains to be at low risk of bias, the study recruited a small number of participants with relatively mild tics and provided limited data for our key outcomes. The effects of botulinum toxin injections on tic frequency, measured by videotape or rated subjectively, and on premonitory urge, are uncertain (very low-quality evidence). The quality of evidence for adverse events following botulinum toxin was very low. Nine people had muscle weakness following the injection, which could have led to unblinding of treatment group assignment. No data were available to evaluate whether botulinum injections led to immunoresistance to botulinum. We are uncertain about botulinum toxin effects in the treatment of focal motor and phonic tics in select cases, as we assessed the quality of the evidence as very low. Additional randomised controlled studies are needed to demonstrate the benefits and harms of botulinum toxin therapy for the treatment of motor and phonic tics in patients with Tourette’s syndrome.
One new included study as well as further participants to a study already included was added to this update involving a further 39 participants. There were a total of three studies included involving 162 participants for this update. For this review two RCTs were included investigating secondary lymphoedema in 60 women after breast cancer surgery and 20 men and women after head and neck cancer surgery. One ongoing trial with preliminary results of 82 participants was also identified studying radiotherapy induced diarrhoea as a secondary outcome. All studies had considerable drawbacks with regards to quality and reporting. One study on secondary lymphoedema reported a decreased number of recurrent erysipela infections in the selenium supplementation group compared to placebo. The second study reported a decreased facial swelling in the selenium group in a two-week period following surgical tumour resection. However, results must be interpreted with caution and cannot be generalised to other populations. The ongoing trial on radiotherapy associated diarrhoea preliminarily reported a lower incidence of diarrhoea in participants receiving selenium supplementation concomitant to pelvic radiation, however, no data were presented. We must await publication of final results to discuss these findings in detail. No RCTs were found studying the effect of selenium supplementation on other therapy-associated toxicities or quality of life/performance status in cancer patients. There is insufficient evidence at present that selenium supplementation alleviates the side effects of tumour specific chemotherapy or radiotherapy treatments or that it improves the after-effects of surgery, or improves quality-of-life in cancer patients or reduces secondary lymphoedema. To date, research findings do not provide a basis for any recommendation in favour or against selenium supplementation in cancer patients. Potential hazards of supplementing a trace mineral should be kept in mind. Since the last version of this review, the one new additional study has not provided information to change the conclusions of the original review.
Seven studies including 494 participants formed the evidence base for this review. Drug treatments assessed in studies in the review included cholinergic agents, alpha-blockers, sedatives and prostaglandin on their own or in combinations. No statistically significant associations were reported between successful treatment or any other outcome and cholinergic agents, alpha-blockers and sedatives as monotherapies. A statistically significant association between intravesically administered prostaglandin and successful voiding was detected, Risk Ratio 3.07 (95% CI 1.22 to 7.72). A statistically significant association was detected between cholinergic agents combined with sedative and an improved likelihood of spontaneous voiding compared with placebo, Risk Ratio 1.39 (95% CI 1.07 to 1.82). Significant heterogeneity was identified between the two studies in this analysis, however. Whilst it may appear that cholinergic agents and intravesically administered prostaglandin offer most promise in the treatment of post-operative urinary retention, the evidence is weak. There is a need for further research into pharmacological alternatives to catheterisation in the treatment of this common surgical complication.
We included three studies involving 275 women (data reported for 271) with PPROM at up to 34 weeks' gestation. All three studies were conducted in the United States. Each study investigated different methods of fetal assessment. One study compared weekly endovaginal ultrasound scans with no assessment (n = 93), one compared amniocentesis with no assessment (n = 47), and one compared daily nonstress testing with daily modified biophysical profiling (n = 135). We were unable to perform a meta-analysis, but were able to report data from individual studies. There was no convincing evidence of increased risk of neonatal death in the group receiving endovaginal ultrasound scans compared with the group receiving no assessment (risk ratio (RR) 7.30, 95% confidence interval (CI) 0.39 to 137.54; one study, 92 women), or in the group receiving amniocentesis compared with the group receiving no amniocentesis (RR 1.00, 95% CI 0.07 to 15.00; one study, 44 women). For both these interventions, we inferred that there were no fetal deaths in the intervention or control groups. The study comparing daily nonstress testing with daily modified biophysical profiling did not report fetal or neonatal death. Primary outcomes of maternal death and serious maternal morbidity were not reported in any study. Overall, there were few statistically significant differences in outcomes between the comparisons. The overall quality of evidence is poor, because participant blinding was not possible for any study. There is insufficient evidence on the benefits and harms of fetal assessment methods for improving neonatal and maternal outcomes in women with PPROM to draw firm conclusions. The overall quality of evidence that does exist is poor. Further high-quality randomised controlled trials are required to guide clinical practice.
Fifty six trials met the inclusion criteria, involving 3257 children of whom 2412 used an alarm. The quality of many trials was poor, and evidence for many comparisons was inadequate. Most alarms used audio methods. Compared to no treatment, about two thirds of children became dry during alarm use (RR for failure 0.38, 95% CI 0.33 to 0.45). Nearly half who persisted with alarm use remained dry after treatment finished, compared to almost none after no treatment (RR of failure or relapse 45 of 81 (55%) versus 80 of 81 (99%), RR 0.56, 95% CI 0.46 to 0.68). There was insufficient evidence to draw conclusions about different types of alarm, or about how alarms compare to other behavioural interventions. Relapse rates were lower when overlearning was added to alarm treatment (RR 1.92, 95% CI 1.27 to 2.92) or if dry bed training was used as well (RR 2.0, 95% CI 1.25 to 3.20). Penalties for wet beds appeared to be counter-productive. Alarms using electric shocks were unacceptable to children or their parents. Although desmopressin may have a more immediate effect, alarms appeared to be as effective by the end of a course of treatment (RR 0.85, 95% CI 0.53 to 1.37) but their relative effectiveness after stopping treatment was unclear from two small trials which compared them directly. Evidence about the benefit of supplementing alarm treatment with desmopressin was conflicting. Alarms were not significantly better than tricyclics during treatment (RR 0.59, 95% CI 0.32 to 1.09) but the relapse rate was less afterwards (7 of 12 (58%) versus 12 of 12 (100%), RR 0.58, 95% CI 0.36 to 0.94). However, other Cochrane reviews of desmopressin and tricyclics suggest that drug treatment alone, while effective for some children during treatment, is unlikely to be followed by sustained cure as almost all the children relapse. Alarm interventions are an effective treatment for nocturnal bedwetting in children. Alarms appear more effective than desmopressin or tricyclics because around half the children remain dry after alarm treatment stops. Overlearning (giving extra fluids at bedtime after successfully becoming dry using an alarm), dry bed training and avoiding penalties may further reduce the relapse rate. Better quality research comparing alarms with other treatments is needed, including follow-up to determine relapse rates.
We included in this review 24 studies with a total of 1250 participants. The trials included various numbers and types of participants. Investigators used a range of methods to warm fluids to temperatures between 37°C and 41°C. We found that evidence was of moderate quality because descriptions of trial design were often unclear, resulting in high or unclear risk of bias due to inappropriate or unclear randomization and blinding procedures. These factors may have influenced results in some way. Our protocol specified the risk of hypothermia as the primary outcome; as no trials reported this, we decided to include data related to mean core temperature. The only secondary outcome reported in the trials that provided useable data was shivering. Evidence was unclear regarding the effects of fluid warming on bleeding. No data were reported on our other specified outcomes of cardiovascular complications, infection, pressure ulcers, bleeding, mortality, length of stay, unplanned intensive care admission and adverse events. Researchers found that warmed intravenous fluids kept the core temperature of study participants about half a degree warmer than that of participants given room temperature intravenous fluids at 30, 60, 90 and 120 minutes, and at the end of surgery. Warmed intravenous fluids also further reduced the risk of shivering compared with room temperature intravenous fluids Investigators reported no statistically significant differences in core body temperature or shivering between individuals given warmed and room temperature irrigation fluids. Warm intravenous fluids appear to keep patients warmer during surgery than room temperature fluids. It is unclear whether the actual differences in temperature are clinically meaningful, or if other benefits or harms are associated with the use of warmed fluids. It is also unclear if using fluid warming in addition to other warming methods confers any benefit, as a ceiling effect is likely when multiple methods of warming are used.
Two Chinese RCTs involving 158 women were included in this review. Although both these trials described adequate methodology they were of limited quality. Neither trial compared CHM with placebo treatment. There was no evidence of a significant difference in rates of symptomatic relief between CHM and gestrinone administered subsequent to laparoscopic surgery (RR 1.04, 95% CI 0.91 to 1.18). There was no significant difference between the CHM and gestrinone groups with regard to the total pregnancy rate (69.6% versus 59.1%; RR 1.18, 95% CI 0.87 to 1.59, one RCT). CHM administered orally and then in conjunction with a herbal enema resulted in a greater proportion of women obtaining symptomatic relief than with danazol (RR 5.06, 95% CI 1.28 to 20.05; RR 5.63, 95% CI 1.47 to 21.54, respectively). Oral plus enema administration of CHM resulted in a greater reduction in average dysmenorrhoea pain scores than did danazol (mean difference (MD) -2.90, 95% CI -4.55 to -1.25).  For lumbosacral pain, rectal discomfort, or vaginal nodules tenderness, there was no significant difference between CHM and danazol. Overall, 100% of women in both studies showed some improvement in their symptoms. Women taking CHM had fewer side effects than those taking either gestrinone or danazol. Post-surgical administration of CHM may have comparable benefits to gestrinone. Oral CHM may have a better overall treatment effect than danazol and it may be more effective in relieving dysmenorrhoea when used in conjunction with a CHM enema. CHM appears to have fewer side effects than either gestrinone or danazol. However, more rigorous research is required to accurately assess the potential role of CHM in treating endometriosis.
We included 54 studies in the review (50 in the meta-analyses), containing 5660 patients, of whom 586 had proven or probable invasive aspergillosis. When using an optical density index (ODI) of 0.5 as a cut-off value, the sensitivity of the test was 78% (70% to 85%) and the specificity was 85% (78% to 91%). At a cut-off value of 1.0 ODI, the sensitivity was 71% (63% to 78%) and the specificity was 90% (86% to 93%). At a cut-off value of 1.5 ODI, the sensitivity was 63% (49% to 78%) and the specificity was 93% (89% to 97%). None of the potential sources of heterogeneity had a statistically significant effect on either sensitivity or specificity. If we used the test at a cut-off value of 0.5 ODI in a population of 100 patients with a disease prevalence of 11% (overall median prevalence), two patients who have invasive aspergillosis would be missed (sensitivity 78%, 22% false negatives), and 13 patients would be treated unnecessarily or referred unnecessarily for further testing (specificity 85%, 15% false negatives). If we used the test at a cut-off value of 1.5 in the same population, that would mean that four invasive aspergillosis patients would be missed (sensitivity 61%, 39% false negatives), and six patients would be treated or referred for further testing unnecessarily (specificity 93%, 7% false negatives). These numbers should, however, be interpreted with caution because the results were very heterogeneous.
Twenty-three trials (1459 patients) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 mL/min (95% CI 5 to 28) and potassium output by 38 mmol/day (95% CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 μmol/L, 95% CI -3 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenac, ketorolac, indomethacin, ketoprofen or etodolac. No cases of postoperative renal failure requiring dialysis were described. The trials were not heterogeneous for the primary outcome. NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.
Forty-one trials involving more than 13,000 young people met our inclusion criteria (26 individually randomized controlled trials and 15 cluster-randomized trials). We judged the majority of studies to be at high or unclear risk of bias in at least one domain. Interventions were varied, with the majority adopting forms of individual or group counselling, with or without additional self-help materials to form complex interventions. Eight studies used primarily computer or messaging interventions, and four small studies used pharmacological interventions (nicotine patch or gum, or bupropion). There was evidence of an intervention effect for group counselling (9 studies, risk ratio (RR) 1.35, 95% confidence interval (CI) 1.03 to 1.77), but not for individual counselling (7 studies, RR 1.07, 95% CI 0.83 to 1.39), mixed delivery methods (8 studies, RR 1.26, 95% CI 0.95 to 1.66) or the computer or messaging interventions (pooled RRs between 0.79 and 1.18, 9 studies in total). There was no clear evidence for the effectiveness of pharmacological interventions, although confidence intervals were wide (nicotine replacement therapy 3 studies, RR 1.11, 95% CI 0.48 to 2.58; bupropion 1 study RR 1.49, 95% CI 0.55 to 4.02). No subgroup precluded the possibility of a clinically important effect. Studies of pharmacotherapies reported some adverse events considered related to study treatment, though most were mild, whereas no adverse events were reported in studies of behavioural interventions. Our certainty in the findings for all comparisons is low or very low, mainly because of the clinical heterogeneity of the interventions, imprecision in the effect size estimates, and issues with risk of bias. There is limited evidence that either behavioural support or smoking cessation medication increases the proportion of young people that stop smoking in the long-term. Findings are most promising for group-based behavioural interventions, but evidence remains limited for all intervention types. There continues to be a need for well-designed, adequately powered, randomized controlled trials of interventions for this population of smokers.
Three studies with 606 participants compared mirtazapine with placebo (but not other drugs) over seven to 13 weeks. Two studies were at unclear or high risk of bias in six or seven of eight domains. We judged the evidence for all outcomes to be low- or very low-quality because of poor study quality, indirectness, imprecision, risk of publication bias, and sometimes low numbers of events. There was no difference between mirtazapine and placebo for any primary outcome: participant-reported pain relief of 50% or greater (22% versus 16%; RD 0.05, 95% confidence interval (CI) -0.01 to 0.12; three studies with 591 participants; low-quality evidence); no data available for PGIC; only a single serious adverse event for evaluation of safety (RD -0.00, 95% CI -0.01 to 0.02; three studies with 606 participants; very low-quality evidence); and tolerability as frequency of dropouts due to adverse events (3% versus 2%; RD 0.00, 95% CI -0.02 to 0.03; three studies with 606 participants; low-quality evidence). Mirtazapine showed a clinically-relevant benefit compared to placebo for some secondary outcomes: participant-reported pain relief of 30% or greater (47% versus 34%; RD 0.13, 95% CI 0.05 to 0.21; number needed to treat for an additional beneficial outcome (NNTB) 8, 95% CI 5 to 20; three studies with 591 participants; low-quality evidence); participant-reported mean pain intensity (SMD -0.29, 95% CI -0.46 to -0.13; three studies with 591 participants; low-quality evidence); and participant-reported sleep problems (SMD -0.23, 95% CI -0.39 to -0.06; three studies with 573 participants; low-quality evidence). There was no benefit for improvement of participant-reported improvement of HRQoL of 20% or greater (58% versus 50%; RD 0.08, 95% CI -0.01 to 0.16; three studies with 586 participants; low-quality evidence); participant-reported fatigue (SMD -0.02, 95% CI -0.19 to 0.16; two studies with 533 participants; low-quality evidence); participant-reported negative mood (SMD -0.67, 95% CI -1.44 to 0.10; three studies with 588 participants; low-quality evidence); or withdrawals due to lack of efficacy (1.5% versus 0.1%; RD 0.01, 95% CI -0.01 to 0.02; three studies with 605 participants; very low-quality evidence). There was no difference between mirtazapine and placebo for participants reporting any adverse event (76% versus 59%; RD 0.12, 95 CI -0.01 to 0.26; three studies with 606 participants; low-quality evidence). There was a clinically-relevant harm with mirtazapine compared to placebo: in the number of participants with somnolence (42% versus 14%; RD 0.24, 95% CI 0.18 to 0.30; number needed to treat for an additional harmful outcome (NNTH) 5, 95% CI 3 to 6; three studies with 606 participants; low-quality evidence); weight gain (19% versus 1%; RD 0.17, 95% CI 0.11 to 0.23; NNTH 6, 95% CI 5 to 10; three studies with 606 participants; low-quality evidence); and elevated alanine aminotransferase (13% versus 2%; RD 0.13, 95% CI 0.04 to 0.22; NNTH 8, 95% CI 5 to 25; two studies with 566 participants; low-quality evidence). Studies demonstrated no benefit of mirtazapine over placebo for pain relief of 50% or greater, PGIC, improvement of HRQoL of 20% or greater, or reduction of fatigue or negative mood. Clinically-relevant benefits were shown for pain relief of 30% or greater, reduction of mean pain intensity, and sleep problems. Somnolence, weight gain, and elevated alanine aminotransferase were more frequent with mirtazapine than placebo. The quality of evidence was low or very low, with two of three studies of questionable quality and issues over indirectness and risk of publication bias. On balance, any potential benefits of mirtazapine in fibromyalgia were outweighed by its potential harms, though, a small minority of people with fibromyalgia might experience substantial symptom relief without clinically-relevant adverse events.
We added four studies for the 2019 update. The review now includes 38 trials, recruiting a total of 10,377 participants. Studies lasted between two months and three years and investigated a range of mucolytics, including N-acetylcysteine, carbocysteine, erdosteine, and ambroxol, given at least once daily. Many studies did not clearly describe allocation concealment, and we had concerns about blinding and high levels of attrition in some studies. The primary outcomes were exacerbations and number of days of disability. Results of 28 studies including 6723 participants show that receiving mucolytics may be more likely to be exacerbation-free during the study period compared to those given placebo (Peto odds ratio (OR) 1.73, 95% confidence interval (CI) 1.56 to 1.91; moderate-certainty evidence). However, more recent studies show less benefit of treatment than was reported in earlier studies in this review. The overall number needed to treat with mucolytics for an average of nine months to keep an additional participant free from exacerbations was eight (NNTB 8, 95% CI 7 to 10). High heterogeneity was noted for this outcome (I² = 62%), so results need to be interpreted with caution. The type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Longer studies showed smaller effects of mucolytics than were reported in shorter studies. Mucolytic use was associated with a reduction of 0.43 days of disability per participant per month compared with use of placebo (95% CI -0.56 to -0.30; studies = 9; I² = 61%; moderate-certainty evidence). With mucolytics, the number of people with one or more hospitalisations was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; participants = 1788; studies = 4; I² = 58%; moderate-certainty evidence). Investigators reported improved quality of life with mucolytics (mean difference (MD) -1.37, 95% CI -2.85 to 0.11; participants = 2721; studies = 7; I² = 64%; moderate-certainty evidence). However, the mean difference did not reach the minimal clinically important difference of -4 units, and the confidence interval includes no difference. Mucolytic treatment was associated with a possible reduction in adverse events (OR 0.84, 95% CI 0.74 to 0.94; participants = 7264; studies = 24; I² = 46%; moderate-certainty evidence), but the pooled effect includes no difference if a random-effects model is used. Several studies that could not be included in the meta-analysis reported high numbers of adverse events, up to a mean of five events per person during follow-up. There was no clear difference between mucolytics and placebo for mortality, but the confidence interval is too wide to confirm that treatment has no effect on mortality (Peto OR 0.98, 95% CI 0.51 to 1.87; participants = 3527; studies = 11; I² = 0%; moderate-certainty evidence). In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics leads to a small reduction in the likelihood of having an acute exacerbation, in days of disability per month and possibly hospitalisations, but is not associated with an increase in adverse events. There appears to be limited impact on lung function or health-related quality of life. Results are too imprecise to be certain whether or not there is an effect on mortality. Our confidence in the results is reduced by high levels of heterogeneity in many of the outcomes and the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies. This may be a result of greater risk of selection or publication bias in earlier trials, thus benefits of treatment may not be as great as was suggested by previous evidence.
We identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I2 greater than 90%). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality. When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I2 greater than 60%) and we considered the evidence to be of moderate quality). The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence). Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 95% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moderate-quality evidence). Based on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.
We identified seven RCTs (1728 participants) evaluating prolonged thromboprophylaxis with LMWH compared with in-hospital thromoprophylaxis followed by placebo or no thromboprophylaxis after discharge. The searches resulted in 1632 studies, of which we excluded 1528. One hundred and four abstracts, eligible for inclusion, were assessed of which seven studies met the inclusion criteria. For the primary outcome, the incidence of overall VTE after major abdominal or pelvic surgery was 13.2% in the control group compared to 5.3% in the patients receiving out-of-hospital LMWH (Mantel Haentzel (M-H) odds ratio (OR) 0.38, 95% confidence interval (CI) 0.26 to 0.54; I2 = 28%; moderate-quality evidence). For the secondary outcome of all DVT, seven studies, n = 1728, showed prolonged thromboprophylaxis with LMWH to be associated with a statistically significant reduction in the incidence of all DVT (M-H OR 0.39, 95% CI 0.27 to 0.55; I2 = 28%; moderate-quality evidence). We found a similar reduction when analysis was limited to incidence in proximal DVT (M-H OR 0.22, 95% CI 0.10 to 0.47; I2 = 0%; moderate-quality evidence). The incidence of symptomatic VTE was also reduced from 1.0% in the control group to 0.1% in patients receiving prolonged thromboprophylaxis, which approached significance (M-H OR 0.30, 95% CI 0.08 to 1.11; I2 = 0%; moderate-quality evidence). No difference in the incidence of bleeding between the control and LMWH group was found, 2.8% and 3.4%, respectively (M-H OR 1.10, 95% CI 0.67 to 1.81; I2 = 0%; moderate-quality evidence). No difference in mortality between the control and LMWH group was found, 3.8% and 3.9%, respectively (M-H OR 1.15, 95% CI 0.72 to 1.84; moderate-quality evidence). Estimates of heterogeneity ranged between 0% and 28% depending on the analysis, suggesting low or unimportant heterogeneity. Prolonged thromboprophylaxis with LMWH significantly reduces the risk of VTE compared to thromboprophylaxis during hospital admittance only, without increasing bleeding complications or mortality after major abdominal or pelvic surgery. This finding also holds true for DVT alone, and for both proximal and symptomatic DVT. The quality of the evidence is moderate and provides moderate support for routine use of prolonged thromboprophylaxis. Given the low heterogeneity between studies and the consistent and moderate evidence of a decrease in risk for VTE, our findings suggest that additional studies may help refine the degree of risk reduction but would be unlikely to significantly influence these findings. This updated review provides additional evidence and supports the previous results reported in the 2009 review.
We identified five randomised clinical trials with 290 patients. All trials were considered to have high risk of bias. Patients in the experimental group received compound phyllanthus for three months to 12 months. Patients in the antiviral drug group received lamivudine, interferon alpha, thymosin, or thymosin alpha 1. None of the trials reported mortality, hepatitis B-related morbidity, quality of life, or liver histology. Phyllanthus seemed to have a superior effect on clearance of serum HBeAg at the end of treatment in conventional meta-analysis (RR 0.76; 95% CI 0.64 to 0.91, P = 0.002; I2 = 0%), but not when trial sequential analysis was applied. Phyllanthus had no significant effect on clearance of serum HBsAg (RR 1.00; 95% CI 0.93 to 1.08, P = 0.92; I2 = 0%) or HBV DNA (RR 0.83; 95% CI 0.53 to 1.31, P = 0.43; I2 = 70%) when compared with antiviral drugs. Data on HBeAg seroconversion was reported in one trial and no significant difference was found comparing phyllanthus versus lamivudine (RR 0.89; 95% CI 0.71 to 1.11). No data were reported on adverse events in the five trials. There is currently insufficient evidence to support or refute the use of phyllanthus for patients with chronic hepatitis B virus infection. Researchers who are interested in conducting further randomised clinical trials on phyllanthus ought to monitor both beneficial and harmful effects and should primarily test the herb against placebo in addition to antiviral drugs that are known to offer more benefit than harm. Only in this way new interventions can be assessed without compromising personal ethical considerations.
Of the 1125 records screened for eligibility, four RCTs (N = 201 participants), and one on-going study, met the inclusion criteria. Two classes of antidepressants were investigated in two separate comparisons with placebo: a tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitors (SSRIs). TCA versus placebo Only one RCT (N = 30 participants) provided results for this comparison. Primary outcomes The TCA (nortriptyline) reduced depressive symptoms post-treatment compared to placebo (MD -10.20, 95% CI -16.75 to -3.65; P = 0.007; very low-quality evidence), as measured by the Hamilton Depression Rating Scale (HAM-D). Three participants withdrew from the trial due to adverse events related to the tested antidepressant (dry mouth, sedation, orthostatic hypotension). Secondary outcomes The overall results post-treatment indicated that nortriptyline was not effective in improving the quality of life of individuals with COPD, as measured by the Sickness Impact Profile (MD -2.80, 95% CI -11.02 to 5.42; P = 0.50; very low-quality evidence). The results for the change in dyspnoea for the domains examined (e.g. dyspnoea scores for 'most day-to-day activities') post-treatment showed no improvement in the intervention group (MD 9.80, 95% CI -6.20 to 25.80; P = 0.23; very low-quality evidence). No data were reported for change in FEV1, change in exercise tolerance, change in hospital utilisation, or cost-effectiveness. The TCA study provided short-term results, with the last follow-up data collection at 12 weeks. The quality of the evidence for all the outcomes evaluated was very low due to a small sample size, imprecision, attrition, and selection and reporting bias. SSRIs versus placebo Three RCTs (N = 171 participants) provided results for this comparison. Primary outcomes The pooled results for two studies showed no difference for the change in depressive symptoms post-intervention (SMD 0.75, 95% CI -1.14 to 2.64; 148 participants; 2 studies; P = 0.44; very low-quality evidence). High heterogeneity was observed (I² = 95%), limiting the reliability of these findings. While it was not possible to meta-analyse the total adverse events rates across the studies, it was possible to combine the results for two medication-specific adverse effects: nausea and dizziness. There were no significant post-treatment group differences for nausea (OR 2.32, 95% CI 0.66 to 8.12; 171 participants; 3 studies; P = 0.19; very low-quality evidence) or dizziness (OR 0.61, 95% CI 0.09 to 4.06; 143 participants; 2 studies; P = 0.61; very low-quality evidence). Secondary outcomes The pooled analysis of two trials reporting data for the change in quality of life did not show improvement post-treatment in the intervention group compared to placebo (SMD 1.17, 95% CI -0.80 to 3.15; 148 participants; 2 studies; P = 0.25; very low-quality evidence). There was no difference between groups in change in FEV1 post-treatment (MD 0.01, 95% CI -0.03 to 0.05; 148 participants; 2 studies; P = 0.60; low-quality evidence). However, two trials reported improvement in exercise tolerance in the SSRI group versus the placebo group (MD 13.88, 95% CI 11.73 to 16.03; 148 participants; 2 studies; P < 0.001; very low-quality evidence). The trials included in this comparison did not report data related to the change in dyspnoea, hospital utilisation rates, or cost-effectiveness. There is insufficient evidence to make definitive statements about the efficacy or safety of antidepressants for treating COPD-related depression. New RCTs are needed; with better methodological quality and more accurate reporting of the methods used. Moreover, longer-term follow-up data collection is needed, including outcomes such as adverse events, hospital utilisation and cost-effectiveness.
We identified 3745 citations through electronic searches and reviews of reference lists after deduplication of search results. We excluded 3619 records during title and abstract review and assessed 126 articles at full-text review for eligibility. We included one controlled study enrolling 46 participants. We rated this RCT at high risk for performance and detection bias due to a lack of blinding. The included RCT compared preventive use of mindfulness-based cognitive therapy (MBCT) with treatment as usual (TAU) in participants with a history of SAD. MBCT was administered in spring in eight weekly individual 45- to 60-minute sessions. In the TAU group participants did not receive any preventive treatment but were invited to start light therapy as first depressive symptoms occurred. Both groups were assessed weekly for occurrence of a new depressive episode measured with the Inventory of Depressive Syptomatology-Self-Report (IDS-SR, range 0-90) from September 2011 to mid-April 2012. The incidence of a new depressive episode in the upcoming winter was similar in both groups. In the MBCT group 65% of 23 participants developed depression (IDS-SR ≥ 20), compared to 74% of 23 people in the TAU group (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.60 to 1.30; 46 participants; very low quality-evidence). For participants with depressive episodes, severity of depression was comparable between groups. Participants in the MBCT group had a mean score of 26.5 (SD 7.0) on the IDS-SR, and TAU participants a mean score of 25.3 (SD 6.3) (mean difference (MD) 1.20, 95% CI -3.44 to 5.84; 32 participants; very low quality-evidence). The overall discontinuation rate was similar too, with 17% discontinuing in the MBCT group and 13% in the TAU group (RR 1.33, 95% CI 0.34 to 5.30; 46 participants; very low quality-evidence). Reasons for downgrading the quality of evidence included high risk of bias of the included study and imprecision. Investigators provided no information on adverse events. We could not find any studies that compared psychological therapy with other interventions of interest such as second-generation antidepressants, light therapy, melatonin or agomelatine. The evidence on psychological therapies to prevent the onset of a new depressive episode in people with a history of SAD is inconclusive. We identified only one study including 46 participants focusing on one type of psychological therapy. Methodological limitations and the small sample size preclude us from drawing a conclusion on benefits and harms of MBCT as a preventive intervention for SAD. Given that there is no comparative evidence for psychological therapy versus other preventive options, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences and other preventive interventions that are supported by evidence.
The review currently includes 27 blinded randomised controlled trials, which involved 3099 participants. Twelve randomised control trials compared clozapine with olanzapine, five with quetiapine, nine with risperidone, one with ziprasidone and two with zotepine. Attrition from these studies was high (overall 30.1%), leaving the interpretation of results problematic. Clozapine had a higher attrition rate due to adverse effects than olanzapine (9 RCTs, n=1674, RR 1.60 CI 1.07 to 2.40, NNT 25 CI 15 to 73) and risperidone (6 RCTs, n=627, RR 1.88 CI 1.11 to 3.21, NNT 16 CI 9 to 59). Fewer participants in the clozapine groups left the trials early due to inefficacy than risperidone (6 RCTs, n=627, RR 0.40 CI 0.23 to 0.70, NNT 11 CI 7 to 21), suggesting a certain higher efficacy of clozapine. Clozapine was more efficacious than zotepine in improving the participants general mental state (BPRS total score: 1 RCT, n=59, MD -6.00 CI -9.83 to -2.17), but not consistently more than olanzapine, quetiapine, risperidone and ziprasidone. There was no significant difference between clozapine and olanzapine or risperidone in terms of positive or negative symptoms of schizophrenia. According to two studies from China quetiapine was more efficacious for negative symptoms than clozapine (2 RCTs, n=142, MD 2.23 CI 0.99 to 3.48). Clozapine produced somewhat fewer extrapyramidal side-effects than risperidone (use of antiparkinson medication: 6 RCTs, n=304, RR 0.39 CI 0.22 to 0.68, NNT 7 CI 5 to 18) and zotepine (n=59, RR 0.05 CI 0.00 to 0.86, NNT 3 CI 2 to 5). More participants in the clozapine group showed decreased white blood cells than those taking olanzapine, more hypersalivation and sedation than those on olanzapine, risperidone and quetiapine and more seizures than people on olanzapine and risperidone. Also clozapine produced an important weight gain not seen with risperidone. Other differences in adverse effects were less documented and should be replicated, for example, clozapine did not alter prolactin levels whereas olanzapine, risperidone and zotepine did; compared with quetiapine, clozapine produced a higher incidence of electrocardiogram (ECG) alterations; and compared with quetiapine and risperidone clozapine produced a higher increase of triglyceride levels. Other findings that should be replicated were: clozapine improved social functioning less than risperidone and fewer participants in the clozapine group had to be hospitalised to avoid suicide attempts compared to olanzapine. Other important outcomes such as service use, cognitive functioning, satisfaction with care or quality of life were rarely reported. Clozapine may be a little more efficacious than zotepine and risperidone but further trials are required to confirm this finding. Clozapine differs more clearly in adverse effects from other second generation antipsychotics and the side-effect profile could be key in the selection of treatment depending on the clinical situation and a patient’s preferences. Data on other important outcomes such as cognitive functioning, quality of life, death or service use are currently largely missing, making further large and well-designed trials necessary. It is also important to take into account that the large number of people leaving the studies early limits the validity and interpretation of our findings.
In this review update, we added one study with 219 children. A total of two RCTs with 249 children (n = 240 completed) were eligible for inclusion in this review. Both studies contributed to our primary and secondary outcomes, but we assessed the quality of evidence for our three primary outcomes as low, owing to the small numbers of studies and participants; and high attrition in one of the studies. Data show no significant differences between treatment groups for our primary outcomes: proportion of children (n = 249) who had persistent symptoms at follow-up (odds ratio (OR) 0.69, 95% confidence interval (CI) 0.37 to 1.28; fixed-effect model); and number of children (n = 240) rehospitalised with respiratory illness within six months (OR 0.54, 95% CI 0.05 to 6.21; random-effects model). We were unable to analyse exacerbation rate because studies used different methods to report this information. Data showed no significant differences between treatment groups for our secondary outcome: proportion of children (n = 240) with wheeze at six months (OR 0.47, 95% CI 0.06 to 3.95; random-effects model). One study reported bacterial resistance, but only at 48 hours (thus with limited applicability for this review). Another study reported adverse events from which all children recovered and remained in the study. Current evidence is insufficient to inform whether antibiotics should be used to treat or prevent persistent respiratory symptoms in the post-acute bronchiolitis phase. Future RCTs are needed to evaluate the efficacy of antibiotics for reducing persistent respiratory symptoms. This is particularly important in populations with high acute and post-acute bronchiolitis morbidity (e.g. indigenous populations in Australia, New Zealand, and the USA).
Six studies (477 participants) were included in the review. All participants were adult kidney transplant recipients and 70% of participants underwent live-donor kidney transplantation. The overall risk of bias was low for selection bias and unclear for remaining domains. There was no difference in the risk of delayed graft function (3 studies, 298 participants: RR 1.03, 95% CI 0.62 to 1.70) or hyperkalaemia (2 studies, 199 participants: RR 0.48, 95% CI 0.04 to 6.10) for participants who received balanced electrolyte solutions compared to normal saline. Intraoperative balanced electrolyte solutions compared to normal saline were associated with higher blood pH (3 studies, 193 participants: MD 0.07, 95% CI 0.05 to 0.09), higher serum bicarbonate (3 studies, 215 participants: MD 3.02 mEq/L, 95% CI 2.00 to 4.05) and lower serum chloride (3 studies, 215 participants: MD -9.93 mmol/L, 95% CI -19.96 to 0.11). There were four cases of graft loss in the normal saline group and one in the balanced electrolyte solution group, and four cases of acute rejection in the normal saline group compared to two cases in the balanced electrolyte solution group. Balanced electrolyte solutions are associated with less hyperchloraemic metabolic acidosis compared to normal saline, however it remains uncertain whether lower-chloride solutions lead to improved graft outcomes compared to normal saline.
We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs. Funding: 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
Nine studies in dental, orthopedic and gynaecological surgery met the inclusion criteria, testing doses of diflunisal from 125 mg to 1000 mg. For diflunisal 1000 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.1 (1.8 to 2.6) (6 studies, 391 participants); the NNT to prevent remedication within 6 hours was 1.9 (1.7 to 2.3), and within 12 hours was 2.2 (1.9 to 2.7) (6 studies, 409 participants). More participants experienced adverse events with diflunisal 100 mg than with placebo, but none were serious or led to withdrawal. For diflunisal 500 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.6 (2.1 to 3.3) (6 studies, 357 participants); the NNT to prevent remedication within 6 hours was 2.6 (2.1 to 3.4) (6 studies, 390 participants), and within 12 hours was 2.9 (2.3 to 4.0) (5 studies, 329 participants). Adverse events did not differ significantly from placebo. Diflunisal has an analgesic effect similar to other NSAIDs in single dose, but benefits from providing significant analgesia for about twelve hours. This property may be useful when regular dosing is needed, or when taking several doses of a shorter acting analgesic is impractical.
We included in the meta-analysis 10 studies with 762 participants across one or more comparisons. The sample size of included studies ranged from 11 to 206 participants. Nine out of 10 studies involving all levels of COPD severity were conducted in China with adults from 55 to 88 years of age, a higher proportion of whom were male (78%). Nine out of 10 studies provided tai chi and/or qigong programmes as AMBMT, and one study provided yoga. Overall, the term 'PR' has been uncritically applied in the vast majority of studies, which limits comparison of AMBMT and PR. For example, eight out of 10 studies considered walking training as equal to PR and used this as conventional exercise training within PR. Overall study quality for main comparisons was moderate to very low mainly owing to imprecision, indirectness (exercise component inconsistent with recommendations), and risk of bias issues. The primary outcomes for our review were quality of life, dyspnoea, and serious adverse events. When researchers compared AMBMT versus PR alone (mainly unstructured walking training), statistically significant improvements in disease-specific quality of life (QoL) (St. George's Respiratory Questionnaire (SGRQ) total score) favoured AMBMT: mean difference (MD) -5.83, 95% confidence interval (CI) -8.75 to -2.92; three trials; 249 participants; low-quality evidence. The common effect size, but not the 95% CI around the pooled treatment effect, exceeded the minimal clinically important difference (MCID) of minus four. The COPD Assessment Test (CAT) also revealed statistically significant improvements favouring AMBMT over PR, with scores exceeding the MCID of three, with an MD of 6.58 units (95% CI -9.16 to – 4.00 units; one trial; 74 participants; low-quality evidence). Results show no between-group differences with regard to dyspnoea measured by the modified Medical Research Council Scale (MD 0.00 units, 95% CI -0.37 to 0.37; two trials; 127 participants; low-quality evidence), the Borg Scale (MD 0.44 units, 95% CI -0.88 to 0.00; one trial; 139 participants; low-quality evidence), or the Chronic Respiratory Questionnaire (CRQ) Dyspnoea Scale (MD -0.21, 95% CI -2.81 to 2.38; one trial; 11 participants; low-quality evidence). Comparisons of AMBMT versus PR alone did not include assessments of generic quality of life, adverse events, limb muscle function, exacerbations, or adherence. Comparisons of AMBMT added to PR versus PR alone (mainly unstructured walking training) revealed significant improvements in generic QoL as measured by Short Form (SF)-36 for both the SF-36 general health summary score (MD 5.42, 95% CI 3.82 to 7.02; one trial; 80 participants; very low-quality evidence) and the SF-36 mental health summary score (MD 3.29, 95% CI 1.45 to 4.95; one trial; 80 participants; very low-quality evidence). With regard to disease-specific QoL, investigators noted no significant improvement with addition of AMBMT to PR versus PR alone (SGRQ total score: MD -2.57, 95% CI -7.76 to 2.62 units; one trial; 192 participants; moderate-quality evidence; CRQ Dyspnoea Scale score: MD 0.04, 95% CI -2.18 to 2.26 units; one trial; 80 participants; very low-quality evidence). Comparisons of AMBMT + PR versus PR alone did not include assessments of dyspnoea, adverse events, limb muscle function, exacerbations, or adherence. Given the quality of available evidence, the effects of AMBMT versus PR or of AMBMT added to PR versus PR alone in people with stable COPD remain inconclusive. Evidence of low quality suggests better disease-specific QoL with AMBMT versus PR in people with stable COPD, and evidence of very low quality suggests no differences in dyspnoea between AMBMT and PR. Evidence of moderate quality shows that AMBMT added to PR does not result in improved disease-specific QoL, and evidence of very low quality suggests that AMBMT added to PR may lead to better generic QoL versus PR alone. Future studies with adequate descriptions of conventional exercise training (i.e. information on duration, intensity, and progression) delivered by trained professionals with a comprehensive understanding of respiratory physiology, exercise science, and the pathology of COPD are needed before definitive conclusions can be drawn regarding treatment outcomes with AMBMT versus PR or AMBMT added to PR versus PR alone for patients with COPD.
We included 67 trials, involving 6300 participants. Fifty-one trials reported the primary outcome, a measure of activities of daily living. The estimated effects of physical rehabilitation at the end of the intervention were an improvement in Barthel Index (0 to 100) scores of six points (95% confidence interval (CI) 2 to 11, P = 0.008, seven studies), Functional Independence Measure (0 to 126) scores of five points (95% CI -2 to 12, P = 0.1, four studies), Rivermead Mobility Index (0 to 15) scores of 0.7 points (95% CI 0.04 to 1.3, P = 0.04, three studies), Timed Up and Go test of five seconds (95% CI -9 to 0, P = 0.05, seven studies), and walking speed of 0.03 m/s (95% CI -0.01 to 0.07, P = 0.1, nine studies). Synthesis of secondary outcomes suggested there is a beneficial effect on strength, flexibility, and balance, and possibly on mood, although the size of any such effect is unknown. There was insufficient evidence of the effect on other secondary outcomes. Based on 25 studies (3721 participants), rehabilitation does not increase risk of mortality in this population (risk ratio 0.95, 95% CI 0.80 to 1.13). However, it is possible bias has resulted in overestimation of the positive effects of physical rehabilitation. Physical rehabilitation for long-term care residents may be effective, reducing disability with few adverse events, but effects appear quite small and may not be applicable to all residents. There is insufficient evidence to reach conclusions about improvement sustainability, cost-effectiveness, or which interventions are most appropriate. Future large-scale trials are justified.
Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl® cream, RGD peptide dressing, topical antibiotics). Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, RGD peptide matrix significantly reduced ulcer size compared with a control group, mean reduction 6.60cm2 (95% CI 5.51 to 7.69; very low quality of evidence). Three trials reported on the incidence of complete closure (isoxsuprine, arginine butyrate, RGD peptide matrix; ranging between low and very low quality of evidence). None reported a significant effect. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; or incidence of amputation. There was no reported information on the safety of these interventions. There is evidence that a topical intervention (RGD peptide matrix) reduced ulcer size in treated participants compared to controls. This evidence of efficacy is limited by the generally high risk of bias associated with these reports. We planned to analyse results according to general groups: pharmaceutical interventions (systemic and topical); and non-pharmaceutical interventions (surgical and non-surgical). However, we were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the unit of randomisation and the unit of analysis. This heterogeneity, along with a paucity of identified trials, prevented us performing any meta-analyses. This Cochrane review provides some evidence for the effectiveness of one topical intervention - RGD peptide matrix. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having a high risk of bias. We recommend that readers interpret the trial results with caution. The safety profile of the all interventions was inconclusive.
One parallel trial conducted in Turkey was included. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The quality of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate quality evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate quality evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period. A small single trial contributed evidence of moderate quality that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.
We included 17 studies involving 8787 participants: nine in multidisciplinary mental health care, six in psychological therapy settings, and two in primary care. Pooling of outcome data to provide a summary estimate of effect across studies was possible only for those studies using the compound Outcome Questionnaire (OQ-45) or Outcome Rating System (ORS) PROMs, which were all conducted in multidisciplinary mental health care or psychological therapy settings, because both primary care studies identified used single symptom outcome measures, which were not directly comparable to the OQ-45 or ORS. Meta-analysis of 12 studies including 3696 participants using these PROMs found no evidence of a difference in outcome in terms of symptoms, between feedback and no-feedback groups (standardised mean difference (SMD) -0.07, 95% confidence interval (CI) -0.16 to 0.01; P value = 0.10). The evidence for this comparison was graded as low quality however, as all included studies were considered at high risk of bias, in most cases due to inadequate blinding of assessors and significant attrition at follow-up. Quality of life was reported in only two studies, social functioning in one, and costs in none. Information on adverse events (thoughts of self-harm or suicide) was collected in one study, but differences between arms were not reported. It was not possible to pool data on changes in drug treatment or referrals as only two studies reported these. Meta-analysis of seven studies including 2608 participants found no evidence of a difference in management of CMHDs between feedback and no-feedback groups, in terms of the number of treatment sessions received (mean difference (MD) -0.02 sessions, 95% CI -0.42 to 0.39; P value = 0.93). However, the evidence for this comparison was also graded as low quality. We found insufficient evidence to support the use of routine outcome monitoring using PROMs in the treatment of CMHDs, in terms of improving patient outcomes or in improving management. The findings are subject to considerable uncertainty however, due to the high risk of bias in the large majority of trials meeting the inclusion criteria, which means further research is very likely to have an important impact on the estimate of effect and is likely to change the estimate. More research of better quality is therefore required, particularly in primary care where most CMHDs are treated. Future research should address issues of blinding of assessors and attrition, and measure a range of relevant symptom outcomes, as well as possible harmful effects of monitoring, health-related quality of life, social functioning, and costs. Studies should include people treated with drugs as well as psychological therapies, and should follow them up for longer than six months.
Three studies (146 participants) met our selection criteria. Two studies compared multidisciplinary, fast-track palliative care versus multidisciplinary standard care while on a waiting-list control, and one study compared a multidisciplinary palliative approach versus multidisciplinary standard care at different time points (12, 16, and 24 weeks). Two were RCTs with parallel design (total 94 participants) and one was a cross-over design (52 participants). The three studies assessed palliative care as a home-based intervention. One of the three studies included participants with 'neurodegenerative diseases', with MS people being a subset of the randomised population. We assessed the risk of bias of included studies using Cochrane's 'Risk of Bias' tool. We found no evidence of differences between intervention and control groups in long-time follow-up (> six months post-intervention) for the following outcomes: mean change in health-related quality of life (SEIQoL - higher scores mean better quality of life; MD 4.80, 95% CI -12.32 to 21.92; participants = 62; studies = 1; very low-certainty evidence), serious adverse events (RR 0.97, 95% CI 0.44 to 2.12; participants = 76; studies = 1, 22 events, low-certainty evidence) and hospital admission (RR 0.78, 95% CI 0.24 to 2.52; participants = 76; studies = 1, 10 events, low-certainty evidence). The three included studies did not assess the following outcomes at long term follow-up (> six months post intervention): fatigue, anxiety, depression, disability, cognitive function, relapse-free survival, and sustained progression-free survival. We did not find any trial that compared different types of palliative care with each other. Based on the findings of the RCTs included in this review, we are uncertain whether palliative care interventions are beneficial for people with MS. There is low- or very low-certainty evidence regarding the difference between palliative care interventions versus usual care for long-term health-related quality of life, adverse events, and hospital admission in patients with MS. For intermediate-term follow-up, we are also uncertain about the effects of palliative care for the outcomes: health-related quality of life (measured by different assessments: SEIQoL or MSIS), disability, anxiety, and depression.
We identified a total of 9188 citations and included 15 RCTs conducted on 2242 participants in this review. All trials used the LMA Classic in American Society of Anesthesiologists (ASA) physical status I or II for patients undergoing elective general anaesthesia. Children were enrolled in 11 trials and adults in five trials. None of the trials were of high methodological quality. Eight of the 15 studies had adequate generation of random sequence, whereas only one trial had adequate concealment of random sequence. Three trials had blinded the outcome assessor. Thus, the majority of the studies appeared to have a high risk of bias in the study design. Using the GRADE approach, we found low quality evidence that the risk of laryngospasm was similar with early removal of the LMA (3.3%) versus late removal (2.7%): risk ratio (RR) 1.23, 95% confidence interval (CI) 0.74 to 2.03; 11 trials, 1615 participants. The quality of evidence was very low that the risk of coughing was less after early removal (13.9%) than late removal (19.4%): RR 0.52, 95% CI 0.29 to 0.94; 11 trials, 1430 participants. The quality of evidence for the risk of desaturation was also very low; there was no difference between early removal (7.9%) and late removal (10.1%): RR 0.68, 95% CI 0.4 to 1.16; 13 trials, 2037 participants. We found low quality evidence that the risk of airway obstruction was higher with early removal (15.6%) compared to late removal of the LMA (4.6%): RR 2.69, 95% CI 1.32 to 5.5; eight trials, 1313 participants. This systematic review suggests that current best evidence comparing early versus late removal of the LMA in participants undergoing general anaesthesia does not demonstrate superiority of either intervention. However, the quality of evidence available is either low or very low. There is a paucity of well designed RCTs and a need for large scale RCTs to demonstrate whether early removal or late removal of the LMA is better after general anaesthesia.
Five RCTs involving 309 people are included in this review. Overall, the results were inconclusive. There was no statistically significant superior effect of any locomotor training approach on walking function after SCI compared with any other kind of physical rehabilitation. The use of bodyweight supported treadmill training as locomotor training for people after SCI did not significantly increase walking velocity (0.03 m/sec with a 95% confidence interval (CI) -0.05 to 0.11; P = 0.52; I2 = 22%) nor did it increase walking capacity (-1.3 metres (95% CI -41 to 40); P = 0.95; I2 = 62%). However, in one study involving 74 people the group receiving robotic-assisted locomotor training had reduced walking capacity compared with people receiving any other intervention, a finding which needs further investigation. In all five studies there were no differences in adverse events or drop-outs between study groups. There is insufficient evidence from RCTs to conclude that any one locomotor training strategy improves walking function more than another for people with SCI. The effects especially of robotic-assisted locomotor training are not clear, therefore research in the form of large RCTs, particularly for robotic training, is needed. Specific questions about which type of locomotor training might be most effective in improving walking function for people with SCI need to be explored.
One randomised clinical trial fulfilled the inclusion criteria of the review. Forty participants with multiple liver metastases of colorectal cancer and no evidence of extrahepatic disease were randomly assigned. Thirty of these participants (14 females and 16 males) were included in the analysis: 14 participants received microwave coagulation and 16 underwent conventional surgery (hepatectomy or liver resection). The diagnosis of colorectal cancer (Stage IB to IIIC; tumour (T)2 node (N)0 to T3N2) and liver metastases was confirmed by histological assessment. Mean participant age was 61 years. The tumours were resectable. The risk of bias in the trial was judged to be high. Participants were followed for three years. Mortality at the last follow-up was 64% (9/14) in the microwave group and 75% (12/16) in the conventional surgery group (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.53 to 1.39), that is, no significant difference was observed. In the microwave coagulation group, 71%, 57%, and 14% survived 1, 2, and 3 years, and in the conventional surgery group, the percentages were 69%, 56%, and 23%. The hazard ratio calculated using the Parmar method was 0.91 (0.39 to 2.15). Mean survival time was 27 months in the microwave group and 25 months in the conventional surgery group, and the mean disease-free interval was 11.3 months in the microwave group and 13.3 months in the hepatectomy group. Differences for both outcomes were not statistically significant. Reported frequency of adverse events was similar between the microwave coagulation and conventional surgery groups, except for the required blood transfusion, which was more common in the conventional surgery group. No intervention-related mortality was observed. After treatment, the carcinoembryonic antigen level decreased significantly in both groups. On the basis of one randomised clinical trial, which did not describe allocation concealment or blinding, and which excluded from analysis 25% of participants after random assignment, evidence is insufficient to show whether microwave coagulation brings any significant benefit in terms of survival or recurrence compared with conventional surgery for participants with liver metastases from colorectal cancer. The number of adverse events, except for the requirement for blood transfusion, which was more common in the liver resection group, was similar in both groups. At present, microwave therapy cannot be recommended outside randomised clinical trials.
We included 63 trials randomising a total of 85,550 participants (mean age 57.4 years). Only one trial was at low risk of bias. The remaining trials were at high risk of bias. The quality of the evidence according to GRADE ranged from very low to high. Fifty-six trials commenced beta-blockers during the acute phase of acute myocardial infarction and seven trials during the subacute phase. At our primary time point 'less than three months follow-up', meta-analysis showed that beta-blockers versus placebo or no intervention probably reduce the risk of a reinfarction during follow-up (risk ratio (RR) 0.82, 98% confidence interval (CI) 0.73 to 0.91; 67,562 participants; 18 trials; moderate-quality evidence) with an absolute risk reduction of 0.5% and a number needed to treat for an additional beneficial outcome (NNTB) of 196 participants. However, we found little or no effect of beta-blockers when assessing all-cause mortality (RR 0.94, 97.5% CI 0.90 to 1.00; 80,452 participants; 46 trials/47 comparisons; high-quality evidence) with an absolute risk reduction of 0.4% and cardiovascular mortality (RR 0.99, 95% CI 0.91 to 1.08; 45,852 participants; 1 trial; moderate-quality evidence) with an absolute risk reduction of 0.4%. Regarding angina, it is uncertain whether beta-blockers have a beneficial or harmful effect (RR 0.70, 98% CI 0.25 to 1.84; 98 participants; 3 trials; very low-quality evidence) with an absolute risk reduction of 7.1%. None of the trials specifically assessed nor reported serious adverse events according to ICH-GCP. Only two trials specifically assessed major adverse cardiovascular events, however, no major adverse cardiovascular events occurred in either trial. At maximum follow-up beyond three months, meta-analyses showed that beta-blockers versus placebo or no intervention probably reduce the risk of all-cause mortality (RR 0.93, 97.5% CI 0.86 to 0.99; 25,210 participants; 21 trials/22 comparisons; moderate-quality evidence) with an absolute risk reduction of 1.1% and a NNTB of 91 participants, and cardiovascular mortality (RR 0.90, 98% CI 0.83 to 0.98; 22,457 participants; 14 trials/15 comparisons; moderate-quality evidence) with an absolute risk reduction of 1.2% and a NNTB of 83 participants. However, it is uncertain whether beta-blockers have a beneficial or harmful effect when assessing major adverse cardiovascular events (RR 0.81, 97.5% CI 0.40 to 1.66; 475 participants; 4 trials; very low-quality evidence) with an absolute risk reduction of 1.7%; reinfarction (RR 0.89, 98% CI 0.75 to 1.08; 6825 participants; 14 trials; low-quality evidence) with an absolute risk reduction of 0.9%; and angina (RR 0.64, 98% CI 0.18 to 2.0; 844 participants; 2 trials; very low-quality evidence). None of the trials specifically assessed nor reported serious adverse events according to ICH-GCP. None of the trials assessed quality of life. We identified two ongoing randomised clinical trials investigating the effect of early administration of beta-blockers after percutaneous coronary intervention or thrombolysis to patients with an acute myocardial infarction and one ongoing trial investigating the effect of long-term beta-blocker therapy. Our present review indicates that beta-blockers for suspected or diagnosed acute myocardial infarction probably reduce the short-term risk of a reinfarction and the long-term risk of all-cause mortality and cardiovascular mortality. Nevertheless, it is most likely that beta-blockers have little or no effect on the short-term risk of all-cause mortality and cardiovascular mortality. Regarding all remaining outcomes (serious adverse events according to ICH-GCP, major adverse cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial infarction during follow-up), the long-term risk of a reinfarction during follow-up, quality of life, and angina), further information is needed to confirm or reject the clinical effects of beta-blockers on these outcomes for people with or suspected of acute myocardial infarction.
We included seven trials of antifungal agents in children with prolonged fever and neutropenia (suspected fungal infection) and candidaemia or invasive candidiasis (proven fungal infection). Four trials compared a lipid preparation of amphotericin B with conventional amphotericin B (395 participants), one trial compared an echinocandin with a lipid preparation of amphotericin B (82 participants) in suspected infection; one trial compared an echinocandin with a lipid preparation of amphotericin B in children with candidaemia or invasive candidiasis (109 participants) and one trial compared different azole antifungals in children with candidaemia (43 participants). No difference in all-cause mortality and other primary endpoints (mortality related to fungal infection or complete resolution of fungal infections) were observed. No difference in breakthrough fungal infection was observed in children with prolonged fever and neutropenia. When lipid preparations and conventional amphotericin B were compared in children with prolonged fever and neutropenia, nephrotoxicity was less frequently observed with a lipid preparation (RR 0.43, 95% CI 0.21 to 0.90, P = 0.02) however substantial heterogeneity was observed (I2 = 59%, P = 0.06). Children receiving liposomal amphotericin B were less likely to develop infusion-related reactions compared with conventional amphotericin B (chills: RR 0.37, 95% CI 0.21 to 0.64, P = 0.0005). Children receiving a colloidal dispersion were more likely to develop such reactions than with liposomal amphotericin B (chills: RR 1.76, 95% CI 1.09 to 2.85, P = 0.02). The rate of other clinically significant adverse reactions attributed to the antifungal agent (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy; hypokalaemia and hepatotoxicity) were not significantly different. When echinocandins and lipid preparations were compared, the rate of clinically significant adverse reactions (total reactions; total reactions leading to treatment discontinuation, dose reduction or change in therapy) were not significantly different. Limited paediatric data are available comparing antifungal agents in children with proven, probable or suspected invasive fungal infection. No differences in mortality or treatment efficacy were observed when antifungal agents were compared. Children are less likely to develop nephrotoxicity with a lipid preparation of amphotericin B compared with conventional amphotericin B. Further comparative paediatric antifungal drug trials and epidemiological and pharmacological studies are required highlighting the differences between neonates, children and adults with invasive fungal infections.
We included 49 studies involving 4807 women: 13 studies evaluated pelvic endometriosis, 10 endometriomas and 15 DIE, and 33 studies addressed endometriosis at specific anatomical sites. Most studies were of poor methodological quality. The most studied modalities were transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI), with outcome measures commonly demonstrating diversity in diagnostic estimates; however, sources of heterogeneity could not be reliably determined. No imaging test met the criteria for a replacement or triage test for detecting pelvic endometriosis, albeit TVUS approached the criteria for a SpPin triage test. For endometrioma, TVUS (eight studies, 765 participants; sensitivity 0.93 (95% confidence interval (CI) 0.87, 0.99), specificity 0.96 (95% CI 0.92, 0.99)) qualified as a SpPin triage test and approached the criteria for a replacement and SnNout triage test, whereas MRI (three studies, 179 participants; sensitivity 0.95 (95% CI 0.90, 1.00), specificity 0.91 (95% CI 0.86, 0.97)) met the criteria for a replacement and SnNout triage test and approached the criteria for a SpPin test. For DIE, TVUS (nine studies, 12 data sets, 934 participants; sensitivity 0.79 (95% CI 0.69, 0.89) and specificity 0.94 (95% CI 0.88, 1.00)) approached the criteria for a SpPin triage test, and MRI (six studies, seven data sets, 266 participants; sensitivity 0.94 (95% CI 0.90, 0.97), specificity 0.77 (95% CI 0.44, 1.00)) approached the criteria for a replacement and SnNout triage test. Other imaging tests assessed in small individual studies could not be statistically evaluated. TVUS met the criteria for a SpPin triage test in mapping DIE to uterosacral ligaments, rectovaginal septum, vaginal wall, pouch of Douglas (POD) and rectosigmoid. MRI met the criteria for a SpPin triage test for POD and vaginal and rectosigmoid endometriosis. Transrectal ultrasonography (TRUS) might qualify as a SpPin triage test for rectosigmoid involvement but could not be adequately assessed for other anatomical sites because heterogeneous data were scant. Multi-detector computerised tomography enema (MDCT-e) displayed the highest diagnostic performance for rectosigmoid and other bowel endometriosis and met the criteria for both SpPin and SnNout triage tests, but studies were too few to provide meaningful results. Diagnostic accuracies were higher for TVUS with bowel preparation (TVUS-BP) and rectal water contrast (RWC-TVS) and for 3.0TMRI than for conventional methods, although the paucity of studies precluded statistical evaluation. None of the evaluated imaging modalities were able to detect overall pelvic endometriosis with enough accuracy that they would be suggested to replace surgery. Specifically for endometrioma, TVUS qualified as a SpPin triage test. MRI displayed sufficient accuracy to suggest utility as a replacement test, but the data were too scant to permit meaningful conclusions. TVUS could be used clinically to identify additional anatomical sites of DIE compared with MRI, thus facilitating preoperative planning. Rectosigmoid endometriosis was the only site that could be accurately mapped by using TVUS, TRUS, MRI or MDCT-e. Studies evaluating recent advances in imaging modalities such as TVUS-BP, RWC-TVS, 3.0TMRI and MDCT-e were observed to have high diagnostic accuracies but were too few to allow prudent evaluation of their diagnostic role. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Future well-designed diagnostic studies undertaken to compare imaging tests for diagnostic test accuracy and costs are recommended.
Eight trials with a total of 348 participants were included. Comparing EN to TPN for acute pancreatitis, the relative risk (RR) for death was 0.50 (95% CI 0.28 to 0.91), for multiple organ failure (MOF) was 0.55 (95% CI 0.37 to 0.81), for systemic infection was 0.39 (95% CI 0.23 to 0.65), for operative interventions was 0.44 (95% CI 0.29 to 0.67), for local septic complications was 0.74 (95% CI 0.40 to 1.35), and for other local complications was 0.70 (95% CI 0.43 to 1.13). Mean length of hospital stay was reduced by 2.37 days in EN vs TPN groups (95% CI -7.18 to 2.44). Furthermore, a subgroup analysis for EN vs TPN in patients with severe acute pancreatitis showed a RR for death of 0.18 (95% CI 0.06 to 0.58) and a RR for MOF of 0.46 (95% CI 0.16 to 1.29). In patients with acute pancreatitis, enteral nutrition significantly reduced mortality, multiple organ failure, systemic infections, and the need for operative interventions compared to those who received TPN. In addition, there was a trend towards a reduction in length of hospital stay. These data suggest that EN should be considered the standard of care for patients with acute pancreatitis requiring nutritional support.
We included 13 RCTs (701 people). Six of the RCTs included only children aged 1 to 18 years and seven involved only adults (from 18 to 65 years of age). The mean TBSA of the included participants was greater than 49%. Twelve studies compared rhGH with placebo and one study compared rhGH with oxandrolone. Two trials found that compared with placebo, burn wounds in adults treated with rhGH healed more quickly (by 9.07 days; 95% confidence interval (CI) 4.39 to 13.76, I² = 0%). The donor site healing time was significantly shorter in rhGH-treated adults compared with placebo-treated participants (by 3.15 days; 95% CI 1.54 to 4.75, I² = 0%). Two studies in children with the outcome of donor site healing time could be pooled and the donor site healing time was shorter in the rhGH-treated children (by 1.70 days; 95% CI 0.87 to 2.53, I² = 0%). No studies reporting the outcome of wound infection were found. The incidence of hyperglycaemia was higher in adults during rhGH treatment compared with placebo (risk ratio (RR) 2.43; 95% CI 1.54 to 3.85), but not in children. Pooling the studies of adults and children yielded a significantly higher incidence of hyperglycaemia in the rhGH-treated participants (RR 2.65; 95% CI 1.68 to 4.16). There is some evidence that using rhGH in people with large burns (more than 40% of the total body surface area) could result in more rapid healing of the burn wound and donor sites in adults and children, and in reduced length of hospital stay, without increased mortality or scarring, but with an increased risk of hyperglycaemia. This evidence is based on studies with small sample sizes and risk of bias and requires confirmation in higher quality, adequately powered trials.
A total of 1092 participants randomly assigned to the low pressure group (509 participants) and the standard pressure group (583 participants) in 21 trials provided information for this review on one or more outcomes. Three additional trials comparing low pressure pneumoperitoneum with standard pressure pneumoperitoneum (including 179 participants) provided no information for this review. Most of the trials included low anaesthetic risk participants undergoing elective laparoscopic cholecystectomy. One trial including 140 participants was at low risk of bias. The remaining 20 trials were at high risk of bias. The overall quality of evidence was low or very low. No mortality was reported in either the low pressure group (0/199; 0%) or the standard pressure group (0/235; 0%) in eight trials that reported mortality. One participant experienced the outcome of serious adverse events (low pressure group 1/179, 0.6%; standard pressure group 0/215, 0%; seven trials; 394 participants; RR 3.00; 95% CI 0.14 to 65.90; very low quality evidence). Quality of life, return to normal activity, and return to work were not reported in any of the trials. The difference between groups in the conversion to open cholecystectomy was imprecise (low pressure group 2/269, adjusted proportion 0.8%; standard pressure group 2/287, 0.7%; 10 trials; 556 participants; RR 1.18; 95% CI 0.29 to 4.72; very low quality evidence) and was compatible with an increase, a decrease, or no difference in the proportion of conversion to open cholecystectomy due to low pressure pneumoperitoneum. No difference in the length of hospital stay was reported between the groups (five trials; 415 participants; MD -0.30 days; 95% CI -0.63 to 0.02; low quality evidence). Operating time was about two minutes longer in the low pressure group than in the standard pressure group (19 trials; 990 participants; MD 1.51 minutes; 95% CI 0.07 to 2.94; very low quality evidence). Laparoscopic cholecystectomy can be completed successfully using low pressure in approximately 90% of people undergoing laparoscopic cholecystectomy. However, no evidence is currently available to support the use of low pressure pneumoperitoneum in low anaesthetic risk patients undergoing elective laparoscopic cholecystectomy. The safety of low pressure pneumoperitoneum has to be established. Further well-designed trials are necessary, particularly in people with cardiopulmonary disorders who undergo laparoscopic cholecystectomy.
Six trials met all our eligibility criteria and provided extractable data. Three trials were at low risk of bias, one trial was at unclear risk, and two trials were at high risk of bias. Five trials were conducted in Asian populations. In preventing development of subsequent gastric cancer, H. pylori eradication therapy was superior to placebo or no treatment (6 trials, 6497 participants, risk ratio (RR) of developing subsequent gastric cancer 0.66; 95% confidence interval (CI) 0.46 to 0.95; moderate-quality evidence). Only one trial reported effect of eradication of H. pylori on development of subsequent oesophageal cancer (2 (0.2%) among 817 participants assigned to eradication therapy, compared with 1 (0.1%) of 813 participants allocated to placebo; RR 1.99; 95% CI 0.18 to 21.91). The effect of H. pylori eradication on preventing death from gastric cancer compared with placebo or no treatment was uncertain due to wide confidence intervals (3 trials, 4475 participants, RR 0.67; 95% CI 0.40 to 1.11; moderate-quality evidence). There was no evidence of an effect on all-cause mortality (4 trials, 5253 participants, RR 1.09; 95% CI 0.86 to 1.38; moderate-quality evidence). Adverse events data were poorly reported. We found limited, moderate-quality evidence that searching for and eradicating H. pylori reduces the incidence of gastric cancer in healthy asymptomatic infected Asian individuals, but we cannot necessarily extrapolate this data to other populations.
We included 26 trials, which randomised 4979 participants, in this review. Meta-analysis of 10 trials clearly demonstrated reduction of onset of VF defects in treated OHT (OR 0.62, 95% CI 0.47 to 0.81). No single drug showed a significant VF protection compared to placebo or untreated controls. We did identify some border line evidence for a positive influence of treatment on VF prognosis (OR 0.67, 95% CI 0.45 to 1.00) for the beta-blockers . The results of this review support the current practice of IOP lowering treatment of OHT. A visual field protective effect has been clearly demonstrated for medical IOP lowering treatment. Positive but weak evidence for a beneficial effect of the class of beta-blockers has been shown. Direct comparisons of prostaglandins or brimonidine to placebo are not available and the comparison of dorzolamide to placebo failed to demonstrate a protective effect. However, absence of data or failure to prove effectiveness should not be interpreted as proof of absence of any effect. The decision to treat a patient or not, as well as the decision regarding the drug with which to start treatment, should remain individualised, taking in to account the amount of damage, the level of IOP, age and other patient characteristics.
We identified no new trials for the 2016 update. This review includes two trials, but we included only one trial, with 24 women, in the analyses. The overall risk of bias was unclear owing to lack of methodological detail. Using the GRADE method, we judged the quality of the evidence to be very low. We downgraded evidence for risk of bias and for imprecision (wide confidence intervals and evidence based on a single small trial). Comparison of NSAIDs (naproxen) versus placebo revealed no evidence of a positive effect on pain relief (odds ratio (OR) 3.27, 95% confidence interval (CI) 0.61 to 17.69; one trial, 24 women; very low-quality evidence) in women with endometriosis. Evidence indicating whether women taking NSAIDs (naproxen) were less likely to require additional analgesia (OR 0.12, 95% CI 0.01 to 1.29; one trial, 24 women; very low-quality evidence) or to experience side effects (OR 0.46, 95% CI 0.09 to 2.47; one trial, 24 women; very low-quality evidence) when compared with placebo was inconclusive. Studies provided no data on quality of life, effects on daily activities, absence from work or school, need for more invasive treatment or participant satisfaction with treatment. Owing to lack of high-quality evidence and lack of reporting of outcomes of interest for this review, we can make no judgement as to whether NSAIDs (naproxen) are effective in managing pain caused by endometriosis. There is no evidence that one NSAID is more effective than another. As shown in other Cochrane reviews, women taking NSAIDs must be aware that these drugs may cause unintended effects.
The original review included eight studies on migraine. Overall, we now include 11 studies on five SSRIs and one SNRI with a total of 585 participants. Six studies were placebo-controlled, four compared a SSRI or SNRI to amitriptyline, and one was a head-to-head comparison (escitalopram versus venlafaxine). Most studies had methodological or reporting shortcomings (or both): all studies were at unclear risk of selection and reporting bias. Follow-up rarely extended beyond three months. The lack of adequate power of most of the studies is also a major concern. Few studies explored the effect of SSRIs or SNRIs on migraine frequency, the primary endpoint. Two studies with unclear reporting compared SSRIs and SNRIs to placebo, suggesting a lack of evidence for a difference. Two studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency (standardised mean difference (SMD) 0.04, 95% confidence interval (CI) -0.72 to 0.80; I2 = 72%), or other secondary outcomes such as migraine intensity and duration. SSRIs or SNRIs were generally more tolerable than tricyclics. However, the two groups did not differ in terms of the number of participants who withdrew due to adverse advents or for other reasons (one study, odds ratio (OR) 0.39, 95% CI 0.10 to 1.50 and OR 0.42, 95% CI 0.13 to 1.34). We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. antiepileptics and anti-hypertensives). Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine as preventive drugs for migraine. There is no evidence to consider SSRIs or venlafaxine as more effective than placebo or amitriptyline in reducing migraine frequency, intensity, and duration over two to three months of treatment. No reliable information is available at longer-term follow-up. Our conclusion is that the use of SSRIs and SNRIs for migraine prophylaxis is not supported by evidence.
A total of 16 randomised controlled trials (overall 5735 participants) were included in this systematic review. Of these, three trials were unpublished. We found 11 studies (overall 3304 participants) comparing duloxetine with one selective serotonin reuptake inhibitor (SSRI) (six studies versus paroxetine, three studies versus escitalopram and two versus fluoxetine), four studies (overall 1978 participants) comparing duloxetine with a newer antidepressants (three with venlafaxine and one with desvenlafaxine, respectively) and one study (overall 453 participants) comparing duloxetine with an antipsychotic drug which is also used as an antidepressive agent, quetiapine. No studies were found comparing duloxetine with tricyclic antidepressants. The pooled confidence intervals were rather wide and there were no statistically significant differences in efficacy when comparing duloxetine with other antidepressants. However, when compared with escitalopram or venlafaxine, there was a higher rate of drop out due to any cause in the patients randomised to duloxetine (odds ratio (OR) 1.62; 95% confidence interval (CI) 1.01 to 2.62 and OR 1.56; 95% CI 1.14 to 2.15, respectively). There was also some weak evidence suggesting that patients taking duloxetine experienced more adverse events than paroxetine (OR 1.24; 95% CI 0.99 to 1.55). Duloxetine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. No differences in terms of efficacy were found, even though duloxetine was worse than some SSRIs (most of all, escitalopram) and newer antidepressants (like venlafaxine) in terms of acceptability and tolerability. Unfortunately, we only found evidence comparing duloxetine with a handful of other active antidepressive agents and only a few trials per comparison were found (in some cases we retrieved just one trial). This limited the power of the review to detect moderate, but clinically meaningful differences between the drugs. As many statistical tests have been used in the review, the findings from this review are better thought of as hypothesis forming rather than hypothesis testing and it would be very comforting to see the conclusions replicated in future trials. Most of included studies were sponsored by the drug industry manufacturing duloxetine. As for all other new investigational compounds, the potential for overestimation of treatment effect due to sponsorship bias should be borne in mind. In the present review no trials reported economic outcomes. Given that several SSRIs and the great majority of antidepressants are now available as generic formulation (only escitalopram, desvenlafaxine and duloxetine are still on patent), more comprehensive economic estimates of antidepressant treatment effect should be considered to better inform healthcare policy.
Twenty-seven studies (29 experimental groups) met the review entry criteria, randomising a total of 1925 participants. The studies identified assessed the effects of 21 different herbal preparations. Study quality varied considerably, and the sample sizes were often small. For primary outcomes (exacerbations, steroids use and lung function measurements): Two out of six studies reporting change in FEV1 were positive, with very few data available on the frequency of exacerbations. One study which did report these data was negative. Health-related quality of life was only measured in one trial. The evidence base for the effects of herbal treatments is hampered by the variety of treatments assessed, poor reporting quality of the studies and lack of available data. The data that are available from the studies provide only a small insight into the long-term efficacy and harm profiles of these treatments. The absence of common endpoint measurements limits the validity of our findings further. Positive findings in this review warrant additional well-designed trials in this area.
We included 13 studies: one cluster randomised controlled trial (CRCT) and 12 ITS studies, involving 40 hospitals, 51 intensive care units (ICUs), 27 wards, and more than 3504 patients and 1406 healthcare professionals. Six of the included studies targeted adherence to guidelines to prevent central line-associated blood stream infections (CLABSIs); another six studies targeted adherence to guidelines to prevent ventilator-associated pneumonia (VAP), and one study focused on interventions to improve urinary catheter practices. We judged all included studies to be at moderate or high risk of bias. The largest median effect on rates of VAP was found at nine months follow-up with a decrease of 7.36 (-10.82 to 3.14) cases per 1000 ventilator days (five studies and 15 sites). The one included cluster randomised controlled trial (CRCT) observed, improved urinary catheter practices five weeks after the intervention (absolute difference 12.2 percentage points), however, the statistical significance of this is unknown given a unit of analysis error. It is worth noting that N = 6 interventions that did result in significantly decreased infection rates involved more than one active intervention, which in some cases, was repeatedly administered over time, and further, that one intervention involving specialised oral care personnel showed the largest step change (-22.9 cases per 1000 ventilator days (standard error (SE) 4.0), and also the largest slope change (-6.45 cases per 1000 ventilator days (SE 1.42, P = 0.002)) among the included studies. We attempted to combine the results for studies targeting the same indwelling medical device (central line catheters or mechanical ventilators) and reporting the same outcomes (CLABSI and VAP rate) in two separate meta-analyses, but due to very high statistical heterogeneity among included studies (I2 up to 97%), we did not retain these analyses. Six of the included studies reported post-intervention adherence scores ranging from 14% to 98%. The effect on rates of infection were mixed and the effect sizes were small, with the largest median effect for the change in level (interquartile range (IQR)) for the six CLABSI studies being observed at three months follow-up was a decrease of 0.6 (-2.74 to 0.28) cases per 1000 central line days (six studies and 36 sites). This change was not sustained over longer follow-up times. The low to very low quality of the evidence of studies included in this review provides insufficient evidence to determine with certainty which interventions are most effective in changing professional behaviour and in what contexts. However, interventions that may be worth further study are educational interventions involving more than one active element and that are repeatedly administered over time, and interventions employing specialised personnel, who are focused on an aspect of care that is supported by evidence e.g. dentists/dental auxiliaries performing oral care for VAP prevention.
We included six randomized controlled trials (RCTs). Four studies had unclear risk of bias and two had high risk of bias. The results of these RCTs were not consistent; two demonstrated no differences between blinded and unblinded assessments, two found that blinded assessments had significantly lower quality scores, and another observed significantly higher quality scores for blinded assessments. The remaining study did not report the level of significance. We pooled five studies reporting sufficient information in a meta-analysis. We observed no statistically significant difference in risk of bias assessments between blinded or unblinded assessments (standardized mean difference -0.13, 95% confidence interval -0.42 to 0.16). The mean difference might be slightly inaccurate, as we did not adjust for clustering in our meta-analysis. We observed inconsistency of results visually and noted statistical heterogeneity. Our review highlights that discordance exists between studies examining blinded versus unblinded risk of bias assessments at the systematic review level. The best approach to risk of bias assessment remains unclear, however, given the increased time and resources required to conceal reports effectively, it may not be necessary for risk of bias assessments to be conducted under blinded conditions in a systematic review.
With 8 studies added in this update, 17 met our inclusion criteria and had a total of 63,813 women. We focus here on 12 studies that provided high, moderate, or low quality evidence. Most did not show a higher pregnancy risk among overweight or obese women. Of five COC studies, two found BMI to be associated with pregnancy but in different directions. With an OC containing norethindrone acetate and ethinyl estradiol (EE), pregnancy risk was higher for overweight women, i.e. with BMI ≥ 25 versus those with BMI < 25 (reported relative risk 2.49, 95% CI 1.01 to 6.13). In contrast, a trial using an OC with levonorgestrel and EE reported a Pearl Index of 0 for obese women (BMI ≥ 30) versus 5.59 for nonobese women (BMI < 30). The same trial tested a transdermal patch containing levonorgestrel and EE. Within the patch group, obese women in the "treatment-compliant" subgroup had a higher reported Pearl Index than nonobese women (4.63 versus 2.15). Of five implant studies, two that examined the six-capsule levonorgestrel implant showed differences in pregnancy by weight. One study showed higher weight was associated with higher pregnancy rate in years 6 and 7 combined (reported P < 0.05). In the other, pregnancy rates differed in year 5 among the lower weight groups only (reported P < 0.01) and did not involve women weighing 70 kg or more. Analysis of data from other contraceptive methods indicated no association of pregnancy with overweight or obesity. These included depot medroxyprogesterone acetate (subcutaneous), levonorgestrel IUC, the two-rod levonorgestrel implant, and the etonogestrel implant. The evidence generally did not indicate an association between higher BMI or weight and effectiveness of hormonal contraceptives. However, we found few studies for most contraceptive methods. Studies using BMI, rather than weight alone, can provide information about whether body composition is related to contraceptive effectiveness. The contraceptive methods examined here are among the most effective when used according to the recommended regimen. We considered the overall quality of evidence to be low for the objectives of this review. More recent reports provided evidence of varying quality, while the quality was generally low for older studies. For many trials the quality would be higher for their original purpose rather than the non-randomized comparisons here. Investigators should consider adjusting for potential confounding related to BMI or contraceptive effectiveness. Newer studies included a greater proportion of overweight or obese women, which helps in examining effectiveness and side effects of hormonal contraceptives within those groups.
Seven randomised trials were included, four of which reported usable data on 472 children with asthma one to 18 years of age who were admitted to paediatric wards. No trials included patients admitted to the ICU. The anticholinergic used, ipratropium bromide 250 μg, was given every one to eight hours over a period from four hours to the entire length of the hospital stay. Two of four trials (50%) contributing data were deemed of high methodological quality. The addition of anticholinergics to β2-agonists showed no evidence of effect on the duration of hospital admission (mean difference (MD) -0.28 hours, 95% confidence interval (CI) -5.07 to 4.52, 3 studies, 327 participants, moderate quality evidence) and no serious or non-serious adverse events were reported in any included trials. As a result of the similarity of trials, we could not explore the influence of age, admission site, intensity of anticholinergic treatment and co-interventions on primary outcomes. No statistically significant group difference was noted in other secondary outcomes, including the need for supplemental asthma therapy, time to short-acting β2-agonists spaced at four hours or longer, asthma clinical scores, lung function and overall withdrawals for any reason. In children hospitalised for an acute asthma exacerbation, no evidence of benefit for length of hospital stay and other markers of response to therapy was noted when nebulised anticholinergics were added to short-acting β2-agonists. No adverse health effects were reported, yet the small number of trials combined with inadequate reporting prevent firm reassurance regarding the safety of anticholinergics. In the absence of trials conducted in ICUs, no conclusion can be drawn regarding children with impending respiratory failure. These findings support current national and international recommendations indicating that healthcare practitioners should refrain from using anticholinergics in children hospitalised for acute asthma.
We identified six randomised comtrolled trials of auditory integration therapy and one of Tomatis therapy, involving a total of 182 individuals aged three to 39 years. Two were cross-over trials. Five trials had fewer than 20 participants. Allocation concealment was inadequate for all studies. Twenty different outcome measures were used and only two outcomes were used by three or more studies. Meta-analysis was not possible due to very high heterogeneity or the presentation of data in unusable forms. Three studies (Bettison 1996; Zollweg 1997; Mudford 2000) did not demonstrate any benefit of auditory integration therapy over control conditions. Three studies (Veale 1993; Rimland 1995; Edelson 1999) reported improvements at three months for the auditory integration therapy group based on the Aberrant Behaviour Checklist, but they used a total score rather than subgroup scores, which is of questionable validity, and Veale's results did not reach statistical significance. Rimland 1995 also reported improvements at three months in the auditory integration therapy group for the Aberrant Behaviour Checklist subgroup scores. The study addressing Tomatis therapy (Corbett 2008) described an improvement in language with no difference between treatment and control conditions and did not report on the behavioural outcomes that were used in the auditory integration therapy trials. There is no evidence that auditory integration therapy or other sound therapies are effective as treatments for autism spectrum disorders. As synthesis of existing data has been limited by the disparate outcome measures used between studies, there is not sufficient evidence to prove that this treatment is not effective. However, of the seven studies including 182 participants that have been reported to date, only two (with an author in common), involving a total of 35 participants, report statistically significant improvements in the auditory intergration therapy group and for only two outcome measures (Aberrant Behaviour Checklist and Fisher's Auditory Problems Checklist). As such, there is no evidence to support the use of auditory integration therapy at this time.
We identified 18 potential studies, of which two, currently reported only as abstracts, met the inclusion criteria for this review. Too little information was available for us to present full results or adequately assess risk of bias. The participants were children aged five to 15 years with DMD, ambulant and non-ambulant. The interventions were risedronate versus no treatment in one trial (13 participants) and whole-body vibration versus a placebo device in the second (21 participants). Both studies reported improved bone mineral density with the active treatments, with no improvement in the control groups, but the abstracts did not compare treatment and control conditions. All children tolerated whole-body vibration treatment. No study provided information on adverse events. Two studies are ongoing: one investigating whole-body vibration, the other investigating zoledronic acid. We know of no high-quality evidence from RCTs to guide use of treatments to prevent or treat corticosteroid-induced osteoporosis and reduce the risk of fragility fractures in children and adults with DMD; only limited results from two trials reported in abstracts were available. We await formal trial reports. Findings from two ongoing relevant studies and two trials, for which only abstracts are available, will be important in future updates of this review.
We found six randomised, double-blind trials of at least two weeks' duration eligible for inclusion. These trials included 460 participants with neuropathic pain, with most participants having painful diabetic neuropathy. Four studies were of cross-over design and two were parallel trials. Only one trial was both parallel design and placebo-controlled. Mean age of participants ranged from 48 to 59 years. In three studies (Forssell 2004, Jia 2006 and Tasmuth 2002), only mean data were reported. Comparators included placebo, imipramine, and carbamazepine and duration of treatment ranged from two to eight weeks. The risk of bias was considerable overall in the review, especially due to the small size of most studies and due to attrition bias. Four of the six studies reported some positive benefit for venlafaxine. In the largest study by Rowbotham, 2004, 56% of participants receiving venlafaxine 150 to 225 mg achieved at least a 50% reduction in pain intensity versus 34% of participants in the placebo group and the number needed to treat for an additional beneficial outcome was 4.5. However, this study was subject to significant selection bias. Known adverse effects of venlafaxine, including somnolence, dizziness, and mild gastrointestinal problems, were reported in all studies but were not particularly problematic and, overall, adverse effects were equally prominent in placebo or other active comparator groups. We found little compelling evidence to support the use of venlafaxine in neuropathic pain. While there was some third-tier evidence of benefit, this arose from studies that had methodological limitations and considerable risk of bias. Placebo effects were notably strong in several studies. Given that effective drug treatments for neuropathic pain are in current use, there is no evidence to revise prescribing guidelines to promote the use of venlafaxine in neuropathic pain. Although venlafaxine was generally reasonably well tolerated, there was some evidence that it can precipitate fatigue, somnolence, nausea, and dizziness in a minority of people.
We included four trials, with a combined total of 1439 women in the review; each trial examined a different method of induction and we were unable to pool the results from trials. 1. Vaginal PGE2 (two studies including 1028 women). There were no differences between women managed as outpatients versus inpatients for most review outcomes. There was no evidence of a difference between the likelihood of women requiring instrumental delivery in either setting (risk ratio (RR) 1.29; 95% confidence interval (CI) 0.79 to 2.13). The overall length of hospital stay was similar in the two groups. 2. Controlled release PGE2 10 mg (one study including 300 women). There was no evidence of differences between groups for most review outcomes, including success of induction. During the induction period itself, women in the outpatient group were more likely to report high levels of satisfaction with their care (satisfaction rated seven or more on a nine-point scale, RR 1.42; 95% CI 1.11 to 1.81), but satisfaction scores measured postnatally were similar in the two groups. 3. Foley catheter (one study including 111 women). There was no evidence of differences between groups for caesarean section rates, total induction time and the numbers of babies admitted to neonatal intensive care. The data available to evaluate the efficacy or potential hazards of outpatient induction are limited. It is, therefore, not yet possible to determine whether induction of labour is effective and safe in outpatient settings.
In this update, we included three trials involving 1398 postoperative participants. Participants were submitted to general surgical procedures, minor and major, and the minimum mean age was 49 years. Pooled analysis showed a significant reduction in the risk of HIT with LMWH compared with UFH (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.07 to 0.73); low-quality evidence. The number needed to treat for an additional beneficial outcome (NNTB) was 59. The risk of HIT was consistently reduced comparing participants undergoing major surgical procedures exposed to LMWH or UFH (RR 0.22, 95% CI 0.06 to 0.75); low-quality evidence. The occurrence of HIT complicated by venous thromboembolism was significantly lower in participants receiving LMWH compared with UFH (RR 0.22, 95% CI 0.06 to 0.84); low-quality evidence. The NNTB was 75. Arterial thrombosis occurred in only one participant who received UFH. There were no amputations or deaths documented. Although limited evidence is available, it appears that HIT induced by both types of heparins is common in people undergoing major surgical procedures (incidence greater than 1% and less than 10%). This updated review demonstrated low-quality evidence of a lower incidence of HIT, and HIT complicated by venous thromboembolism, in postoperative patients undergoing thromboprophylaxis with LMWH compared with UFH. Similarily, the risk of HIT in people undergoing major surgical procedures was lower when treated with LMWH compared to UFH (low-quality evidence). The quality of the evidence was downgraded due to concerns about the risk of bias in the included studies and imprecision of the study results. These findings may support current clinical use of LMWH over UFH as front-line heparin therapy. However, our conclusions are limited and there was an unexpected paucity of RCTs including HIT as an outcome. To address the scarcity of clinically-relevant information on HIT, HIT must be included as a core harmful outcome in future RCTs of heparin.
Six treatment trials involving 1906 children with clinical influenza and 450 children with influenza diagnosed on rapid near-patient influenza testing were included. Of these 2356 children, 1255 had laboratory-confirmed influenza. Three prophylaxis trials involving 863 children exposed to influenza were also included. In children with laboratory-confirmed influenza oseltamivir reduced median duration of illness by 36 hours (26%, P < 0.001). One trial of oseltamivir in children with asthma who had laboratory-confirmed influenza showed only a small reduction in illness duration (10.4 hours, 8%), which was not statistically significant (P = 0.542). Laninamivir octanoate 20 mg reduced symptom duration by 2.8 days (60%, P < 0.001) in children with oseltamivir-resistant influenza A/H1N1. Zanamivir reduced median duration of illness by 1.3 days (24%, P < 0.001). Oseltamivir significantly reduced acute otitis media in children aged one to five years with laboratory-confirmed influenza (risk difference (RD) -0.14, 95% confidence interval (CI) -0.24 to -0.04). Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in developing influenza after the introduction of a case into a household (RD -0.08, 95% CI -0.12 to -0.05, P < 0.001). The adverse event profile of zanamivir was no worse than placebo but vomiting was more commonly associated with oseltamivir (number needed to harm = 17, 95% CI 10 to 34). The adverse event profiles of laninamivir octanoate and oseltamivir were similar. Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. In addition, the inclusion of data from published trials only may have resulted in significant publication bias. Based on published trial data, oseltamivir reduces the incidence of acute otitis media in children aged one to five years but is associated with a significantly increased risk of vomiting. One study demonstrated that laninamivir octanoate was more effective than oseltamivir in shortening duration of illness in children with oseltamivir-resistant influenza A/H1N1. The benefit of oseltamivir and zanamivir in preventing the transmission of influenza in households is modest and based on weak evidence. However, the clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups.
Four studies (199 participants) met the inclusion criteria and were predominantly conducted in children with cystic fibrosis. Only one study had a combined cohort of adult and paediatric participants. The description of study methods was inadequate to assess the risk of bias, particularly with regard to blinding of assessors and selective reporting. One study was conducted in an inpatient setting with follow up in the outpatient setting; while the remaining three studies were conducted in individuals with stable respiratory disease in the outpatient setting. All included studies used exercise training to promote participation in physical activity, with the duration of the intervention period ranging from 18 days to three years. No improvement in physical activity participation was reported with any intervention period less than or equal to six months. Improvements in physical activity participation were only seen where follow up occurred beyond 12 months. There was no significant impact on quality of life from any of the intervention strategies. Although participation in physical activity is generally regarded as beneficial for people with cystic fibrosis, there is a lack of evidence regarding strategies to promote the uptake and the continued participation in physical activity for this population. This review provides very limited evidence that activity counselling and exercise advice, undertaken over at least six months, to engage in a home exercise programme may result in improved physical activity participation in people with cystic fibrosis. Further research is needed to determine the effect of strategies such as health coaching or telemedicine applications, in promoting the uptake and adherence to regular participation in physical activity. In addition, establishing the ideal duration of any interventions that promote physical activity, including exercise training programmes, will be important in addressing issues relating to participation in physical activity for people with cystic fibrosis.
Results of only a limited number of studies could be combined, in view of different types of interventions and variable quality of data. We found six trials of proprietary herbal mixtures and one of whole system Ayurvedic treatment. These studies enrolled 354 participants ( 172 on treatment, 158 on controls, 24 allocation unknown). The treatment duration ranged from 3 to 6 months. All these studies included adults with type 2 diabetes mellitus. With regard to our primary outcomes, significant reductions in glycosylated haemoglobin A1c (HbA1c), fasting blood sugar (FBS) or both were observed with Diabecon, Inolter and Cogent DB compared to placebo or no additional treatment, while no significant hypoglycaemic response was found with Pancreas tonic and Hyponidd treatment. The study of whole system Ayurvedic treatment did not provide data on HbA1c and FBS values. One study of Pancreas tonic treatment did not detect a significant change in health-related quality of life. The main adverse effects reported were drug hypersensitivity (one study, one patient in the treatment arm); hypoglycaemic episodes (one study, one participant in the treatment arm; none had severe hypoglycaemia) and gastrointestinal side effects in one study (1 of 20 in the intervention group and 0 of 20 participants in the control group). None of the included studies reported any deaths, renal, hematological or liver toxicity. With regard to our secondary outcomes, post prandial blood sugar (PPBS) was lower among participants treated with Diabecon, was unchanged with Hyponidd and was higher in patients treated with Cogent DB. Treatment with Pancreas tonic and Hyponidd did not affect lipid profile significantly, while patients treated with Inolter had significantly higher HDL- and lower LDL-cholesterol as well as lower triglycerides. Cogent DB treated participants also had lower total cholesterol and triglycerides. Studies of treatment with Diabecon reported increased fasting insulin levels; one study of treatment with Diabecon reported higher stimulated insulin levels and fasting C-peptide levels in the treatment group. There was no significant difference in fasting and stimulated C-peptide and insulin levels with Hyponidd, Cogent DB and Pancreas tonic treatment. The study of Inolter did not assess these outcomes. No study reported on or was designed to investigate diabetic complications, death from any cause and economic data. Although there were significant glucose-lowering effects with the use of some herbal mixtures, due to methodological deficiencies and small sample sizes we are unable to draw any definite conclusions regarding their efficacy. Though no significant adverse events were reported, there is insufficient evidence at present to recommend the use of these interventions in routine clinical practice and further studies are needed.
108 trials were located using the specified search strategy in 2001. An additional three trials were located when the search strategy was repeated in 2004. Of the total number of trials located in both searches, only two trials, involving a total of 64 patients, were of sufficient quality to meet inclusion criteria. The available evidence suggests these substances were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78). However, the evidence was of insufficient quality to be conclusive. A large number of studies appear to address the research questions, but few are of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluate the efficacy and safety of 5-HTP and tryptophan before their widespread use can be recommended. The possible association between these substances and the potentially fatal Eosinophilia-Myalgia Syndrome has not been elucidated. Because alternative antidepressants exist which have been proven to be effective and safe the clinical usefulness of 5-HTP and tryptophan is limited at present.
We included 15 studies (1722 participants) in the review. There are also four ongoing studies and four studies await classification. The 15 included studies evaluated four comparisons: removable retainers versus fixed retainers (three studies); different types of fixed retainers (four studies); different types of removable retainers (eight studies); and one study compared a combination of upper thermoplastic and lower bonded versus upper thermoplastic with lower adjunctive procedures versus positioner. Four studies had a low risk of bias, four studies had an unclear risk of bias and seven studies had a high risk of bias. Removable versus fixed retainers Thermoplastic removable retainers provided slightly poorer stability in the lower arch than multistrand fixed retainers: MD (Little's Irregularity Index, 0 mm is stable) 0.6 mm (95% CI 0.17 to 1.03). This was based on one trial with 84 participants that was at high risk of bias; it was low quality evidence. Results on retainer failure were inconsistent. There was evidence of less gingival bleeding with removable retainers: RR 0.53 (95% CI 0.31 to 0.88; one trial, 84 participants, high risk of bias, low quality evidence), but participants found fixed retainers more acceptable to wear, with a mean difference on a visual analogue scale (VAS; 0 to 100; 100 being very satisfied) of -12.84 (95% CI -7.09 to -18.60). Fixed versus fixed retainers The studies did not report stability, adverse effects or participant satisfaction. It was possible to pool the data on retention failure from three trials that compared polyethylene ribbon bonded retainer versus multistrand retainer in the lower arch with an RR of 1.10 (95% CI 0.77 to 1.57; moderate heterogeneity; three trials, 228 participants, low quality evidence). There was no evidence of a difference in failure rates. It was also possible to pool the data from two trials that compared the same types of upper fixed retainers, with a similar finding: RR 1.25 (95% CI 0.87 to 1.78; low heterogeneity; two trials, 174 participants, low quality evidence). Removable versus removable retainers One study at low risk of bias comparing upper and lower part-time thermoplastic versus full-time thermoplastic retainer showed no evidence of a difference in relapse (graded moderate quality evidence). Another study, comparing part-time and full-time wear of lower Hawley retainers, found no evidence of any difference in relapse (low quality evidence). Two studies at high risk of bias suggested that stability was better in the lower arch for thermoplastic retainers versus Hawley, and for thermoplastic full-time versus Begg (full-time) (both low quality evidence). In one study, participants wearing Hawley retainers reported more embarrassment more often than participants wearing thermoplastic retainers: RR 2.42 (95% CI 1.30 to 4.49; one trial, 348 participants, high risk of bias, low quality evidence). They also found Hawley retainers harder to wear. There was conflicting evidence about survival rates of Hawley and thermoplastic retainers. Other retainer comparisons Another study with a low risk of bias looked at three different approaches to retention for people with crowding, but normal jaw relationships. The study found that there was no evidence of a difference in relapse between the combination of an upper thermoplastic and lower canine to canine bonded retainer and the combination of an upper thermoplastic retainer and lower interproximal stripping, without a lower retainer. Both these approaches are better than using a positioner as a retainer. We did not find any evidence that wearing thermoplastic retainers full-time provides greater stability than wearing them part-time, but this was assessed in only a small number of participants. Overall, there is insufficient high quality evidence to make recommendations on retention procedures for stabilising tooth position after treatment with orthodontic braces. Further high quality RCTs are needed.
We included four RCTs involving 758 participants. We did not pool data because of heterogeneity in study designs, outcomes and time points. The studies provided sparse information about effects longer than a few hours, as three of four included studies were short trials of only four to six hours. Participants treated with acetaminophen had significant improvements in nasal obstruction in two of the four studies. One study showed that acetaminophen was superior to placebo in decreasing rhinorrhoea severity, but was not superior for treating sneezing and coughing. Acetaminophen did not improve sore throat or malaise in two of the four studies. Results were inconsistent for some symptoms. Two studies showed that headache and achiness improved more in the acetaminophen group than in the placebo group, while one study showed no difference between the acetaminophen and placebo group. None of the included studies reported the duration of common cold symptoms. Minor side effects (including gastrointestinal adverse events, dizziness, dry mouth, somnolence and increased sweating) in the acetaminophen group were reported in two of the four studies. One of them used a combination of pseudoephedrine and acetaminophen. Acetaminophen may help relieve nasal obstruction and rhinorrhoea but does not appear to improve some other cold symptoms (including sore throat, malaise, sneezing and cough). However, two of the four included studies in this review were small and allocation concealment was unclear in all four studies. The data in this review do not provide sufficient evidence to inform practice regarding the use of acetaminophen for the common cold in adults. Further large-scale, well-designed trials are needed to determine whether this intervention is beneficial in the treatment of adults with the common cold.
Thirty-one published RCTs of all forms of surgical treatment for degenerative lumbar spondylosis were identified. The trials varied in quality: only the more recent trials used appropriate methods of randomization, blinding and independent assessment of outcome. Most of the earlier published results were of technical surgical outcomes with some crude ratings of clinical outcome. More of the recent trials also reported patient-centered outcomes of pain or disability, but there is still very little information on occupational outcomes. There was a particular lack of long term outcomes beyond two to three years. Seven heterogeneous trials on spondylolisthesis, spinal stenosis and nerve compression permitted limited conclusions. Two new trials on the effectiveness of fusion showed conflicting results. One showed that fusion gave better clinical outcomes than conventional physiotherapy, while the other showed that fusion was no better than a modern exercise and rehabilitation programme. Eight trials showed that instrumented fusion produced a higher fusion rate (though that needs to be qualified by the difficulty of assessing fusion in the presence of metal-work), but any improvement in clinical outcomes is probably marginal, while there is other evidence that it may be associated with higher complication rates. Three trials with conflicting results did not permit any conclusions about the relative effectiveness of anterior, posterior or circumferential fusion. Preliminary results of two small trials of intra-discal electrotherapy showed conflicting results. Preliminary data from three trials of disc arthroplasty did not permit any firm conclusions. Limited evidence is now available to support some aspects of surgical practice. Surgeons should be encouraged to perform further RCTs in this field.
We did not identify any new trials from the updated search so the results remain unchanged as follows. We included four trials involving 852 women. Three trials (involving 500 women) evaluating the effects of IAP versus no treatment were included. The use of IAP did not significantly reduce the incidence of all cause mortality, mortality from GBS infection or from infections caused by bacteria other than GBS. The incidence of early GBS infection was reduced with IAP compared to no treatment (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk difference -0.04, 95% CI -0.07 to -0.01; number needed to treat to benefit 25, 95% CI 14 to 100, I² 0%). The incidence of LOD or sepsis from organisms other than GBS and puerperal infection was not significantly different between groups. One trial (involving 352 women) compared intrapartum ampicillin versus penicillin and reported no significant difference in neonatal or maternal outcomes. We found a high risk of bias for one or more key domains in the study methodology and execution. Intrapartum antibiotic prophylaxis appeared to reduce EOGBSD, but this result may well be due to bias as we found a high risk of bias for one or more key domains in the study methodology and execution. There is lack of evidence from well designed and conducted trials to recommend IAP to reduce neonatal EOGBSD. Ideally the effectiveness of IAP to reduce neonatal GBS infections should be studied in adequately sized double-blind controlled trials. The opportunity to conduct such trials has likely been lost, as practice guidelines (albeit without good evidence) have been introduced in many jurisdictions.
One hundred and eighteen studies with 138 treatment groups and 17,364 participants were included in this review. Fifty-seven of these studies were included in the original version of this review while 61 were added, including 27 on interventions that were not considered in the original version. Interventions included amiodarone, beta-blockers, sotalol, magnesium, atrial pacing and posterior pericardiotomy. Each of the studied interventions significantly reduced the rate of post-operative atrial fibrillation after cardiac surgery compared with a control. Beta-blockers (odds ratio (OR) 0.33; 95% confidence interval) CI 0.26 to 0.43; I2 = 55%) and sotalol (OR 0.34; 95% CI 0.26 to 0.43; I2 = 3%) appear to have similar efficacy while magnesium's efficacy (OR 0.55; 95% CI 0.41 to 0.73; I2 = 51%) may be slightly less. Amiodarone (OR 0.43; 95% CI 0.34 to 0.54; I2 = 63%), atrial pacing (OR 0.47; 95% CI 0.36 to 0.61; I2 = 50%) and posterior pericardiotomy (OR 0.35; 95% CI 0.18 to 0.67; I2 = 66%) were all found to be effective. Prophylactic intervention decreased the hospital length of stay by approximately two-thirds of a day and decreased the cost of hospital treatment by roughly $1250 US. Intervention was also found to reduce the odds of post-operative stroke, though this reduction did not reach statistical significance (OR 0.69; 95% CI 0.47 to 1.01; I2 = 0%). No significant effect on all-cause or cardiovascular mortality was demonstrated. Prophylaxis to prevent atrial fibrillation after cardiac surgery with any of the studied pharmacological or non-pharmacological interventions may be favored because of its reduction in the rate of atrial fibrillation, decrease in the length of stay and cost of hospital treatment and a possible decrease in the rate of stroke. However, this review is limited by the quality of the available data and heterogeneity between the included studies. Selection of appropriate interventions may depend on the individual patient situation and should take into consideration adverse effects and the cost associated with each approach.
We identified 115 trial reports representing 55 trials, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials (98 participants) compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second (very-low quality evidence). Similarly, forced vital capacity (low-quality evidence) and quality of life (very-low quality evidence) were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small trials in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant. In one trial (25 participants), morning versus evening inhalation had no impact on lung function or symptoms (low-quality evidence). The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and trials with variable follow-up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alfa inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.
Sixty-six trials met our inclusion criteria for one or more of the comparisons in the review. Thirteen trials compared a group programme with a self-help programme; there was an increase in cessation with the use of a group programme (N = 4395, risk ratio (RR) 1.88, 95% confidence interval (CI) 1.52 to 2.33, I2 = 0%). We judged the GRADE quality of evidence to be moderate, downgraded due to there being few studies at low risk of bias. Fourteen trials compared a group programme with brief support from a health care provider. There was a small increase in cessation (N = 7286, RR 1.22, 95% CI 1.03 to 1.43, I2 = 59%). We judged the GRADE quality of evidence to be low, downgraded due to inconsistency in addition to risk of bias. There was also low quality evidence of benefit of a group programme compared to no-intervention controls, (9 trials, N = 1098, RR 2.60, 95% CI 1.80 to 3.76 I2 = 55%). We did not detect evidence that group therapy was more effective than a similar intensity of individual counselling (6 trials, N = 980, RR 0.99, 95% CI 0.76 to 1.28, I2 = 9%). Programmes which included components for increasing cognitive and behavioural skills were not shown to be more effective than same-length or shorter programmes without these components. Group therapy is better for helping people stop smoking than self-help, and other less intensive interventions. There is not enough evidence to evaluate whether groups are more effective, or cost-effective, than intensive individual counselling. There is not enough evidence to support the use of particular psychological components in a programme beyond the support and skills training normally included.
We identified nine eligible trials that randomised 4940 participants, who had received surgical resection or curative radiotherapy, to either an immunotherapy group or a control group. Included immunological interventions were active immunotherapy (i.e. Bacillus Calmette-Guérin (BCG)), adoptive cell transfer (i.e. transfer factor (TF), tumour-infiltrating lymphocytes (TIL), dendritic cell-cytokine induced killer (DC-CIK), and antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25). Except for one small trial, which provided insufficient information for risk assessment, we assessed five studies at high risk of bias for at least one of the seven biases studied; we considered the risk of bias in the other three trials to be low. We included data from seven of the nine trials in the meta-analyses (4695 participants). We pooled data from 3693 participants from the three high quality RCTs to evaluate overall survival (OS) and progression-free survival (PFS). We found a small, but not statistically significant, improvement in OS (HR 0.94, 95% CI 0.83 to 1.06; P = 0.35), and PFS (HR 0.93, 95% CI 0.81 to 1.07; P = 0.19; high-quality evidence). The addition of immunotherapy resulted in a small, but not statistically significant, increased risk of having any adverse event (RR 1.15, 95% CI 0.97 to 1.37; P = 0.11, three trials, 3955 evaluated participants, moderate-quality evidence), or severe adverse events (RR 1.10, 95% CI 0.88 to 1.39; four trials, 4362 evaluated participants; low-quality evidence). We analysed data from six studies for one-, two-, and three-year survival rates (4265 participants), and from six studies for five-year survival rates (4234 participants). We observed no clear between-group differences (low-quality evidence for one- and two-year survival rates, and moderate-quality evidence for three- and five-year survival rate). No trial reported the overall response rates; only one trial provided health-related quality of life results. The current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for patients with localised NSCLC (stages I to III). The addition of vaccine-based immunotherapy might increase the risk of adverse events. Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights for role of immunotherapy for patients with stages I to III NSCLC.
Eight studies were included, which represented 233 males with all severities of haemophilia A and B, ranging in age from eight years to 49 years. Study duration ranged from four to 12 weeks. Exercise interventions varied greatly and included resistance exercises, isometric exercises, bicycle ergometry, treadmill walking and hydrotherapy; therefore, comparison between studies was difficult. None of the studies measured or reported adverse effects from the interventions. None of the studies reported outcomes regarding bleed frequency, quality of life or aerobic activity. Overall risk of bias across all studies was assessed as unclear. Very few studies provided sufficient information for comparison. None of the studies reported data that favoured the control group. One study reported that six weeks of resistance training improved joint health status (Colorado score) compared to controls. The addition of pulsed electromagnetic fields also improved ankle scores compared to exercises alone, but this was not seen in the elbows or knees. Two studies reported statistically significant improvements in pain intensity after exercise interventions compared to controls. Hydrotherapy exercises produced significant decreases in pain compared to controls and land-based exercise groups. Two studies found improvement in joint motion in the exercise group compared to controls. One study compared land- and water-based exercises; there was no difference in the range of motion between the two groups; however, the water-based exercise group did show improvement over the control group. One study, comparing joint traction and proprioceptive neuromuscular facilitation for the elbow to a control group, showed no differences in biceps girth or strength after 12 weeks of intervention. Some studies reported comparisons between interventions. In one study, treadmill training significantly improved balance in children compared to bicycle ergometry. Another study added partial weight bearing exercises to quadriceps exercises and showed improved walking tolerance. Four studies evaluated quadriceps or hamstring strength (or both). The addition of bicycle ergometry and exercises with weights was more effective than static exercises and treadmill walking for strengthening knee flexors and extensors. Partial weight-bearing exercises through range were more effective than static and short arc exercises for improving knee extensor strength. The addition of treadmill walking to ultrasound, stretching and strengthening exercises showed increased peak torque of knee flexors and extensors and decrease in knee effusion. The results should be interpreted with caution due to the quality of evidence (GRADE) as outlined in the summary of findings tables, which demonstrates that all but one of the outcomes assessed were rated as low or very low due to the small sample sizes and potential bias. These results must be considered with caution. There is a lack of confidence in the results due to the small number of included studies and the inability to pool the results due to the heterogeneity of outcome measures. Most exercise interventions produced improvement in one or more of the measured outcomes including pain, range of motion, strength and walking tolerance. Hydrotherapy may be more effective than land exercises for pain relief in adults. Functional exercises such as treadmill walking and partial weight bearing exercises seem to be more effective than static or short arc exercises for improving muscle strength. These findings are consistent with the many non-controlled intervention reports in the haemophilia literature. No adverse effects were reported as a result of any of the interventions. However, some groups used prophylactic factor prior to exercise and other groups studied only subjects with moderate haemophilia. Therefore, the safety of these techniques for persons with severe haemophilia remains unclear.
Two studies involving a total of 467 participants, aged over 18 years, were eligible for inclusion. Both studies assessed losigamone 1200 mg/day or 1500 mg/day as an add-on therapy for focal epilepsy. We assessed one study as being of good methodological quality while the other was of uncertain quality. For the efficacy outcomes, results showed that participants taking losigamone were significantly more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.76, 95% CI 1.14 to 2.72; 2 studies, 467 participants; moderate-quality evidence), but associated with a significant increase of treatment withdrawal when compared with those taking placebo (RR 2.16, 95% CI 1.28 to 3.67; 2 studies, 467 participants; moderate-quality evidence). For the tolerability outcomes, results indicated that the proportion of participants who experienced adverse events in the losigamone group was higher than in the placebo group (RR 1.34, 95% CI 1.00 to 1.80; 2 studies, 467 participants; moderate-quality evidence). Dizziness was the only adverse event significantly reported in relation to losigamone (RR 3.82, 99% CI 1.69 to 8.64; 2 studies; 467 participants; moderate-quality evidence). Neither study reported the proportion of participants achieving seizure freedom. A subgroup analysis according to different doses of losigamone showed that a higher dose of losigamone (1500 mg/day) was associated with a greater reduction in seizure frequency than lower doses, but was also associated with more dropouts due to adverse events. The results of this review showed that losigamone did reduce seizure frequency but was associated with more treatment withdrawals when used as an add-on therapy for people with focal epilepsy. However, the included studies were of short-term duration and uncertain quality. Future well-designed randomized, double-blind, placebo-controlled studies with a longer-term duration are needed. We did not find any new studies since the last version of this review. We judged the overall quality of the evidence for the outcomes assessed as moderate.
We included 16 trials with 3048 participants. None of the studies reported hypertension as a dichotomous outcome. The effect on systolic and diastolic blood pressure was mean difference (MD) -1.43 mmHg (95% confidence interval (CI) -2.15 to -0.72) and -0.98 mmHg (95%CI -1.46 to -0.50) respectively. The effect on systolic and diastolic blood pressure for those younger than 35 years (7 trials with 399 participants) was -2.11 mmHg (95%CI -3.58 to -0.64) / -2.61 mmHg (95% CI -3.74, -1.49). The effect on systolic and diastolic blood pressure for those 35 years or more (9 trials with 2649 participants) was -0.96 mmHg (95%CI -1.83 to -0.09) / -0.59 mmHg (95%CI -1.13 to -0.06). The effect on systolic and diastolic blood pressure for women (6 trials with 1823 participants) was -1.45 mmHg (95% CI -2.78 to -0.12) / -0.92 mmHg (95% CI -1.71 to -0.14). The effect on systolic and diastolic blood pressure for men (5 trials with 617 participants) was -2.07 (95%CI -3.56 to -0.59] / -1.91 (95%CI -2.80 to -1.02).The quality of evidence for each of these outcomes was high. The effect is consistent in both genders regardless of baseline calcium intake. The effect on systolic blood pressure was 0.08 mmHg (95% CI -2.16 to 2.32) with doses less than 1000 mg, -1.14 mmHg (95% CI -2.01 to -0.27) with 1000 - 1500 mg, and -2.79 mmHg (95% CI -4.71 to -0.86) with more than 1500 mg. The effect on diastolic blood pressure was -0.54 mmHg (95% CI -2.23 to 1.15), -0.71 mmHg (95% CI -1.37 to -0.06) and -1.43 mmHg (95% CI -2.22 to -0.64) respectively. The quality of evidence for each of these outcomes was high. None of the studies reported adverse events. An increase in calcium intake slightly reduces both systolic and diastolic blood pressure in normotensive people, particularly in young people, suggesting a role in the prevention of hypertension. These results should be interpreted with caution, since the proposed biological mechanism explaining the relationship between calcium and blood pressure has not been fully confirmed. The effect across multiple prespecified subgroups and a possible dose response effect reinforce this conclusion. Even small reductions in blood pressure could have important health implications for reducing vascular disease. There is a great need for adequately-powered clinical trials randomising young people. Subgroup analysis should involve basal calcium intake, age, sex, basal blood pressure, and body mass index. We also require assessment of side effects, optimal doses and the best strategy to improve calcium intake.
We included twelve trials (577 participants). Ten trials (531 participants) enrolled people with a diabetic foot ulcer: pooled data of five trials with 205 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 2.35, 95% confidence interval (CI) 1.19 to 4.62; P = 0.01) with HBOT at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We identified one trial (30 participants) which enrolled patients with non-healing diabetic ulcers as well as venous ulcers ("mixed ulcers types") and patients were treated for 30 days. For this "mixed ulcers" there was a significant benefit of HBOT in terms of reduction in ulcer area at the end of treatment (30 days) (MD 61.88%, 95% CI 41.91 to 81.85, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers. In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias.
We included 33 trials with 5710 participants total; 29 were published from 2010 to 2015. Studies examined lidocaine, misoprostol, NSAIDs, and other interventions. Here we synthesize results from trials with sufficient outcome data and moderate- or high-quality evidence. For lidocaine, meta-analysis showed topical 2% gel had no effect on pain at tenaculum placement (two trials) or on pain during IUC insertion (three trials). Other formulations were effective compared with placebo in individual trials. Mean score for IUC-insertion pain was lower with lidocaine and prilocaine cream (MD -1.96, 95% CI -3.00 to -0.92). Among nulliparous women, topical 4% formulation showed lower scores for IUC-insertion pain assessed within 10 minutes (MD -15.90, 95% CI -22.77 to -9.03) and at 30 minutes later (MD -11.10, 95% CI -19.05 to -3.15). Among parous women, IUC-insertion pain was lower with 10% spray (median 1.00 versus 3.00). Compared with no intervention, pain at tenaculum placement was lower with 1% paracervical block (median 12 versus 28). For misoprostol, meta-analysis showed a higher mean score for IUC insertion compared with placebo (SMD 0.27, 95% CI 0.07 to 0.46; four studies). In meta-analysis, cramping was more likely with misoprostol (OR 2.64, 95% CI 1.46 to 4.76; four studies). A trial with nulliparous women found a higher score for IUC-insertion pain with misoprostol (median 46 versus 34). Pain before leaving the clinic was higher for misoprostol in two trials with nulliparous women (MD 7.60, 95% CI 6.48 to 8.72; medians 35.5 versus 20.5). In one trial with nulliparous women, moderate or severe pain at IUC insertion was less likely with misoprostol (OR 0.30, 95% CI 0.16 to 0.55). In the same trial, the misoprostol group was more likely to rate the experience favorably. Within two trials of misoprostol plus diclofenac, shivering, headache, or abdominal pain were more likely with misoprostol. Participants had no vaginal delivery. One trial showed the misoprostol group less likely to choose or recommend the treatment. Among multiparous women, mean score for IUC-insertion pain was lower for tramadol 50 mg versus naproxen 550 mg (MD -0.63, 95% CI -0.94 to -0.32) and for naproxen versus placebo (MD -1.94, 95% CI -2.35 to -1.53). The naproxen group was less likely than the placebo group to report the insertion experience as unpleasant and not want the medication in the future. An older trial showed repeated doses of naproxen 300 mg led to lower pain scores at one hour (MD -1.04, 95% CI -1.67 to -0.41) and two hours (MD -0.98, 95% CI -1.64 to -0.32) after insertion. Most women were nulliparous and also had lidocaine paracervical block. Nearly all trials used modern IUC. Most effectiveness evidence was of moderate quality, having come from single trials. Lidocaine 2% gel, misoprostol, and most NSAIDs did not help reduce pain. Some lidocaine formulations, tramadol, and naproxen had some effect on reducing IUC insertion-related pain in specific groups. The ineffective interventions do not need further research.
Seventeen studies were included in the review, involving 3097 participants. Based on all 17 studies, SSRIs as a group were more effective than placebo in reducing the symptoms of OCD between 6 and 13 weeks post-treatment, measured using the Yale-Brown Obsessive Compulsive Scale (YBOCS) (WMD -3.21, 95% CI -3.84 to -2.57). The WMD for individual SSRI drugs were similar and not statistically different. Based on 13 studies (2697 participants), SSRIs were more effective than placebo in achieving clinical response at post-treatment (RR 1.84, 95% CI 1.56 to 2.17). The pooled RR was shown to be similar between individual SSRI drugs. Although reported adverse effects data were more limited, with few exceptions, the overall and individual adverse effects for the different SSRIs were always worse than for placebo and, in the majority of cases, the difference was statistically significant. Nausea, headache and insomnia were always reported amongst the most common adverse effects in trials of each of the drugs. SSRIs are more effective than placebo for OCD, at least in the short-term, although there are differences between the adverse effects of individual SSRI drugs. The longer term efficacy and tolerability of different SSRI drugs for OCD has yet to be established.
We included five RCTs involving 576 people. The trials were largely at low risk of bias, but we considered the quality of the evidence from these trials as moderate to low, largely due to imprecision from small sample sizes. Two out of the five trials reported on improvement in nerve function at one year. These two trials compared prednisolone with placebo. One trial, with 84 participants, treated mild sensory impairment of less than six months' duration, and the other, with 95 participants, treated nerve function impairment of 6 to 24 months' duration. There was no significant difference in nerve function improvement after 12 months between people treated with prednisolone and those treated with placebo. Adverse events were not reported significantly more often with corticosteroids than with placebo. The other three trials did not report on the primary outcome measure. One (334 participants) compared three corticosteroid regimens for severe type 1 reactions. No serious side effects of steroids were reported in any participant during the follow-up period. Another trial (21 participants) compared low-dose prednisone with high-dose prednisone for ulnar neuropathy. Two participants on the higher dose of prednisone reported adverse effects. The last (42 participants) compared intravenous methylprednisolone and oral prednisolone with intravenous normal saline and oral prednisolone. The trial found no significant differences between the groups in the occurrence of adverse events. Corticosteroids are used for treating acute nerve damage in leprosy, but moderate-quality evidence from two RCTs treating either longstanding or mild nerve function impairment did not show corticosteroids to have a superior effect to placebo on nerve function improvement. A third trial showed significant benefit from a five-month steroid regimen over a three-month regimen in terms of response to treatment (need for additional corticosteroids). Further RCTs are needed to establish optimal corticosteroid regimens and to examine the efficacy and safety of adjuvant or new therapies for treating nerve damage in leprosy. Future trials should address non-clinical aspects, such as costs and impact on quality of life, which are highly relevant indicators for both policymakers and participants.
We included one RCT, involving 48 women who had a miscarriage between eight to 24 weeks of gestation. Of the 19 women in the treatment group, 14 had therapeutic dilatation & curettage (D&C) and five had spontaneous miscarriage; of the 29 women in the control group, 25 had therapeutic D&C and four had spontaneous miscarriage. The treatment group received 300 µg anti-D Ig intramuscular injection and were compared with a control group who received 1 cc homogenous gamma globulin placebo. This review's primary outcomes (development of a positive Kleihauer Betke test (a test that detects fetal cells in the maternal blood; and development of RhD alloimmunisation in a subsequent pregnancy) were not reported in the included study. Similarly, none of the review's secondary outcomes were reported in the included study: the need for increased surveillance for suspected fetal blood sampling and fetal transfusions in subsequent pregnancies, neonatal morbidity such as neonatal anaemia, jaundice, bilirubin encephalopathy, erythroblastosis, prematurity, hypoglycaemia (low blood sugar) in subsequent pregnancies, maternal adverse events of anti-D administration including anaphylactic reaction and blood-borne infections. The included study did report subsequent Rh-positive pregnancies in three women in the treatment group and six women in the control group. However, due to the small sample size, the study failed to show any difference in maternal sensitisation or development of Rh alloimmunisation in the subsequent pregnancies. There are insufficient data available to evaluate the practice of anti-D administration in an unsensitised Rh-negative mother after spontaneous miscarriage. Thus, until high-quality evidence becomes available, the practice of anti-D Immunoglobulin prophylaxis after spontaneous miscarriage for preventing Rh alloimmunisation cannot be generalised and should be based on the standard practice guidelines of each country.
Thirty-one RCTs were included in the review. They compared fluoxetine, paroxetine, sertraline, escitalopram and citalopram versus placebo. SSRIs reduced overall self-rated symptoms significantly more effectively than placebo. The effect size was moderate when studies reporting end scores were pooled (for moderate dose SSRIs: SMD -0.65, 95% CI -0.46 to -0.84, nine studies, 1276 women; moderate heterogeneity (I2 = 58%), low quality evidence). The effect size was small when studies reporting change scores were pooled (for moderate dose SSRIs: SMD -0.36, 95% CI -0.20 to -0.51, four studies, 657 women; low heterogeneity (I2=29%), moderate quality evidence). SSRIs were effective for symptom relief whether taken only in the luteal phase or continuously, with no clear evidence of a difference in effectiveness between these modes of administration. However, few studies directly compared luteal and continuous regimens and more evidence is needed on this question. Withdrawals due to adverse effects were significantly more likely to occur in the SSRI group (moderate dose: OR 2.55, 95% CI 1.84 to 3.53, 15 studies, 2447 women; no heterogeneity (I2 = 0%), moderate quality evidence). The most common side effects associated with a moderate dose of SSRIs were nausea (NNH = 7), asthenia or decreased energy (NNH = 9), somnolence (NNH = 13), fatigue (NNH = 14), decreased libido (NNH = 14) and sweating (NNH = 14). In secondary analyses, SSRIs were effective for treating specific types of symptoms (that is psychological, physical and functional symptoms, and irritability). Adverse effects were dose-related. The overall quality of the evidence was low to moderate, the main weakness in the included studies being poor reporting of methods. Heterogeneity was low or absent for most outcomes, though (as noted above) there was moderate heterogeneity for one of the primary analyses. SSRIs are effective in reducing the symptoms of PMS, whether taken in the luteal phase only or continuously. Adverse effects are relatively frequent, the most common being nausea and asthenia. Adverse effects are dose-dependent.
No eligible published trials were identified. We identified a completed randomised controlled trial that was designed to evaluate the effects of a diet and exercise intervention compared with standard care in women with a history of GDM, however to date, it has only published results on women who were pregnant at randomisation (and not women in the interconception period). We also identified an ongoing trial, in obese women with a history of GDM planning a subsequent pregnancy, which is assessing the effects of an intensive lifestyle intervention, supported with liraglutide treatment, compared with usual care. We also identified a trial that was designed to evaluate the effects of a weight loss and exercise intervention compared with lifestyle education also in obese women with a history of GDM planning a subsequent pregnancy, however it has not yet been published. These trials will be re-considered for inclusion in the next review update. The role of interconception care for women with a history of GDM remains unclear. Randomised controlled trials are required evaluating different forms and protocols of interconception care for these women on perinatal and long-term maternal and infant health outcomes, acceptability of such interventions and cost-effectiveness.
In the 2014 update of the review, 15 trials have been included, with a total of 453 participants across seven comparison groups. The included trials had either a low or unclear risk of bias for most of the parameters used for risk assessment. Only short-term outcomes could be assessed due to the short duration of follow up in the included trials. None of the primary outcomes, (incidence of ischaemic heart disease, number of deaths and age at death) were evaluated in any of the included trials. No significant differences were noted for the majority of secondary outcomes for any of the planned comparisons. However, a significant difference was found for the following comparisons and outcomes: for the comparison between plant sterols and cholesterol-lowering diet (in favour of plant sterols), total cholesterol levels, mean difference 0.30 mmol/l (95% confidence interval 0.12 to 0.48); decreased serum LDL cholesterol, mean difference -0.60 mmol/l (95% CI -0.89 to -0.31). Fasting serum HDL cholesterol levels were elevated, mean difference -0.04 mmol/l (95% CI -0.11 to 0.03) and serum triglyceride concentration was reduced, mean difference -0.03 mmol/l (95% CI -0.15 to -0.09), although these changes were not statistically significant. Similarly, guar gum when given as an add on therapy to bezafibrate reduced total cholesterol and LDL levels as compared to bezafibrate alone. No conclusions can be made about the effectiveness of a cholesterol-lowering diet, or any of the other dietary interventions suggested for familial hypercholesterolaemia, for the primary outcomes: evidence and incidence of ischaemic heart disease, number of deaths and age at death,due to the lack of data on these. Large, parallel, randomised controlled trials are needed to investigate the effectiveness of a cholesterol-lowering diet and the addition of omega-3 fatty acids, plant sterols or stanols, soya protein, dietary fibers to a cholesterol-lowering diet.
Seventeen studies (1586 children) were included. All studies enrolled children at increased risk of AOM. In seven studies the children were prone to otitis media. The majority were high-quality studies and most (16 studies) reported data for our primary outcomes. One reported AOM with perforation or CSOM. Long-term antibiotics reduced any episode of AOM (14 studies, 1461 children, risk ratio (RR) 0.65, 95% CI 0.53 to 0.79; random-effects model) and number of episodes of AOM (13 studies, 1327 children, incidence rate ratio (IRR) 0.51, 95% CI 0.39 to 0.66; random-effects model). Approximately five children would need to be treated long-term to prevent one child experiencing AOM whilst on treatment. Antibiotics prevented 1.5 episodes of AOM for every 12 months of treatment per child. We explored statistical heterogeneity. Long-term antibiotics were not associated with a significant increase in adverse events (12 studies, 817 children, RR 1.99, 95% CI 0.25 to 15.89; random-effects model). For children at risk, antibiotics given once or twice daily will reduce the probability of AOM while the child is on treatment. In similar populations, antibiotics will reduce the number of episodes of AOM per year from around three to around 1.5. We believe that larger absolute benefits are likely in high-risk children. These conclusions were not affected by sensitivity analyses.
Twelve studies (4755 participants) compared intranasal sumatriptan with placebo or an active comparator. Most of the data were for the 10 mg and 20 mg doses. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 10 mg versus placebo the NNTs were 7.3, 7.4, and 5.5 for pain-free at two hours, and headache relief at one and two hours, respectively. For sumatriptan 20 mg versus placebo the NNTs were 4.7, 4.9, and 3.5, respectively, for the same outcomes. The 20 mg dose was significantly better than the 10 mg dose for each of these three primary efficacy outcomes. Relief of headache-associated symptoms, including nausea, photophobia, and phonophobia, was greater with sumatriptan than with placebo, and use of rescue medication was lower with sumatriptan than placebo. For the most part, adverse events were transient and mild and were more common with sumatriptan than placebo. Direct comparison of sumatriptan with active treatments was limited to two studies, one comparing sumatriptan 20 mg and dihydroergotamine (DHE) 1 mg, and one comparing sumatriptan 20 mg with rizatriptan 10 mg. Intranasal sumatriptan is effective as an abortive treatment for acute migraine attacks, relieving pain, nausea, photophobia, phonophobia, and functional disability, but is associated with increased adverse events compared with placebo.
Nine trials comparing either agalsidase alfa or beta in 351 participants fulfilled the selection criteria. Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores measured by the Brief Pain Inventory severity, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval -3.79 to -0.41; at up to five months, mean difference -1.90 (95% confidence interval -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% confidence interval -3.66 to -0.34). There was a significant difference in the Brief Pain Inventory pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% confidence interval -3.92 to -0.28) but not at other time points. Death was not an outcome in either of the trials. One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% confidence interval -2.09 to -1.31); heart, mean difference -0.90 (95% confidence interval -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% confidence interval -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain. Only two trials compared agalsidase alfa to agalsidase beta. One of them showed no significant difference between the groups regarding adverse events, risk ratio 0.36 (95% confidence interval 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; (95% confidence interval 0.03 to 2.57). Two trials compared different dosing schedules of agalsidase alfa. One of them involved three different doses (0.2 mg/kg every two weeks; 0.1 mg/kg weekly and; 0.2 mg/kg weekly), the other trial evaluated two further doses to the dosage schedules: 0.4 mg/kg every week and every other week. Both trials failed to show significant differences with various dosing schedules on globotriaosylceramide levels. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. One trial comparing agalsidase alfa to agalsidase beta showed no significant difference for any adverse events such as dyspnoea and hypertension. The methodological quality of the included trials was generally unclear for the random sequence generation and allocation concealment. Trials comparing enzyme replacement therapy to placebo show significant improvement with enzyme replacement therapy in regard to microvascular endothelial deposits of globotriaosylceramide and in pain-related quality of life. There is, however, no evidence identifying if the alfa or beta form is superior or the optimal dose or frequency of enzyme replacement therapy. With regards to safety, adverse events (i.e., rigors, fever) were more significant in the agalsidase beta as compared to placebo. The long-term influence of enzyme replacement therapy on risk of morbidity and mortality related to Anderson-Fabry disease remains to be established. This review highlights the need for continued research into the use of enzyme replacement therapy for Anderson-Fabry disease.
Twenty studies with 1969 women were included in this review. These studies compared GnRHa, danazol and progestogens versus placebo or no treatment; GnRHa versus danazol, progestogens, GnRH antagonists or dilatation & curettage; and danazol versus progestogens. Four studies performed more than one comparison. When compared with no treatment, GnRHa used before hysteroscopic resection were associated with a higher rate of postoperative amenorrhoea at 12 months (RR 1.6, 95% CI 1.2 to 2.0, 7 RCTs, 605 women, moderate heterogeneity; I2 = 40%) and at 24 months (RR 1.62, 95% CI 1.04 to 2.52, 2 RCTs, 357 women, no heterogeneity; I2 = 0%), a slightly shorter duration of surgery (-3.5 minutes, 95% CI -4.7 to -2.3, 5 RCTs, 156 women, substantial heterogeneity; I2 = 72%) and greater ease of surgery (RR 0.32, 95% CI 0.22 to 0.46, 2 RCTs, 415 women, low heterogeneity; I2 = 4%). Postoperative dysmenorrhoea was reduced (RR 0.59, 95% CI 0.40 to 0.87, 2 RCTs, 133 women, no heterogeneity; I2 = 0%). The use of GnRHa had no effect on intraoperative complication rates (RR 1.47, 95% CI 0.35 to 6.06, 5 RCTs, 592 women, no heterogeneity; I2 = 0%), and participant satisfaction with this surgery was high irrespective of the use of pre-operative endometrial thinning agents (RR 0.99, 95% CI 0.93 to 1.05, 6 RCTs, 599 women, low heterogeneity; I2 = 11%). GnRHa produced more consistent endometrial atrophy than was produced by danazol (RR 1.84, 95% CI 1.23 to 2.75, 2 RCTs, 142 women, no heterogeneity; I2 = 0%). For other intraoperative and postoperative outcomes, any differences were minimal, and no benefits of GnRHa pretreatment were noted in studies in which women underwent second-generation ablation techniques. Both GnRHa and danazol produced side effects in a significant proportion of women, although few studies reported these in detail. Few randomised data were available to allow assessment of the effectiveness of progestogens as endometrial thinning agents. When reported, the long-term effects of endometrial thinning agents on benefits such as postoperative amenorrhoea were reduced with time. The main study weaknesses were that most participants received no follow-up beyond 24 months and that the studies used a small sample size. Heterogeneity for outcomes reported ranged from none to substantial. More than half the trials had no blinding of participants or outcome assessment. Most of the trials were determined to have uncertain selection and reporting bias, as they did not report allocation concealment and evidence of selective reporting was noted. The quality of reporting of adverse events was generally poor, but, when described in the studies, they included menopausal symptoms such as hot flushes, vaginal dryness, hirsutism, decreased libido and voice changes, as well as other side effects such as headache and weight gain. Low-quality evidence suggests that endometrial thinning with GnRHa and danazol before hysteroscopic surgery improves operating conditions and short-term postoperative outcomes. GnRHa produced slightly more consistent endometrial thinning than was produced by danazol, although both achieved satisfactory results. The effect of these agents on longer-term postoperative outcomes was reduced with time. No benefits of GnRHa pretreatment were apparent with second-generation ablation techniques. Also, side effects were more common when these agents were used.
We included four studies, all of which enrolled adults with frequent episodic TTH. They all specified using the IHS diagnostic criteria and reported mean baseline pain of at least moderate intensity. While 1253 people with TTH participated in these studies, the numbers available for any analysis were lower than this because outcomes were inconsistently reported and because many participants received active comparators. None of the included studies were at low risk of bias across all domains considered, although for most studies and domains this was likely to be due to inadequate reporting rather than poor methods. We judged one study to be at high risk of bias due to small size. Useful information was available only for ketoprofen 25 mg. For the IHS preferred outcome of being pain-free at two hours the NNT for ketoprofen 25 mg compared with placebo was 9.0 (95% confidence interval (CI) 4.8 to 72) in two studies (272 participants; low quality evidence). The NNT was 3.7 (95% CI 2.6 to 6.3) for pain-free or mild pain at two hours in two studies (272 participants; moderate quality evidence). Fewer people needed rescue medication with ketoprofen 25 mg than with placebo, with a number needed to treat to prevent one event (NNTp) of 6.2 (95% CI 4.3 to 11) in three studies (605 participants; moderate quality evidence). The number of participants reporting any adverse event was higher with ketoprofen 25 mg than placebo (NNH 15, (95% CI 8.7 to 45)) in three studies (651 participants with 66 events; low quality evidence). Most events were of mild to moderate intensity. Ketoprofen 25 mg was not different from paracetamol 1000 mg in two studies with 276 participants for any efficacy outcomes (low to moderate quality evidence); the RR for pain-free at two hours was 1.3 (95% CI 0.9 to 2.0). The number of participants reporting any adverse event was higher with ketoprofen 25 mg than with paracetamol (NNH 17, 95% CI 8.9 to 130)) in two studies (582 participants, 68 events; low quality evidence). Studies reported no serious adverse events. We judged the quality of the evidence comparing ketoprofen 25 mg with placebo or paracetamol 1000 mg as moderate to very low. Where evidence was downgraded it was because of the small number of studies and events. Ketoprofen 25 mg provided a small benefit compared with placebo in terms of being pain-free at two hours or having mild or no pain at two hours for people with frequent episodic TTH who have an acute headache of moderate or severe intensity. Its use was associated with more people experiencing adverse events. Ketoprofen 25 mg was not superior to paracetamol 1000 mg for any efficacy outcome.
We identified seven RCTs. These trials differ in inclusion criteria, comparison with alternative treatment and outcomes. In a trial comparing IVIg with placebo, including 51 participants with myasthenia gravis worsening, the mean difference (MD) in quantitative myasthenia gravis score (QMGS) (MD 95% CI) after 14 days was: -1.60 (95% CI - 3.23 to 0.03) this result being borderline statistically significant in favour of IVIg. In an unblinded study of 87 participants with exacerbation comparing IVIg and plasma exchange there was no difference in myasthenic muscle score (MMS) after 15 days (MD -1.00; 95% CI -7.72 to 5.72). In a study of 84 participants with worsening myasthenia gravis there was no difference in change in QMGS 14 days after IVIg or plasma exchange (MD -1.50; 95% CI -3.43 to 0.43). In a study of 12 participants with moderate or severe myasthenia gravis, which was at high risk of bias from skewed allocation, the mean fall in QMGS both for IVIg and plasma exchange after four weeks was significant (P < 0.05). A study with 15 participants with mild or moderate myasthenia gravis found no difference in change in QMGS 42 days after IVIg or placebo (MD 1.60; 95% CI -1.92 to 5.12). A study included 33 participants with moderate exacerbations of myasthenia gravis and showed no difference in change in QMGS 14 days after IVIg or methylprednisolone (MD -0.42; 95% CI -1.20 to 0.36). All these three smaller studies were underpowered. The last trial, including 168 people with exacerbations, showed no evidence of superiority of IVIg 2 g/kg over IVIg 1 g/kg on the change of MMS after 15 days (MD 3.84; 95% CI -0.98 to 8.66). Adverse events due to IVIg were moderate (fever, nausea, headache), self-limiting and subjectively less severe than with plasma exchange (although, given the available data, no statistical comparison was possible). Other than where specific limitations are mentioned the trials were generally at low risk of bias. In exacerbation of myasthenia gravis, one RCT of IVIg versus placebo showed some evidence of the efficacy of IVIg and two did not show a significant difference between IVIg and plasma exchange. Another showed no significant difference in efficacy between 1 g/kg and 2 g/kg of IVIg. A further, but underpowered, trial showed no significant difference between IVIg and oral methylprednisolone. In chronic myasthenia gravis, there is insufficient evidence from RCTs to determine whether IVIg is efficacious.
Twelve studies with 13 comparisons were included. Four studies compared dietitian with doctor, seven with self-help resources, and only one study was found for dietitian versus nurse and dietitian versus counsellor comparisons. Participants receiving advice from dietitians experienced a greater reduction in blood cholesterol than those receiving advice only from doctors (-0.25 mmol/L (95% CI -0.37, -0.12 mmol/L)). There was no statistically significant difference in change in blood cholesterol between dietitians and self-help resources (-0.10 mmol/L (95% CI -0.22, 0.03 mmol/L)). No statistically significant differences were detected for secondary outcome measures between any of the comparisons with the exception of dietitian versus nurse for HDLc, where the dietitian group showed a greater reduction (-0.06 mmol/L (95% CI -0.11, -0.01)) and dietitian versus counsellor for body weight, where the dietitian group showed a greater reduction (-5.80 kg (95% CI -8.91, -2.69 kg)). Dietitians were better than doctors at lowering blood cholesterol in the short to medium term, but there was no evidence that they were better than self-help resources. There was no evidence that dietitians provided better outcomes than nurses.  The results should be interpreted with caution as the studies were not of good quality and the analysis was based on a limited number of trials.
We identified only one RCT (N = 200; mean follow up 68 months). This trial compared LDR-BT and RP. The risk of bias was deemed high. Primary outcomes (overall survival, cause-specific mortality, or metastatic-free survival) were not reported. Biochemical recurrence-free survival at 5 years follow up was not significantly different between LDR-BT (78/85 (91.8%)) and RP (81/89 (91.0%)); P = 0.875; relative risk 0.92 (95% CI: 0.35 to 2.42). For severe adverse events reported at 6 months follow up, results favored LDR-BT for urinary incontinence (LDR-BT 0/85 (0.0%) versus RP 16/89 (18.0%); P < 0.001; relative risk 0) and favored RP for urinary irritation (LDR-BT 68/85 (80.0%) versus RP 4/89 (4.5%); P < 0.001; relative risk 17.80, 95% CI 6.79 to 46.66). The occurrence of urinary stricture did not significantly differ between the treatment groups (LDR-BT 2/85 (2.4%) versus RP 6/89 (6.7%); P = 0.221; relative risk 0.35, 95% CI: 0.07 to 1.68). Long-term information was not available. We did not identify significant differences of mean scores between treatment groups for patient-reported outcomes function and bother as well as generic health-related quality of life. Low-dose rate brachytherapy did not reduce biochemical recurrence-free survival versus radical prostatectomy at 5 years. For short-term severe adverse events, low-dose rate brachytherapy was significantly more favorable for urinary incontinence, but radical prostatectomy was significantly more favorable for urinary irritation. Evidence is based on one RCT with high risk of bias.
The review currently includes nine randomised controlled trials (RCTs) with 3361 participants. The overall rate of premature study discontinuation was very high (59.1%). Data for the comparisons of ziprasidone with amisulpride, clozapine, olanzapine, quetiapine and risperidone were available. Ziprasidone was a less acceptable treatment than olanzapine (leaving the studies early for any reason: 5 RCTs, n=1937, RR 1.26 CI 1.18 to 1.35, NNH 7 CI 5 to 10) and risperidone (3 RCTs, n=1029, RR 1.11 CI 1.02 to 1.20, NNH 14 CI 8 to 50), but not than the other second generation antipsychotic drugs. Ziprasidone was less efficacious than amisulpride (leaving the study early due to inefficacy: 1 RCT, n=123, RR 4.72 CI 1.06 to 20.98, NNH 8 CI 5 to 50) olanzapine (PANSS total score: 4 RCTs, n=1291, MD 8.32 CI 5.64 to 10.99) and risperidone (PANSS total score: 3 RCTs, n=1016, MD 3.91 CI 0.27 to 7.55). Based on limited data there were no significant differences in tolerability between ziprasidone and amisulpride or clozapine. Ziprasidone produced less weight gain than olanzapine (5 RCTs, n=1659, MD -3.82 CI -4.69 to -2.96), quetiapine (2 RCTs, n=754, RR 0.45 CI 0.28 to 0.74) or risperidone (3 RCTs, n=1063, RR 0.49 CI 0.33 to 0.74). It was associated with less cholesterol increase than olanzapine, quetiapine and risperidone. Conversely ziprasidone produced slightly more extrapyramidal side-effects than olanzapine (4 RCTs, n=1732, RR 1.43 CI 1.03 to 1.99, NNH not estimable) and more prolactin increase than quetiapine (2 RCTs, n=754, MD 4.77 CI 1.37 to 8.16), but less movement disorders (2 RCTs, n=822, RR 0.70 CI 0.51 to 0.97, NNT not estimable) and less prolactin increase (2 RCTs, n=767, MD -21.97 CI -27.34 to -16.60) than risperidone. Note: the 254 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed. Ziprasidone may be a slightly less efficacious antipsychotic drug than amisulpride, olanzapine and risperidone. Its main advantage is the low propensity to induce weight gain and associated adverse effects. However, the high overall rate of participants leaving the studies early limits the validity of any findings.
We included four studies involving a total of 773 randomised participants aged between 14 months and 16 years. All four studies involved children with asthma, with the case-planning undertaken by a trained nurse educator. However, the discharge planning/education differed among the studies. We could include data from only two studies (361 children) in the meta-analysis. Two further studies enrolled children in both inpatient and outpatient settings, and one of these studies also included children with acute wheezing illness (no previous asthma diagnosis); the data specific to this review could not be obtained. For the primary outcome of exacerbations requiring hospitalisation, those in the intervention group were significantly less likely to be rehospitalised (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.16 to 0.50) compared to controls. This equates to 189 (95% CI 124 to 236) fewer admissions per 1000 children. No adverse events were reported in any study. In the context of substantial statistical heterogeneity between the two studies, there were no statistically significant effects on emergency department (OR 0.37, 95% CI 0.04 to 3.05) or general practitioner (OR 0.87, 95% CI 0.22 to 3.44) presentations. There were no data on cost-effectiveness, length of stay of subsequent hospitalisations, or adherence to medications. One study reported quality of life, with no significant differences observed between the intervention and control groups. We considered three of the studies to have an unclear risk of bias, primarily due to inadequate description of the blinding of participants and investigators. The fourth study was assessed as at high risk of bias as a single unblinded investigator was used. Using the GRADE system, we assessed the quality of the evidence as moderate for the outcome of hospitalisation and low for the outcomes of emergency department visits and general practitioner consultations. Current evidence suggests that individual caseworker-assigned discharge plans, as compared to non-caseworker-assigned plans, may be beneficial in preventing hospital readmissions for acute exacerbations in children with asthma. There was no clear indication that the intervention reduces emergency department and general practitioner attendances for asthma, and there is an absence of data for children with other chronic respiratory conditions. Given the potential benefit and cost savings to the healthcare sector and families if hospitalisations and outpatient attendances can be reduced, there is a need for further randomised controlled trials encompassing different chronic respiratory illnesses, ethnicity, socio-economic settings, and cost-effectiveness, as well as defining the essential components of a complex intervention.
Twenty-two out of 29 included studies (1793 women) contributed data to this review. The included studies did not report some our primary outcomes: maternal death, incidence of maternal postoperative wound infection, maternal postoperative other infection such as endometritis and urinary tract infection, neonatal death. Compared to women who had GA, women who had either epidural anaesthesia or spinal anaesthesia were found to have a significantly lower difference between pre and postoperative haematocrit. For epidural, the mean difference (MD) was 1.70% and 95% confidence interval (CI) 0.47 to 2.93 (one trial, 231 women) and for spinal anaesthesia, the MD was 3.10% and 95% CI 1.73 to 4.47 (one trial, 209 women). Compared with GA, women having either an epidural anaesthesia or spinal anaesthesia had a lower estimated maternal blood loss (epidural versus GA: standardised mean difference (SMD) -0.32 mL; 95% CI -0.56 to -0.07; two trials, 256 women; spinal versus GA anaesthesia: SMD -0.59 mL; 95% CI -0.83 to 0.35; two trials, 279 women). There was evidence of a significant difference in terms of satisfaction with anaesthetic technique -  compared with the epidural or spinal group, more women in the GA group stated they would use the same technique again if they needed CS for a subsequent pregnancy (epidural versus GA: risk ratio (RR) 0.80; 95% CI 0.65 to 0.98; one trial, 223 women; spinal versus GA anaesthesia: RR 0.80; 95% CI 0.65 to 0.99; one trial, 221 women). No significant difference was seen in terms of neonatal Apgar scores of six or less and of four or less at five minutes and the need for neonatal resuscitation with oxygen. There is no evidence from this review to show that RA is superior to GA in terms of major maternal or neonatal outcomes. Further research to evaluate neonatal morbidity and maternal outcomes, such as satisfaction with technique, will be useful.
We included three studies involving 102 preterm or low birth weight infants in the review. The studies compared dilute (double-volume, half-strength) formula with full-strength (20 kcal/oz (˜ 68 to 70 kcal/100 mL)) formula. We assessed all three studies as having unclear risk of bias due to the likely absence of blinding of study personnel and the potential for selection bias in the largest trial. Data for the primary outcome of necrotising enterocolitis were not reported in any of the studies. We could combine two of the studies (88 infants) in the meta-analysis. The evidence suggests that dilute formula with double-volume (half-strength) may lead to fewer episodes of gastric residuals per day (one study; mean difference (MD) −1.20, 95% confidence interval (CI) −2.20 to −0.20; low-certainty evidence), fewer episodes of gastric residuals per baby until attaining 100 kcal/kg (one study; MD −0.80, 95% CI −1.32 to −0.28; low-certainty evidence), fewer episodes of vomiting per day (one study; MD −0.04, 95% CI −0.07 to −0.01; low-certainty evidence) and fewer occurrences of abdominal distension greater than 2 cm (two studies; MD −0.16, 95% CI −0.19 to −0.13; low-certainty evidence). For the secondary outcomes, data suggest that infants in the dilute formula with double-volume (half-strength) group may have attained an adequate energy intake earlier than infants in the full-strength group (two studies; MD −2.26, 95% CI −2.85 to −1.67; low-certainty evidence). There was no evidence of a difference between groups for weight gain one week after commencement of intragastric feeds (one study; MD 0.05 kg, 95% CI −0.06 to 0.15; low-certainty evidence). Data were not reported for length of hospital stay. There is low-certainty evidence from three small, old trials that use of dilute formula in preterm or low birth weight formula-fed infants may lead to an important reduction in the time taken for preterm infants to attain an adequate energy intake. However, our confidence in this result is limited due to uncertainty over risk of bias and sparsity of available data. Dilute formula may reduce incidence of feeding intolerance, but the clinical significance of the reduction is uncertain. The impact on serious gastrointestinal problems, including necrotising enterocolitis, was not reported in any of the trials. Further randomised trials are needed to confirm these results.
We included seven RCTs (350 women analysed). The evidence was of very low to low quality: the main limitations being a low number of included women and surgery-related adverse events, substantial loss to follow-up and a large variety in outcome measures and timing of measurements. No studies reported ovarian cancer incidence after hysterectomy with opportunistic salpingectomy compared to hysterectomy without opportunistic salpingectomy in women undergoing hysterectomy for benign gynaecological indications. For surgery-related adverse events, there were insufficient data to assess whether there was any difference in both intraoperative (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.11 to 3.94; 5 studies, 286 participants; very low-quality evidence) and short-term postoperative (OR 0.13, 95% CI 0.01 to 2.14; 3 studies, 152 participants; very low-quality evidence) complication rates between hysterectomy with opportunistic salpingectomy and hysterectomy without opportunistic salpingectomy because the number of surgery-related adverse events was very low. For postoperative hormonal status, the results were compatible with no difference, or with a reduction in anti-Müllerian hormone (AMH) that would not be clinically relevant (mean difference (MD) -0.94, 95% CI -1.89 to 0.01; I2 = 0%; 5 studies, 283 participants; low-quality evidence). A reduction in AMH would be unfavourable, but due to wide CIs, the postoperative change in AMH can still vary from a substantial decrease to even a slight increase. There were no eligible studies reporting on one of our primary outcomes - the incidence of ovarian cancer specifically after hysterectomy with or without opportunistic salpingectomy. In our meta-analyses we found insufficient data to assess whether there was any difference in surgical adverse events, with a very low number of events in women undergoing hysterectomy with and without opportunistic salpingectomy. For postoperative hormonal status we found no evidence of a difference between the groups. The maximum difference in time to menopause, calculated from the lower limit of the 95% CI and the natural average AMH decline, would be approximately 20 months, which we consider to be not clinically relevant. However, the results should be interpreted with caution and even more so in very young women for whom a difference in postoperative hormonal status is potentially more clinically relevant. Therefore, there is a need for research on the long-term effects of opportunistic salpingectomy during hysterectomy, particularly in younger women, as results are currently limited to six months postoperatively. This limit is especially important as AMH, the most frequently used marker for ovarian reserve, recovers over the course of several months following an initial sharp decline after surgery. In light of the available evidence, addition of opportunistic salpingectomy should be discussed with each woman undergoing a hysterectomy for benign indication, with provision of a clear overview of benefits and risks.
We did not identifiy any new trials for inclusion or exclusion in this 2014 update. One study involving 110 participants (55 participants in each group) met our inclusion criteria. The corticosteroid (prednisolone) showed a benefit in shortening the median time to resolution of headaches (five days in the treatment group versus 13 days in the control group, P value < 0.0001). Corticosteroids were also associated with smaller numbers of participants who still had headaches after a two-week course of treatment (9.1% versus 45.5%, P value < 0.0001). The number of patients who needed repeat lumbar puncture was also smaller in the treatment group (12.7% versus 40%, P value = 0.002). There was a reduction in the median time of analgesic use in participants receiving corticosteroids (10.5 versus 25.0, P value = 0.038). There were no reported adverse effects from prednisolone in the treatment group. Corticosteroids significantly help relieve headache in patients with eosinophilic meningitis, who have a pain score of four or more on a visual analogue scale. However, there is only one RCT supporting this benefit and this trial did not clearly mention allocation concealment and stratification. Therefore, we agreed to grade our included study as a moderate quality trial. Future well-designed RCTs are necessary.
Twenty-one RCTs enrolling a total of 1424 participants were eligible for this review. All were RCTs, but methods used for random allocation were not always clear. Allocation concealment, blinding of the intervention, and blinding of outcome assessments most often were satisfactory. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days) but no reduction in mortality at 36 weeks, at discharge, or at latest reported age. Benefits of delayed steroid treatment included reductions in failure to extubate by 3, 7, or 28 days; bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age; need for late rescue treatment with dexamethasone; discharge on home oxygen; and death or bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age. Data revealed a trend towards increased risk of infection and gastrointestinal bleeding but no increase in risk of necrotising enterocolitis. Short-term adverse affects included hyperglycaemia, glycosuria, and hypertension. Investigators reported an increase in severe retinopathy of prematurity but no significant increase in blindness. Trial results showed a trend towards reduction in severe intraventricular haemorrhage, but only five studies enrolling 247 infants reported this outcome. Trends towards an increase in cerebral palsy or abnormal neurological examination findings were partly offset by a trend in the opposite direction involving death before late follow-up. The combined rate of death or cerebral palsy was not significantly different between steroid and control groups. Major neurosensory disability and the combined rate of death or major neurosensory disability were not significantly different between steroid and control groups. There were no substantial differences between groups for other outcomes in later childhood, including respiratory health or function, blood pressure, or growth, although there were fewer participants with a clinically important reduction in forced expired volume in one second (FEV1) on respiratory function testing in the dexamethasone group. GRADE findings were high for all major outcomes considered, but review authors degraded the quality of evidence by one level because we found evidence of publication bias (bronchopulmonary dysplasia at 36 weeks). Benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. This review of postnatal systemic corticosteroid treatment for bronchopulmonary dysplasia initiated after seven days of age suggests that late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of studies determining long-term outcomes is limited in some cases (some studies assessed surviving children only before school age, when some important neurological outcomes cannot be determined with certainty), and no studies were sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Evidence showing both benefits and harms of treatment and limitations of available evidence suggests that it may be prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation, and to minimise both dose and duration for any course of treatment.
The studies: we included four cross-over studies, with a total of 113 children aged 5 to 13 years, most of whom (83%) were boys. We included two studies with five-year-old children since we were unable to obtain the disaggregated data for those aged six years and above, and all other participants were in our target age range. All participants resided in the USA. The duration of treatment in the cross-over phase was one week for each dose of methylphenidate. Studies used a range of outcome scales, rated by parents, teachers or both; clinicians; or programme staff. We report parent-rated outcomes separately. Risk of bias: we considered three trials to be at high risk of bias due to selective reporting and all trials to be at unclear risk of bias for blinding of participants and assessors, due to the potential for recognising the side effects of methylphenidate. We judged all trials to be at low or unclear risk of bias for other items. Primary outcomes: the meta-analysis suggested that high-dose methylphenidate (0.43 mg/kg/dose to 0.60 mg/kg/dose) had a significant and clinically relevant benefit on hyperactivity, as rated by teachers (SMD −0.78, 95% confidence interval (CI) −1.13 to −0.43; 4 studies, 73 participants; P < 0.001; low-quality evidence) and parents (mean difference (MD) −6.61 points, 95% CI −12.19 to −1.03, rated on the hyperactivity subscale of the Aberrant Behviour Checklist, range 0 to 48; 2 studies, 71 participants; P = 0.02; low-quality evidence). Meta-analysis also showed a significant but not clinically relevant benefit on teacher-rated inattention (MD −2.72 points, 95% CI −5.37 to −0.06, rated on the inattention subscale of the Swanson, Nolan and Pelham, Fourth Version questionnaire, range 0 to 27; 2 studies, 51 participants; P = 0.04; low-quality evidence). There were inadequate data to conduct a meta-analysis on the symptom of impulsivity. There was no evidence that methylphenidate worsens the core symptoms of ASD or benefits social interaction (SMD −0.51, 95% CI −1.07 to 0.05; 3 studies, 63 participants; P = 0.07; very low-quality evidence), stereotypical behaviours (SMD −0.34, 95% CI −0.84 to 0.17; 3 studies, 69 participants; P = 0.19; low-quality evidence), or overall ASD (SMD −0.53, 95% CI −1.26 to 0.19; 2 studies, 36 participants; P = 0.15; low-quality evidence), as rated by teachers. There were inadequate data to conduct a meta-analysis on the symptom of impaired communication. Secondary outcomes: no data were available for the secondary outcomes of caregiver well-being; need for institutionalisation, special schooling options or therapy to achieve learning outcomes; or overall quality of life. No trials reported serious adverse events. The only adverse effect that was significantly more likely with treatment was reduced appetite as rated by parents (risk ratio 8.28, 95% CI 2.57 to 26.73; 2 studies, 74 participants; P < 0.001; very low-quality evidence). Subgroup analysis by dose did not identify any significant differences in effect on our primary outcomes between low-, medium- or high-dose ranges. We found that short-term use of methylphenidate might improve symptoms of hyperactivity and possibly inattention in children with ASD who are tolerant of the medication, although the low quality of evidence means that we cannot be certain of the true magnitude of any effect. There was no evidence that methylphenidate has a negative impact on the core symptoms of ASD, or that it improves social interaction, stereotypical behaviours, or overall ASD. The evidence for adverse events is of very low quality because trials were short and excluded children intolerant of methylphenidate in the test-dose phase. Future RCTs should consider extending the duration of treatment and follow-up. The minimum clinically important difference also needs to be confirmed in children with ASD using outcome scales validated for this population.
Four studies with a total of 277 participants were included. These studies assessed the efficacy of FMT for treatment of UC in adults; no eligible trials were found for the treatment of CD. Most participants had mild to moderate UC. Two studies were conducted in Australia, one study was conducted in Canada, and another in the Netherlands. Three of the included studies administered FMT via the rectal route and one study administered FMT via the nasoduodenal route. Three studies were rated as low risk of bias. One study (abstract publication) was rated as unclear risk of bias. Combined results from four studies (277 participants) suggest that FMT increases rates of clinical remission by two-fold in patients with UC compared to controls. At 8 weeks, 37% (52/140) of FMT participants achieved remission compared to 18% (24/137) of control participants (RR 2.03, 95 % CI, 1.07 to 3.86; I² = 50%; low certainty evidence). One study reported data on relapse at 12 weeks among participants who achieved remission. None of the FMT participants (0/7) relapsed at 12 weeks compared to 20% of control participants (RR 0.28, 95% CI 0.02 to 4.98, 17 participants, very low certainty evidence). It is unclear whether there is a difference in serious adverse event rates between the intervention and control groups. Seven per cent (10/140) of FMT participants had a serious adverse event compared to 5% (7/137) of control participants (RR 1.40, 95% CI 0.55 to 3.58; 4 studies; I² = 0%; low certainty evidence). Serious adverse events included worsening of UC necessitating intravenous steroids or surgery; infection such as Clostridium difficile and cytomegalovirus, small bowel perforation and pneumonia. Adverse events were reported by two studies and the pooled data did not show any difference between the study groups. Seventy-eight per cent (50/64) of FMT participants had an adverse event compared to 75% (49/65) of control participants (RR 1.03, 95% CI 0.81 to 1.31; I² = 31%; moderate certainty evidence). Common adverse events included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Four studies reported on clinical response at 8 weeks. Forty-nine per cent (68/140) of FMT participants had a clinical response compared to 28% (38/137) of control participants (RR 1.70, 95% CI 0.98 to 2.95, I² = 50%, low certainty evidence). Endoscopic remission at 8 weeks was reported by three studies and the combined results favored FMT over the control group. Thirty per cent (35/117) of FMT participants achieved endoscopic remission compared to 10% (11/112) of control participants (RR 2.96, 95 % CI 1.60 to 5.48, I² = 0%; low certainty evidence). Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious adverse events. As a result, no solid conclusions can be drawn at this time. Additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity. No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants. In addition, no studies assessed long-term maintenance of remission in UC or CD. Future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD.
Five studies were identified which enrolled a total of 1302 infants. In two studies allocation was randomised and the caregivers were blinded to intervention group. In the other three studies, allocation was quasi-randomised and the caregivers were not blinded. Pooled analysis of the four trials reporting effect on death showed a significant reduction in the rate of death in the group resuscitated with room air [typical RR 0.71 (0.54, 0.94), typical RD -0.05 (-0.08, -0.01), NNT 20 (12, 100)]. There were no significant differences between the groups with respect to rates of grade 2 or 3 hypoxic ischaemic encephalopathy. One of the four trials reported a statistically significant difference in median 5 minute Apgar scores, favouring the group allocated to room air. However, the absolute difference between the medians was small and there were no significant differences in the median 10 minute Apgar scores in the three trials reporting this outcome. One trial followed up a selected subgroup of survivors to 18-24 months. There were no significant differences in rates of adverse neurodevelopmental outcomes including cerebral palsy and failure to achieve various milestones; however, the proportion of eligible patients seen was less than 70%. Analyses that were planned for this review, but not able to be carried out because of lack of published data, included a sub-analysis stratified by gestational age and assessments of the effect on bronchopulmonary dysplasia and retinopathy of prematurity. There is insufficient evidence at present on which to recommend a policy of using room air over 100% oxygen, or vice versa, for newborn resuscitation. A reduction in mortality has been seen in infants resuscitated with room air, and no evidence of harm has been demonstrated. However, the small number of identified studies and their methodologic limitations dictate caution in interpreting and applying these results. We note the use of back-up 100% oxygen in more than a quarter of infants randomised to room air. Therefore, on the basis of currently available evidence, if one chooses room air as the initial gas for resuscitation, supplementary oxygen should continue to be made available.
We included three RCTs that randomly assigned a total of 1089 participants recruited from 43 ICUs in Australia, Canada, Saudi Arabia, Spain and the USA. Risk of bias of the included studies was low. Only data for mortality and barotrauma could be combined in the meta-analysis. We downgraded the quality of evidence for the three mortality outcomes on the basis of serious imprecision around the effect estimates. For mortality in hospital, the RR with PCV compared with VCV was 0.83 (95% CI 0.67 to 1.02; three trials, 1089 participants; moderate-quality evidence), and for mortality in the ICU, the RR with PCV compared with VCV was 0.84 (95% CI 0.71 to 0.99; two trials, 1062 participants; moderate-quality evidence). One study provided no evidence of clear benefit with the ventilatory mode for mortality at 28 days (RR 0.88, 95% CI 0.73 to 1.06; 983 participants; moderate-quality evidence). The difference in effect on barotrauma between PCV and VCV was uncertain as the result of imprecision and different co-interventions used in the studies (RR 1.24, 95% CI 0.87 to 1.77; two trials, 1062 participants; low-quality evidence). Data from one trial with 983 participants for the mean duration of ventilation, and from another trial with 78 participants for the mean number of extrapulmonary organ failures that developed with PCV or VCV, were skewed. None of the trials reported on infection during ventilation or quality of life after discharge. Currently available data from RCTs are insufficient to confirm or refute whether pressure-controlled or volume-controlled ventilation offers any advantage for people with acute respiratory failure due to acute lung injury or acute respiratory distress syndrome. More studies including a larger number of people given PCV and VCV may provide reliable evidence on which more firm conclusions can be based.
Eleven trials were identified of which seven were excluded and four with 312 participants were included. No trial reported live birth outcomes. One trial compared gonadotropin-releasing hormone (GnRH) agonist with GnRH antagonist. There was no evidence of a difference for clinical pregnancy rate (CPR), however the number of mature oocytes retrieved (NMOR) was greater with GnRH agonists (MD -1.60, 95% CI -2.44 to -0.76) and the ovarian response was increased (estradiol (E2) levels on day of human chorionic gonadotropin (hCG) injection) (MD -456.30, 95% CI -896.06 to -16.54). Surgery (aspiration or cystectomy) versus expectant management (EM) showed no evidence of a benefit for clinical pregnancy with either technique. Aspiration was associated with greater NMOR (MD 0.50, 95% CI 0.02 to 0.98) and increased ovarian response (E2 levels on day of hCG injection) (MD 685.3, 95% CI 464.50 to 906.10) compared to EM.Cystectomy was associated with a decreased ovarian response to controlled ovarian hyperstimulation (COH) (MD -510.00, 95% CI -676.62 to -343.38); no evidence of an effect on the NMOR compared to EM. Aspiration versus cystectomy showed no evidence of a difference in CPR or the NMOR. There was no evidence of an effect on reproductive outcomes in any of the four included trials. Further RCTs of management of endometrioma in women undergoing ART are required.
We identified eight trials that met the inclusion criteria. One trial including 17 surgical trainees did not contribute to the meta-analysis. We included seven trials (249 surgical trainees belonging to various postgraduate years ranging from year one to four) in which the participants were randomised to supplementary box model training (122 trainees) versus standard training (127 trainees). Only one trial (50 trainees) was at low risk of bias. The box trainers used in all the seven trials were video trainers. Six trials were conducted in USA and one trial in Canada. The surgeries in which the final assessments were made included laparoscopic total extraperitoneal hernia repairs, laparoscopic cholecystectomy, laparoscopic tubal ligation, laparoscopic partial salpingectomy, and laparoscopic bilateral mid-segment salpingectomy. The final assessments were made on a single operative procedure. There were no deaths in three trials (0/82 (0%) supplementary box model training versus 0/86 (0%) standard training; RR not estimable; very low quality evidence). The other trials did not report mortality. The estimated effect on serious adverse events was compatible with benefit and harm (three trials; 168 patients; 0/82 (0%) supplementary box model training versus 1/86 (1.1%) standard training; RR 0.36; 95% CI 0.02 to 8.43; very low quality evidence). None of the trials reported patient quality of life. The operating time was significantly shorter in the supplementary box model training group versus the standard training group (1 trial; 50 patients; MD -6.50 minutes; 95% CI -10.85 to -2.15). The proportion of patients who were discharged as day-surgery was significantly higher in the supplementary box model training group versus the standard training group (1 trial; 50 patients; 24/24 (100%) supplementary box model training versus 15/26 (57.7%) standard training; RR 1.71; 95% CI 1.23 to 2.37). None of the trials reported trainee satisfaction. The operating performance was significantly better in the supplementary box model training group versus the standard training group (seven trials; 249 trainees; SMD 0.84; 95% CI 0.57 to 1.10). None of the trials compared box model training versus animal model training or versus different methods of box model training. There is insufficient evidence to determine whether laparoscopic box model training reduces mortality or morbidity. There is very low quality evidence that it improves technical skills compared with standard surgical training in trainees with limited previous laparoscopic experience. It may also decrease operating time and increase the proportion of patients who were discharged as day-surgery in the first total extraperitoneal hernia repair after box model training. However, the duration of the benefit of box model training is unknown. Further well-designed trials of low risk of bias and random errors are necessary. Such trials should assess the long-term impact of box model training on clinical outcomes and compare box training with other forms of training.
We identified 26 studies (8835 participants). Risk of bias was high in 17, unclear in 6and low in three studies. There was high risk of attrition bias in six studies. Only two studies measured AKI. The use of NSAIDs had uncertain effects on the incidence of AKI compared to placebo (7066 participants: RR 1.79, 95% CI 0.40 to 7.96; I2 = 59%; very low certainty evidence). One study was stopped early by the data monitoring committee due to increased rates of AKI in the NSAID group. Moreover, both of these studies were examining NSAIDs for indications other than analgesia and therefore utilised relatively low doses. Compared to placebo, NSAIDs may slightly increase serum SCr (15 studies, 794 participants: MD 3.23 μmol/L, 95% CI -0.80 to 7.26; I2 = 63%; low certainty evidence). Studies displayed moderate to high heterogeneity and had multiple exclusion criteria including age and so were not representative of patients undergoing surgery. Three of these studies excluded patients if their creatinine rose post-operatively. NSAIDs may make little or no difference to post-operative urine output compared to placebo (6 studies, 149 participants: SMD -0.02, 95% CI -0.31 to 0.27). No reliable conclusions could be drawn from these studies due to the differing units of measurements and measurement time points. It is uncertain whether NSAIDs leads to the need for RRT because the certainty of this evidence is very low (2 studies, 7056 participants: RR 1.57, 95% CI 0.49 to 5.07; I2 = 26%); there were few events and the results were inconsistent. It is uncertain whether NSAIDs lead to more deaths (2 studies, 312 participants: RR 1.44, 95% CI 0.19 to 11.12; I2 = 38%) or increased the length of hospital stay (3 studies, 410 participants: MD 0.12 days, 95% CI -0.48 to 0.72; I2 = 24%). Overall NSAIDs had uncertain effects on the risk of post-operative AKI, may slightly increase post-operative SCr, and it is uncertain whether NSAIDs lead to the need for RRT, death or increases the length of hospital stay. The available data therefore does not confirm the safety of NSAIDs in patients undergoing surgery. Further larger studies using the Kidney Disease Improving Global Outcomes definition for AKI including patients with co-morbidities are required to confirm these findings. .
Three RCTs (involving 386 women) were included in the review. Peri-implantation low molecular weight heparin (LMWH) during IVF/ICSI was given at or after egg collection or at embryo transfer in these studies. The characteristics of the participants differed across studies. One included women having their first IVF cycle, with no blood clotting disorder; another included women with at least one blood clotting disorder and the third included women who had undergone at least two previous unsuccessful ART cycles. Our findings differed according to choice of statistical model. When we used a fixed effect analysis, the evidence suggested that peri-implantation heparin was associated with an improvement in live birth rate compared with placebo or no heparin (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.07 to 2.90, three studies, 386 women, I2 = 51%, very low quality evidence) and also an improvement in the clinical pregnancy rate (OR 1.61, 95% CI 1.03 to 2.53, three studies, 386 women, I2 = 29%, low quality evidence). However when a random effects model was used there was no longer a difference between the groups for either live birth (OR 1.85, 95% CI 0.80 to 4.24) or clinical pregnancy (OR 1.66, 95% CI 0.94 to 2.90). Moreover there was high heterogeneity (I2 = 51%) for the analysis of live birth. Adverse events were poorly reported in all the included studies. Events such as bleeding, and thrombocytopenia were reported in women receiving heparin and affected 5-7% of women in the heparin group in one study. However no studies reported data suitable for analysis and so no firm conclusions could be drawn regarding adverse effects. The main limitations in the evidence were inconsistency, imprecision and inadequate reporting of adverse events. It is unclear whether peri-implantation heparin in assisted reproduction treatment (ART) cycles improves live birth and clinical pregnancy rates in subfertile women, as the evidence was sensitive to choice of statistical model and no benefit was apparent when a random effects model was used. Side effects have been reported with use of heparin and no firm conclusions can be drawn regarding its safety. Our results do not justify the use of heparin in this context, except in well-conducted research trials. These findings need to be further investigated with well-designed, adequately powered, double-blind, randomised, placebo-controlled, multicentre trials. Further investigations could also focus on the effects of the local (uterine) and non-systemic application of heparin during ART.
Thirty-two trials (9605 patients) were included. For symptomatic failure rates, no difference between three-day and 5-10 day antibiotic regimen was seen short-term (RR 1.06, 95% CI 0.88 to 1.28) and long-term follow-up (RR 1.09, 95% CI 0.94 to 1.27). Comparison of the bacteriological failure rates showed that three-day therapy was less effective than 5-10 day therapy for the short-term follow-up, however this difference was observed only in the subgroup of trials that used the same antibiotic in the two treatment arms (RR 1.37, 95% CI 1.07 to 1.74, P = 0.01). This difference was more significant at long-term follow-up (RR 1.43, 95% CI 1.19 to 1.73, P = 0.0002). Adverse effects were significantly more common in the 5-10 day treatment group (RR 0.83, 95% CI 0.74 to 0.93, P = 0.0010). Results were consistent for subgroup and sensitivity analyses. Three days of antibiotic therapy is similar to 5-10 days in achieving symptomatic cure during uncomplicated UTI treatment, while the longer treatment is more effective in obtaining bacteriological cure. In spite of the higher rate of adverse effects, treatment for 5-10 days could be considered for treatment of women in whom eradication of bacteriuria is important.
We included 16 eligible trials with a total of 1251 infant participants. Trials were of variable methodological quality, with lack of allocation concealment and incomplete follow-up identified as major potential sources of bias. Trials (N = 11) that compared feeding infants with 'postdischarge formula' (energy density about 74 kcal/100 mL) versus standard term formula (about 67 kcal/100 mL) did not find consistent evidence of effects on growth parameters up to 12 to 18 months post term. GRADE assessments indicated that evidence was of moderate quality, and that inconsistency within pooled estimates was the main quality issue. Trials (N = 5) that compared feeding with 'preterm formula' (about 80 kcal/100 mL) versus term formula found evidence of higher rates of growth throughout infancy (weighted mean differences at 12 to 18 months post term: about 500 g in weight, 5 to 10 mm in length, 5 mm in head circumference). GRADE assessments indicated that evidence was of moderate quality, and that imprecision of estimates was the main quality issue. Few trials assessed neurodevelopmental outcomes, and these trials did not detect differences in developmental indices at 18 months post term. Data on growth or development through later childhood have not been provided. Recommendations to prescribe 'postdischarge formula' for preterm infants after hospital discharge are not supported by available evidence. Limited evidence suggests that feeding 'preterm formula' (which is generally available only for in-hospital use) to preterm infants after hospital discharge may increase growth rates up to 18 months post term.
We included six trials published between 2007 and 2014 that randomised 599 adult participants. Study size ranged from 46 to 158 participants. Participants were aged between 18 years and 80 years; we could not derive gender proportions, as participants' sex was not reported in all studies. One study was available in abstract form only. We did not find a significant difference in outcomes between people who exercised and those who did not exercise before receiving influenza vaccination. Pre-vaccination exercises included endurance activities such as walking or using a treadmill, and resistance activities included biceps curls and lateral raises. Five of the studies provided one session of exercise between 25 and 50 minutes. In five studies, exercise was undertaken on the same day as the vaccination. One study provided exercise over a period of eight weeks before vaccination, with one 2½ hour supervised session, plus daily home exercise practice of 45 minutes. Exercise intensity ranged from 55% to 85% of maximal heart rate. Control group participants undertook a range of activities, including quiet rest, sitting, reading, meditation or unspecified activity. One study reported numbers of people who contracted influenza; no significant difference was reported between exercise and no-exercise participants. None of the included studies reported complications related to influenza illness. Only one study, which we assessed as providing low-quality evidence, reported numbers of people who experienced adverse events. This study reported no significant difference in outcomes between people who exercised and those who did not. No studies reported numbers of working days or days lost related to influenza illness. Only two studies reported participant-centred outcomes. Overall, study quality was unclear; we assessed five of the six included studies to have at least four unclear 'Risk of bias' domains (allocation concealment, blinding of outcome assessment, selective reporting and other bias). Insufficient reporting in four studies about selective reporting did not provide enough information to enable judgement; only two studies were included in trials registers. From the available evidence, we found that exercising before influenza vaccination is neither beneficial nor harmful. However, study data were limited and of low quality. Small sample sizes, study design limitations, exercise types, and focus on biochemical rather than participant-centred outcomes strongly influenced our findings.
We included two studies in the review, with a total of 344 participants. Studies lasted 8 weeks and 12 weeks and compared TC versus placebo. 0.1%. TC was applied in gel form to the painful area two to three times daily. Studies included in this review were subject to potential bias and were classified as of moderate or low quality. One drug manufacturer supported both studies. We found no top-tier evidence for TC in neuropathic pain. Second-tier evidence indicated slight improvement after the drug was used in study participants with painful diabetic neuropathy (PDN). A greater number of participants in the TC group had at least 30% reduction in pain compared with placebo (risk ratio (RR) 1.35, 95% confidence interval (CI) 1.03 to 1.77; number needed to treat for an additional beneficial outcome (NNTB) 8.33, 95% CI 4.3 to 50). Third-tier evidence indicated that TC was no better than placebo for achieving at least 50% reduction in pain intensity and on the Patient Global Impression of Change Scale. The two included studies could be subject to significant bias. We found no studies that reported other neuropathic pain conditions. The rate of adverse events did not differ between groups, with the exception of a higher incidence of mild skin reactions in the placebo group, which should have no clinical significance. Limited evidence from a small number of studies of moderate to low quality suggests that TC may provide some benefit in peripheral diabetic neuropathy. The drug may be useful in situations for which no better treatment options are available because of lack of efficacy, contraindications or adverse events. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine how patients who have a chance to respond to the drug should be selected for treatment.
We identified three trials with 390 patients that compared cyclosporin A versus placebo. Two of them were assessed methodologically adequate with low-bias risk. Cyclosporin A did not significantly reduce mortality risk (RR 0.92, 95% CI 0.59 to 1.45), and mortality or liver transplantation (RR 0.85, 95% CI 0.60 to 1.20). Cyclosporin A significantly improved pruritus (SMD -0.38, 95% CI -0.63 to -0.14), but not fatigue. Cyclosporin A significantly reduced alanine aminotransferase (WMD -41 U/L, 95% CI -63 to -18) and increased serum albumin level (WMD 1.66 g/L, 95% CI 0.26 to 3.05). Significantly more patients experienced adverse events in the cyclosporin A group than in the placebo group, especially renal dysfunction (Peto odds ratio 5.56, 95% CI 2.52 to 12.27) and hypertension (SMD 0.88, 95% CI 0.27 to 1.48). We found no evidence supporting or refuting that cyclosporin A may delay death, death or liver transplantation, or progression of primary biliary cirrhosis. Cyclosporin A caused more adverse events than placebo, like renal dysfunction and hypertension. We do not recommend the use of cyclosporin A outside randomised clinical trials.
We include one RCT with relevant data on 29 participants in this review. The trial had a parallel design and was double-blind, but blinding procedures were not described. The trial included people who were non-responsive to fluphenazine 20 mg/day administered for 4 weeks. Participants were randomly assigned to continuing treatment with fluphenazine 20 mg/day, increasing the dose to fluphenazine 80 mg/day or switching to haloperidol 20 mg/day for four additional weeks. Data were reported only for 47 out of 58 initially randomised participants. The trial was published in 1993. The fact that only one RCT with a small sample size (N = 29) was included in the analysis limits the quality of the evidence. Overall, no clear difference was found between groups in terms of the three available outcomes: global state (number of participants with clinically relevant response (RR 1.63, 95% CI 0.17 to 15.99, very low quality evidence); general mental state (endpoint score, BPRS total) (MD 2.00, 95% CI −4.20 to 8.20, very low quality evidence); and negative symptoms (endpoint score, SANS) (MD 3.40, 95% CI −12.56 to 19.36). No data were reported for leaving the study early, adverse effects, time in hospital, quality of life, satisfaction with care and functioning. There is extremely limited evidence and no clear conclusions can be drawn. There is an urgent need for further trials in order to determine the optimal treatment strategy for people with schizophrenia who do not respond to their initial antipsychotic treatment.
We found 17 randomised controlled trials of iNO therapy in preterm infants. We grouped these trials post hoc into three categories on the basis of entry criteria: treatment during the first three days of life for impaired oxygenation, routine use in preterm babies along with respiratory support and later treatment for infants at increased risk for bronchopulmonary dysplasia (BPD). We performed no overall analyses. Eight trials providing early rescue treatment for infants on the basis of oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD (typical risk ratio (RR) 0.94, 95% confidence interval (CI) 0.87 to 1.01; 958 infants). Four studies examining routine use of iNO in infants with pulmonary disease reported no significant reduction in death or BPD (typical RR 0.94, 95% CI 0.87 to 1.02; 1924 infants), although this small effect approached significance. Later treatment with iNO based on risk of BPD (three trials) revealed no significant benefit for this outcome in analyses of summary data (typical RR 0.92, 95% CI 0.85 to 1.01; 1075 infants). Investigators found no clear effect of iNO on the frequency of all grades of IVH nor severe IVH. Early rescue treatment was associated with a non-significant 20% increase in severe IVH. We found no effect on the incidence of neurodevelopmental impairment. iNO does not appear to be effective as rescue therapy for the very ill preterm infant. Early routine use of iNO in preterm infants with respiratory disease does not prevent serious brain injury or improve survival without BPD. Later use of iNO to prevent BPD could be effective, but current 95% confidence intervals include no effect; the effect size is likely small (RR 0.92) and requires further study.
We included in our review three studies (Moy 2015; Tabak 2013; Voncken-Brewster 2015) with a total of 1580 randomised participants. From Voncken-Brewster 2015, we included the subgroup of individuals with a diagnosis of COPD (284 participants) and excluded those at risk of COPD who had not received a diagnosis (1023 participants). As a result, the total population available for analysis included 557 participants; 319 received smart technology to support self-management and 238 received face-to-face verbal/written or digital information and education about self-management. The average age of participants was 64 years. We included more men than women because the sample from one of the studies consisted of war veterans, most of whom were men. These studies measured five of our nine defined outcomes. None of these studies included outcomes such as self-efficacy, cost-effectiveness, functional capacity, lung function, or anxiety and depression. All three studies included our primary outcome - health-related quality of life (HRQoL) as measured by the Clinical COPD Questionnaire (CCQ) or St George's Respiratory Questionnaire (SGRQ). One study reported our other primary outcomes - hospital admissions and acute exacerbations. Two studies included our secondary outcome of physical activity as measured by daily step counts. One study addressed smoking by providing a narrative analysis. Only one study reported adverse events and noted significant differences between groups, with 43 events noted in the intervention group and eight events in the control group (P = 0.001). For studies that measured outcomes at week four, month four, and month six, the effect of smart technology on self-management and subsequent HRQoL in terms of symptoms and health status was significantly better than when participants received face-to-face/digital and/or written support for self-management of COPD (SMD -0.22, 95% confidence interval (CI) -0.40 to -0.03; P = 0.02). The single study that reported HRQoL at 12 months described no significant between-group differences (MD 1.1, 95% CI -2.2 to 4.5; P = 0.50). Also, hospitalisations (logistic regression odds ratio (OR) 1.6, 95% CI 0.8 to 3.2; P = 0.19) and exacerbations (logistic regression OR 1.4, 95% CI 0.7 to 2.8; P = 0.33) did not differ between groups in the single study that reported these outcomes at 12 months. The activity level of people with COPD at week four, month four, and month six was significantly higher when smart technology was used than when face-to-face/digital and/or written support was provided (MD 864.06 daily steps between groups, 95% CI 369.66 to 1358.46; P = 0.0006). The only study that measured activity levels at 12 months reported no significant differences between groups (mean -108, 95% CI -720 to 505; P = 0.73). Participant engagement in this study was not sustained between four and 12 months. The only study that included smoking cessation found no significant treatment effect (OR 1.06, 95%CI 0.43 to 2.66; P = 0.895). Meta-analyses showed no significant heterogeneity between studies (Chi² = 0.39, P = 0.82; I² = 0% and Chi² = 0.01, P = 0.91; I² = 0%, respectively). Although our review suggests that interventions aimed at facilitating, supporting, and sustaining self-managment in people with COPD and delivered via smart technology significantly improved HRQoL and levels of activity up to six months compared with interventions given through face-to-face/digital and/or written support, no firm conclusions can be drawn. This improvement may not be sustained over a long duration. The only included study that measured outcomes up to 12 months highlighted the need to ensure sustained engagement with the technology over time. Limited evidence suggests that using computer and mobile technology for self-management for people with COPD is not harmful and may be more beneficial for some people than for others, for example, those with an interest in using technology may derive greater benefit. The evidence, provided by three studies at high risk of bias, is of poor quality and is insufficient for advising healthcare professionals, service providers, and members of the public with COPD about the health benefits of using smart technology as an effective means of supporting, encouraging, and sustaining self-management. Further research that focuses on outcomes relevant to different stages of COPD is needed. Researchers should provide clear information on how self-management is assessed and should include longitudinal measures that allow comment on behavioural change.
In this updated review, we identified eight trials as potentially relevant from our searches. Again, only one trial met the inclusion criteria. This trial randomly assigned 146 participants to either a garlic supplement (with 180 mg of allicin content) or a placebo (once daily) for 12 weeks. The trial reported 24 occurrences of the common cold in the garlic intervention group compared with 65 in the placebo group (P value < 0.001), resulting in fewer days of illness in the garlic group compared with the placebo group (111 versus 366). The number of days to recovery from an occurrence of the common cold was similar in both groups (4.63 versus 5.63). Only one trial met the inclusion criteria, therefore limited conclusions can be drawn. The trial relied on self reported episodes of the common cold but was of reasonable quality in terms of randomisation and allocation concealment. Adverse effects included rash and odour. There is insufficient clinical trial evidence regarding the effects of garlic in preventing or treating the common cold. A single trial suggested that garlic may prevent occurrences of the common cold but more studies are needed to validate this finding. Claims of effectiveness appear to rely largely on poor-quality evidence.
For the treatment of primary dysmenorrhoea there was some evidence of the effectiveness of laparoscopic uterine nerve ablation (LUNA) when compared to a control or no treatment. The comparison between LUNA and laparoscopic presacral neurectomy (LPSN) for primary dysmenorrhoea showed no significant difference in pain relief in the short term; however, long-term LPSN was shown to be significantly more effective than LUNA. For the treatment of secondary dysmenorrhoea six identified RCTs addressed endometriosis and one included women with uterine myomas. The treatment of LUNA combined with surgical treatment of endometrial implants versus surgical treatment of endometriosis alone showed that the addition of LUNA did not aid pain relief. For PSN combined with endometriosis treatment versus endometriosis treatment alone there was an overall difference in pain relief although the data suggests this may be specific to laparoscopy and for midline abdominal pain only. Adverse events were significantly more common for presacral neurectomy; however, the majority were complications such as constipation, which may spontaneously improve. There is insufficient evidence to recommend the use of nerve interruption in the management of dysmenorrhoea, regardless of cause. Future methodologically sound and sufficiently powered RCTs should be undertaken.
We identified 11 trials (862 participants). All trials were in neonatal or paediatric populations. The trials covered only three areas of interest: restrictive versus liberal transfusion triggers (two trials), leukoreduction versus non-leukoreduction (two trials) and standard versus non-standard cardiopulmonary bypass (CPB) prime (seven trials). Owing to the clinical diversity in the participant groups (cyanotic (three trials), acyanotic (four trials) or mixed (four trials)) and the intervention groups, it was not appropriate to pool data in a meta-analysis. No study reported data for all the outcomes of interest to this review. Risk of bias was mixed across the included trials, with only attrition bias being low across all trials. Blinding of study personnel and participants was not always possible, depending on the intervention being used. Five trials (628 participants) reported the primary outcome: 30-day mortality. In three trials (a trial evaluating restrictive and liberal transfusion (125 participants), a trial of cell salvage during CPB (309 participants) and a trial of washed red blood cells during CPB (128 participants)), there was no clear difference in mortality at 30 days between the intervention arms. In two trials comparing standard and non-standard CPB prime, there were no deaths in either randomised group. Long-term mortality was similar between randomised groups in one trial each comparing restrictive and liberal transfusion or standard and non-standard CPB prime. Four trials explored a range of adverse effects following red cell transfusion. Kidney failure was the only adverse event that was significantly different: patients receiving cell salvaged red blood cells during CPB were less likely to have renal failure than patients not exposed to cell salvage (risk ratio (RR) 0.26, 95% confidence interval (CI) 0.09 to 0.79, 1 study, 309 participants). There was insufficient evidence to determine whether there was a difference between transfusion strategies for any other severe adverse events. The duration of mechanical ventilation was measured in seven trials (768 participants). Overall, there was no consistent difference in the duration of mechanical ventilation between the intervention and control arms. The duration of intensive care unit (ICU) stay was measured in six trials (459 participants). There was no clear difference in the duration of ICU stay between the intervention arms in the transfusion trigger and leukoreduction trials. In the standard versus non-standard CPB prime trials, one trial examining the impact of washing transfused bypass prime red blood cells showed no clear difference in duration of ICU stay between the intervention arms, while the trial assessing ultrafiltration of the priming blood showed a shorter duration of ICU stay in the ultrafiltration group. There are only a small number of small and heterogeneous trials so there is insufficient evidence to assess the impact of red cell transfusion on patients with congenital heart disease undergoing cardiac surgery accurately. It is possible that the presence or absence of cyanosis impacts on trial outcomes, which would necessitate different clinical management of two groups. Further adequately powered, specific, high-quality trials are warranted to assess this fully.
Three studies were identified that met the inclusion criteria (Peoples 1982; Robb 1986; Toseland 1997) incorporating data on a total of 116 patients (42 in experimental groups, and 74 in the control groups (usual care 43 and social contact 21, 10 in reality orientation). It was not possible to pool the data from the 3 included studies, either because of the different lengths of treatment or choice of different control treatments, or because the outcome measures were not comparable. Two significant results were found:  Peoples 1982 - Validation versus usual care. Behaviour at 6 weeks [MD --5.97, 95% CI (-9.43 to -2.51) P=0.0007, completers analysis] favours validation therapy.  Toseland 1997 - Validation versus social contact. Depression at 12 months (MOSES) [MD -4.01, 95% CI (-7.74 to - 0.28) P=0.04, completers analysis] favours validation. There were no statistically significant differences between validation and social contact or between validation and usual therapy. There were no assessments of carers. There is insufficient evidence from randomised trials to allow any conclusion about the efficacy of validation therapy for people with dementia or cognitive impairment.
In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer’s disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis. Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.
We included 10 studies, with 623 participants (900 ears). Interventions included: oil-based treatments (triethanolamine polypeptide, almond oil, benzocaine, chlorobutanol), water-based treatments (docusate sodium, carbamide peroxide, phenazone, choline salicylate, urea peroxide, potassium carbonate), other active comparators (e.g. saline or water alone) and no treatment. Nine of the studies were more than 15 years old. The overall risk of bias across the 10 included studies was low or unclear. Primary outcome: proportion of patients (or ears) with complete clearance of ear wax Six studies (360 participants; 491 ears) contributed quantitative data and were included in our meta-analyses. Active treatment versus no treatment Only one study addressed this comparison. The proportion of ears with complete clearance of ear wax was higher in the active treatment group (22%) compared with the no treatment group (5%) after five days of treatment (risk ratio (RR) 4.09, 95% confidence interval (CI) 1.00 to 16.80); one study; 117 ears; NNTB = 8) (low-quality evidence). Active treatment versus water or saline We found no evidence of a difference in the proportion of patients (or ears) with complete clearance of ear wax when the active treatment group was compared to the water or saline group (RR 1.47, 95% CI 0.79 to 2.75; three studies; 213 participants; 257 ears) (low-quality evidence). Two studies applied drops for five days, but one study only applied the drops for 15 minutes. When we excluded this study in a sensitivity analysis it did not change the result. Water or saline versus no treatment This comparison was only addressed in the single study cited above (active versus no treatment) and there was no evidence of a difference in the proportion of ears with complete wax clearance when comparing water or saline with no treatment after five days of treatment (RR 4.00, 95% CI 0.91 to 17.62; one study; 76 ears) (low-quality evidence). Active treatment A versus active treatment B Several single studies evaluated 'head-to-head' comparisons between two active treatments. We found no evidence to show that one was superior to any other. Subgroup analysis of oil-based active treatments versus non-oil based active treatments We found no evidence of a difference in this outcome when oil-based treatments were compared with non-oil-based active treatments. Primary outcome: adverse effects: discomfort, irritation or pain Only seven studies planned to measure and did report this outcome. Only two (141 participants;176 ears) provided useable data. There was no evidence of a significant difference in the number of adverse effects between the types of ear drops in these two studies. We summarised the remaining five studies narratively. All events were mild and reported in fewer than 30 participants across the seven studies (low-quality evidence). Secondary outcomes Three studies reported 'other' adverse effects (how many studies planned to report these is unclear). The available information was limited and included occasional reports of dizziness, unpleasant smell, tinnitus and hearing loss. No significant differences between groups were reported. There were no emergencies or serious adverse effects reported in any of the 10 studies. There was very limited or no information available on our remaining secondary outcomes. Although a number of studies aimed to evaluate whether or not one type of cerumenolytic is more effective than another, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain. A single study suggests that applying ear drops for five days may result in a greater likelihood of complete wax clearance than no treatment at all. However, we cannot conclude whether one type of active treatment is more effective than another and there was no evidence of a difference in efficacy between oil-based and water-based active treatments. There is no evidence to show that using saline or water alone is better or worse than commercially produced cerumenolytics. Equally, there is also no evidence to show that using saline or water alone is better than no treatment.
We included 11 trials involving 1069 participants at low anaesthetic risk. The sample size varied from 40 to 300 participants. We included 23 comparisons. All trials were at a high risk of bias. We were unable to perform a meta-analysis because there were no two trials involving the same comparison. Primary outcomes included perioperative mortality, serious morbidity and proportion of patients who were discharged on the same day. There were no perioperative deaths or serious adverse events in either group in the only trial that reported this information (0/60). There was no clear evidence of a difference in the proportion of patients who were discharged on the same day between any of the comparisons. Overall, 472/554 patients (85%) included in this review were discharged as day-procedure laparoscopic cholecystectomy patients. Secondary outcomes included hospital readmissions, health-related quality of life, pain, return to activity and return to work. There was no clear evidence of a difference in hospital readmissions within 30 days in the only comparison in which this outcome was reported. One readmission was reported in the 60 patients (2%) in whom this outcome was assessed. Quality of life was not reported in any of the trials. There was no clear evidence of a difference in the pain intensity, measured by a visual analogue scale, between comparators in the only trial which reported the pain intensity at between four and eight hours after surgery. Times to return to activity and return to work were not reported in any of the trials. There is currently insufficient evidence to conclude that one anaesthetic regimen for day-procedure laparoscopic cholecystectomy is to be preferred over another. However, the data are sparse (that is, there were few trials under each comparison and the trials had few participants) and further well designed randomized trials at low risk of bias and which are powered to measure differences in clinically important outcomes are necessary to determine the optimal anaesthetic regimen for day-procedure laparoscopic cholecystectomy, one of the commonest procedures performed in the western world.
Only four small randomised controlled trials fulfilled the selection criteria. For one of these trials, no data are available for the control group. Two studies compared lavage using diluted surfactant with standard care. Meta-analysis of these two studies did not show a significant effect on mortality (typical relative risk 0.42, 95% confidence interval [CI] 0.12 to 1.46; typical risk difference -0.10, 95% CI -0.24 to 0.04) or the use of ECMO (typical relative risk 0.27, 95% CI 0.04 to 1.86; typical risk difference -0.15, 95% CI -0.35 to 0.04). For the composite outcome of death or use of ECMO, a significant effect favoured the lavage group (typical relative risk 0.33, 95% CI 0.11 to 0.96; typical risk difference -0.19, 95% CI -0.34 to -0.03; number needed to benefit [NNTB] 5). No other benefits were reported. The other published study compared surfactant lavage followed by a surfactant bolus with surfactant bolus therapy alone in MAS complicated by pulmonary hypertension. No significant improvements in mortality, pneumothorax, duration of mechanical ventilation. or duration of hospitalisation were observed. In infants with meconium aspiration syndrome, lung lavage with diluted surfactant may be beneficial, but additional controlled clinical trials of lavage therapy should be conducted to confirm the treatment effect, to refine the method of lavage treatment, and to compare lavage treatment with other approaches, including surfactant bolus therapy. Long-term outcomes should be evaluated in further clinical trials.
One hundred and eight randomised trials involving 10,655 participants were included. Ninety-nine different Chinese herbal medicines were tested and compared with placebo (three trials), no intervention (five trials) or conventional medicine (61 trials), or Chinese herbal medicines plus western medicine were compared with western medicine (47 trials). The risk of bias across all studies was unclear for most domains primarily due to inadequate reporting of study design. Although we rated the risk of selective reporting for all studies as unclear, only a few studies contributed numerical data to the key outcomes. Seven trials reported fracture incidence, but they were small in sample size, suffered from various biases and tested different Chinese herbal medicines. These trials compared Kanggusong capsules versus placebo, Kanggusong granule versus Caltrate or ipriflavone plus Caltrate, Yigu capsule plus calcium versus placebo plus calcium, Xianlinggubao capsule plus Caltrate versus placebo plus Caltrate, Bushen Zhuanggu granules plus Caltrate versus placebo granules plus Caltrate, Kanggusong soup plus Caltrate versus Caltrate, Zhuangguqiangjin tablets and Shujinbogu tablets plus calcitonin ampoule versus calcitonin ampoule. The results were inconsistent. One trial showed that Bushenhuoxue therapy plus calcium carbonate tablets and alfacalcidol had a better effect on quality of life score (scale 0 to 100, higher is better) than calcium carbonate tablets and alfacalcidol (mean difference (MD) 5.30; 95% confidence interval (CI) 3.67 to 6.93). Compared with placebo in three separate trials, Chinese herbal medicines (Migu decoction, Bushen Yigu soft extract, Kanggusong capsules) showed a statistically significant increase in bone mineral density (BMD) (e.g. Kanggusong capsules, MD 0.06 g/cm3; 95% CI 0.02 to 0.10). Compared with no intervention in five trials, only two showed that Chinese herbal medicines had a statistically significant effect on increase in BMD (e.g. Shigu yin, MD 0.08 g/cm3; 95% CI 0.03 to 0.13). Compared with conventional medicine in 61 trials, 23 showed that Chinese herbal medicines had a statistically significant effect on increase in BMD. In 48 trials evaluating Chinese herbal medicines plus western medication against western medication, 26 showed better effects of the combination therapy on increase in BMD. No trial reported death or serious adverse events of Chinese herbal medicines, while some trials reported minor adverse effects such as nausea, diarrhoea, etc. Current findings suggest that the beneficial effect of Chinese herbal medicines in improving BMD is still uncertain and more rigorous studies are warranted.
We identified nine RCTs that met the inclusion criteria, but four were ongoing trials, and were not included in this analysis. We included five RCTs, with 8373 participants, in the NMA (two RCTs compared apixaban to a vitamin K antagonist, two RCTs compared rivaroxaban to a vitamin K antagonist, and one RCT compared dabigatran to a vitamin K antagonist). Very low- to moderate-certainty evidence suggests little or no difference between NOACs and vitamin K antagonists in death from cardiovascular causes (not reported in the dabigatran trial), myocardial infarction, stroke, death from any cause, and stent thrombosis. Apixaban (RR 0.85, 95% CI 0.77 to 0.95), high dose rivaroxaban (RR 0.86, 95% CI 0.74 to 1.00), and low dose rivaroxaban (RR 0.80, 95% CI 0.68 to 0.92) probably reduce the risk of recurrent hospitalisation compared with vitamin K antagonists. No studies looked at health-related quality of life. Very low- to moderate-certainty evidence suggests that NOACs may be safer than vitamin K antagonists in terms of bleeding. Both high dose dabigatran (RR 0.53, 95% CI 0.29 to 0.97), and low dose dabigatran (RR 0.38, 95% CI 0.21 to 0.70) may reduce major bleeding more than vitamin K antagonists. High dose dabigatran (RR 0.83, 95% CI 0.72 to 0.96), low dose dabigatran (RR 0.66, 95% CI 0.58 to 0.75), apixaban (RR 0,67 , 95% Cl 0.51 to 0.88), high dose rivaroxaban (RR 0.66, 95% CI 0.52 to 0.83), and low dose rivaroxaban (RR 0.71, 95% CI 0.57 to 0.88) probably reduce non-major bleeding more than vitamin K antagonists. The results from the NMA were inconclusive between the different NOACs for all primary and secondary outcomes. Very low- to moderate-certainty evidence suggests no meaningful difference in efficacy outcomes between non-vitamin K antagonist oral anticoagulants (NOAC) and vitamin K antagonists following percutaneous coronary interventions (PCI) in people with non-valvular atrial fibrillation. NOACs probably reduce the risk of recurrent hospitalisation for adverse events compared with vitamin K antagonists. Low- to moderate-certainty evidence suggests that dabigatran may reduce the rates of major and non-major bleeding, and apixaban and rivaroxaban probably reduce the rates of non-major bleeding compared with vitamin K antagonists. Our network meta-analysis did not show superiority of one NOAC over another for any of the outcomes. Head to head trials, directly comparing NOACs against each other, are required to provide more certain evidence.
We identified 56 eligible trials (3781 randomised participants). Eighteen trials did not report the primary outcomes of subjective cure, improvement of SUI or incontinence-specific quality of life (QoL). The risk of bias was generally unclear, as most trials provided little detail when reporting their methods. We assessed 25% of the included trials as being at high risk of bias for a variety of reasons, including industry funding and baseline differences between groups. We did not identify any economic evaluations. For subjective cure of SUI, we found moderate-quality evidence that ES is probably better than no active treatment (risk ratio (RR) 2.31, 95% CI 1.06 to 5.02). We found a similar result for cure or improvement of SUI (RR 1.73, 95% CI 1.41 to 2.11), but the quality of evidence was lower. We are very uncertain if there is a difference between ES and sham treatment in terms of subjective cure because of the very low quality of evidence (RR 2.21, 95% CI 0.38 to 12.73). For subjective cure or improvement, ES may be better than sham treatment (RR 2.03, 95% CI 1.02 to 4.07). The effect estimate was 660/1000 women cured/improved with ES compared to 382/1000 with no active treatment (95% CI 538 to 805 women); and for sham treatment, 402/1000 women cured/improved with ES compared to 198/1000 with sham treatment (95% CI 202 to 805 women). Low-quality evidence suggests that there may be no difference in cure or improvement for ES versus PFMT (RR 0.85, 95% CI 0.70 to 1.03), PFMT plus ES versus PFMT alone (RR 1.10, 95% CI 0.95 to 1.28) or ES versus vaginal cones (RR 1.09, 95% CI 0.97 to 1.21). Electrical stimulation probably improves incontinence-specific QoL compared to no treatment (moderate quality evidence) but there may be little or no difference between electrical stimulation and PFMT (low quality evidence). It is uncertain whether adding electrical stimulation to PFMT makes any difference in terms of quality of life, compared with PFMT alone (very low quality evidence). There may be little or no difference between electrical stimulation and vaginal cones in improving incontinence-specific QoL (low quality evidence). The impact of electrical stimulation on subjective cure/improvement and incontinence-specific QoL, compared with vaginal cones, PFMT plus vaginal cones, or drugs therapy, is uncertain (very low quality evidence). In terms of subjective cure/improvement and incontinence-specific QoL, the available evidence comparing ES versus drug therapy or PFMT plus vaginal cones was very low quality and inconclusive. Similarly, comparisons of different types of ES to each other and of ES plus surgery to surgery are also inconclusive in terms of subjective cure/improvement and incontinence-specific QoL (very low-quality evidence). Adverse effects were rare: in total nine of the women treated with ES in the trials reported an adverse effect. We identified insufficient evidence to compare the risk of adverse effects in women treated with ES compared to any other treatment. We were unable to identify any economic data. The current evidence base indicated that electrical stimulation is probably more effective than no active or sham treatment, but it is not possible to say whether ES is similar to PFMT or other active treatments in effectiveness or not. Overall, the quality of the evidence was too low to provide reliable results. Without sufficiently powered trials measuring clinically important outcomes, such as subjective assessment of urinary incontinence, we cannot draw robust conclusions about the overall effectiveness or cost-effectiveness of electrical stimulation for stress urinary incontinence in women.
We included 44 trials in the review with 1809 participants comparing an intervention with a placebo or a control. The age of participants ranged from 17 to 77 years. Most of the trials reported on short-term follow-up (ranging from one week to four weeks). Only one trial reported long-term follow-up (three months). Three studies were at low overall risk of bias, 16 at high overall risk of bias, and the remaining 25 at unclear overall risk of bias. We compared different types of interventions which were categorised as mechanical debridement, chewing gums, systemic deodorising agents, topical agents, toothpastes, mouthrinse/mouthwash, tablets, and combination methods. Mechanical debridement: for mechanical tongue cleaning versus no tongue cleaning, the evidence was very uncertain for the outcome dentist-reported organoleptic test (OLT) scores (MD -0.20, 95% CI -0.34 to -0.07; 2 trials, 46 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Chewing gums: for 0.6% eucalyptus chewing gum versus placebo chewing gum, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.10, 95% CI -0.31 to 0.11; 1 trial, 65 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Systemic deodorising agents: for 1000 mg champignon versus placebo, the evidence was very uncertain for the outcome patient-reported visual analogue scale (VAS) scores (MD -1.07, 95% CI -14.51 to 12.37; 1 trial, 40 participants; very low-certainty evidence). No data were reported for dentist-reported OLT score or adverse events. Topical agents: for hinokitiol gel versus placebo gel, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.27, 95% CI -1.26 to 0.72; 1 trial, 18 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Toothpastes: for 0.3% triclosan toothpaste versus control toothpaste, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -3.48, 95% CI -3.77 to -3.19; 1 trial, 81 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Mouthrinse/mouthwash: for mouthwash containing chlorhexidine and zinc acetate versus placebo mouthwash, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.20, 95% CI -0.58 to 0.18; 1 trial, 44 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Tablets: no data were reported on key outcomes for this comparison. Combination methods: for brushing plus cetylpyridium mouthwash versus brushing, the evidence was uncertain for the outcome dentist-reported OLT scores (MD -0.48, 95% CI -0.72 to -0.24; 1 trial, 70 participants; low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. We found low- to very low-certainty evidence to support the effectiveness of interventions for managing halitosis compared to placebo or control for the OLT and patient-reported outcomes tested. We were unable to draw any conclusions regarding the superiority of any intervention or concentration. Well-planned RCTs need to be conducted by standardising the interventions and concentrations.
We included eight trials with 15,445 participants randomised. The largest trial with 14,641 participants provided data on our primary outcomes. Seven trials reported on CVD risk factors. Three of the eight trials were regarded at high risk of bias for either reporting or attrition bias, most of the 'Risk of bias' domains for the remaining trials were judged as unclear, with the exception of the largest trial where most domains were judged to be at low risk of bias. The composite endpoint, major CVD events was not different between the vitamin C and placebo group (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.89 to 1.10; 1 study; 14,641 participants; low-quality evidence) in the Physicians Health Study II over eight years of follow-up. Similar results were obtained for all-cause mortality HR 1.07, 95% CI 0.97 to 1.18; 1 study; 14,641 participants; very low-quality evidence, total myocardial infarction (MI) (fatal and non-fatal) HR 1.04 (95% CI 0.87 to 1.24); 1 study; 14,641 participants; low-quality evidence, total stroke (fatal and non-fatal) HR 0.89 (95% CI 0.74 to 1.07); 1 study; 14,641 participants; low-quality evidence, CVD mortality HR 1.02 (95% 0.85 to 1.22); 1 study; 14,641 participants; very low-quality evidence, self-reported coronary artery bypass grafting (CABG)/percutaneous transluminal coronary angioplasty (PTCA) HR 0.96 (95% CI 0.86 to 1.07); 1 study; 14,641 participants; low-quality evidence, self-reported angina HR 0.93 (95% CI 0.84 to 1.03); 1 study; 14,641 participants; low-quality evidence. The evidence for the majority of primary outcomes was downgraded (low quality) because of indirectness and imprecision. For all-cause mortality and CVD mortality, the evidence was very low because more factors affected the directness of the evidence and because of inconsistency. Four studies did not state sources of funding, two studies declared non-commercial funding and two studies declared both commercial and non-commercial funding. Currently, there is no evidence to suggest that vitamin C supplementation reduces the risk of CVD in healthy participants and those at increased risk of CVD, but current evidence is limited to one trial of middle-aged and older male physicians from the USA. There is limited low- and very low-quality evidence currently on the effect of vitamin C supplementation and risk of CVD risk factors.
Eighty-two studies met the inclusion criteria. These showed considerable diversity in the targeted health issue and the aims, content, and outcomes of interventions. The majority were conducted in high income countries (n = 55) but many of these focused on low income and minority populations. The diversity of included studies limited meta-analysis to outcomes for four study groups. These analyses found evidence of moderate quality of the effectiveness of LHWs in promoting immunisation childhood uptake (RR 1.22, 95% CI 1.10 to 1.37; P = 0.0004); promoting initiation of breastfeeding (RR = 1.36, 95% CI 1.14 to 1.61; P < 0.00001), any breastfeeding (RR 1.24, 95% CI 1.10 to 1.39; P = 0.0004), and exclusive breastfeeding (RR 2.78, 95% CI 1.74 to 4.44; P <0.0001); and improving pulmonary TB cure rates (RR 1.22 (95% CI 1.13 to 1.31) P <0.0001), when compared to usual care. There was moderate quality evidence that LHW support had little or no effect on TB preventive treatment completion (RR 1.00, 95% CI 0.92 to 1.09; P = 0.99). There was also low quality evidence that LHWs may reduce child morbidity (RR 0.86, 95% CI 0.75 to 0.99; P = 0.03) and child (RR 0.75, 95% CI 0.55 to 1.03; P = 0.07) and neonatal (RR 0.76, 95% CI 0.57 to 1.02; P = 0.07) mortality, and increase the likelihood of seeking care for childhood illness (RR 1.33, 95% CI 0.86 to 2.05; P = 0.20). For other health issues, the evidence is insufficient to draw conclusions regarding effectiveness, or to enable the identification of specific LHW training or intervention strategies likely to be most effective. LHWs provide promising benefits in promoting immunisation uptake and breastfeeding, improving TB treatment outcomes, and reducing child morbidity and mortality when compared to usual care. For other health issues, evidence is insufficient to draw conclusions about the effects of LHWs.
IPD were available for 595 participants out of 1102 eligible individuals, from four out of 11 trials (i.e. 54% of the potential data). For remission outcomes, a HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, a HR greater than 1 indicates an advantage for carbamazepine. Most participants included in analysis (78%) were classified as experiencing focal onset seizures at baseline and only 22% were classified as experiencing generalised onset seizures; the results of this review are therefore mainly applicable to individuals with focal onset seizures. Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 546 participants: 0.94, 95% CI 0.70 to 1.26, moderate-certainty evidence); time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 546 participants: 0.99, 95% CI 0.69 to 1.41, moderate-certainty evidence); both showing no clear difference between the drugs and time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 546 participants: 1.27, 95% CI 0.87 to 1.86, moderate-certainty evidence), showing that treatment failure due to adverse events may occur earlier on carbamazepine than phenytoin, but we cannot rule out a slight advantage to carbamazepine or no difference between the drugs. For our secondary outcomes (pooled HRs adjusted for seizure type), we did not find any clear differences between carbamazepine and phenytoin: time to first seizure post-randomisation (582 participants): 1.15, 95% CI 0.94 to 1.40, moderate-certainty evidence); time to 12-month remission (551 participants): 1.00, 95% CI 0.79 to 1.26, moderate-certainty evidence); and time to six-month remission (551 participants): 0.90, 95% CI 0.73 to 1.12, moderate-certainty evidence). For all outcomes, results for individuals with focal onset seizures were similar to overall results (moderate-certainty evidence), and results for the small subgroup of individuals with generalised onset seizures were imprecise, so we cannot rule out an advantage to either drug, or no difference between drugs (low-certainty evidence). There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to treatment failure'. Heterogeneity was present in analysis of 'time to first seizure' for individuals with generalised onset seizures, which could not be explained by subgroup analysis or sensitivity analyses. Limited information was available about adverse events in the trials and we could not compare the rates of adverse events between carbamazepine and phenytoin. Some adverse events reported on both drugs were abdominal pain, nausea, and vomiting, drowsiness, motor and cognitive disturbances, dysmorphic side effects (such as rash). Moderate-certainty evidence provided by this systematic review does not show any differences between carbamazepine and phenytoin in terms of effectiveness (retention) or efficacy (seizure recurrence and seizure remission) for individuals with focal onset or generalised onset seizures. However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies, which may have had an impact on the results of this review. We therefore do not suggest that results of this review alone should form the basis of a treatment choice for a person with newly-onset seizures. We did not find any evidence to support or refute current treatment policies. We implore that future trials be designed to the highest quality possible, with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.
The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only. Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis. Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-α (IFN-α). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs. Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments, and here in particular a combined therapeutic regimen of chemotherapy and electron beam, bexarotene, or denileukin diftitox, showed more adverse effects than topical or skin-directed treatments. In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-α and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival. This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.
Three eligible trials were identified. Two trials, including one trial with a much larger sample size than the others combined, were from geographical areas with low population selenium concentrations. Meta-analysis of the pooled data showed a significant reduction in the proportion of infants having one or more episodes of sepsis associated with selenium supplementation [summary RR 0.73 (0.57 to 0.93); RD -0.10 (-0.17 to -0.02); NNT 10 (5.9 to 50)]. Supplementation with selenium was not associated with improved survival, a reduction in neonatal chronic lung disease or retinopathy of prematurity. Supplementing very preterm infants with selenium is associated with benefit in terms of a reduction in one or more episodes of sepsis. Supplementation was not associated with improved survival, a reduction in neonatal chronic lung disease or retinopathy of prematurity. Supplemental doses of selenium for infants on parenteral nutrition higher than those currently recommended may be beneficial. The data are dominated by one large trial from a country with low selenium concentrations and may not be readily translated to other populations.
We included eight trials randomising 232 preterm infants in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. The meta-analyses of the studies showed a reduced risk in favor of inhalation steroids regarding failure to extubate at seven days (typical RR (TRR) 0.80, 95% CI 0.66 to 0.98; 5 studies, 79 infants) and at the latest reported time point after treatment onset (TRR 0.60, 95% CI 0.45 to 0.80; 6 studies, 90 infants). However, both analyses showed increased statistical heterogeneity (I2 statistic 73% and 86%, respectively). Furthermore, inhalation steroids did not impact total duration of mechanical ventilation or oxygen dependency. There was a trend toward a reduction in the use of systemic corticosteroids in infants receiving inhalation corticosteroids (TRR 0.51, 95% CI 0.26 to 1.00; 4 studies, 74 infants; very low-quality evidence). There was a paucity of data on short- and long-term adverse effects. Our results should be interpreted with caution because the total number of randomised participants is relatively small, and most trials differed considerably in participant characteristics, inhalation therapy, and outcome definitions. Based on the results of the currently available evidence, inhalation corticosteroids initiated at ≥ 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids.
Fourteen trials met all inclusion criteria and were included in this review. In most of the studies, hawthorn was used as an adjunct to conventional treatment. Ten trials including 855 patients with chronic heart failure (New York Heart Association classes I to III) provided data that were suitable for meta-analysis. For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo (WMD (Watt) 5.35, 95% CI 0.71 to 10.00, P < 0.02, n = 380). Exercise tolerance were significantly increased by hawthorn extract (WMD (Watt x min) 122.76, 95% CI 32.74 to 212.78, n = 98). The pressure-heart rate product, an index of cardiac oxygen consumption, also showed a beneficial decrease with hawthorn treatment (WMD (mmHg/min) -19.22, 95% CI -30.46 to -7.98, n = 264). Symptoms such as shortness of breath and fatigue improved significantly with hawthorn treatment as compared with placebo (WMD -5.47, 95% CI -8.68 to -2.26, n = 239). No data on relevant mortality and morbidity such as cardiac events were reported, apart from one trial, which reported deaths (three in active, one in control) without providing further details. Reported adverse events were infrequent, mild, and transient; they included nausea, dizziness, and cardiac and gastrointestinal complaints. These results suggest that there is a significant benefit in symptom control and physiologic outcomes from hawthorn extract as an adjunctive treatment for chronic heart failure.
Two randomised trials assessed the effectiveness of oral plus inhaled dual therapy versus oral monotherapy in a total of 118 adults with a mean age of 62.8 years. One multi-centre trial compared inhaled tobramycin plus oral ciprofloxacin versus ciprofloxacin alone, and one single-centre trial compared nebulised gentamicin plus systemic antibiotics versus a systemic antibiotic alone. Published papers did not report study funding sources. Effect estimates from one small study with 53 adults showed no evidence of treatment benefit with oral plus inhaled dual therapy for the following primary outcomes at the end of the study: successful management of exacerbation - cure at day 42 (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.22 to 2.01; 53 participants; one study; very low-quality evidence); number of participants with Pseudomonas aeruginosa eradication at day 21 (OR 2.33, 95% CI 0.66 to 8.24; 53 participants; one study; very low-quality evidence); and serious adverse events (OR 0.48, 95% CI 0.08 to 2.87; 53 participants; one study; very low-quality evidence). Similarly, researchers provided no evidence of treatment benefit for the following secondary outcomes: clinical response rates - relapse at day 42 (OR 0.57, 95% CI 0.12 to 2.69; 53 participants; one study; very low-quality evidence); microbiological response rate at day 21 - eradicated (OR 2.40, 95% CI 0.67 to 8.65; 53 participants; one study; very low-quality evidence); and adverse events - incidence of wheeze (OR 5.75, 95% CI 1.55 to 21.33). Data show no evidence of benefit in terms of sputum volume, lung function, or antibiotic resistance. Outcomes from a second small study with 65 adults, available only as an abstract, were not included in the quantitative data synthesis. The included studies did not report our other primary outcomes: duration; frequency; and time to next exacerbation; nor our secondary outcomes: systemic markers of infection; exercise capacity; and quality of life. We did not identify any trials that included children. A small number of studies in adults have generated high-quality evidence that is insufficient to inform robust conclusions, and studies in children have provided no evidence. We identified only one dual-therapy combination of oral and inhaled antibiotics. Results from this single trial of 53 adults that we were able to include in the quantitative synthesis showed no evidence of treatment benefit with oral plus inhaled dual therapy in terms of successful treatment of exacerbations, serious adverse events, sputum volume, lung function, and antibiotic resistance. Further high-quality research is required to determine the efficacy and safety of other combinations of dual antibiotics for both adults and children with bronchiectasis, particularly in terms of antibiotic resistance.
For this update, we included seven additional studies, making a total of 21 included studies, which involved a total of 1400 participants: 635 received SET, 320 received HBET, and 445 received WA. In general, SET and HBET programs consisted of three exercise sessions per week. Follow-up ranged from six weeks to two years. Most trials used a treadmill walking test to investigate effects of exercise therapy on walking capacity. However, two trials assessed only quality of life, functional impairment, and/or walking behavior (i.e., daily steps measured by pedometer). The overall methodological quality of included trials was moderate to good. However, some trials were small with respect to numbers of participants, ranging from 20 to 304. SET groups showed clear improvement in MWD/T compared with HBET and WA groups, with overall SMDs at three months of 0.37 (95% confidence interval [CI] 0.12 to 0.62; P = 0.004; moderate-quality evidence) and 0.80 (95% CI 0.53 to 1.07; P < 0.00001; high-quality evidence), respectively. This translates to differences in increased MWD of approximately 120 and 210 meters in favor of SET groups. Data show improvements for up to six and 12 months, respectively. The HBET group did not show improvement in MWD/T compared with the WA group (SMD 0.30, 95% CI -0.45 to 1.05; P = 0.43; moderate-quality evidence). Compared with HBET, SET was more beneficial for PFWD/T but had no effect on quality of life parameters nor on self-reported functional impairment. Compared with WA, SET was more beneficial for PFWD/T and self-reported functional impairment, as well as for some quality of life parameters (e.g., physical functioning, pain, and physical component summary after 12 months), and HBET had no effect. Data show no obvious effects on mortality rates. Thirteen of the 1400 participants died, but no deaths were related to exercise therapy. Overall, adherence to SET was approximately 80%, which was similar to that reported with HBET. Only limited adherence data were available for WA groups. Evidence of moderate and high quality shows that SET provides an important benefit for treadmill-measured walking distance (MWD and PFWD) compared with HBET and WA, respectively. Although its clinical relevance has not been definitively demonstrated, this benefit translates to increased MWD of 120 and 210 meters after three months in SET groups. These increased walking distances are likely to have a positive impact on the lives of patients with IC. Data provide no clear evidence of a difference between HBET and WA. Trials show no clear differences in quality of life parameters nor in self-reported functional impairment between SET and HBET. However, evidence is of low and very low quality, respectively. Investigators detected some improvements in quality of life favoring SET over WA, but analyses were limited by small numbers of studies and participants. Future studies should focus on disease-specific quality of life and other functional outcomes, such as walking behavior and physical activity, as well as on long-term follow-up.
We found five double-blind placebo-controlled trials that met our inclusion criteria. These trials assessed effectiveness and safety of drugs in a total of 50 people with intellectual disability demonstrating SIB. Four trials compared the effects of naltrexone versus placebo and one trial compared clomipramine versus placebo. One of the naltrexone versus placebo trials reported that naltrexone had clinically significant effects (≥ 33% reduction) on the daily rates of three of the four participants' most severe form of SIB and modest to substantial reductions in SIB for all participants; however, this study did not report on statistical significance. Another trial reported that naltrexone attenuated SIB in all four participants, with 25 mg and 50 mg doses producing a statistically significant decrease in SIB (P value < 0.05). Another trial (eight people) indicated that naltrexone administration was associated with significantly fewer days of high frequency self injury and significantly more days with low frequency self injury. Naltrexone had different effects depending on the form and location of self injury. Another trial with only 26 participants found that neither single-dose (100 mg) nor long-term (50 and 150 mg) naltrexone treatment had any therapeutic effect on SIB. Comparison of clomipramine versus placebo found no statistically significant benefit for any outcome measure, which included SIB rate and intensity, stereotypy and adverse events. However, it showed clinically significant improvement in the rate and intensity of SIB and stereotypy. There were very few noteworthy adverse events to report in any of the four trials in which these were reported. All trials were at high risk of bias, apart from one trial (Lewis 1996), which was probably at low risk of bias. The short period of follow-up was a significant drawback in the design of all five trials, as it did not allow long-term assessment of behaviour over time. We were unable to examine the efficacy of antidepressants other than clomipramine, antipsychotics, mood stabilisers or beta-blockers as we did not identify any relevant placebo-controlled trials. There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating SIB. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo.
We selected 10 studies for inclusion in the review from 5236 studies identified in the search. These 10 studies included a total of 709 participants. Risk of bias for the included studies was assessed as high in six studies and as unclear in four studies. Two RCTs reported all-cause mortality. Among 413 participants, there was no clear evidence of a difference in mortality between CPAP and control groups, and considerable heterogeneity between trials was noted (risk ratio (RR) 1.28, 95% confidence interval (CI) 0.35 to 4.66; I2 = 75%). Six studies reported demonstrable atelectasis in the study population. A reduction in atelectasis was observed in the CPAP group, although heterogeneity between studies was substantial (RR 0.62, 95% CI 0.45 to 0.86; I2 = 61%). Pneumonia was reported in five studies, including 563 participants; CPAP reduced the rate of pneumonia, and no important heterogeneity was noted (RR 0.43, 95% CI 0.21 to 0.84; I2 = 0%). The number of participants identified as having serious hypoxia was reported in two studies, with no clear difference between CPAP and control groups, given imprecise results and substantial heterogeneity between trials (RR 0.48, 95% CI 0.22 to 1.02; I2 = 67%). A reduced rate of reintubation was reported in the CPAP group compared with the control group in two studies, and no important heterogeneity was identified (RR 0.14, 95% CI 0.03 to 0.58; I2 = 0%). Admission into the intensive care unit (ICU) for invasive ventilation and supportive care was reduced in the CPAP group, but this finding did not reach statistical significance (RR 0.45, 95% CI 0.18 to 1.14; I2 = 0). Secondary outcomes such as length of hospital stay and adverse effects were only minimally reported. A summary of findings table was constructed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) principle. The quality of evidence was determined to be very low. Very low-quality evidence from this review suggests that CPAP initiated during the postoperative period might reduce postoperative atelectasis, pneumonia and reintubation, but its effects on mortality, hypoxia or invasive ventilation are uncertain. Evidence is not sufficiently strong to confirm the benefits or harms of CPAP during the postoperative period in those undergoing major abdominal surgery. Most of the included studies did not report on adverse effects attributed to CPAP. New, high-quality research is much needed to evaluate the use of CPAP in preventing mortality and morbidity following major abdominal surgery. With increasing availability of CPAP to our surgical patients and its potential to improve outcomes (possibly in conjunction with intraoperative lung protective ventilation strategies), unanswered questions regarding its efficacy and safety need to be addressed. Any future study must report on the adverse effects of CPAP.
This update located nine new studies, which were added to the six studies from our last update in 2008. This review now includes 15 studies (eight RCTs, five CBA and two ITS studies). All of these studies measured the effectiveness of IPE interventions compared to no educational intervention. Seven studies indicated that IPE produced positive outcomes in the following areas: diabetes care, emergency department culture and patient satisfaction; collaborative team behaviour and reduction of clinical error rates for emergency department teams; collaborative team behaviour in operating rooms; management of care delivered in cases of domestic violence; and mental health practitioner competencies related to the delivery of patient care. In addition, four of the studies reported mixed outcomes (positive and neutral) and four studies reported that the IPE interventions had no impact on either professional practice or patient care. This updated review reports on 15 studies that met the inclusion criteria (nine studies from this update and six studies from the 2008 update). Although these studies reported some positive outcomes, due to the small number of studies and the heterogeneity of interventions and outcome measures, it is not possible to draw generalisable inferences about the key elements of IPE and its effectiveness. To improve the quality of evidence relating to IPE and patient outcomes or healthcare process outcomes, the following three gaps will need to be filled: first, studies that assess the effectiveness of IPE interventions compared to separate, profession-specific interventions; second, RCT, CBA or ITS studies with qualitative strands examining processes relating to the IPE and practice changes; third, cost-benefit analyses.
None of the studies of clinically-relevant hyperkalaemia reported mortality or cardiac arrhythmias. Reports focused on serum potassium levels. Many studies were small, and not all intervention groups had sufficient data for meta-analysis to be performed. On the basis of small studies, inhaled beta-agonists, nebulised beta-agonists, and intravenous (IV) insulin-and-glucose were all effective, and the combination of nebulised beta agonists with IV insulin-and-glucose was more effective than either alone. Dialysis is effective. Results were equivocal for IV bicarbonate. K-absorbing resin was not effective by four hours, and longer follow up data on this intervention were not available from RCTs. Nebulised or inhaled salbutamol, or IV insulin-and-glucose are the first-line therapies for the management of emergency hyperkalaemia that are best supported by the evidence. Their combination may be more effective than either alone, and should be considered when hyperkalaemia is severe. When arrhythmias are present, a wealth of anecdotal and animal data suggests that IV calcium is effective in treating arrhythmia. Further studies of the optimal use of combination treatments and of the adverse effects of treatments are needed.
One study (34 patients) met our inclusion criteria although it was not yet a peer reviewed publication. The study randomised patients with chronic frontal sinusitis who had failed a prolonged course of medical treatment into two groups: balloon dilatation of the frontal recess (plus conventional FESS of other involved sinuses) versus conventional FESS (Draf type 1/2a procedures on the frontal sinuses). At 12 months follow up there was no statistically significant difference in radiological resolution of frontal sinuses between the two groups. The percentages of directly observed patent frontal recesses at 12 months were 75% in the balloon dilation group versus 63% in the FESS-only group. The authors state that this was statistically significant but details of the analysis were not presented. Indeed the study as a whole suffers from a bias in the way its outcome measures were reported. No major complications were reported. Three patients in the FESS-only group required further revision frontal sinus surgery compared to one in the balloon dilation group, although synechiae were more common in the latter. At present there is no convincing evidence supporting the use of endoscopic balloon sinus ostial dilation compared to conventional surgical modalities in the management of CRS refractory to medical treatment. With the escalating use of balloon sinuplasty, there is an urgent need for more randomised controlled trials to determine its efficacy over conventional surgical treatment modalities.
Of seventeen included studies, thirteen found no evidence of an effect for continuous smoking abstinence following the intervention. Meta-analysis of 14 studies for point prevalence of smoking produced a statistically and clinically significant effect in favour of the intervention (OR 1.36, 95% CI 1.20 to 1.55, p= 0.004). Meta-analysis of eight studies that reported continuous abstinence was also statistically significant (OR 1.60, 95% CI 1.26 to 2.03, p= 0.03). Healthcare professionals who had received training were more likely to perform tasks of smoking cessation than untrained controls, including: asking patients to set a quit date (p< 0.0001), make follow-up appointments (p< 0.00001), counselling of smokers (p< 0.00001), provision of self-help material (p< 0.0001) and prescription of a quit date (p< 0.00001). No evidence of an effect was observed for the provision of nicotine gum/replacement therapy. Training health professionals to provide smoking cessation interventions had a measurable effect on the point prevalence of smoking, continuous abstinence and professional performance. The one exception was the provision of nicotine gum or replacement therapy, which did not differ between groups.
We included 22 studies involving 7436 participants comparing nine different types of securement device or dressing. All included studies were at unclear or high risk of performance bias due to the different appearances of the dressings and securement devices. The extent of blinding of outcome assessment was unclear in most studies. The quality of evidence varied between different comparisons and outcomes. We mainly downgraded the quality of evidence for imprecision, indirectness, risk of bias and inconsistency. It is unclear whether there is a difference in the rate of catheter-related BSI between securement with gauze and tape and standard polyurethane (SPU) (RR 0.64, 95% CI 0.26 to 1.63, low quality evidence), or between chlorhexidine gluconate-impregnated (CGI) dressings and SPU (RR 0.65, 95% CI 0.40 to 1.05, moderate quality evidence). There is high quality evidence that medication-impregnated dressings reduce the incidence of catheter-related BSI relative to all other dressing types (RR 0.60, 95% CI 0.39 to 0.93). There is moderate quality evidence that CGI dressings reduce the frequency of catheter-related BSI per 1000 patient days compared with SPU dressings (RR 0.51, 95% CI 0.33 to 0.78). There is moderate quality evidence that catheter tip colonisation is reduced with CGI dressings compared with SPU dressings (RR 0.58, 95% CI 0.47 to 0.73), but the relative effects of gauze and tape and SPU are unclear (RR 0.95, 95% CI 0.51 to 1.77, very low quality evidence). It is unclear if there is a difference in rates of skin irritation or damage when CGI dressings are compared with SPU dressings (moderate quality evidence) (RR 11.17, 95% CI 0.84 to 149.48). A multiple treatment meta-analysis found sutureless securement devices as likely to be the most effective at reducing the incidence of catheter-related BSI (low quality evidence), with CGI dressings ranked second (low quality evidence). Medication-impregnated dressing products reduce the incidence of catheter-related BSI relative to all other dressing types. There is some evidence that CGI dressings, relative to SPU dressings, reduce catheter-related BSI for the outcomes of frequency of infection per 1000 patient days, risk of catheter tip colonisation and possibly risk of catheter-related BSI. A multiple treatment meta-analysis found that sutureless securement devices are likely to be the most effective at reducing catheter-related BSI though this is low quality evidence. Most studies were conducted in intensive care unit (ICU) settings. More, high quality research is needed regarding the relative effects of dressing and securement products for CVCs. Future research may adjust the estimates of effect for the products included in this review and is needed to assess the effectiveness of new products.
Eight RCTs with a total of 8915 participants (4545 invasive strategies, 4370 conservative strategies) were eligible for inclusion. We included three new studies and 1099 additional participants in this review update. In the all-study analysis, evidence did not show appreciable risk reductions in all-cause mortality (RR 0.87, 95% CI 0.64 to 1.18; eight studies, 8915 participants; low quality evidence) and death or non-fatal MI (RR 0.93, 95% CI 0.71 to 1.2; seven studies, 7715 participants; low quality evidence) with invasive strategies compared to conservative (selective invasive) strategies at six to 12 months follow-up. There was appreciable risk reduction in MI (RR 0.79, 95% CI 0.63 to 1.00; eight studies, 8915 participants; moderate quality evidence), refractory angina (RR 0.64, 95% CI 0.52 to 0.79; five studies, 8287 participants; moderate quality evidence) and re-hospitalisation (RR 0.77, 95% CI 0.63 to 0.94; six studies, 6921 participants; moderate quality evidence) with routine invasive strategies compared to conservative (selective invasive) strategies also at six to 12 months follow-up. Evidence also showed increased risks in bleeding (RR 1.73, 95% CI 1.30 to 2.31; six studies, 7584 participants; moderate quality evidence) and procedure-related MI (RR 1.87, 95% CI 1.47 to 2.37; five studies, 6380 participants; moderate quality evidence) with routine invasive strategies compared to conservative (selective invasive) strategies. The low quality evidence were as a result of serious risk of bias and imprecision in the estimate of effect while moderate quality evidence was only due to serious risk of bias. In the all-study analysis, the evidence failed to show appreciable benefit with routine invasive strategies for unstable angina and non-ST elevation MI compared to conservative strategies in all-cause mortality and death or non-fatal MI at six to 12 months. There was evidence of risk reduction in MI, refractory angina and re-hospitalisation with routine invasive strategies compared to conservative (selective invasive) strategies at six to 12 months follow-up. However, routine invasive strategies were associated with a relatively high risk (almost double the risk) of procedure-related MI, and increased risk of bleeding complications. This systematic analysis of published RCTs supports the conclusion that, in patients with UA/NSTEMI, a selectively invasive (conservative) strategy based on clinical risk for recurrent events is the preferred management strategy.
We included five randomised controlled trials (RCTs) with 232 participants comparing haloperidol discontinuation with haloperidol continuation. Discontinuation was achieved in all five studies by replacing haloperidol with placebo. The trials' size ranged between 23 and 87 participants. The methods of randomisation, allocation concealment and blinding were poorly reported. Participants allocated to discontinuing haloperidol treatment were more likely to show no improvement in global state compared with those in the haloperidol continuation group (n = 49; 1 RCT; RR 2.06, 95% CI 1.33 to 3.20; very low quality evidence: our confidence in the effect estimate is limited due to relevant methodological shortcomings of included trials). Those who continued haloperidol treatment were less likely to experience a relapse compared to people who discontinued taking haloperidol (n = 165; 4 RCTs; RR 1.80, 95% CI 1.18 to 2.74; very low quality evidence). Satisfaction with treatment (measured as numbers leaving the study early) was similar between groups (n = 43; 1 RCT; RR 0.13, 95% CI 0.01 to 2.28; very low quality evidence). No usable mental state, general functioning, general behaviour or adverse effect data were reported by any of the trials. This review provides limited evidence derived from small, short-term studies. The longest study was for one year, making it difficult to generalise the results to a life-long disorder. Very low quality evidence shows that discontinuation of haloperidol is associated with an increased risk of relapse and a reduction in the risk of 'global state improvement'. However, participant satisfaction with haloperidol treatment was not different from participant satisfaction with haloperidol discontinuation as measured by leaving the studies early. Due to the very low quality of these results, firm conclusions cannot be made. In addition, the available studies did not report usable data regarding the adverse effects of haloperidol treatment. Considering that haloperidol is one of the most widely used antipsychotic drugs, it was surprising that only a small number of studies into the benefit and harm of haloperidol discontinuation were available. Moreover, the available studies did not report on outcomes that are important to clinicians and to people with schizophrenia, particularly adverse effects and social outcomes. Better designed trials are warranted.
We included 69 trials with 4860 participants: 2404 given epidural analgesia and 2456 receiving comparators (systemic analgesia, peripheral nerve block, intrapleural analgesia, or wound infiltration). The mean (or median) age of participants varied between 43.5 years and 74.6 years. Surgeries performed were coronary artery bypass grafting or valvular procedures and surgeries for congenital heart disease. We judged that no trials were at low risk of bias for all domains, and that all trials were at unclear/high risk of bias for blinding of participants and personnel taking care of study participants. Epidural analgesia versus systemic analgesia Trials show there may be no difference in mortality at 0 to 30 days (risk difference (RD) 0.00, 95% confidence interval (CI) −0.01 to 0.01; 38 trials with 3418 participants; low-quality evidence), and there may be a reduction in myocardial infarction at 0 to 30 days (RD −0.01, 95% CI −0.02 to 0.00; 26 trials with 2713 participants; low-quality evidence). Epidural analgesia may reduce the risk of 0 to 30 days respiratory depression (RD −0.03, 95% CI −0.05 to −0.01; 21 trials with 1736 participants; low-quality evidence). There is probably little or no difference in risk of pneumonia at 0 to 30 days (RD −0.03, 95% CI −0.07 to 0.01; 10 trials with 1107 participants; moderate-quality evidence), and epidural analgesia probably reduces the risk of atrial fibrillation or atrial flutter at 0 to 2 weeks (RD −0.06, 95% CI −0.10 to −0.01; 18 trials with 2431 participants; moderate-quality evidence). There may be no difference in cerebrovascular accidents at 0 to 30 days (RD −0.00, 95% CI −0.01 to 0.01; 18 trials with 2232 participants; very low-quality evidence), and none of the included trials reported any epidural haematoma events at 0 to 30 days (53 trials with 3982 participants; low-quality evidence). Epidural analgesia probably reduces the duration of tracheal intubation by the equivalent of 2.4 hours (standardized mean difference (SMD) −0.78, 95% CI −1.01 to −0.55; 40 trials with 3353 participants; moderate-quality evidence). Epidural analgesia reduces pain at rest and on movement up to 72 hours after surgery. At six to eight hours, researchers noted a reduction in pain, equivalent to a reduction of 1 point on a 0 to 10 pain scale (SMD −1.35, 95% CI −1.98 to −0.72; 10 trials with 502 participants; moderate-quality evidence). Epidural analgesia may increase risk of hypotension (RD 0.21, 95% CI 0.09 to 0.33; 17 trials with 870 participants; low-quality evidence) but may make little or no difference in the need for infusion of inotropics or vasopressors (RD 0.00, 95% CI −0.06 to 0.07; 23 trials with 1821 participants; low-quality evidence). Epidural analgesia versus other comparators Fewer studies compared epidural analgesia versus peripheral nerve blocks (four studies), intrapleural analgesia (one study), and wound infiltration (one study). Investigators provided no data for pulmonary complications, atrial fibrillation or flutter, or for any of the comparisons. When reported, other outcomes for these comparisons (mortality, myocardial infarction, neurological complications, duration of tracheal intubation, pain, and haemodynamic support) were uncertain due to the small numbers of trials and participants. Compared with systemic analgesia, epidural analgesia may reduce the risk of myocardial infarction, respiratory depression, and atrial fibrillation/atrial flutter, as well as the duration of tracheal intubation and pain, in adults undergoing cardiac surgery. There may be little or no difference in mortality, pneumonia, and epidural haematoma, and effects on cerebrovascular accident are uncertain. Evidence is insufficient to show the effects of epidural analgesia compared with peripheral nerve blocks, intrapleural analgesia, or wound infiltration.
Eight studies are included in this review; six employed a crossover design. In the overall comparison of radiant warmers vs incubators, radiant warmers caused a statistically significant increase in insensible water loss (IWL) [WMD 0.94g/Kg/day (95% CI 0.47, 1.41)] and a trend towards increased oxygen consumption which was not statistically significant [WMD 0.27mL/kg/min (95% CI -0.09, 0.63)]. Due to small numbers, effects on important clinical outcomes could not be adequately assessed. A comparison of radiant warmers with heat shields vs incubators without heat shields showed a trend for increased IWL in the radiant warmer group, which was not statistically significant. No difference was shown in oxygen consumption. Radiant warmers result in increased IWL compared to incubators. This needs to be taken into account when calculating daily fluid requirements. The results of this review do not provide sufficient evidence concerning effects on important outcomes to guide clinical practice. Further randomised controlled trials are required to assess the effects of radiant warmers versus incubators in neonatal care on important short and long term outcomes, with particular attention to extremely low birthweight infants in the early neonatal period.
Thirty-nine studies which reported quantitative or qualitative data, or both, were included in the review. Thirty-three quantitative studies were identified. This included five randomised controlled trials (RCTs) and 10 non-experimental studies of warmth improvements, 12 non-experimental studies of rehousing or retrofitting, three non-experimental studies of provision of basic improvements in low or mIddle Income countries (LMIC), and three non-experimental historical studies of rehousing from slums. Fourteen quantitative studies (42.4%) were assessed to be poor quality and were not included in the synthesis. Twelve studies reporting qualitative data were identified. These were studies of warmth improvements (n = 7) and rehousing (n = 5). Three qualitative studies were excluded from the synthesis due to lack of clarity of methods. Six of the included qualitative studies also reported quantitative data which was included in the review. Very little quantitative synthesis was possible as the data were not amenable to meta-analysis. This was largely due to extreme heterogeneity both methodologically as well as because of variations in the intervention, samples, context, and outcome; these variations remained even following grouping of interventions and outcomes. In addition, few studies reported data that were amenable to calculation of standardized effect sizes. The data were synthesised narratively. Data from studies of warmth and energy efficiency interventions suggested that improvements in general health, respiratory health, and mental health are possible. Studies which targeted those with inadequate warmth and existing chronic respiratory disease were most likely to report health improvement. Impacts following housing-led neighbourhood renewal were less clear; these interventions targeted areas rather than individual households in most need. Two poorer quality LMIC studies reported unclear or small health improvements. One better quality study of rehousing from slums (pre-1960) reported some improvement in mental health. There were few reports of adverse health impacts following housing improvement. A small number of studies gathered data on social and socio-economic impacts associated with housing improvement. Warmth improvements were associated with increased usable space, increased privacy, and improved social relationships; absences from work or school due to illness were also reduced. Very few studies reported differential impacts relevant to equity issues, and what data were reported were not amenable to synthesis. Housing investment which improves thermal comfort in the home can lead to health improvements, especially where the improvements are targeted at those with inadequate warmth and those with chronic respiratory disease. The health impacts of programmes which deliver improvements across areas and do not target according to levels of individual need were less clear, but reported impacts at an area level may conceal health improvements for those with the greatest potential to benefit. Best available evidence indicates that housing which is an appropriate size for the householders and is affordable to heat is linked to improved health and may promote improved social relationships within and beyond the household. In addition, there is some suggestion that provision of adequate, affordable warmth may reduce absences from school or work. While many of the interventions were targeted at low income groups, a near absence of reporting differential impacts prevented analysis of the potential for housing improvement to impact on social and economic inequalities.
We included 36 RCTs (2706 participants), of which 31 examined topical steroids; seven, calcineurin inhibitors; and three, lithium salts. The comparative interventions included placebo, azoles, calcipotriol, a non-steroidal anti-inflammatory compound, and zinc, as well as different anti-inflammatory treatments compared against each other. Our outcomes of interest were total clearance of symptoms, erythema, scaling or pruritus scores, and adverse effects. The risk of bias in studies was most frequently classified as unclear, due to unclear reporting of methods. Steroid treatment resulted in total clearance more often than placebo in short-term trials (four weeks or less) (relative risk (RR) 3.76, 95% confidence interval (CI) 1.22 to 11.56, three RCTs, 313 participants) and in one long-term trial (lasting 12 weeks). Steroids were also more effective in reducing erythema, scaling, and pruritus. Adverse effects were similar in both groups. There may be no difference between steroids and calcineurin inhibitors in total clearance in the short-term (RR 1.08, 95% 0.88 to 1.32, two RCTs, 60 participants, low-quality evidence). Steroids and calcineurin inhibitors were found comparable in all other assessed efficacy outcomes as well (five RCTs, 237 participants). Adverse events were less common in the steroid group compared with the calcineurin group in the short-term (RR 0.22, 95% CI 0.05 to 0.89, two RCTs, 60 participants). There were comparable rates of total clearance in the steroid and azole groups (RR 1.11, 95% CI 0.94 to 1.32, eight RCTs, 464 participants, moderate-quality evidence) as well as of adverse effects in the short-term, but less erythema or scaling with steroids. We found mild (class I and II) and strong (class III and IV) steroids comparable in the assessed outcomes, including adverse events. The only exception was total clearance in long-term use, which occurred more often with a mild steroid (RR 0.79, 95% CI 0.63 to 0.98, one RCT, 117 participants, low-quality evidence). In one study, calcineurin inhibitor was more effective than placebo in reducing erythema and scaling, but there were similar rates in total clearance or adverse events for short-term treatment. In another study, calcineurin inhibitor was comparable with azole when erythema, scaling, or adverse effects were measured for longer-term treatment. Lithium was more effective than placebo with regard to total clearance (RR 8.59, 95% CI 2.08 to 35.52, one RCT, 129 participants) with a comparable safety profile. Compared with azole, lithium resulted in total clearance more often (RR 1.79, 95% CI 1.10 to 2.90 in short-term treatment, one RCT, 288 participants, low-quality evidence). Topical steroids are an effective treatment for seborrhoeic dermatitis of the face and scalp in adolescents and adults, with no differences between mild and strong steroids in the short-term. There is some evidence of the benefit of topical calcineurin inhibitor or lithium salt treatment. Treatment with azoles seems as effective as steroids concerning short-term total clearance, but in other outcomes, strong steroids were more effective. Calcineurin inhibitor and azole treatment appeared comparable. Lithium salts were more effective than azoles in producing total clearance. Steroids are similarly effective to calcineurin inhibitors but with less adverse effects. Most of the included studies were small and short, lasting four weeks or less. Future trials should be appropriately blinded; include more than 200 to 300 participants; and compare steroids to calcineurin inhibitors or lithium salts, and calcineurin inhibitors to azoles or lithium salts. The follow-up time should be at least one year, and quality of life should be addressed. There is also a need for the development of well-validated outcome measures.
We included 16 studies (eight individually randomised trials, four cluster randomised trials, three non-randomised trials, and one controlled before-after study). Twelve studies were conducted in the USA, while there was one study each from: Australia, Sweden, Tanzania, and the UK. Ten studies had unclear or high risk of bias. We categorised interventions as recipient-oriented, provider-oriented, or health systems-oriented. The interventions targeted adolescent boys or girls or both (seven studies), parents (four studies), and providers (two studies). Five studies had mixed participants that included adolescents and parents, adolescents and healthcare providers, and parents and healthcare providers. The outcomes included uptake of human papillomavirus (HPV) (11 studies); hepatitis B (three studies); and tetanus–diphtheria–acellular–pertussis (Tdap), meningococcal, HPV, and influenza (three studies) vaccines among adolescents. Health education improves HPV vaccine uptake compared to usual practice (RR 1.43, 95% CI 1.16 to 1.76; I² = 0%; 3 studies, 1054 participants; high-certainty evidence). In addition, one large study provided evidence that a complex multi-component health education intervention probably results in little to no difference in hepatitis B vaccine uptake compared to simplified information leaflets on the vaccine (RR 0.98, 95% CI 0.97 to 0.99; 17,411 participants; moderate-certainty evidence). Financial incentives may improve HPV vaccine uptake compared to usual practice (RR 1.45, 95% CI 1.05 to 1.99; 1 study, 500 participants; low-certainty evidence). However, we are uncertain whether combining health education and financial incentives has an effect on hepatitis B vaccine uptake, compared to usual practice (RR 1.38, 95% CI 0.96 to 2.00; 1 study, 104 participants; very low certainty evidence). Mandatory vaccination probably leads to a large increase in hepatitis B vaccine uptake compared to usual practice (RR 3.92, 95% CI 3.65 to 4.20; 1 study, 6462 participants; moderate-certainty evidence). Provider prompts probably make little or no difference compared to usual practice, on completion of Tdap (OR 1.28, 95% CI 0.59 to 2.80; 2 studies, 3296 participants), meningococcal (OR 1.09, 95% CI 0.67 to 1.79; 2 studies, 3219 participants), HPV (OR 0.99, 95% CI 0.55 to 1.81; 2 studies, 859 participants), and influenza (OR 0.91, 95% CI 0.61 to 1.34; 2 studies, 1439 participants) vaccination schedules (moderate-certainty evidence). Provider education with performance feedback may increase the proportion of adolescents who are offered and accept HPV vaccination by clinicians, compared to usual practice. Compared to adolescents visiting non-participating clinicians (in the usual practice group), the adolescents visiting clinicians in the intervention group were more likely to receive the first dose of HPV during preventive visits (5.7 percentage points increase) and during acute visits (0.7 percentage points for the first and 5.6 percentage points for the second doses of HPV) (227 clinicians and more than 200,000 children; low-certainty evidence). A class-based school vaccination strategy probably leads to slightly higher HPV vaccine uptake than an age-based school vaccination strategy (RR 1.09, 95% CI 1.06 to 1.13; 1 study, 5537 participants; moderate-certainty evidence). A multi-component provider intervention (including an education session, repeated contacts, individualised feedback, and incentives) probably improves uptake of HPV vaccine compared to usual practice (moderate-certainty evidence). A multi-component intervention targeting providers and parents involving social marketing and health education may improve HPV vaccine uptake compared to usual practice (RR 1.41, 95% CI 1.25 to 1.59; 1 study, 25,869 participants; low-certainty evidence). Various strategies have been evaluated to improve adolescent vaccination including health education, financial incentives, mandatory vaccination, and class-based school vaccine delivery. However, most of the evidence is of low to moderate certainty. This implies that while this research provides some indication of the likely effect of these interventions, the likelihood that the effects will be substantially different is high. Therefore, additional research is needed to further enhance adolescent immunisation strategies, especially in low- and middle-income countries where there are limited adolescent vaccination programmes. In addition, it is critical to understand the factors that influence hesitancy, acceptance, and demand for adolescent vaccination in different settings. This is the topic of an ongoing Cochrane qualitative evidence synthesis, which may help to explain why and how some interventions were more effective than others in increasing adolescent HPV vaccination coverage.
Overall, there were 75 trials (13,793 women); these were of mixed quality. In nine trials comparing oral misoprostol with placebo (1109 women), women using oral misoprostol were more likely to give birth vaginally within 24 hours (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.05 to 0.49; one trial; 96 women) and less likely to undergo caesarean birth (RR 0.72, 95% CI 0.54 to 0.95; 8 trials; 1029 women). Differences in ‘uterine hyperstimulation with fetal heart rate changes’ were compatible with no effect (RR 2.71, 95% CI 0.84 to 8.68; 7 trials; 669 women). Ten trials compared oral misoprostol with vaginal prostaglandin (dinoprostone) (3,240 women). There was little difference in the frequency of: vaginal birth within 24 hours (RR 1.10, 95% CI 0.99 to 1.22; 5 trials; 2,128 women), uterine hyperstimulation with fetal heart rate changes (RR 0.95, 95% CI 0.59 to 1.53; 7 trials; 2,352 women), and caesarean birth (RR 0.92, 95% CI 0.81 to 1.04; 10 trials; 3240 women). Five trials compared administration of oral misoprostol with intracervical prostaglandin E2 (681 women). Oral misoprostol was associated with fewer instances of failure to achieve vaginal birth within 24 hours (RR 0.78, 95% CI 0.63 to 0.97; 3 trials; 452 women) but more frequent uterine hyperstimulation with fetal heart rate changes (RR 3.57, 95% CI 1.11 to 11.54; 3 trials; 490 women). The available data for this comparison were however limited and the differences in caesarean birth were small (RR 0.85, 95% CI 0.63 to 1.16; 5 trials; 742 women). Nine trials compared oral misoprostol with intravenous oxytocin (1282 women). There were no obvious differences in the frequency of: vaginal birth within 24 hours (RR 0.79, 95% CI 0.59 to 1.05; 6 trials; 789 women), or uterine hyperstimulation with fetal heart rate changes (RR 1.30, 95% CI 0.43 to 3.91; 7 trials; 947 women). There were, however, fewer caesarean births with oral misoprostol (RR 0.77, 95% CI 0.60 to 0.98; 9 trials; 1282 women). Thirty-seven trials compared oral misoprostol with vaginal misoprostol (6417 women). There was little difference in the frequency of: vaginal birth within 24 hours (RR 1.08, 95% CI 0.86 to 1.36; 14 trials; 2,448 women), uterine hyperstimulation with fetal heart rate changes (RR 0.71, 95% CI 0.47 to 1.08; 29 trials; 5,503 women), and caesarean birth (RR 0.93, 95% CI 0.81 to 1.07; 35 trials; 6,326 women). The incidence of serious neonatal or maternal morbidity or death was rare and no meaningful results were available for any of the comparisons. Oral misoprostol as an induction agent is effective at achieving vaginal birth. It is more effective than placebo, as effective as vaginal misoprostol and vaginal dinoprostone, and results in fewer caesarean sections than oxytocin alone. Where misoprostol remains unlicensed for the induction of labour, many practitioners will prefer to use a licensed product like dinoprostone. If using oral misoprostol, the evidence suggests that the dose should be 20 to 25 mcg in solution. Given that safety is the primary concern, the evidence supports the use of oral regimens over vaginal regimens. This is especially important in situations where the risk of ascending infection is high and the lack of staff means that women cannot be intensely monitored.
Fourteen studies (n = 1245) met the inclusion criteria. Eleven studies compared CBT with control and comparisons at 0 to 3 months post-treatment showed beneficial effects of therapy that ranged from medium (when defined by financial loss from gambling: SMD -0.52; 95% confidence interval (CI) -0.71 to -0.33, n = 505) to very large (for gambling symptom severity: SMD -1.82; 95% CI -2.61 to -1.02, n = 402). Only one study (n = 147) compared groups at 9 to 12 months follow-up and produced smaller effects that were not significant. Four studies of motivational interviewing therapy were identified and mainly considered samples demonstrating less severe gambling (relative to studies of pathological gamblers). Data suggested reduced financial loss from gambling following motivational interviewing therapy at 0 to 3 months post-treatment (SMD -0.41; 95% CI -0.75 to -0.07, n = 244), although comparisons on other outcomes were not significant. The effect approached zero when defined by gambling symptom severity (SMD -0.03; 95% CI -0.55 to 0.50, n = 163). Studies compared groups at 9 to 12 months follow-up and found a significant effect of motivational interviewing therapy in terms of frequency of gambling (SMD -0.53; 95% CI -1.04 to -0.02, n = 62), with comparisons on other outcomes that were not significant. Two studies of integrative therapies also considered samples demonstrating overall low gambling severity, and found no significant effects of therapy at 0 to 3 months post-treatment. Comparisons at 9 to 12 months follow-up suggested a medium effect from therapy in terms of gambling symptom severity, with no significant differences for other outcomes. One study (n = 18) considered another psychological therapy (i.e.Twelve-Step Facilitated Group Therapy) and suggested beneficial effects in terms of most outcomes at 0 to 3 months post-treatment. The evidence supporting these various classes of therapy ranged from very low to low quality. This review supports the efficacy of CBT in reducing gambling behaviour and other symptoms of pathological and problem gambling immediately following therapy. However, the durability of therapeutic gain is unknown. There is preliminary evidence for some benefits from motivational interviewing therapy in terms of reduced gambling behaviour, although not necessarily other symptoms of pathological and problem gambling. However, the findings are based on few studies and additional research is needed to inform conclusions. There is also evidence suggestive of some possible benefit from integrative therapies, and other psychological therapies for pathological and problem gambling. However, there are too few studies and evidence is insufficient to evaluate these therapies. The majority of studies in this review varied in risk of bias, and much of the evidence comes from studies with multiple limitations. The current data may thus reflect overestimates of treatment efficacy.
We included six studies that reported data on 2452 participants with ESKD. Interventions investigated were folic acid with or without other vitamins (vitamin B6, vitamin B12). Participants' mean age was 48 to 65 years, and proportions of male participants ranged from 50% to 98%. Homocysteine-lowering therapy probably leads to little or no effect on cardiovascular mortality (4 studies, 1186 participants: RR 0.93, 95% CI 0.70 to 1.22). There was no evidence of heterogeneity among the included studies (I² = 0%). Homocysteine-lowering therapy had little or no effect on all-cause mortality or any other of this review's secondary outcomes. All prespecified subgroup and sensitivity analyses demonstrated little or no difference. Reported adverse events were mild and there was no increase in the incidence of adverse events from homocysteine-lowering therapies (3 studies, 1248 participants: RR 1.12, 95% CI 0.51 to 2.47; I2 = 0%). Overall, studies were assessed as being at low risk of bias and there was no evidence of publication bias. Homocysteine-lowering therapies were not found to reduce mortality (cardiovascular and all-cause) or cardiovascular events among people with ESKD.
Twenty-five trials randomising 4651 people are now included in this review. We chose seven main outcomes of interest for the 'Summary of findings' table. More people allocated haloperidol improved in the first six weeks of treatment than those given placebo (4 RCTs n = 472, RR 0.67 CI 0.56 to 0.80, moderate quality evidence). A further eight trials also found a difference favouring haloperidol across the six weeks to six months period (8 RCTs n = 307 RR 0.67 CI 0.58 to 0.78, moderate quality evidence). Relapse data from two trials favoured haloperidol at < 52 weeks but the evidence was very low quality (2 RCTs n = 70, RR 0.69 CI 0.55 to 0.86). Moderate quality evidence showed about half of those entering studies failed to complete the short trials (six weeks to six months), although, at up to six weeks, 16 studies found a difference that marginally favoured haloperidol (n = 1812, RR 0.87 CI 0.80 to 0.95). Adverse effect data does, nevertheless, support clinical impression that haloperidol is a potent cause of movement disorders, at least in the short term. Moderate quality evidence indicates that haloperidol caused parkinsonism (5 RCTs n = 485, RR 5.48 CI 2.68 to 11.22), akathisia (6 RCTs n = 695, RR 3.66 CI 2.24 to 5.97, and acute dystonia (5 RCTs n = 471, RR 11.49 CI 3.23 to 10.85). Discharge from hospital was equivocal between groups (1 RCT n = 33, RR 0.85 CI 0.47 to 1.52, very low quality evidence). Data were not reported for death and patient satisfaction. Haloperidol is a potent antipsychotic drug but has a high propensity to cause adverse effects. Where there is no treatment option, use of haloperidol to counter the damaging and potentially dangerous consequences of untreated schizophrenia is justified. However, where a choice of drug is available, people with schizophrenia and clinicians may wish to prescribe an alternative antipsychotic with less likelihood of adverse effects such as parkinsonism, akathisia and acute dystonias. Haloperidol should be less favoured as a control drug for randomised trials of new antipsychotics.
The four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow-up information. One study included economic evaluation. The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation. All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53). The UK trial provided follow up information about death or severe disability, and cost-effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost-effective as other intensive care technologies in common use. A policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear. Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life.
We included 12 trials representing 2607 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall RR for reduction in seizure frequency of 50% or more compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55; 6 trials, 1206 participants; moderate-quality evidence). Dose regression analysis (for trials in adults) showed increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to gabapentin 1800 mg compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49; 6 trials, 1206 participants; moderate-quality evidence). Adverse effects were significantly associated with gabapentin compared to placebo. RRs were as follows: ataxia 2.01 (99% CI 0.98 to 4.11; 3 studies, 787 participants; low-quality evidence), dizziness 2.43 (99% CI 1.44 to 4.12; 6 studies, 1206 participants; moderate-quality evidence), fatigue 1.95 (99% CI 0.99 to 3.82; 5 studies, 1161 participants; low-quality evidence) and somnolence 1.93 (99% CI 1.22 to 3.06; 6 studies, 1206 participants; moderate-quality evidence). There were no significant differences for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35; 6 studies, 1206 participants; moderate-quality evidence) or nausea (RR 0.95, 99% CI 0.52 to 1.73; 4 trials, 1034 participants; moderate-quality evidence). Overall, the studies were rated at low to unclear risk of bias due to information on each risk of bias domain not being available. We judged the overall quality of evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide confidence intervals. Gabapentin has efficacy as an add-on treatment in people with drug-resistant focal epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.
Eleven studies, 1592 participants, fulfilled the criteria of inclusion and were included in the review. The studies considered five different psychosocial interventions and two pharmacological treatments (methadone and buprenorphine). Compared to any pharmacological treatment alone, the association of any psychosocial with any pharmacological was shown to significantly reduce dropouts RR 0.71 (95% CI 0.59 to 0.85), use of opiate during the treatment, RR 0.82 (95% CI 0.71 to 0.93), at follow up RR 0.66 (95% IC 0.53 to 0.82) and clinical absences during the treatment RR 0.48 (95%CI 0.38 to 0.59). Moreover, with the evidence currently available, there are no data supporting a single psychosocial approach. Psychosocial treatments offered in addition to pharmacological detoxification treatments are effective in terms of completion of treatment, use of opiate, participants abstinent at follow-up and clinical attendance. The evidence produced by this review is limited due to the small number of participants included in the studies, the heterogeneity of the assessment or the lack of detailed outcome information that prevented the possibility of cumulative analysis for several outcomes. Nevertheless it seems desirable to develop adjunct psychosocial approaches that might make detoxification more effective.
We included 36 RCTs (8125 women). The quality of the evidence ranged from very low to moderate. The main limitations were risk of bias (associated with poor reporting of methods) and imprecision. Live birth rates: There was insufficient evidence to determine whether there was a difference between rLH combined with rFSH versus rFSH alone in live birth rates (OR 1.32, 95% CI 0.85 to 2.06; n = 499; studies = 4; I2 = 63%, very low-quality evidence). The evidence suggests that if the live birth rate following treatment with rFSH alone is 17% it will be between 15% and 30% using rLH combined with rFSH. OHSS: There may be little or no difference between rLH combined with rFSH versus rFSH alone in OHSS rates (OR 0.38, 95% CI 0.14 to 1.01; n = 2178; studies = 6; I2 = 10%, low-quality evidence). The evidence suggests that if the rate of OHSS following treatment with rFSH alone is 1%, it will be between 0% and 1% using rLH combined with rFSH. Ongoing pregnancy rate: The use of rLH combined with rFSH probably improves ongoing pregnancy rates, compared to rFSH alone (OR 1.20, 95% CI 1.01 to 1.42; participants = 3129; studies = 19; I2 = 2%, moderate-quality evidence). The evidence suggests that if the ongoing pregnancy rate following treatment with rFSH alone is 21%, it will be between 21% and 27% using rLH combined with rFSH. Miscarriage rate: The use of rLH combined with rFSH probably makes little or no difference to miscarriage rates, compared to rFSH alone (OR 0.93, 95% CI 0.63 to 1.36; n = 1711; studies = 13; I2 = 0%, moderate-quality evidence). The evidence suggests that if the miscarriage rate following treatment with rFSH alone is 7%, the miscarriage rate following treatment with rLH combined with rFSH will be between 4% and 9%. Cancellation rates: There may be little or no difference between rLH combined with rFSH versus rFSH alone in rates of cancellation due to low response (OR 0.77, 95% CI 0.54 to 1.10; n = 2251; studies = 11; I2 = 16%, low quality evidence). The evidence suggests that if the risk of cancellation due to low response following treatment with rFSH alone is 7%, it will be between 4% and 7% using rLH combined with rFSH. We are uncertain whether use of rLH combined with rFSH improves rates of cancellation due to imminent OHSS compared to rFSH alone. Use of a fixed effect model suggested a benefit in the combination group (OR 0.60, 95% CI 0.40 to 0.89; n = 2976; studies = 8; I2 = 60%, very low quality evidence) but use of a random effects model did not support the conclusion that there was a difference between the groups (OR 0.82, 95% CI 0.34 to 1.97). We found no clear evidence of a difference between rLH combined with rFSH and rFSH alone in rates of live birth or OHSS. The evidence for these comparisons was of very low-quality for live birth and low quality for OHSS. We found moderate quality evidence that the use of rLH combined with rFSH may lead to more ongoing pregnancies than rFSH alone. There was also moderate-quality evidence suggesting little or no difference between the groups in rates of miscarriage. There was no clear evidence of a difference between the groups in rates of cancellation due to low response or imminent OHSS, but the evidence for these outcomes was of low or very low quality. We conclude that the evidence is insufficient to encourage or discourage stimulation regimens that include rLH combined with rFSH in IVF/ICSI cycles.
We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high drop-out rate (30% to 40%) and this was unbalanced between groups. Methadone versus buprenorphine: the drop-out rate from treatment was lower in the methadone group (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.41 to 1.01, three studies, 223 participants). There was no statistically significant difference in the use of primary substance between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.69, two studies, 151 participants). For both, we judged the quality of evidence as low. Birth weight was higher in the buprenorphine group in the two trials that could be pooled (mean difference (MD) -365.45 g (95% CI -673.84 to -57.07), two studies, 150 participants). The third study reported that there was no statistically significant difference. For APGAR score neither of the studies which compared methadone with buprenorphine found a significant difference. For both, we judged the quality of evidence as low. Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, did not differ significantly between groups. We judged the quality of evidence as very low. Methadone versus slow-release morphine: there was no drop-out in either treatment group. Oral slow-release morphine seemed superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants). We judged the quality of evidence as moderate. Only one study which compared methadone with buprenorphine reported side effects. For the mother there was no statistically significant difference; for the newborns in the buprenorphine group there were significantly fewer serious side effects. In the comparison between methadone and slow-release morphine no side effects were reported for the mother, whereas one child in the methadone group had central apnoea and one child in the morphine group had obstructive apnoea. We did not find sufficient significant differences between methadone and buprenorphine or slow-release morphineto allow us to conclude that one treatment is superior to another for all relevant outcomes. While methadone seems superior in terms of retaining patients in treatment, buprenorphine seems to lead to less severe neonatal abstinence syndrome. Additionally, even though a multi-centre, international trial with 175 pregnant women has recently been completed and its results published and included in this review, the body of evidence is still too small to draw firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.
We included four RCTs involving a total of 831 participants who were more than three months poststroke. All RCTs were of MN that applied electrical stimuli to the peroneal nerve. All studies included conditioning protocols to adapt participants to MN use, after which participants used MN from up to eight hours per day to all-day use for ambulation in daily activities performed in the home or community context. All studies compared the use of MN versus another assistive device (ankle-foot orthosis [AFO]). There was a high risk of bias for at least one assessed domain in three of the four included studies. No studies reported outcomes related to independence in ADL. There was low-certainty evidence that AFO was more beneficial than MN on activities involving limbs such as walking speed until six months of device use (mean difference (MD) −0.05 m/s, 95% confidence interval (CI) −0.10 to −0.00; P = 0.03; 605 participants; 2 studies; I2 = 0%; low-certainty evidence); however, this difference was no longer present in our sensitivity analysis (MD −0.07 m/s, 95% CI −0.16 to 0.02; P = 0.13; 110 participants; 1 study; I2 = 0%). There was low to moderate certainty that MN was no more beneficial than AFO on activities involving limbs such as walking speed between 6 and 12 months of device use (MD 0.00 m/s, 95% CI −0.05 to 0.05; P = 0.93; 713 participants; 3 studies; I2 = 17%; low-certainty evidence), Timed Up and Go (MD 0.51 s, 95% CI −4.41 to 5.43; P = 0.84; 692 participants; 2 studies; I2 = 0%; moderate-certainty evidence), and modified Emory Functional Ambulation Profile (MD 14.77 s, 95% CI −12.52 to 42.06; P = 0.29; 605 participants; 2 studies; I2 = 0%; low-certainty evidence). There was no significant difference in walking speed when MN was delivered with surface or implantable electrodes (test for subgroup differences P = 0.09; I2 = 65.1%). For our secondary outcomes, there was very low to moderate certainty that MN was no more beneficial than another assistive device for participation scales of HRQoL (standardized mean difference 0.26, 95% CI −0.22 to 0.74; P = 0.28; 632 participants; 3 studies; I2 = 77%; very low-certainty evidence), exercise capacity (MD −9.03 m, 95% CI −26.87 to 8.81; P = 0.32; 692 participants; 2 studies; I2 = 0%; low-certainty evidence), and balance (MD −0.34, 95% CI −1.96 to 1.28; P = 0.68; 692 participants; 2 studies; I2 = 0%; moderate-certainty evidence). Although there was low- to moderate-certainty evidence that the use of MN did not increase the number of serious adverse events related to intervention (risk ratio (RR) 0.35, 95% CI 0.04 to 3.33; P = 0.36; 692 participants; 2 studies; I2 = 0%; low-certainty evidence) or number of falls (RR 1.20, 95% CI 0.92 to 1.55; P = 0.08; 802 participants; 3 studies; I2 = 33%; moderate-certainty evidence), there was low-certainty evidence that the use of MN in people after stroke may increase the risk of participants dropping out during the intervention (RR 1.48, 95% CI 1.11 to 1.97; P = 0.007; 829 participants; 4 studies; I2 = 0%). Current evidence indicates that MN is no more beneficial than another assistive technology device for improving activities involving limbs measured by Timed Up and Go, balance (moderate-certainty evidence), activities involving limbs measured by walking speed and modified Emory Functional Ambulation Profile, exercise capacity (low-certainty evidence), and participation scale of HRQoL (very low-certainty evidence). Evidence was insufficient to estimate the effect of MN on independence in ADL. In comparison to other assistive devices, MN does not appear to increase the number of falls (moderate-certainty evidence) or serious adverse events (low-certainty evidence), but may result in a higher number of dropouts during intervention period (low-certainty evidence).
Eleven studies met our eligibility criteria and all were at medium or high risk of bias. Only five studies gave the total number of participants (totalling 7372 participants). Three studies used a randomised design, with the others using pre-post comparisons. Several different strategies were investigated. Four studies examined the impact of additional visits or information for the study site, with no increases in recruitment demonstrated. Increased recruitment rates were reported in two studies that used a dedicated clinical recruiter, and five studies that introduced an automated alert system for identifying eligible participants. The studies were embedded into trials evaluating care in oncology mainly but also in emergency departments, diabetes and lower back pain. There is no strong evidence for any single strategy to help healthcare professionals to recruit participants in research studies. Additional visits or information did not appear to increase recruitment by healthcare professionals. The most promising strategies appear to be those with a dedicated resource (e.g. a clinical recruiter or automated alert system) for identifying suitable participants that reduced the demand on healthcare professionals, but these were assessed in studies at high risk of bias.
Eleven studies (3912 participants) met the inclusion criteria of the review. Small benefits of ipratropium over a short-acting beta-2 agonist were demonstrated on lung function outcomes. There were small benefits in favour of ipratropium on quality of life (HRQL), as well as a reduction in the requirement for oral steroids. Combination therapy with ipratropium plus a short-acting beta-2 agonist conferred benefits over a short-acting beta-2 agonist alone in terms of post-bronchodilator lung function. There was no significant benefit of combination therapy in subjective improvements in HRQL, but again there was a reduction in the requirement for oral steroids. The available data from the trials included in this review suggest that the advantage of regular long term use of ipratropium alone or in combination with a short-acting beta-2 agonist or over a beta-2 agonist alone are small, if the aim is to improve lung function, symptoms and exercise tolerance. Until further data are available, the strategy of providing a short-acting beta-2 agonist on a PRN basis, and then either continuing with the short-acting beta-2 agonist regularly or conducting an "n of 1" trial of regular beta-2 agonist or regular anticholinergic to determine the treatment that gives the best relief of symptoms (and continuing with it), would seem cost effective. This strategy does need formal evaluation. Patient preference is also important, as is the relative importance of avoiding the use of systemic corticosteroids.
We located 23 studies: two RCTs with 1414 workplaces, two CBAs with 9903 workplaces, one ITS with six outcome measurements, 12 panel studies and six qualitative studies with 310 participants. Studies evaluated the effects of inspections in general and the effects of their consequences, such as penalties. Studies on the effects of prosecution, warnings or closure were not available or were of such quality that we could not include their results. The effect was measured on injury rates, on exposure to physical workload and on compliance with regulation, with a follow-up varying from one to four years. All studies had serious limitations and therefore the quality of the evidence was low to very low. The injury rates in the control groups varied across studies from 1 to 23 injuries per 100 person-years and compliance rates varied from 40% to 75% being compliant. The effects of inspections were inconsistent in seven studies: injury rates decreased or stayed at a similar level compared to no intervention at short and medium-term follow-up. In studies that found a decrease the effect was small with a 10% decrease of the injury rate. At long-term follow-up, in one study there was a significant decrease of 23% (95% confidence interval 8% to 23%) in injury rates and in another study a substantial decrease in accident rates, both compared to no intervention. First inspections, follow-up inspections, complaint and accident inspections resulted in higher compliance rates compared to the average effect of any other type of inspections. In small firms, inspections with citations or with more penalties could result in fewer injuries or more compliance in the short term but not in the medium term. Longer inspections and more frequent inspections probably do not result in more compliance. In two studies, there was no adverse effect of inspections on firm survival, employment or sales. Qualitative studies show that there is support for enforcement among workers. However, workers doubt if the inspections are effective because inspections are rare and violations can be temporarily fixed to mislead inspectors. There is evidence that inspections decrease injuries in the long term but not in the short term. The magnitude of the effect is uncertain. There are no studies that used chemical or physical exposures as outcome. Specific, focused inspections could have larger effects than inspections in general. The effect of fines and penalties is uncertain. The quality of the evidence is low to very low and therefore these conclusions are tentative and can be easily changed by better future studies. There is an urgent need for better designed evaluations, such as pragmatic randomised trials, to establish the effects of existing and novel enforcement methods, especially on exposure and disorders.
Nine studies with 658 infants fulfilled the inclusion criteria. Term and preterm infants with Rh or ABO (or both) incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.35, 95% CI 0.25 to 0.49; typical RD -0.22, 95% CI -0.27 to -0.16; NNTB 5). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (MD -0.34, 95% CI -0.50 to -0.17). However, sensitivity analysis by risk of bias showed that in the only two studies in which the treatment was masked by use of a placebo and outcome assessment was blinded, the results differed; there was no difference in the need for exchange transfusions (RR 0.98, 95% CI 0.48 to 1.98) or number of exchange transfusions (MD -0.04, 95% CI -0.18 to 0.10). Two studies assessed long-term outcomes and found no cases of kernicterus, deafness or cerebral palsy. Although overall results show a significant reduction in the need for exchange transfusion in infants treated with IVIg, the applicability of the results is limited because of low to very low quality of evidence. Furthermore, the two studies at lowest risk of bias show no benefit of IVIg in reducing the need for and number of exchange transfusions. Based on these results, we have insufficient confidence in the effect estimate for benefit of IVIg to make even a weak recommendation for the use of IVIg for the treatment of alloimmune HDN. Further studies are needed before the use of IVIg for the treatment of alloimmune HDN can be recommended, and should include blinding of the intervention by use of a placebo as well as sufficient sample size to assess the potential for serious adverse effects.
Of 493 records that we identified from databases as a result of the search (excluding duplicates), we regarded 70 abstracts/titles as potentially relevant studies. Independent scrutiny of these 70 titles and abstracts identified 29 potentially relevant studies. Of the 29 potentially relevant studies, one study met the criteria for inclusion. This study was a RCT that compared participants undergoing RSI and endotracheal intubation in the context of elective surgery requiring a general anaesthetic. Forty participants were recruited, 20 of whom had cricoid pressure applied and 20 of whom had cricoid pressure simulated. The main outcomes reported were systolic arterial pressure and heart rate after laryngoscopy and tracheal intubation. We did not consider these outcomes relevant for the purposes of this systematic review. The search also identified one study that could potentially be included in an updated systematic review in the future, but was at the time of the search a proposal for a trial only and had no reported outcomes at this time. There is currently no information available from published RCTs on clinically relevant outcome measures with respect to the application of cricoid pressure during RSI in the context of endotracheal intubation. On the basis of the findings of non-RCT literature, however, cricoid pressure may not be necessary to undertake RSI safely, and therefore well-designed and conducted RCTs should nonetheless be encouraged to properly assess the safety and effectiveness of cricoid pressure.
We included seven studies from the earlier review and two new studies (nine studies, 649 participants) of 6 to 24 weeks' duration, enrolling between 22 and 208 participants; none had 50 or more participants in each treatment arm. Two studies used a cross-over design. The daily dose of amitriptyline was 25 mg to 50 mg, and some studies had an initial titration period. There was no first or second tier evidence for amitriptyline in the treatment of fibromyalgia. Using third tier evidence the risk ratio (RR) for at least 50% pain relief, or equivalent, with amitriptyline compared with placebo was 3.0 (95% confidence interval (CI) 1.7 to 4.9), with an NNT) of 4.1 (2.9 to 6.7) (very low quality evidence). There were no consistent differences between amitriptyline and placebo or other active comparators for relief of symptoms such as fatigue, poor sleep, quality of life, or tender points. More participants experienced at least one adverse event with amitriptyline (78%) than with placebo (47%). The RR was 1.5 (1.3 to 1.8) and the NNH was 3.3 (2.5 to 4.9). Adverse event and all-cause withdrawals were not different, but lack of efficacy withdrawals were more common with placebo (12% versus 5%; RR 0.42 (0.19 to 0.95)) (very low quality evidence). Amitriptyline has been a first-line treatment for fibromyalgia for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against years of successful treatment in many patients with fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline will be one option in the treatment of fibromyalgia, while recognising that only a minority of patients will achieve satisfactory pain relief. It is unlikely that any large randomised trials of amitriptyline will be conducted in fibromyalgia to establish efficacy statistically, or measure the size of the effect.
Eight studies met our inclusion criteria: three RCTs and five ITS studies involving a total of 135 general practices/primary care clinics, seven hospitals and one outpatient clinic. The studies were heterogeneous in terms of types of interventions, elective procedures and clinical conditions; this made meta-analysis unfeasible. One ITS study evaluating prioritisation of demand through a system for streamlining elective surgery services reduced the number of semi-urgent participants waiting longer than the recommended time (< 90 days) by 28 participants/mo, while no effects were found for urgent (< 30 days) versus non-urgent participants (< 365 days). Interventions aimed at restructuring the intake assessment/referral process were evaluated in seven studies. Four studies (two RCTs and two ITSs) evaluated open access, or direct booking/referral: One RCT, which showed that open access to laparoscopic sterilisation reduced waiting times, had very high attrition (87%); the other RCT showed that open access to investigative services reduced waiting times (30%) for participants with lower urinary tract syndrome (LUTS) but had no effect on waiting times for participants with microscopic haematuria. In one ITS study, same-day scheduling for paediatric health clinic appointments reduced waiting times (direct reduction of 25.2 days, and thereafter a decrease of 3.03 days per month), while another ITS study showed no effect of a direct booking system on proportions of participants receiving a colposcopy appointment within the recommended time. One RCT and one ITS showed no effect of distant consultancy (instant photography for dermatological conditions and telemedicine for ear nose throat (ENT) conditions) on waiting times; another ITS study showed no effect of a pooled waiting list on the number of participants waiting for uncomplicated spinal surgery. Overall quality of the evidence for all outcomes, assessed using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) tool, ranged from low to very low. We found no studies evaluating interventions to increase capacity or to ration demand. As only a handful of low-quality studies are presently available, we cannot draw any firm conclusions about the effectiveness of the evaluated interventions in reducing waiting times. However, interventions involving the provision of more accessible services (open access or direct booking/referral) show some promise.
We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy. We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated. Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone. Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing. When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL. We did not find any survival advantages when comparing 5FU combinations to 5FU alone. Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.
Twenty-two studies (3215 participants) were included. The majority of studies enrolled patients with mild to moderate CDI who could tolerate oral antibiotics. Sixteen of the included studies excluded patients with severe CDI and few patients with severe CDI were included in the other six studies. Twelve different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin, cadazolid, LFF517, surotomycin and fidaxomicin. Most of the studies were active comparator studies comparing vancomycin with other antibiotics. One small study compared vancomycin to placebo. There were no other studies that compared antibiotic treatment to a placebo or a 'no treatment' control group. The risk of bias was rated as high for 17 of 22 included studies. Vancomycin was found to be more effective than metronidazole for achieving symptomatic cure. Seventy-two per cent (318/444) of metronidazole patients achieved symptomatic cure compared to 79% (339/428) of vancomycin patients (RR 0.90, 95% CI 0.84 to 0.97; moderate quality evidence). Fidaxomicin was found to be more effective than vancomycin for achieving symptomatic cure. Seventy-one per cent (407/572) of fidaxomicin patients achieved symptomatic cure compared to 61% (361/592) of vancomycin patients (RR 1.17, 95% CI 1.04 to 1.31; moderate quality evidence). Teicoplanin may be more effective than vancomycin for achieving a symptomatic cure. Eightly-seven per cent (48/55) of teicoplanin patients achieved symptomatic cure compared to 73% (40/55) of vancomycin patients (RR 1.21, 95% CI 1.00 to 1.46; very low quality evidence). For other comparisons including the one placebo-controlled study the quality of evidence was low or very low due to imprecision and in many cases high risk of bias because of attrition and lack of blinding. One hundred and forty deaths were reported in the studies, all of which were attributed by study authors to the co-morbidities of the participants that lead to acquiring CDI. Although many other adverse events were reported during therapy, these were attributed to the participants' co-morbidities. The only adverse events directly attributed to study medication were rare nausea and transient elevation of liver enzymes. Recent cost data (July 2016) for a 10 day course of treatment shows that metronidazole 500 mg is the least expensive antibiotic with a cost of USD 13 (Health Warehouse). Vancomycin 125 mg costs USD 1779 (Walgreens for 56 tablets) compared to fidaxomicin 200 mg at USD 3453.83 or more (Optimer Pharmaceuticals) and teicoplanin at approximately USD 83.67 (GBP 71.40, British National Formulary). No firm conclusions can be drawn regarding the efficacy of antibiotic treatment in severe CDI as most studies excluded patients with severe disease. The lack of any 'no treatment' control studies does not allow for any conclusions regarding the need for antibiotic treatment in patients with mild CDI beyond withdrawal of the initiating antibiotic. Nonetheless, moderate quality evidence suggests that vancomycin is superior to metronidazole and fidaxomicin is superior to vancomycin. The differences in effectiveness between these antibiotics were not too large and the advantage of metronidazole is its far lower cost compared to the other two antibiotics. The quality of evidence for teicoplanin is very low. Adequately powered studies are needed to determine if teicoplanin performs as well as the other antibiotics. A trial comparing the two cheapest antibiotics, metronidazole and teicoplanin, would be of interest.
We identified 6600 references (4647 references in our initial review) and included 10 trials (3575 participants). Follow-up ranged from 30 days to one year. Nine trials provided mortality data (3218 participants, 466 events), with a risk ratio of 1.02 (95% CI 0.87 to 1.19) (low-certainty evidence). Seven trials provided hospital readmission data (2843 participants, 1043 events) with a risk ratio of 0.95 (95% CI 0.87 to 1.04) (high-certainty evidence). Four trials provided emergency department contact data (1442 participants, 244 events) with a risk ratio of 0.73 (95% CI 0.52 to 1.03) (low-certainty evidence). The estimated reduction in emergency department contacts of 27% (with a CI ranging from 48% reduction to 3% increase in contacts) corresponds to a number needed to treat for an additional beneficial outcome of 37 for a low-risk population and 12 for a high-risk population over one year. Subgroup and sensitivity analyses did not significantly alter our results. We found no evidence that medication review reduces mortality or hospital readmissions, although we did find evidence that medication review may reduce emergency department contacts. However, because of short follow-up ranging from 30 days to one year, important treatment effects may have been overlooked. High-quality trials with long-term follow-up (i.e. at least up to a year) are needed to provide more definitive evidence for the effect of medication review on clinically important outcomes such as mortality, readmissions and emergency department contacts, and on outcomes such as adverse events. Therefore, if used in clinical practice, medication reviews should be undertaken as part of a clinical trial with long-term follow-up.
Of 39 identified studies, four met the criteria for inclusion. Two of the included studies reported a significant decrease in paediatric burn and scald injury in the intervention compared with the control communities. The failure of the other two studies to show a positive result may have been due to limited time-frame for the intervention and/or failure to adequately implement the counter-measures in the communities. There are a very limited number of research studies allowing conclusions to be drawn about the effectiveness of community-based injury prevention programmes to prevent burns and scalds in children. There is a pressing need to evaluate high-quality community-based intervention programmes based on efficacious counter-measures to reduce burns and scalds in children. It is important that a framework for considering the problem of burns and scalds in children from a prevention perspective be articulated, and that an evidence-based suite of interventions be combined to create programme guidelines suitable for implementation in communities throughout the world.
We included six trials with 498 participants with TS, 267 participants were randomised to oxandrolone plus GH treatment and 231 participants were randomised to GH only treatment. The individual trial sample size ranged between 22 and 133 participants. The included trials were conducted in 65 different paediatric endocrinology healthcare facilities including clinics, centres, hospitals and academia in the USA and Europe. The duration of interventions ranged between 3 and 7.6 years. The mean age of participants at start of therapy ranged from 9 to 12 years. Overall, we judged only one trial at low risk of bias in all domains and another trial at high risk of bias in most domains. We downgraded the level of evidence mainly because of imprecision (low number of trials, low number of participants or both). Comparing oxandrolone plus GH with GH only for final adult height showed a mean difference (MD) of 2.7 cm in favour of oxandrolone plus GH treatment (95% confidence interval (CI) 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; moderate-quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm. For adverse events, we based our main analysis on reliable date from two trials with overall low risk of bias. There was no evidence of a difference between oxandrolone plus GH and GH for adverse events (RR 1.81, 95% CI 0.83 to 3.96; P = 0.14; 2 trials, 170 participants; low-quality evidence). Six out of 86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events, mainly signs of virilisation (e.g. deepening of the voice). One trial each investigated the effects of treatments on speech (voice frequency; 88 participants), cognition (51 participants) and psychological status (106 participants). The overall results for these comparisons were inconclusive (very low-quality evidence). No trial reported on health-related quality of life or all-cause mortality. Addition of oxandrolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS. Adverse effects identified included virilising effects such as deepening of the voice, but reporting was inadequate in some trials.
Twenty-seven studies involving 11,398 participants met the eligibility and study quality criteria for inclusion. Twenty studies compared stand alone clinical pathways with usual care. These studies indicated a reduction in in-hospital complications (odds ratio (OR) 0.58; 95% confidence interval (CI) 0.36 to 0.94) and improved documentation (OR 11.95: 95%CI 4.72 to 30.30). There was no evidence of differences in readmission to hospital or in-hospital mortality. Length of stay was the most commonly employed outcome measure with most studies reporting significant reductions. A decrease in hospital costs/ charges was also observed, ranging from WMD +261 US$ favouring usual care to WMD -4919 US$ favouring clinical pathways (in US$ dollar standardized to the year 2000). Considerable heterogeneity prevented meta-analysis of length of stay and hospital cost results.  An assessment of whether lower hospital costs contributed to cost shifting to another health sector was not undertaken. Seven studies compared clinical pathways as part of a multifaceted intervention with usual care. No evidence of differences were found between intervention and control groups. Clinical pathways are associated with reduced in-hospital complications and improved documentation without negatively impacting on length of stay and hospital costs.
We included 40 publications, describing seven unique RCT's. The follow-up of the studies was 24 months, with only one extended to five years. Five studies had a low risk of bias, although there is a risk of bias in the included studies due to sponsoring and absence of any kind of blinding. One study compared disc replacement against rehabilitation and found a statistically significant advantage in favour of surgery, which, however, did not reach the predefined threshold for clinical relevance. Six studies compared disc replacement against fusion and found that the mean improvement in VAS back pain was 5.2 mm (of 100 mm) higher (two studies, 676 patients; 95% confidence interval (CI) 0.18 to 10.26) with a low quality of evidence while from the same studies leg pain showed no difference. The improvement of Oswestry score at 24 months in the disc replacement group was 4.27 points more than in the fusion group (five studies; 1207 patients; 95% CI 1.85 to 6.68) with a low quality of evidence. Both upper bounds of the confidence intervals for VAS back pain and Oswestry score were below the predefined clinically relevant difference. Choice of control group (circumferential or anterior fusion) did not appear to result in different outcomes. Although statistically significant, the differences between disc replacement and conventional fusion surgery for degenerative disc disease were not beyond the generally accepted clinical important differences with respect to short-term pain relief, disability and Quality of Life. Moreover, these analyses only represent a highly selected population. The primary goal of prevention of adjacent level disease and facet joint degeneration by using total disc replacement, as noted by the manufacturers and distributors, was not properly assessed and not a research question at all. Unfortunately, evidence from observational studies could not be used because of the high risk of bias, while these could have improved external validity assessment of complications in less selected patient groups. Non-randomised studies should however be very clear about patient selection and should incorporate independent, blinded outcome assessment, which was not the case in the excluded studies. Therefore, because we believe that harm and complications may occur after years, we believe that the spine surgery community should be prudent about adopting this technology on a large scale, despite the fact that total disc replacement seems to be effective in treating low-back pain in selected patients, and in the short term is at least equivalent to fusion surgery.
For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below. Incomplete data were available for one published study comparing early and late initiation of NIV (13 participants). We contacted the trial authors, who were not able to provide the missing data. The conclusions of the review were therefore based on a single study of 41 participants comparing NIV with standard care. Lack of (or uncertain) blinding represented a risk of bias for participant- and clinician-assessed outcomes such as quality of life, but it was otherwise a well-conducted study with a low risk of bias. The study provided moderate-quality evidence that overall median survival was significantly different between the group treated with NIV and the standard care group. The median survival in the NIV group was 48 days longer (219 days compared to 171 days for the standard care group (estimated 95% confidence interval 12 to 91 days, P = 0.0062)). This survival benefit was accompanied by an enhanced quality of life. On subgroup analysis, in the subgroup with normal to moderately impaired bulbar function (20 participants), median survival was 205 days longer (216 days in the NIV group versus 11 days in the standard care group, P = 0.0059), and quality of life measures were better than with standard care (low-quality evidence). In the participants with poor bulbar function (21 participants), NIV did not prolong survival or improve quality of life, although there was significant improvement in the mean symptoms domain of the Sleep Apnea Quality of Life Index by some measures. Neither trial reported clinical data on intervention-related adverse effects. Moderate-quality evidence from a single RCT of NIV in 41 participants suggests that it significantly prolongs survival, and low-quality evidence indicates that it improves or maintains quality of life in people with ALS. Survival and quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment. Adverse effects related to NIV should be systematically reported, as at present there is little information on this subject. More RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable. Future studies should examine the benefits of early intervention with NIV and establish the most appropriate timing for initiating NIV in order to obtain its maximum benefit. The effect of adding cough augmentation techniques to NIV also needs to be investigated in an RCT. Future studies should examine the health economics of NIV. Access to NIV remains restricted in many parts of the world, including Europe and North America. We need to understand the factors, personal and socioeconomic, that determine access to NIV.
We included 41 studies involving 28,700 people. Nineteen new studies were identified in this update, adding to the 22 studies included in the previous two iterations of the review. Three studies measured informed decision with regard to the uptake of screening following personalised risk communication as a part of their intervention. All of these three studies were at low risk of bias and there was strong evidence that the interventions enhanced informed decision making, although with heterogeneous results. Overall 45.2% (592/1309) of participants who received personalised risk information made informed choices, compared to 20.2% (229/1135) of participants who received generic risk information. The overall odds ratios (ORs) for informed decision were 4.48 (95% confidence interval (CI) 3.62 to 5.53 for fixed effect) and 3.65 (95% CI 2.13 to 6.23 for random effects). Nine studies measured increase in knowledge, using different scales. All of these studies showed an increase in knowledge with personalised risk communication. In three studies the interventions showed a trend towards more accurate risk perception, but the evidence was of poor quality. Four out of six studies reported non-significant changes in anxiety following personalised risk communication to the participants. Overall there was a small non-significant decrease in the anxiety scores. Most studies (32/41) measured the uptake of screening tests following interventions. Our results (OR 1.15 (95% CI 1.02 to 1.29)) constitute low quality evidence, consistent with a small effect, that personalised risk communication in which a risk score was provided (6 studies) or the participants were given their categorised risk (6 studies), increases uptake of screening tests. There is strong evidence from three trials that personalised risk estimates incorporated within communication interventions for screening programmes enhance informed choices. However the evidence for increasing the uptake of such screening tests with similar interventions is weak, and it is not clear if this increase is associated with informed choices. Studies included a diverse range of screening programmes. Therefore, data from this review do not allow us to draw conclusions about the best interventions to deliver personalised risk communication for enhancing informed decisions. The results are dominated by findings from the topic area of mammography and colorectal cancer. Caution is therefore required in generalising from these results, and particularly for clinical topics other than mammography and colorectal cancer screening.
We included data from two studies (619 eyes of 401 participants) that compared FA implants with standard-of-care therapy. Both studies used similar standard-of-care therapy that included administration of prednisolone and, if needed, immunosuppressive agents. The studies included participants from Australia, France, Germany, Israel, Italy, Portugal, Saudi Arabia, Spain, Switzerland, Turkey, the United Kingdom, and the United States. We assessed both studies at high risk of performance and detection bias. Only one study reported our primary outcome, recurrence of uveitis at any point during the study through 24 months. The evidence, judged as moderate-quality, showed that a FA implant probably prevents recurrence of uveitis compared with standard-of-care therapy (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.14 to 0.59; 132 eyes). Both studies reported safety outcomes, and moderate-quality evidence showed increased risks of needing cataract surgery (RR 2.98, 95% CI 2.33 to 3.79; 371 eyes) and surgery to lower intraocular pressure (RR 7.48, 95% CI 3.94 to 14.19; 599 eyes) in the implant group compared with standard-of-care therapy through two years of follow-up. No studies compared dexamethasone implants with standard-of-care therapy. After considering both benefits and harms reported from two studies in which corticosteroids implants were compared with standard-of-care therapy, we are unable to conclude that the implants are superior to traditional systemic therapy for the treatment of non-infectious uveitis. These studies exhibited heterogeneity in design and outcomes that measured efficacy. Pooled findings regarding safety outcomes suggest increased risks of post-implant surgery for cataract and high intraocular pressure compared with standard-of-care therapy.
We included four studies with 1029 participants. All the studies used a parallel-group design, and included an initial titration phase to determine the maximum effective and tolerated dose, followed by a maintenance phase. Tapentadol medication was taken twice daily and doses ranged from 50 to 500 mg per day. Rescue medication (morphine or oxycodone immediate-release) was available to participants in all studies. Overall, 440 participants were randomised in classically designed RCTs, and 589 participants were enrolled in enriched-enrolment, randomised-withdrawal (EERW) trials. A total of 476 participants were randomised to titration with tapentadol and 338 participants took tapentadol throughout the maintenance phase of their trial. All studies used numerical rating scores, Patient Global Impression of Change scores, and use of rescue medication as measures of efficacy, and all reported on adverse events and withdrawals. All studies enrolled fewer than 200 participants per treatment arm and were therefore at risk of overestimating efficacy. One study was terminated early due to problems with supply of rescue medication, with fewer than 20 participants enrolled per treatment arm in the maintenance phase of the trial. We judged another study at high risk of bias due to an open-label design. There were insufficient data for pooling and statistical analysis. Response rates for pain intensity were comparable across treatment groups in each study. In one EERW study, response rates were high across both treatment and placebo arms during the maintenance phase (62% tapentadol, 69% morphine, 50% placebo). For pain relief, tapentadol is no more and no less effective than oxycodone or morphine (low quality evidence). Treatment emergent adverse event rates were high, approximately 50% to 90%. The most common adverse events were gastrointestinal (nausea, vomiting, constipation) (low quality evidence). There was no advantage of tapentadol over morphine or oxycodone in terms of serious adverse events. The number of people experiencing effects on consciousness, appetite, or thirst was low. Information from RCTs on the effectiveness and tolerability of tapentadol was limited. The available studies were of moderate or small size and used different designs, which prevented pooling of data. Pain relief and adverse events were comparable between the tapentadol and morphine and oxycodone groups.
We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin. Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%). Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.
The updated searches identified one additional published study, and one clinical trial registry report. We included five studies reporting on 687 participants; 637 had painful diabetic neuropathy and 50 had postherpetic neuralgia. Two studies used a cross-over design and three used a parallel group design; all studies used a placebo comparator, although one study used an active placebo (benztropine). Modified-release oxycodone (oxycodone MR) was titrated to effect and tolerability. One study used a fixed dose combination of oxycodone MR and naloxone. Two studies added oxycodone therapy to ongoing, stable treatment with either pregabalin or gabapentin. All studies had one or more sources of potential major bias. No study reported the proportion of participants experiencing 'substantial benefit' (at least 50% pain relief or who were very much improved). Three studies (537 participants) in painful diabetic neuropathy reported outcomes equivalent to 'moderate benefit' (at least 30% pain relief or who were much or very much improved), which was experienced by 44% of participants with oxycodone and 27% with placebo (number needed to treat for one additional beneficial outcome (NNT) 5.7). All studies reported group mean pain scores at the end of treatment. Three studies reported a greater pain intensity reduction and better patient satisfaction with oxycodone MR alone than with placebo. There was a similar result in the study adding oxycodone MR to stable, ongoing gabapentin, but adding oxycodone MR plus naloxone to stable, ongoing pregabalin did not show any additional effect. More participants experienced adverse events with oxycodone MR alone (86%) than with placebo (63%); the number needed to treat for an additional harmful outcome (NNH) was 4.3. Serious adverse events (oxycodone 3.4%, placebo 7.0%) and adverse event withdrawals (oxycodone 11%, placebo 6.4%) were not significantly different between groups. Withdrawals due to lack of efficacy were less frequent with oxycodone MR (1.1%) than placebo (11%), with a number needed to treat to prevent one withdrawal of 10. The add-on studies reported similar results. We downgraded the quality of the evidence to very low for all outcomes, due to limitations in the study methods, heterogeneity in the pain condition and study methods, and sparse data. There was only very low quality evidence that oxycodone (as oxycodone MR) is of value in the treatment of painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other neuropathic pain conditions. Adverse events typical of opioids appeared to be common.
We identified four trials involving 1314 children. Three trials investigated the use of amoxicillin/clavulanic acid to prevent otitis and one investigated ampicillin to prevent pneumonia. The use of amoxicillin/clavulanic acid compared to placebo to prevent otitis showed a risk ratio (RR) of 0.70 (95% confidence interval (CI) 0.45 to 1.11, three trials, 414 selected children, moderate-quality evidence). Methods of random sequence generation and allocation concealment were not clearly stated in two trials. Performance, detection and reporting bias could not be ruled out in three trials. Ampicillin compared to supportive care (continuation of breastfeeding, clearing of the nose and paracetamol for fever control) to prevent pneumonia showed a RR of 1.05 (95% CI 0.74 to 1.49, one trial, 889 selected children, moderate-quality evidence). The trial was non-blinded. Random sequence generation and allocation concealment methods were not clearly stated, so the possibility of reporting bias could not be ruled out. Harm outcomes could not be analysed as they were expressed only in percentages. We found no studies assessing mastoiditis, quinsy, abscess, meningitis, hospital admission or death. There is insufficient evidence for antibiotic use as a means of reducing the risk of otitis or pneumonia in children up to five years of age with undifferentiated ARIs. Further high-quality research is needed to provide more definitive evidence of the effectiveness of antibiotics in this population.
We included 20 RCTs with 1574 participants in this updated review. All trials were published in Chinese language journals. We included 14 trials that we had excluded in the previous version of the review after we added a new outcome in this update. Time windows within which the participants were randomised ranged from 4.5 hours to 10 days. Ischaemic stroke was confirmed by computerised tomography (CT) or magnetic resonance imaging (MRI) in 18 trials. Meta-analysis of two trials with 164 participants showed that treatment with puerarin did not reduce death or dependency at final follow-up (RR 0.79, 95% CI 0.45 to 1.36). One trial with 83 participants reported that the mean value of the Barthel Index in the puerarin group was below that in the control group. Meta-analysis of 16 trials with 1305 participants showed that puerarin reduced the proportion of participants without improvement of neurological deficit at the end of follow-up (RR 0.42, 95% CI 0.33 to 0.55). None of the included trials reported serious adverse effects.The quality of evidence was low due to incomplete reporting of the methods and short-term follow-up. There is not enough evidence to evaluate the effect of puerarin on survival or dependency in people with ischaemic stroke. High quality and large-scale RCTs with long-term follow-up are needed to assess its efficacy.
Three trials randomly allocating people with age-related cataract to MSICS or ECCE were included in this review (n = 953 participants). Two trials were conducted in India and one in Nepal. Trial methods, such as random allocation and allocation concealment, were not clearly described; in only one trial was an effort made to mask outcome assessors. The three studies reported follow-up six to eight weeks after surgery. In two studies, more participants in the MSICS groups achieved unaided visual acuity of 6/12 or 6/18 or better compared to the ECCE group, but overall not more than 50% of people achieved good functional vision in the two studies. 10/806 (1.2%) of people enrolled in two trials had a poor outcome after surgery (best-corrected vision less than 6/60) with no evidence of difference in risk between the two techniques (risk ratio (RR) 1.58, 95% confidence interval (CI) 0.45 to 5.55). Surgically induced astigmatism was more common with the ECCE procedure than MSICS in the two trials that reported this outcome. In one study there were more intra- and postoperative complications in the MSICS group. One study reported that the costs of the two procedures were similar. There are no other studies from other countries other than India and Nepal and there are insufficient data on cost-effectiveness of each procedure. Better evidence is needed before any change may be implemented. Future studies need to have longer-term follow-up and be conducted to minimize biases revealed in this review with a larger sample size to allow examination of adverse events.
Three randomised clinical trials (307 patients) that followed patients for three months or more after the end of treatment were included. The methodological quality was poor. The herbal compound 'Jianpi Wenshen recipe' had significant effects on viral markers compared to interferon: relative risk 2.40 (95% CI 1.01 to 5.72) for clearance of serum HBsAg, 2.03 (95% CI 0.98 to 4.20) for clearance of HBeAg, and 2.54 (95% CI 1.13 to 5.70) for seroconversion of HBeAg to anti-HBe. Phyllanthus amarus and Astragalus membranaceus showed no significant antiviral effect compared with placebo. Analysis of pooling eight randomised clinical trials with less than three months follow-up did not show a significant benefit of Chinese medicinal herbs on viral markers. Data on long-term clinical outcomes and quality of life were lacking. Based on one low quality trial, the medicinal herb 'Jianpi Wenshen recipe' may have an antiviral activity in asymptomatic carriers of hepatitis B virus. However, rigorous randomised, double-blind, placebo-controlled trials are needed before herbs should be used for this condition.
We included eight studies evaluating the effectiveness of different interventions designed to support the uptake of systematic review evidence. The overall quality of the evidence was very low to moderate. Two cluster RCTs evaluated the effectiveness of multifaceted interventions, which contained access to systematic reviews relevant to reproductive health, to change obstetric care; the high baseline performance in some of the key clinical indicators limited the findings of these studies. There were no statistically significant effects on clinical practice for all but one of the clinical indicators in selected obstetric units in Thailand (median effect size 4.2%, range -11.2% to 18.2%) and none in Mexico (median effect size 3.5%, range 0.1% to 19.0%). In the second cluster RCT there were no statistically significant differences in selected obstetric units in the UK (median effect RR 0.92; range RR 0.57 to RR 1.10). One RCT evaluated the perceived understanding and ease of use of summary of findings tables in Cochrane Reviews. The median effect of the differences in responses for the acceptability of including summary of findings tables in Cochrane Reviews versus not including them was 16%, range 1% to 28%. One RCT evaluated the effect of an analgesic league table, derived from systematic review evidence, and there was no statistically significant effect on self-reported pain. Only one RCT evaluated an organisational intervention (which included a knowledge broker, access to a repository of systematic reviews and provision of tailored messages), and reported no statistically significant difference in evidence informed programme planning. Three interrupted time series studies evaluated the dissemination of printed bulletins based on evidence from systematic reviews. A statistically significant reduction in the rates of surgery for glue ear in children under 10 years (mean annual decline of -10.1%; 95% CI -7.9 to -12.3) and in children under 15 years (quarterly reduction -0.044; 95% CI -0.080 to -0.011) was reported. The distribution to general practitioners of a bulletin on the treatment of depression was associated with a statistically significant lower prescribing rate each quarter than that predicted by the rates of prescribing observed before the distribution of the bulletin (8.2%; P = 0.005). Mass mailing a printed bulletin which summarises systematic review evidence may improve evidence-based practice when there is a single clear message, if the change is relatively simple to accomplish, and there is a growing awareness by users of the evidence that a change in practice is required. If the intention is to develop awareness and knowledge of systematic review evidence, and the skills for implementing this evidence, a multifaceted intervention that addresses each of these aims may be required, though there is insufficient evidence to support this approach.
We included 12 studies (430 participants) in the review: seven RCTs and five CCTs where it was not clear whether participants were randomly allocated to groups. We did not include any unpublished studies. Participants included children and adults of both sexes. Only one study included pregnant women. All studies were conducted in high-income countries. The quality of the 11 studies in the initial meta-analysis was moderate, although we classified no study as having a low risk of bias on all criteria. We included 11 studies in the initial meta-analysis of gamma-globulin (concentrated polyclonal immunoglobulins) versus control (saline or no treatment) for rubella cases. The result favoured the intervention group (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.45 to 0.83) but was heterogenous (Chi² test = 36.59, df = 10 (P value < 0.0001); I² statistic = 73%). Heterogeneity was explained by subgrouping studies according to the estimated volume of gamma-globulin administered per pound of bodyweight and then removing those studies where the intervention was administered more than five days after participant exposure to rubella (post hoc analysis). The test of subgroup differences demonstrated heterogeneity between subgroups according to our protocol definition (P value < 0.1; I² statistic > 60%) and there appeared to be greater effectiveness of the intervention when a greater volume of gamma-globulin was administered ('0.027 to 0.037 ml/lb' RR 1.60 (95% CI 0.57 to 4.52); '0.1 to 0.15 ml/lb' RR 0.53 (95% CI 0.29 to 0.99); '0.2 to 0.5 ml/lb' RR 0.20 (95% CI 0.04 to 1.00)). None of the studies reported the outcome 'congenital rubella infection'. One included study reported on congenital rubella syndrome, with no cases among participants who were fewer than nine weeks pregnant at enrolment and who were randomised to one of two gamma-globulin groups ('high' or 'low' rubella titre). However, the study did not report how congenital rubella syndrome was measured and did not report the length of follow-up according to intervention group. This study did not include a non-treatment group. No included study measured adverse events. Compared to no treatment, polyclonal immunoglobulins seem to be of benefit for preventing rubella. The available evidence suggests that this intervention may be of benefit up to five days after exposure, and that effectiveness is dependent on dose. Considering the attack rate for rubella cases in the control group of the highest volume gamma-globulin subgroup (333 per 1000), the absolute risk reduction (calculated from the RR) for this volume of gamma-globulin was 266 (95% CI 0 to 320) and the number needed to treat to benefit is four (95% CI 3 to incalculable). The included studies did not measure rubella-specific antibodies in the immunoglobulin products used in a standard way and thus estimation of the dose of rubella-specific antibodies in international units administered was not possible. As the concentration of rubella-specific antibodies in today's polyclonal immunoglobulin products may vary from those products used in the studies in the review, the volume required per pound of bodyweight to produce similar results may also vary. There is insufficient evidence to make direct conclusions about the effectiveness of polyclonal immunoglobulins for preventing congenital rubella syndrome. This is an area requiring further research.
We included nine RCTs, that involved 2633 people with STEMI and multi-vessel coronary disease randomly assigned to either a complete (n = 1381) versus culprit-only (n = 1252) revascularisation strategy. The complete and the culprit-only revascularisation strategies did not differ for long-term all-cause mortality (65/1274 (5.1%) in complete group versus 72/1143 (6.3%) in culprit-only group; RR 0.80, 95% CI 0.58 to 1.11; participants = 2417; studies = 8; I2 = 0%; very low quality evidence). Compared with culprit-only intervention, the complete revascularisation strategy was associated with a lower proportion of long-term cardiovascular mortality (28/1143 (2.4%) in complete group versus 51/1086 (4.7%) in culprit-only group; RR 0.50, 95% CI 0.32 to 0.79; participants = 2229; studies = 6; I2 = 0%; very low quality evidence) and long-term non-fatal myocardial infarction (47/1095 (4.3%) in complete group versus 70/1004 (7.0%) in culprit-only group; RR 0.62, 95% CI 0.44 to 0.89; participants = 2099; studies = 6; I2 = 0%; very low quality evidence). The complete and the culprit-only revascularisation strategies did not differ in combined adverse events (51/2096 (2.4%) in complete group versus 57/1990 (2.9%) in culprit-only group; RR 0.84, 95% CI 0.58 to 1.21; participants = 4086; I2 = 0%; very low quality evidence). Complete revascularisation was associated with lower proportion of long-term revascularisation (145/1374 (10.6%) in complete group versus 258/1242 (20.8%) in culprit-only group; RR 0.47, 95% CI 0.39 to 0.57; participants = 2616; studies = 9; I2 = 31%; very low quality evidence). TSA of long-term all-cause mortality, long-term cardiovascular mortality, and long-term non-fatal myocardial infarction showed that more RCTs are needed to reach more conclusive results on these outcomes. Regarding long-term repeat revascularisation more RCTs may not change our present result. The quality of the evidence was judged to be very low for all primary and the majority of the secondary outcomes mainly due to risk of bias, imprecision, and indirectness. Compared with culprit-only intervention, the complete revascularisation strategy may be superior due to lower proportions of long-term cardiovascular mortality, long-term revascularisation, and long-term non-fatal myocardial infarction, but these findings are based on evidence of very low quality. TSA also supports the need for more RCTs in order to draw stronger conclusions regarding the effects of complete revascularisation on long-term all-cause mortality, long-term cardiovascular mortality, and long-term non-fatal myocardial infarction.
A single randomised controlled trial enrolling 92 participants was eligible for this review. Researchers have not reported long-term neurodevelopmental outcomes, including the primary outcome of this review - death or long-term major neurodevelopmental disability in infancy (18 months to three years of age). Cooling plus xenon was not associated with reduced mortality at latest follow-up, based upon low quality evidence. Investigators noted no substantial differences between groups for other secondary outcomes of this review, such as biomarkers of brain damage assessed with magnetic resonance imaging and occurrence of seizures during primary hospitalisation. Available data do not show an increased adverse event rate in the cooling plus xenon group compared with the cooling alone group. Current evidence from one small randomised controlled pilot trial is inadequate to show whether cooling plus xenon is safe or effective in near-term and term newborns with HIE. Further trials reporting long-term neurodevelopmental outcomes are needed.
We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group. The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I2 = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534. The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise. Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events. We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review. We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.
We included 11 RCTs in this review update (3352 participants older than 12 years with a diagnosis of CAP); 10 RCTs assessed nine antibiotic pairs (3321 participants) and one RCT assessed four antibiotics (31 participants) in people with CAP. The study quality was generally good, with some differences in the extent of the reporting. A variety of clinical, bacteriological and adverse events were reported. Overall, there was no significant difference in the efficacy of the various antibiotics. Studies evaluating clarithromycin and amoxicillin provided only descriptive data regarding the primary outcome. Though the majority of adverse events were similar between all antibiotics, nemonoxacin demonstrated higher gastrointestinal and nervous system adverse events when compared to levofloxacin, while cethromycin demonstrated significantly more nervous system side effects, especially dysgeusia, when compared to clarithromycin. Similarly, high-dose amoxicillin (1 g three times a day) was associated with higher incidence of gastritis and diarrhoea compared to clarithromycin, azithromycin and levofloxacin. Available evidence from recent RCTs is insufficient to make new evidence-based recommendations for the choice of antibiotic to be used for the treatment of CAP in outpatient settings. Pooling of study data was limited by the very low number of studies assessing the same antibiotic pairs. Individual study results do not reveal significant differences in efficacy between various antibiotics and antibiotic groups. However, two studies did find significantly more adverse events with use of cethromycin as compared to clarithromycin and nemonoxacin when compared to levofloxacin. Multi-drug comparisons using similar administration schedules are needed to provide the evidence necessary for practice recommendations. Further studies focusing on diagnosis, management, cost-effectiveness and misuse of antibiotics in CAP and LRTI are warranted in high-, middle- and low-income countries.
Eighty studies were identified. Fifty-eight were excluded for various reasons, usually as there was no prospective trial design with randomised treatment allocation. Of the 21 included studies 13 provided data on survival, 7 on tumour response, 16 on measures of QOL or psychological outcomes, or prevalence of chemotherapy-related adverse effects and 12 on side effects of mistletoe treatment; overall comprising 3484 randomised cancer patients. Interventions evaluated were 5 preparations of mistletoe extracts from 5 manufacturers and one commercially not available preparation. The general reporting of RCTs was poor. Of the 13 trials investigating survival, 6 showed some evidence of a benefit, but none of them was of high methodological quality. The results of two trials in patients with melanoma and head and neck cancer gave some evidence that the used mistletoe extracts are not effective for improving survival. Of the 16 trials investigating the efficacy of mistletoe extracts for either improving QOL, psychological measures, performance index, symptom scales or the reduction of adverse effects of chemotherapy, 14 showed some evidence of a benefit, but only 2 of them including breast cancer patients during chemotherapy were of higher methodological quality. Data on side effects indicated that, depending on the dose, mistletoe extracts were usually well tolerated and had few side effects. The evidence from RCTs to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak. Nevertheless, there is some evidence that mistletoe extracts may offer benefits on measures of QOL during chemotherapy for breast cancer, but these results need replication. Overall, more high quality, independent clinical research is needed to truly assess the safety and effectiveness of mistletoe extracts. Patients receiving mistletoe therapy should be encouraged to take part in future trails.
Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.
Eleven RCTs were identified involving 1067 participants; 568 were randomly allocated to an exercise intervention and 499 to a usual care control group. The majority of participants received treatment for breast cancer (73%). Due to the nature of the intervention, it was not possible to blind the participants or personnel delivering the intervention. The risk of detection bias was either high or unclear in some cases, whilst most other domains were rated as low risk. The included studies were of moderate to very low-certainty evidence. Pooled data demonstrated that exercise training may have little or no difference on physical fitness (VO2 max) compared to usual care (mean difference (MD) 0.05 L/min-1, 95% confidence interval (CI) -0.03 to 0.13; I2 = 0%; 2 studies, 381 participants; low-certainty evidence). Included studies also showed in terms of adverse effects (safety), that it may be of benefit to exercise (8 studies, 507 participants; low-certainty evidence). Furthermore, exercise training probably made little or no difference on HRQoL (EORTC global health status subscale) compared to usual care (MD 2.29, 95% CI -1.06 to 5.65; I2 = 0%; 3 studies, 472 participants; moderate-certainty evidence). However, exercise training probably reduces fatigue (multidimensional fatigue inventory) compared to usual care (MD -1.05, 95% CI -1.83 to -0.28; I2 = 0%; 3 studies, 449 participants moderate-certainty evidence). No studies reported postoperative outcomes. The findings should be interpreted with caution in view of the low number of studies, the overall low-certainty of the combined evidence, and the variation in included cancer types (mainly people with breast cancer), treatments, exercise interventions, and outcomes. Exercise training may, or may not, confer modest benefit on physical fitness and HRQoL. Limited evidence suggests that exercise training is probably not harmful and probably reduces fatigue. These findings highlight the need for more RCTs, particularly in the neoadjuvant setting.
The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17. SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement. SSRIs were superior to placebo in the reduction of depression: SMD -0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05. There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate.
This review included 35 studies which randomised 10,703 people with CHD (14 trials and 2577 participants added to this update). The population included mainly men (median 77.0%) and people post-MI (mean 65.7%) or after undergoing a revascularisation procedure (mean 27.4%). The mean age of participants within trials ranged from 53 to 67 years. Overall trial reporting was poor, with around a half omitting descriptions of randomisation sequence generation, allocation concealment procedures, or the blinding of outcome assessments. The length of follow-up ranged from six months to 10.7 years (median 12 months). Most studies (23/35) evaluated multifactorial interventions, which included therapies with multiple therapeutic components. Ten studies examined psychological interventions targeted at people with a confirmed psychopathology at baseline and two trials recruited people with a psychopathology or another selecting criterion (or both). Of the remaining 23 trials, nine studies recruited unselected participants from cardiac populations reporting some level of psychopathology (3.8% to 53% with depressive symptoms, 32% to 53% with anxiety), 10 studies did not report these characteristics, and only three studies excluded people with psychopathology. Moderate quality evidence showed no risk reduction for total mortality (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.77 to 1.05; participants = 7776; studies = 23) or revascularisation procedures (RR 0.94, 95% CI 0.81 to 1.11) with psychological therapies compared to usual care. Low quality evidence found no risk reduction for non-fatal MI (RR 0.82, 95% CI 0.64 to 1.05), although there was a 21% reduction in cardiac mortality (RR 0.79, 95% CI 0.63 to 0.98). There was also low or very low quality evidence that psychological interventions improved participant-reported levels of depressive symptoms (standardised mean difference (SMD) -0.27, 95% CI -0.39 to -0.15; GRADE = low), anxiety (SMD -0.24, 95% CI -0.38 to -0.09; GRADE = low), and stress (SMD -0.56, 95% CI -0.88 to -0.24; GRADE = very low). There was substantial statistical heterogeneity for all psychological outcomes but not clinical outcomes, and there was evidence of small-study bias for one clinical outcome (cardiac mortality: Egger test P = 0.04) and one psychological outcome (anxiety: Egger test P = 0.012). Meta-regression exploring a limited number of intervention characteristics found no significant predictors of intervention effects for total mortality and cardiac mortality. For depression, psychological interventions combined with adjunct pharmacology (where deemed appropriate) for an underlying psychological disorder appeared to be more effective than interventions that did not (β = -0.51, P = 0.003). For anxiety, interventions recruiting participants with an underlying psychological disorder appeared more effective than those delivered to unselected populations (β = -0.28, P = 0.03). This updated Cochrane Review found that for people with CHD, there was no evidence that psychological treatments had an effect on total mortality, the risk of revascularisation procedures, or on the rate of non-fatal MI, although the rate of cardiac mortality was reduced and psychological symptoms (depression, anxiety, or stress) were alleviated; however, the GRADE assessments suggest considerable uncertainty surrounding these effects. Considerable uncertainty also remains regarding the people who would benefit most from treatment (i.e. people with or without psychological disorders at baseline) and the specific components of successful interventions. Future large-scale trials testing the effectiveness of psychological therapies are required due to the uncertainty within the evidence. Future trials would benefit from testing the impact of specific (rather than multifactorial) psychological interventions for participants with CHD, and testing the targeting of interventions on different populations (i.e. people with CHD, with or without psychopathologies).
Twenty-five RCTs (2310 participants) were included in the review. Fourteen studies were judged to be at high risk of bias due to lack of blinding, incomplete outcome data and selective reporting. Meta-analysis of two studies (101 patients) comparing polyethylene glycol (PEG) with placebo showed a significantly increased number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08). Common adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea, diarrhoea and headache. Participants receiving high dose PEG (0.7 g/kg) had significantly more stools per week than low dose PEG (0.3 g/kg) participants (1 study, 90 participants, MD 1.30, 95% 0.76 to 1.84). Meta-analysis of 6 studies with 465 participants comparing PEG with lactulose showed a significantly greater number of stools per week with PEG (MD 0.70 , 95% CI 0.10 to 1.31), although follow-up was short. Patients who received PEG were significantly less likely to require additional laxative therapies. Eighteen per cent (27/154) of PEG patients required additional therapies compared to 31% (47/150) of lactulose patients (RR 0.55, 95% CI 0.36 to 0.83). No serious adverse events were reported with either agent. Common adverse events in these studies included diarrhoea, abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants comparing PEG with milk of magnesia showed that the stools per week were significantly greater with PEG (MD 0.69, 95% CI 0.48 to 0.89). However, the magnitude of this difference was quite small and may not be clinically significant. One child was noted to be allergic to PEG, but there were no other serious adverse events reported. One study found a significant difference in stools per week favouring milk of magnesia over lactulose (MD -1.51, 95% CI -2.63 to -0.39, 50 patients), Meta-analysis of 2 studies with 287 patients comparing liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in the number of stools per week favouring liquid paraffin (MD 4.94 , 95% CI 4.28 to 5.61). No serious adverse events were reported. Adverse events included abdominal pain, distention and watery stools. No statistically significant differences in the number of stools per week were found between PEG and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1 study, 125 patients, P = 0.481), senna and lactulose (1 study, 21 patients, P > 0.05), lactitol and lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63 to 1.03), hydrolyzed guar gum and lactulose (1 study, 61 patients, MD 1.00, 95% CI -1.80 to 3.80), PEG and flixweed (1 study, 109 patients, MD 0.00, 95% CI -0.33 to 0.33), PEG and dietary fibre (1 study, 83 patients, MD 0.20, 95% CI -0.64 to 1.04), and PEG and liquid paraffin (2 studies, 261 patients, MD 0.35, 95% CI -0.24 to 0.95). The pooled analyses suggest that PEG preparations may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, the results of the pooled analyses should be interpreted with caution because of quality and methodological concerns, as well as clinical heterogeneity, and short follow-up. There is also evidence suggesting the efficacy of liquid paraffin (mineral oil). There is no evidence to demonstrate the superiority of lactulose when compared to the other agents studied, although there is a lack of placebo controlled studies. Further research is needed to investigate the long term use of PEG for childhood constipation, as well as the role of liquid paraffin. The optimal dose of PEG also warrants further investigation.
We included five randomised controlled trials with a total of 212 participants in the analyses. All included participants were under five years of age. Using GRADE, we assessed there was low-quality evidence for all analysed outcomes. We assessed high risk of performance and detection bias for two studies due to their unblinded setting. Levosimendan showed no clear effect on risk of mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.12 to 1.82; participants = 123; studies = 3) and no clear effect on low cardiac output syndrome (RR 0.64, 95% CI 0.39 to 1.04; participants = 83; studies = 2) compared to standard treatments. Data on time-to-death were not available from any of the included studies. There was no conclusive evidence on the effect of levosimendan on the secondary outcomes. The length of intensive care unit stays (mean difference (MD) 0.33 days, 95% CI -1.16 to 1.82; participants = 188; studies = 4), length of hospital stays (MD 0.26 days, 95% CI -3.50 to 4.03; participants = 75; studies = 2), duration of mechanical ventilation (MD -0.04 days, 95% CI -0.08 to 0.00; participants = 208; studies = 5), and the risk of mechanical circulatory support or cardiac transplantation (RR 1.49, 95% CI 0.19 to 11.37; participants = 60; studies = 2) did not clearly differ between the groups. Published data about adverse effects of levosimendan were limited. A meta-analysis of hypotension, one of the most feared side effects of levosimendan, was not feasible because of the heterogeneous expression of blood pressure values. The current level of evidence is insufficient to judge whether prophylactic levosimendan prevents low cardiac output syndrome and mortality in paediatric patients undergoing surgery for congenital heart disease. So far, no significant differences have been detected between levosimendan and standard inotrope treatments in this setting. The authors evaluated the quality of evidence as low, using the GRADE approach. Reasons for downgrading were serious risk of bias (performance and detection bias due to unblinded setting of two RCTs), serious risk of inconsistency, and serious to very serious risk of imprecision (small number of included patients, low event rates).
We included nine RCTs (911 participants), including four different comparisons. None of the studies evaluated our first primary outcome measure, disease-specific HRQL. Fluticasone propionate versus beclomethasone dipropionate We identified two small studies (56 participants with polyps) that evaluated disease severity  and looked at the primary adverse effect: epistaxis  , but no other outcomes. We cannot report any numerical data but the study authors reported no difference between the two steroids. The evidence was of very low quality. Fluticasone propionate versus mometasone furoate We identified only one study (100 participants with polyps) that evaluated disease severity  (nasal symptoms scores), which reported no difference (no numerical data available). The evidence was of very low quality. High-dose versus low-dose steroids We included five studies (663 participants with nasal polyps), three using mometasone furoate (400 µg versus 200 µg in adults and older children, 200 µg versus 100 µg in younger children) and two using fluticasone propionate drops (800 µg versus 400 µg). We found low quality evidence relating to disease severity  and nasal polyps size, with results from the high-dose and low-dose groups being similar. Although all studies reported more improvement in polyp score in the high-dose group, the significance of this is unclear due to the small size of the improvements. The primary adverse effect, epistaxis  , was more common when higher doses were used (risk ratio (RR) 2.06, 95% confidence interval (CI) 1.20 to 3.54, 637 participants, moderate quality evidence). Most of the studies that contributed data to this outcome used a broad definition of epistaxis, which ranged from frank bleeding to bloody nasal discharge to flecks of blood in the mucus. Aqueous nasal spray versus aerosol spray We identified only one poorly reported study (unclear number of participants for comparison of interest, 91 between three treatment arms), in which there were significant baseline differences between the participants in the two groups. We were unable to draw meaningful conclusions from the data. We found insufficient evidence to suggest that one type of intranasal steroid is more effective than another in patients with chronic rhinosinusitis, nor that the effectiveness of a spray differs from an aerosol. We identified no studies that compared drops with spray. It is unclear if higher doses result in better symptom improvements (low quality evidence), but there was moderate quality evidence of an increased risk of epistaxis as an adverse effect of treatment when higher doses were used. This included all levels of severity of epistaxis and it is likely that the proportion of events that required patients to discontinue usage is low due to the low numbers of withdrawals attributed to it. If epistaxis is limited to streaks of blood in the mucus it may be tolerated by the patient and it may be safe to continue treatment. However, it may be a factor that affects compliance. There is insufficient evidence to suggest that the different types of corticosteroid molecule or spray versus aerosol have different effects. Lower doses have similar effectiveness but fewer side effects. Clearly more research in this area is needed, with specific attention given to trial design, disease-specific health-related quality of life outcomes and evaluation of longer-term outcomes and adverse effects.
We included four randomized trials involving 200 participants. Owing to small numbers of studies and participants, it was not possible to combine data for all outcomes. Two trials reported 28-day mortality, and one trial reported hospital mortality; in the third trial, the number of deaths stated did not match the quoted mortality rates. The pooled risk ratio (95% confidence interval) for 28-day mortality associated with HVHF was 0.89 (0.60 to 1.32, two trials, 146 participants, low-quality evidence). One study (137 participants, low-quality evidence) reported length of stay in the ICU. Two trials (170 participants, low-quality evidence) reported organ dysfunction, but we could not pool results owing to reporting differences. Three studies (189 participants, low-quality evidence) reported on haemodynamic changes, but we could not pool results owing to reporting differences. Investigators reported no adverse events. Overall, the included studies had low risk of bias. Investigators reported no adverse effects of HVHF (low-quality evidence). The results of this meta-analysis show that very few studies have been conducted to investigate the use of HVHF in critically ill patients with severe sepsis or septic shock (four studies, 201 participants, low-quality evidence). Researchers should consider additional randomized controlled trials that are large and multi-centred and have clinically relevant outcome measures. The cost-effectiveness of HVHF should also be studied..
One randomised controlled trial with a total of 100 male participants was included in the review. The trial compared hand-assisted laparoscopic repair with EVAR and provided results for in-hospital mortality, operative time, length of hospital stay and lower limb ischaemia. The included study did not report on the other pre-planned outcomes of this review. No in-hospital deaths occurred in the study. Hand-associated laparoscopic repair was associated with a longer operative time (MD 53.00 minutes, 95% CI 36.49 to 69.51) than EVAR. The incidence of lower limb ischaemia was similar between the two treatment groups (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.05 to 5.34). The mean length of hospital stay was 4.2 days and 3.4 days in the hand-assisted laparoscopic repair and EVAR groups respectively but standard deviations were not reported and therefore it was not possible to independently test the statistical significance of this result. The quality of evidence was downgraded for imprecision due to the inclusion of one small study; and wide confidence intervals and indirectness due to the study including male participants only. No study compared laparoscopic repair (total or hand-assisted) with open surgical repair or total laparoscopic surgical repair with EVAR. There is insufficient evidence to draw any conclusions about effectiveness and safety of laparoscopic (total and hand-assisted) surgical repair of AAA versus open surgical repair or EVAR, because only one small randomised trial was eligible for inclusion in this review. High-quality randomised controlled trials are needed.
The search identified 35 references, with 25 studies, but we could only include two studies with a total of 358 participants. The studies had a moderate risk of bias, and therefore risk overestimating any positive effects of ICT-based prompting. Both included studies compared semi-automatised ICT-based prompting intervention with standard care groups in mental health outpatient care. The interventions were SMS-message and an electronic assistant device. One included study reported our primary outcome, compliance. There was not any clear evidence that ICT-based prompts increase improvement in compliance (stop taking medication within six months n = 320, RR 1.11 CI 0.96 to 1.29, moderate quality evidence). There was some low quality evidence that ICT-based prompts have small effects for: mental state (average change in specific symptom scores within three months n = 251, MD -0.30 CI -0.53 to -0.07; severity of illness within three months n = 251, MD -0.10 CI -0.13 to -0.07 and six months n = 251, MD -0.10 CI -0.13 to -0.07; average change in depressive scores within six months n = 251, RR 0.00 CI -0.28 to 0.28; global symptoms within three months n = 251, MD -0.10 CI -0.38 to -0.07; negative symptoms within three months n = 251, MD -0.10 CI -0.38 to 0.18 and six months n = 251, MD -0.30 CI -0.58 to 0.02, low quality evidence). Level of insight improved more among people receiving ICT-based prompt compared with those in the control group at six months (n = 251, MD -0.10 CI -0.13 to -0.07). ICT-based prompts also increased quality of life (average change in quality of life within six months n = 251, RR 0.50 CI 0.19 to 0.81, moderate quality evidence). Based on the existing data, there is no evidence that either intervention is less acceptable than the other (n = 347, 2 RCTs, RR 1.46 CI 0.70 to 3.05, low quality evidence). Included studies did not report outcomes of service utilisation, behaviour, costs or adverse events. The evidence base on the effects of ICT-based prompts is still inconclusive. Data to clarify ICT-based prompting effects are awaited from an ongoing trial, but further well-conducted trials considering the different ICT-based prompts are warranted.
Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified. There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.
Nine trials, including 4654 participants, met our inclusion criteria. Five trials evaluated appointment reminders for people on treatment for active TB, two for people on prophylaxis for latent TB, and four for people undergoing TB screening using skin tests. We classified the interventions into 'pre-appointment' reminders (telephone calls or letters prior to a scheduled appointment) or 'default' reminders (telephone calls, letters, or home visits to people who had missed an appointment). For people being treated for active TB, clinic attendance and TB treatment completion were higher in people receiving pre-appointment reminder phone-calls (clinic attendance: 66% versus 50%; RR 1.32, 95% CI 1.10 to 1.59, one trial (USA), 615 participants, low quality evidence; TB treatment completion: 100% versus 88%; RR 1.14, 95% CI 1.02 to 1.27, one trial (Thailand), 92 participants, low quality evidence). Clinic attendance and TB treatment completion were also higher with default reminders (letters or home visits) (clinic attendance: 52% versus 10%; RR 5.04, 95% CI 1.61 to 15.78, one trial (India), 52 participants, low quality evidence; treatment completion: RR 1.17, 95% CI 1.11 to 1.24, two trials (Iraq and India), 680 participants, moderate quality evidence). For people on TB prophylaxis, clinic attendance was higher with a policy of pre-appointment phone-calls (63% versus 48%; RR 1.30, 95% CI 1.07 to 1.59, one trial (USA), 536 participants); and attendance at the final clinic was higher with regular three-monthly phone-calls or nurse visits (93% versus 65%, one trial (Spain), 318 participants). For people undergoing screening for TB, three trials of pre-appointment phone-calls found little or no effect on the proportion of people returning to clinic for the result of their skin test (three trials, 1189 participants, low quality evidence), and two trials found little or no effect with take home reminder cards (two trials, 711 participants). All four trials were conducted among healthy volunteers in the USA. Policies of sending reminders to people pre-appointment, and contacting people who miss appointments, seem sensible additions to any TB programme, and the limited evidence available suggests they have small but potentially important benefits. Future studies of modern technologies such as short message service (SMS) reminders would be useful, particularly in low-resource settings.
Only one study fulfilled the criteria (Amato 1988). 20 full term babies requiring exchange transfusion for hemolytic jaundice due to ABO incompatibility were randomly allocated to receive single or double volume exchange transfusion. Base line characteristics of both groups were similar with regards to birth weight 3260 (SD 390) g vs. 3350 SD (410) g, gestational age 39 (SD 1) week vs. 40 (SD 0.8) week, immediate pre exchange bilirubin level 199 (SD 33) micromol/L vs. 216 (SD 55) micromol/L. Both groups were treated equally apart from the volume of blood used for exchange transfusion. Total bilirubin levels immediately after exchange transfusion were not significantly different in either group. No long term neurodevelopmental outcome was examined in this study. There was insufficient evidence to support or refute the use of single volume exchange transfusion as opposed to double volume exchange transfusion in jaundiced newborns. A change from the current practice of double volume exchange transfusions for severe jaundice in newborns infant, cannot be recommended on current evidence.
Twelve trials involving 844 participants were included. One trial tested two comparisons. Quality assessment revealed a poor level of methodological rigour in many studies, particularly with regard to concealment of allocation and the lack of assessor blinding. Open surgical treatment compared with non-surgical treatment (6 trials, 536 participants) was associated with a statistically significant lower risk of rerupture (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.21 to 0.77), but a higher risk of other complications including infection (RR 4.89, 95% CI 1.09 to 21.91), adhesions and disturbed skin sensibility (numbness). Functional status including sporting activity was variably and often incompletely reported, including frequent use of non standardised outcome measures, and the results were inconclusive. Open surgical repair compared with percutaneous repair (4 trials, 174 participants) was associated with a higher risk of infection (RR 9.32, 95% CI 1.77 to 49.16). These figures should be interpreted with caution because of the small numbers involved. Similarly, no definitive conclusions could be made regarding different tendon repair techniques (3 trials, 147 participants). Open surgical treatment of acute Achilles tendon ruptures significantly reduces the risk of rerupture compared with non-surgical treatment, but produces significantly higher risks of other complications, including wound infection. The latter may be reduced by performing surgery percutaneously.
For this update, we added 11 studies and included a total of 20 studies (1477 participants). Rehabilitation programmes showed great diversity in terms of exercise training (number of completed exercise sessions; type, intensity and supervision), patient education (from none to extensive self-management programmes) and how they were organised (within one setting, e.g. pulmonary rehabilitation, to across several settings, e.g. hospital, outpatient centre and home). In eight studies, participants completed extensive pulmonary rehabilitation, and in 12 studies, participants completed pulmonary rehabilitation ranging from not extensive to moderately extensive. Eight studies involving 810 participants contributed data on hospital readmissions. Moderate-quality evidence indicates that pulmonary rehabilitation reduced hospital readmissions (pooled odds ratio (OR) 0.44, 95% confidence interval (CI) 0.21 to 0.91), but results were heterogenous (I2 = 77%). Extensiveness of rehabilitation programmes and risk of bias may offer an explanation for the heterogeneity, but subgroup analyses were not statistically significant (P values for subgroup effects were between 0.07 and 0.11). Six studies including 670 participants contributed data on mortality. The quality of evidence was low, and the meta-analysis did not show a statistically significant effect of rehabilitation on mortality (pooled OR 0.68, 95% CI 0.28 to 1.67). Again, results were heterogenous (I2 = 59%). Subgroup analyses showed statistically significant differences in subgroup effects between trials with more and less extensive rehabilitation programmes and between trials at low and high risk for bias, indicating possible explanations for the heterogeneity. Hospital readmissions and mortality studies newly included in this update showed, on average, significantly smaller effects of rehabilitation than were seen in earlier studies. High-quality evidence suggests that pulmonary rehabilitation after an exacerbation improves health-related quality of life. The eight studies that used St George's Respiratory Questionnaire (SGRQ) reported a statistically significant effect on SGRQ total score, which was above the minimal important difference (MID) of four points (mean difference (MD) -7.80, 95% CI -12.12 to -3.47; I2 = 64%). Investigators also noted statistically significant and important effects (greater than MID) for the impact and activities domains of the SGRQ. Effects were not statistically significant for the SGRQ symptoms domain. Again, all of these analyses showed heterogeneity, but most studies showed positive effects of pulmonary rehabilitation, some studies showed large effects and others smaller but statistically significant effects. Trials at high risk of bias because of lack of concealment of random allocation showed statistically significantly larger effects on the SGRQ than trials at low risk of bias. High-quality evidence shows that six-minute walk distance (6MWD) improved, on average, by 62 meters (95% CI 38 to 86; I2 = 87%). Heterogeneity was driven particularly by differences between studies showing very large effects and studies showing smaller but statistically significant effects. For both health-related quality of life and exercise capacity, studies newly included in this update showed, on average, smaller effects of rehabilitation than were seen in earlier studies, but the overall results of this review have not changed to an important extent compared with results reported in the earlier version of this review. Five studies involving 278 participants explicitly recorded adverse events, four studies reported no adverse events during rehabilitation programmes and one study reported one serious event. Overall, evidence of high quality shows moderate to large effects of rehabilitation on health-related quality of life and exercise capacity in patients with COPD after an exacerbation. Some recent studies showed no benefit of rehabilitation on hospital readmissions and mortality and introduced heterogeneity as compared with the last update of this review. Such heterogeneity of effects on hospital readmissions and mortality may be explained to some extent by the extensiveness of rehabilitation programmes and by the methodological quality of the included studies. Future researchers must investigate how the extent of rehabilitation programmes in terms of exercise sessions, self-management education and other components affects the outcomes, and how the organisation of such programmes within specific healthcare systems determines their effects after COPD exacerbations on hospital readmissions and mortality.
We have included seven trials, involving 1396 women. Three trials (1030 women) were good quality. Magnesium sulphate was associated with a reduction in maternal death (seven trials;1396 women; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.38 to 0.92) and recurrence of seizures (seven trials;1390 women; RR 0.43, 95% CI 0.33 to 0.55) compared to diazepam. There were no clear differences in other measures of maternal morbidity. There was no clear difference in perinatal mortality (four trials; 788 infants; RR 1.04, 95% CI 0.81 to 1.34) or neonatal mortality (four trials; 759 infants; RR 1.18, 95% CI 0.75 to 1.84). In the magnesium sulphate group, fewer liveborn babies had an Apgar score less than seven at one minute (two trials; 597 babies; RR 0.75, 95% CI 0.65 to 0.87) or at five minutes (RR 0.70, 95% CI 0.54 to 0.90), and fewer appeared to need intubation at the place of birth (two trials; 591 infants; RR 0.67, 95% CI 0.45 to 1.00). There was no difference in admission to a special care nursery (four trials; 834 infants; RR 0.91, 95% CI 0.79 to 1.05), but fewer babies in the magnesium sulphate group had a length of stay more than seven days (three trials 631 babies; RR 0.66, 95% CI 0.46 to 0.96). Magnesium sulphate for women with eclampsia reduces the risk ratio of maternal death and of recurrence of seizures, compared with diazepam.
We found three studies for inclusion in the review. One recruited males with a biopsy-proven diagnosis of non-metastatic prostate cancer who were not receiving chemotherapy and had elected to receive external-beam radiation therapy; the second study recruited community-living participants who were aged 55 years and older; the third study recruited university students. These studies included subgroups with anxiety and depression as defined by symptom scores and provided data separately for those subgroups. As this included only 25 people with anxiety and 17 with depression and 20 more with either anxiety or depression, but which was not specified, the results could only be reported narratively. They show no evidence that Reiki is either beneficial or harmful in this population. The risk of bias for the included studies was generally rated as unclear or high for most domains, which reduces the certainty of the evidence. There is insufficient evidence to say whether or not Reiki is useful for people over 16 years of age with anxiety or depression or both.
We included 40 trials with 3694 participants randomized to an exercise (n = 1927) or comparison (n = 1764) group. Cancer diagnoses in study participants included breast, colorectal, head and neck, lymphoma, and other. Thirty trials were conducted among participants who had completed active treatment for their primary or recurrent cancer and 10 trials included participants both during and post cancer treatment. Mode of the exercise intervention included strength training, resistance training, walking, cycling, yoga, Qigong, or Tai Chi. HRQoL and its domains were measured using a wide range of measures. The results suggested that exercise compared with control has a positive impact on HRQoL and certain HRQoL domains. Exercise resulted in improvement in: global HRQoL at 12 weeks' (SMD 0.48; 95% confidence interval (CI) 0.16 to 0.81) and 6 months' (0.46; 95% CI 0.09 to 0.84) follow-up, breast cancer concerns between 12 weeks' and 6 months' follow-up (SMD 0.99; 95% CI 0.41 to 1.57), body image/self-esteem when assessed using the Rosenberg Self-Esteem scale at 12 weeks (MD 4.50; 95% CI 3.40 to 5.60) and between 12 weeks' and 6 months' (mean difference (MD) 2.70; 95% CI 0.73 to 4.67) follow-up, emotional well-being at 12 weeks' follow-up (SMD 0.33; 95% CI 0.05 to 0.61), sexuality at 6 months' follow-up (SMD 0.40; 95% CI 0.11 to 0.68), sleep disturbance when comparing follow-up values by comparison group at 12 weeks' follow-up (SMD -0.46; 95% CI -0.72 to -0.20), and social functioning at 12 weeks' (SMD 0.45; 95% CI 0.02 to 0.87) and 6 months' (SMD 0.49; 95% CI 0.11 to 0.87) follow-up. Further, exercise interventions resulted in decreased anxiety at 12 weeks' follow-up (SMD -0.26; 95% CI -0.07 to -0.44), fatigue at 12 weeks' (SMD -0.82; 95% CI -1.50 to -0.14) and between 12 weeks' and 6 months' (SMD -0.42; 95% CI -0.02 to -0.83) follow-up, and pain at 12 weeks' follow-up (SMD -0.29; 95% CI -0.55 to -0.04) when comparing follow-up values by comparison group. Positive trends and impact of exercise intervention existed for depression and body image (when analyzing combined instruments); however, because few studies measured these outcomes the robustness of findings is uncertain. No conclusions can be drawn regarding the effects of exercise interventions on HRQoL domains of cognitive function, physical functioning, general health perspective, role function, and spirituality. Results of the review need to be interpreted cautiously owing to the risk of bias. All the trials reviewed were at high risk for performance bias. In addition, the majority of trials were at high risk for detection, attrition, and selection bias. This systematic review indicates that exercise may have beneficial effects on HRQoL and certain HRQoL domains including cancer-specific concerns (e.g. breast cancer), body image/self-esteem, emotional well-being, sexuality, sleep disturbance, social functioning, anxiety, fatigue, and pain at varying follow-up periods. The positive results must be interpreted cautiously due to the heterogeneity of exercise programs tested and measures used to assess HRQoL and HRQoL domains, and the risk of bias in many trials. Further research is required to investigate how to sustain positive effects of exercise over time and to determine essential attributes of exercise (mode, intensity, frequency, duration, timing) by cancer type and cancer treatment for optimal effects on HRQoL and its domains.
We included four studies of 12 to 52 weeks' duration, involving 3798 participants with COPD. Mean age of participants ranged from 60.1 to 64.6 years; most were males with baseline mean smoking pack-years of 39.2 to 52.3. They had moderate to severe COPD and baseline mean post-bronchodilator forced expiratory volume in one second (FEV1) ranging from 44.5% to 55.1% of predicted normal. As all studies were systematically conducted according to prespecified protocols, we assessed risk of selection, performance, detection, attrition, and reporting biases as low. Compared with those given placebo, participants in the umeclidinium group had a lesser likelihood of developing moderate exacerbations requiring a short course of steroids, antibiotics, or both (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.46 to 0.80; four studies, N = 1922; GRADE: high), but not specifically requiring hospitalisations due to severe exacerbations (OR 0.86, 95% CI 0.25 to 2.92; four studies, N = 1922, GRADE: low). The number needed to treat for an additional beneficial outcome (NNTB) to prevent an acute exacerbation requiring steroids, antibiotics, or both was 18 (95% CI 13 to 37). Quality of life was better in the umeclidinium group (mean difference (MD) -4.79, 95% CI -8.84 to -0.75; three studies, N = 1119), and these participants had a significantly higher chance of achieving a minimal clinically important difference of at least four units in St George's Respiratory Questionnaire (SGRQ) total score compared with those in the placebo group (OR 1.45, 95% CI 1.16 to 1.82; three studies, N = 1397; GRADE: moderate). The NNTB to achieve one person with a clinically meaningful improvement was 11 (95% CI 7 to 29). The likelihood of all-cause mortality, non-fatal serious adverse events (OR 1.33; 95% CI 0.89 to 2.00; four studies, N = 1922, GRADE: moderate), and adverse events (OR 1.06, 95% CI 0.85 to 1.31; four studies, N = 1922; GRADE: moderate) did not differ between umeclidinium and placebo groups. The umeclidinium group demonstrated significantly greater improvement in change from baseline in trough FEV1 compared with the placebo group (MD 0.14, 95% CI 0.12 to 0.17; four studies, N = 1381; GRADE: high). Symptomatic improvement was more likely in the umeclidinium group than in the placebo group, as determined by Transitional Dyspnoea Index (TDI) focal score (MD 0.76, 95% CI 0.43 to 1.09; three studies, N = 1193), and the chance of achieving a minimal clinically important difference of at least one unit improvement was significantly higher with umeclidinium than with placebo (OR 1.71, 95% CI 1.37 to 2.15; three studies, N = 1141; GRADE: high). The NNTB to attain one person with clinically important symptomatic improvement was 8 (95% CI 5 to 14). The likelihood of rescue medication usage (change from baseline in the number of puffs per day) was significantly less for the umeclidinium group than for the placebo group (MD -0.45, 95% CI -0.76 to -0.14; four studies, N = 1531). Umeclidinium reduced acute exacerbations requiring steroids, antibiotics, or both, although no evidence suggests that it decreased the risk of hospital admission due to exacerbations. Moreover, umeclidinium demonstrated significant improvement in quality of life, lung function, and symptoms, along with lesser use of rescue medications. Studies reported no differences in adverse events, non-fatal serious adverse events, or mortality between umeclidinium and placebo groups; however, larger studies would yield a more precise estimate for these outcomes.
Five randomised controlled trials were identified, of which two satisfied the inclusion criteria. The trials were of poor methodological quality. As a result, it was difficult to have confidence in the individual results and it was not appropriate to pool the data. One trial reported no difference in mortality, number of surgeries or length of stay between the control and HBOT groups once these variables were adjusted for the patients' condition. The second trial reported mean healing times that were shorter in patients exposed to HBOT (mean: 19.7 days versus 43.8 days). No further eligible trials were found when the search was updated in June 2009. This systematic review has not found sufficient evidence to support or refute the effectiveness of HBOT for the management of thermal burns. Evidence from the two randomised controlled trials is insufficient to provide clear guidelines for practice. Further research is needed to better define the role of HBOT in the treatment of thermal burns.
Two RCTs and one prospective non-randomised study evaluating pharmacological interventions met the inclusion criteria for this review. As each study evaluated a different drug or intervention using different endpoints, a meta-analysis was not possible. There were no trials of non-pharmacological interventions that met the inclusion criteria. A very small randomised, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100% (7/7) of participants on bevacizumab had reduction in brain oedema by at least 25% and reduction in post-gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both. This was an encouraging finding but due to the small sample size we did not report a relative effect. The authors also failed to provide adequate details regarding the randomisation and blinding procedures Therefore, the certainty of this evidence is low and a larger RCT adhering to reporting standards is needed. An open-label RCT demonstrated a greater reduction in brain oedema (T2 hyperintensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95% CI 0.14 to 5.92; low-certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95% CI - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision). In the RCT of bevacizumab versus placebo, all seven participants receiving bevacizumab were reported to have neurological improvement, whereas five of seven participants on placebo had neurological worsening (very low-certainty evidence due to small sample size and concerns over validity of analyses). While no adverse events were noted with placebo, three severe adverse events were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis. In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95% CI 1.26 to 5.01; low-certainty evidence due to open-label design). No differences in treatment toxicities were observed between arms. One included prospective non-randomised study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment. As only one included study was a double-blinded randomised controlled trial, the other studies were prone to selection and detection biases. None of the included studies reported quality of life outcomes or adequately reported details about corticosteroid requirements. A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable endpoints. There is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. In an RCT of 14 patients, bevacizumab showed radiological response which was associated with minimal improvement in cognition or symptom severity. Although it was a randomised trial by design, the small sample size limits the quality of data. A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding oedema with combination treatment but no effect on the enhancing radionecrosis lesion. Due to the open-label design and wide confidence intervals in the results, the quality of this data was also low. There was no evidence to support any non-pharmacological interventions for the treatment of radionecrosis. Further prospective randomised studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence. Two ongoing RCTs, one evaluating bevacizumab and one evaluating hyperbaric oxygen therapy were identified.
We included seven studies involving 2492 participants. Peer support telephone calls were associated with an increase in mammography screening, with 49% of women in the intervention group and 34% of women in the control group receiving a mammogram since the start of the intervention (P </ = 0.001). In another study, peer telephone support calls were found to maintain mammography screening uptake for baseline adherent women (P = 0.029). Peer support telephone calls for post myocardial infarction patients were associated at six months with a change in diet in the intervention and usual care groups of 54% and 44% respectively (P = 0.03). In another study for post myocardial infarction patients there were no significant differences between groups for self-efficacy, health status and mental health outcomes. Peer support telephone calls were associated with greater continuation of breastfeeding in mothers at 3 months post partum (P = 0.01). Peer support telephone calls were associated with reduced depressive symptoms in mothers with postnatal depression (Edinburgh Postnatal Depression Scale (EPDS) > 12). The peer support intervention significantly decreased depressive symptomatology at the 4-week assessment (odds ratio (OR) 6.23 (95% confidence interval (CI) 1.15 to 33.77; P = 0.02)) and 8-week assessment (OR 6.23 (95% CI 1.40 to 27.84; P = 0.01). One study investigated the use of peer support for patients with poorly controlled diabetes. There were no significant differences between groups for self-efficacy, HbA1C, cholesterol level and body mass index. Whilst this review provides some evidence that peer support telephone calls can be effective for certain health-related concerns, few of the studies were of high quality and so results should be interpreted cautiously. There were many methodological limitations thus limiting the generalisability of findings. Overall, there is a need for further well designed randomised controlled studies to clarify the cost and clinical effectiveness of peer support telephone calls for improvement in health and health-related behaviour.
We found no randomised controlled trials on this topic. We included six non-randomised studies (five retrospective) that compared laparoscopic versus open transhiatal oesophagectomy (334 patients: laparoscopic = 154 patients; open = 180 patients); five studies (326 patients: laparoscopic = 151 patients; open = 175 patients) provided information for one or more outcomes. Most studies included a mixture of adenocarcinoma and squamous cell carcinoma and different stages of oesophageal cancer, without metastases. All the studies were at unclear or high risk of bias; the overall quality of evidence was very low for all the outcomes. The differences between laparoscopic and open transhiatal oesophagectomy were imprecise for short-term mortality (laparoscopic = 0/151 (adjusted proportion based on meta-analysis estimate: 0.5%) versus open = 2/175 (1.1%); RR 0.44; 95% CI 0.05 to 4.09; participants = 326; studies = 5; I² = 0%); long-term mortality (HR 0.97; 95% CI 0.81 to 1.16; participants = 193; studies = 2; I² = 0%); anastomotic stenosis (laparoscopic = 4/36 (11.1%) versus open = 3/37 (8.1%); RR 1.37; 95% CI 0.33 to 5.70; participants = 73; studies = 1); short-term recurrence (laparoscopic = 1/16 (6.3%) versus open = 0/4 (0%); RR 0.88; 95% CI 0.04 to 18.47; participants = 20; studies = 1); long-term recurrence (HR 1.00; 95% CI 0.84 to 1.18; participants = 173; studies = 2); proportion of people who required blood transfusion (laparoscopic = 0/36 (0%) versus open = 6/37 (16.2%); RR 0.08; 95% CI 0.00 to 1.35; participants = 73; studies = 1); proportion of people with positive resection margins (laparoscopic = 15/102 (15.8%) versus open = 27/111 (24.3%); RR 0.65; 95% CI 0.37 to 1.12; participants = 213; studies = 3; I² = 0%); and the number of lymph nodes harvested during surgery (median difference between the groups varied from 12 less to 3 more lymph nodes in the laparoscopic compared to the open group; participants = 326; studies = 5). The proportion of patients with serious adverse events was lower in the laparoscopic group (10/99, (10.3%) compared to the open group = 24/114 (21.1%); RR 0.49; 95% CI 0.24 to 0.99; participants = 213; studies = 3; I² = 0%); as it was for adverse events in the laparoscopic group = 37/99 (39.9%) versus the open group = 71/114 (62.3%); RR 0.64; 95% CI 0.48 to 0.86; participants = 213; studies = 3; I² = 0%); and the median lengths of hospital stay were significantly less in the laparoscopic group than the open group (three days less in all three studies that reported this outcome; number of participants = 266). There was lack of clarity as to whether the median difference in the quantity of blood transfused was statistically significant favouring laparoscopic oesophagectomy in the only study that reported this information. None of the studies reported post-operative dysphagia, health-related quality of life, time-to-return to normal activity (return to pre-operative mobility without caregiver support), or time-to-return to work. There are currently no randomised controlled trials comparing laparoscopic with open transhiatal oesophagectomy for patients with oesophageal cancers. In observational studies, laparoscopic transhiatal oesophagectomy is associated with fewer overall complications and shorter hospital stays than open transhiatal oesophagectomy. However, this association is unlikely to be causal. There is currently no information to determine a causal association in the differences between the two surgical approaches. Randomised controlled trials comparing laparoscopic transhiatal oesophagectomy with other methods of oesophagectomy are required to determine the optimal method of oesophagectomy.
We included 32 studies (6597 women) in this review. Forceps were less likely than the ventouse to fail to achieve a vaginal birth with the allocated instrument (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.45 to 0.94). However, with forceps there was a trend to more caesarean sections, and significantly more third- or fourth-degree tears (with or without episiotomy), vaginal trauma, use of general anaesthesia, and flatus incontinence or altered continence. Facial injury was more likely with forceps (RR 5.10, 95% CI 1.12 to 23.25). Using a random-effects model because of heterogeneity between studies, there was a trend towards fewer cases of cephalhaematoma with forceps (average RR 0.64, 95% CI 0.37 to 1.11). Among different types of ventouse, the metal cup was more likely to result in a successful vaginal birth than the soft cup, with more cases of scalp injury and cephalhaematoma. The hand-held ventouse was associated with more failures than the metal ventouse, and a trend to fewer than the soft ventouse. Overall forceps or the metal cup appear to be most effective at achieving a vaginal birth, but with increased risk of maternal trauma with forceps and neonatal trauma with the metal cup. There is a recognised place for forceps and all types of ventouse in clinical practice. The role of operator training with any choice of instrument must be emphasised. The increasing risks of failed delivery with the chosen instrument from forceps to metal cup to hand-held to soft cup vacuum, and trade-offs between risks of maternal and neonatal trauma identified in this review need to be considered when choosing an instrument.
Five trials recruited a total of 439 participants and between them compared different types of VNS stimulation therapy. Baseline phase ranged from 4 to 12 weeks and double-blind treatment phases from 12 to 20 weeks in the five trials. Overall, two studies were rated as having a low risk of bias and three had an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies of VNS is difficult due to the frequency of stimulation-related side effects such as voice alteration; this may limit the validity of the observed treatment effects. Four trials compared high frequency stimulation to low frequency stimulation and were included in quantitative syntheses (meta-analyses).The overall risk ratio (95% CI) for 50% or greater reduction in seizure frequency across all studies was 1.73 (1.13 to 2.64) showing that high frequency VNS was over one and a half times more effective than low frequency VNS. For this outcome, we rated the evidence as being moderate in quality due to incomplete outcome data in one included study; however results did not vary substantially and remained statistically significant for both the best and worst case scenarios. The risk ratio (RR) for treatment withdrawal was 2.56 (0.51 to 12.71), however evidence for this outcome was rated as low quality due to imprecision of the result and incomplete outcome data in one included study. The RR of adverse effects were as follows: (a) voice alteration and hoarseness 2.17 (99% CI 1.49 to 3.17); (b) cough 1.09 (99% CI 0.74 to 1.62); (c) dyspnea 2.45 (99% CI 1.07 to 5.60); (d) pain 1.01 (99% CI 0.60 to 1.68); (e) paresthesia 0.78 (99% CI 0.39 to 1.53); (f) nausea 0.89 (99% CI 0.42 to 1.90); (g) headache 0.90 (99% CI 0.48 to 1.69); evidence of adverse effects was rated as moderate to low quality due to imprecision of the result and/or incomplete outcome data in one included study. No important heterogeneity between studies was found for any of the outcomes. VNS for partial seizures appears to be an effective and well tolerated treatment in 439 included participants from five trials. Results of the overall efficacy analysis show that VNS stimulation using the high stimulation paradigm was significantly better than low stimulation in reducing frequency of seizures. Results for the outcome "withdrawal of allocated treatment" suggest that VNS is well tolerated as withdrawals were rare. No significant difference was found in withdrawal rates between the high and low stimulation groups, however limited information was available from the evidence included in this review so important differences between high and low stimulation cannot be excluded . Adverse effects associated with implantation and stimulation were primarily hoarseness, cough, dyspnea, pain, paresthesia, nausea and headache, with hoarseness and dyspnea more likely to occur on high stimulation than low stimulation. However, the evidence on these outcomes is limited and of moderate to low quality. Further high quality research is needed to fully evaluate the efficacy and tolerability of VNS for drug resistant partial seizures.
Four studies enrolling 450 participants met our inclusion criteria. Overall risk of bias was judged to be low in one study, unclear in two, and high in one. There was no significant differences in the number of fistulas that were successfully created (4 studies, 433 patients: RR 1.06, 95% CI 0.95 to 1.28; I² = 76%); the number of fistulas that matured at six months (3 studies, 356 participants: RR 1.11, 95% CI 0.98 to 1.25; I² = 0%); number of fistulas that were used successfully for dialysis (2 studies, 286 participants: RR 1.12, 95% CI 0.99 to 1.28; I² = 0%); the number of patients initiating dialysis with a catheter (1 study, 214 patients: RR 0.66, 95% CI 0.42 to 1.04); and in the rate of interventions required to maintain patency (1 study, 70 patients: MD 14.70 interventions/1000 patient-days, 95% CI -7.51 to 36.91) between the use of preoperative imaging technologies compared with standard care (no imaging). Based on four small studies, preoperative vessel imaging did not improve fistula outcomes compared with standard care. Adequately powered prospective studies are required to fully answer this question.
Twelve studies were eligible for inclusion. Allergic disease and / or food hypersensitivity outcomes were assessed by 6 studies enrolling 2080 infants, but outcomes for only 1549 infants were reported. Studies generally had adequate randomisation, allocation concealment and blinding of treatment. However, the findings of this review should be treated with caution due to excess losses in patient follow-up (17% to 61%). Meta-analysis of five studies reporting the outcomes of 1477 infants found a significant reduction in infant eczema (typical RR 0.82, 95% CI 0.70, 0.95). However, there was significant and substantial heterogeneity between studies. One study reported that the difference in eczema between groups persisted to 4 years age. When the analysis was restricted to studies reporting atopic eczema (confirmed by skin prick test or specific IgE), the findings were no longer significant (typical RR 0.80, 95% CI 0.62, 1.02). All studies reporting significant benefits used probiotic supplements containing L. rhamnosus and enrolled infants at high risk of allergy. No other benefits were reported for any other allergic disease or food hypersensitivity outcome. There is insufficient evidence to recommend the addition of probiotics to infant feeds for prevention of allergic disease or food hypersensitivity. Although there was a reduction in clinical eczema in infants, this effect was not consistent between studies and caution is advised in view of methodological concerns regarding included studies. Further studies are required to determine whether the findings are reproducible.
We included five trials in this analysis, all of which were performed in the prehospital setting. The risk of bias was low in four of these studies (n = 1186). The trials accumulated 1254 participants. Aminophylline was found to have no effect on survival to hospital discharge (risk ratio (RR) 0.58, 95% confidence interval (CI) 0.12 to 2.74) or on secondary survival outcome (survival to hospital admission: RR 0.92, 95% CI 0.61 to 1.39; return of spontaneous circulation: RR 1.15, 95% CI 0.89 to 1.49). Survival was rare (6/1254), making data about neurological outcomes and adverse events quite limited. The planned subgroup analysis for early administration of aminophylline included 37 participants. No one in the subgroup survived to hospital discharge. The prehospital administration of aminophylline in bradyasystolic arrest is not associated with improved return of circulation, survival to admission or survival to hospital discharge. The benefits of aminophylline administered early in resuscitative efforts are not known.
We included 14 randomised trials involving 4596 operations, of which 3526 were from the single largest trial (GALA). In general, reporting of methodology in the included studies was poor. All studies were unable to blind patients and surgical teams to randomised treatment allocation and for most studies the blinding of outcome assessors was unclear. There was no statistically significant difference in the incidence of stroke within 30 days of surgery between the local anaesthesia group and the general anaesthesia group. The incidence of strokes in the local anaesthesia group was 3.2% compared to 3.5% in the general anaesthesia group (Peto OR 0.92, 95% CI 0.67 to 1.28). There was no statistically significant difference in the proportion of patients who had a stroke or died within 30 days of surgery. In the local anaesthesia group 3.6% of patients had a stroke or died compared to 4.2% of patients in the general anaesthesia group (Peto OR 0.85, 95% CI 0.63 to 1.16). There was a non-significant trend towards lower operative mortality with local anaesthetic. In the local anaesthesia group 0.9% of patients died within 30 days of surgery compared to 1.5% of patients in the general anaesthesia group (Peto OR 0.62, 95% CI 0.36 to 1.07). However, neither the GALA trial or the pooled analysis were adequately powered to reliably detect an effect on mortality. The proportion of patients who had a stroke or died within 30 days of surgery did not differ significantly between the two types of anaesthetic techniques used during carotid endarterectomy. This systematic review provides evidence to suggest that patients and surgeons can choose either anaesthetic technique, depending on the clinical situation and their own preferences.
Five studies were included. No new eligible studies have been found since the review was initially conducted. Method discontinuation was similar between groups in all trials. Bleeding patterns and side effects were similar in trials that compared immediate with conventional start. In a study of depot medroxyprogesterone acetate (DMPA), immediate start of DMPA showed fewer pregnancies than a 'bridge' method before DMPA (OR 0.36; 95% CI 0.16 to 0.84). Further, more women in the immediate-DMPA group were very satisfied versus those with a 'bridge' method (OR 1.99; 95% CI 1.05 to 3.77). A trial of two immediate-start methods showed the vaginal ring group had less prolonged bleeding (OR 0.42; 95% CI 0.20 to 0.89) and less frequent bleeding (OR 0.23; 95% CI 0.05 to 1.03) than COC users. The ring group also reported fewer side effects. Also, more immediate ring users were very satisfied than immediate COC users (OR 2.88; 95% CI 1.59 to 5.22). We found limited evidence that immediate start of hormonal contraception reduces unintended pregnancies or increases method continuation. However, the pregnancy rate was lower with immediate start of DMPA versus another method. Some differences were associated with contraceptive type rather than initiation method, i.e., immediate ring versus immediate COC. More studies are needed of immediate versus conventional start of the same hormonal contraceptive.
We identified three RCTs for inclusion. One of these studies had serious problems with allocation of the study drug and placebo, so we could not analyse data for intervention effect from it. The remaining two RCTs recruited 104 participants. One randomized 65 participants to receive linezolid or not, in addition to a background regimen; the other randomized 39 participants to addition of linezolid to a background regimen immediately, or after a delay of two months. We included 14 non-randomized cohort studies (two prospective, 12 retrospective), with a total of 1678 participants. Settings varied in terms of income and tuberculosis burden. One RCT and 7 out of 14 non-randomized studies commenced recruitment in or after 2009. All RCT participants and 38.7% of non-randomized participants were reported to have XDR-TB. Dosing and duration of linezolid in studies were variable and reported inconsistently. Daily doses ranged from 300 mg to 1200 mg; some studies had planned dose reduction for all participants after a set time, others had incompletely reported dose reductions for some participants, and most did not report numbers of participants receiving each dose. Mean or median duration of linezolid therapy was longer than 90 days in eight of the 14 non-randomized cohorts that reported this information. Duration of participant follow-up varied between RCTs. Only five out of 14 non-randomized studies reported follow-up duration. Both RCTs were at low risk of reporting bias and unclear risk of selection bias. One RCT was at high risk of performance and detection bias, and low risk for attrition bias, for all outcomes. The other RCT was at low risk of detection and attrition bias for the primary outcome, with unclear risk of detection and attrition bias for non-primary outcomes, and unclear risk of performance bias for all outcomes. Overall risk of bias for the non-randomized studies was critical for three studies, and serious for the remaining 11. One RCT reported higher cure (risk ratio (RR) 2.36, 95% confidence interval (CI) 1.13 to 4.90, very low-certainty evidence), lower failure (RR 0.26, 95% CI 0.10 to 0.70, very low-certainty evidence), and higher sputum culture conversion at 24 months (RR 2.10, 95% CI 1.30 to 3.40, very low-certainty evidence), amongst the linezolid-treated group than controls, with no differences in other primary and secondary outcomes. This study also found more anaemia (17/33 versus 2/32), nausea and vomiting, and neuropathy (14/33 versus 1/32) events amongst linezolid-receiving participants. Linezolid was discontinued early and permanently in two of 33 (6.1%) participants who received it. The other RCT reported higher sputum culture conversion four months after randomization (RR 2.26, 95% CI 1.19 to 4.28), amongst the group who received linezolid immediately compared to the group who had linezolid initiation delayed by two months. Linezolid was discontinued early and permanently in seven of 39 (17.9%) participants who received it. Linezolid discontinuation occurred in 22.6% (141/624; 11 studies), of participants in the non-randomized studies. Total, serious, and linezolid-attributed adverse events could not be summarized quantitatively or comparatively, due to incompleteness of data on duration of follow-up and numbers of participants experiencing events. We found some evidence of efficacy of linezolid for drug-resistant pulmonary tuberculosis from RCTs in participants with XDR-TB but adverse events and discontinuation of linezolid were common. Overall, there is a lack of comparative data on efficacy and safety. Serious risk of bias and heterogeneity in conducting and reporting non-randomized studies makes the existing, mostly retrospective, data difficult to interpret. Further prospective cohort studies or RCTs in high tuberculosis burden low-income and lower-middle-income countries would be useful to inform policymakers and clinicians of the efficacy and safety of linezolid as a component of drug-resistant TB treatment regimens.
We included 13 trials with 567,476 participants randomised to pre- or post-exposure prophylaxis. The trials had high risk of bias. The trials were heterogeneous in terms of study setting, participants, interventions, and outcome measures. Our meta-analysis with six randomised trials showed that immunoglobulins, when used for pre-exposure prophylaxis, significantly reduced the number of adult patients with hepatitis A at 6 to 12 months (1020/286503 versus 761/134529; RR 0.53; 95% CI 0.40 to 0.70; random-effects model) in comparison with no intervention or inactive control. Four trials showed a similar effect in children aged 3 to 17 at 6 to 12 months follow-up (917/210822 versus 677/78960; RR 0.45; 95% CI 0.34 to 0.59). Comparing different doses of immunoglobulins, higher dosage was generally more effective than lower dosage (1.5 ml better than 0.75 ml and 0.75 ml better than 0.1 ml) in preventing hepatitis A. No significant systemic adverse events were reported. One trial showed that immunoglobulin was more effective than placebo for post-exposure prophylaxis. It appeared that there was no significant difference between immunoglobulins and inactivated hepatitis A vaccine in seroconversion to hepatitis A vaccine antibodies at four weeks (RR 1.16; 95% CI 0.98 to 1.38), but immunoglobulins were significantly less effective than vaccine regarding antibody levels at 8, 12, or 24 weeks. Immunoglobulins seem to be effective for pre-exposure and post-exposure prophylaxis of hepatitis A. However, caution is warranted for the positive findings due to the limited number of trials, year of conductance, and risk of bias. Conductance of rigorous trials will be justifiable.
We identified six high quality, up to date Cochrane reviews. Four of these related to the safety of regular formoterol or salmeterol (as monotherapy or combination therapy) and these included 19 studies in children. We added data from two recent studies on salmeterol combination therapy in 689 children which were published after the relevant Cochrane review had been completed, making a total of 21 trials on 7474 children (from four to 17 years of age). The two remaining reviews compared the safety of formoterol with salmeterol from trials randomising participants to one or other treatment, but the reviews only included a single trial in children in which there were 156 participants. Only one child died across all the trials, so impact on mortality could not be assessed. We found a statistically significant increase in the odds of suffering a non-fatal serious adverse event of any cause in children on formoterol monotherapy (Peto odds ratio (OR) 2.48; 95% confidence interval (CI) 1.27 to 4.83, I2 = 0%, 5 trials, N = 1335, high quality) and smaller increases in odds which were not statistically significant for salmeterol monotherapy (Peto OR 1.30; 95% CI 0.82 to 2.05, I2 = 17%, 5 trials, N = 1333, moderate quality), formoterol combination therapy (Peto OR 1.60; 95% CI 0.80 to 3.28, I2 = 32%, 7 trials, N = 2788, moderate quality) and salmeterol combination therapy (Peto OR 1.20; 95% CI 0.37 to 2.91, I2 = 0%, 5 trials, N = 1862, moderate quality). We compared the pooled results of the monotherapy and combination therapy trials. There was no significant difference between the pooled ORs of children with a serious adverse event (SAE) from long-acting beta2-agonist beta agonist (LABA) monotherapy (Peto OR 1.60; 95% CI 1.10 to 2.33, 10 trials, N = 2668) and combination trials (Peto OR 1.50; 95% CI 0.82 to 2.75, 12 trials, N = 4,650). However, there were fewer children with an SAE in the regular inhaled corticosteroid (ICS) control group (0.7%) than in the placebo control group (3.6%). As a result, there was an absolute increase of an additional 21 children (95% CI 4 to 45) suffering such an SAE of any cause for every 1000 children treated over six months with either regular formoterol or salmeterol monotherapy, whilst for combination therapy the increased risk was an additional three children (95% CI 1 fewer to 12 more) per 1000 over three months. We only found a single trial in 156 children comparing the safety of regular salmeterol to regular formoterol monotherapy, and even with the additional evidence from indirect comparisons between the combination formoterol and salmeterol trials, the CI around the effect on SAEs is too wide to tell whether there is a difference in the comparative safety of formoterol and salmeterol (OR 1.26; 95% CI 0.37 to 4.32). We do not know if regular combination therapy with formoterol or salmeterol in children alters the risk of dying from asthma. Regular combination therapy is likely to be less risky than monotherapy in children with asthma, but we cannot say that combination therapy is risk free. There are probably an additional three children per 1000 who suffer a non-fatal serious adverse event on combination therapy in comparison to ICS over three months. This is currently our best estimate of the risk of using LABA combination therapy in children and has to be balanced against the symptomatic benefit obtained for each child. We await the results of large on-going surveillance studies to further clarify the risks of combination therapy in children and adolescents with asthma. The relative safety of formoterol in comparison to salmeterol remains unclear, even when all currently available direct and indirect trial evidence is combined.
Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P < 0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias. Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.
Seventy-seven studies met the entry criteria and randomised 21,248 participants (4625 children and 16,623 adults). Participants were generally symptomatic at baseline with moderate airway obstruction despite their current ICS regimen. Formoterol or salmeterol were most frequently added to low-dose ICS (200 to 400 µg/day of beclomethasone (BDP) or equivalent) in 49% of the studies. The addition of a daily LABA to ICS reduced the risk of exacerbations requiring oral steroids by 23% from 15% to 11% (RR 0.77, 95% CI 0.68 to 0.87, 28 studies, 6808 participants). The number needed to treat with the addition of LABA to prevent one use of rescue oral corticosteroids is 41 (29, 72), although the event rates in the ICS groups varied between 0% and 38%. Studies recruiting adults dominated the analysis (6203 adult participants versus 605 children). The subgroup estimate for paediatric studies was not statistically significant (RR 0.89, 95% CI 0.58 to 1.39) and includes the possibility of the superiority of ICS alone in children. Higher than usual dose of LABA was associated with significantly less benefit. The difference in the relative risk of serious adverse events with LABA was not statistically significant from that of ICS alone (RR 1.06, 95% CI 0.87 to 1.30). The addition of LABA led to a significantly greater improvement in FEV1 (0.11 litres, 95% 0.09 to 0.13) and in the proportion of symptom-free days (11.88%, 95% CI 8.25 to 15.50) compared to ICS monotherapy. It was also associated with a reduction in the use of rescue short-acting ß2-agonists (-0.58 puffs/day, 95% CI -0.80 to -0.35), fewer withdrawals due to poor asthma control (RR 0.50, 95% CI 0.41 to 0.61), and fewer withdrawals due to any reason (RR 0.80, 95% CI 0.75 to 0.87). There was no statistically significant group difference in the risk of overall adverse effects (RR 1.00, 95% 0.97 to 1.04), withdrawals due to adverse health events (RR 1.04, 95% CI 0.86 to 1.26) or any of the specific adverse health events. In adults who are symptomatic on low to high doses of ICS monotherapy, the addition of a LABA at licensed doses reduces the rate of exacerbations requiring oral steroids, improves lung function and symptoms and modestly decreases use of rescue short-acting ß2-agonists. In children, the effects of this treatment option are much more uncertain. The absence of group difference in serious adverse health events and withdrawal rates in both groups provides some indirect evidence of the safety of LABAs at usual doses as add-on therapy to ICS in adults, although the width of the confidence interval precludes total reassurance.
We included 35 trials (13,872 adult participants). Seven included studies were at low risk of bias. We identified eight studies as awaiting classification since we could not obtain the full texts, and had insufficient information to include or exclude them. We included data from 24 trials for quantitative synthesis. The results of meta-analyses showed that nitrous oxide-based techniques increased the incidence of pulmonary atelectasis (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.18 to 2.10, P = 0.002), but had no effects on the inhospital case fatality rate, the incidence of pneumonia, myocardial infarction, stroke, severe nausea and vomiting, venous thromboembolism, wound infection, or the length of hospital stay. The sensitivity analyses suggested that the results of the meta-analyses were all robust except for the outcomes of pneumonia, and severe nausea and vomiting. Two trials reported length of intensive care unit (ICU) stay but the data were skewed so were not pooled. Both trials reported that nitrous oxide-based techniques had no effects on the length of ICU stay. We rated the quality of evidence for two outcomes (pulmonary atelectasis, myocardial infarction) as high, four outcomes (inhospital case fatality rate, stroke, venous thromboembolism, length of hospital stay) as moderate, and three (pneumonia, severe nausea and vomiting, wound infection rate) as low. Given the evidence from this Cochrane review, the avoidance of nitrous oxide may be reasonable in participants with pre-existing poor pulmonary function or at high risk of postoperative nausea and vomiting. Since there are eight studies awaiting classification, selection bias may exist in our systematic review.
We identified seven trials that met the inclusion criteria. Out of these, six trials provided data for the meta-analyses. A total of 488 participants with acute cholecystitis and fit to undergo laparoscopic cholecystectomy were randomised to early laparoscopic cholecystectomy (ELC) (244 people) and delayed laparoscopic cholecystectomy (DLC) (244 people) in the six trials. Blinding was not performed in any of the trials and so all the trials were at high risk of bias. Other than blinding, three of the six trials were at low risk of bias in the other domains such as sequence generation, allocation concealment, incomplete outcome data, and selective outcome reporting. The proportion of females ranged between 43.3% and 80% in the trials that provided this information. The average age of participants ranged between 40 years and 60 years. There was no mortality in any of the participants in five trials that reported mortality. There was no significant difference in the proportion of people who developed bile duct injury in the two groups (ELC 1/219 (adjusted proportion 0.4%) versus DLC 2/219 (0.9%); Peto OR 0.49; 95% CI 0.05 to 4.72 (5 trials)). There was no significant difference between the two groups (ELC 14/219 (adjusted proportion 6.5%) versus DLC 11/219 (5.0%); RR 1.29; 95% CI 0.61 to 2.72 (5 trials)) in terms of other serious complications. None of the trials reported quality of life from the time of randomisation. There was no significant difference between the two groups in the proportion of people who required conversion to open cholecystectomy (ELC 49/244 (adjusted proportion 19.7%) versus DLC 54/244 (22.1%); RR 0.89; 95% CI 0.63 to 1.25 (6 trials)). The total hospital stay was shorter in the early group than the delayed group by four days (MD -4.12 days; 95% CI -5.22 to -3.03 (4 trials; 373 people)). There was no significant difference in the operating time between the two groups (MD -1.22 minutes; 95% CI -3.07 to 0.64 (6 trials; 488 people)). Only one trial reported return to work. The people belonging to the ELC group returned to work earlier than the DLC group (MD -11.00 days; 95% CI -19.61 to -2.39 (1 trial; 36 people)). Four trials did not report any gallstone-related morbidity during the waiting period. One trial reported five gallstone-related morbidities (cholangitis: two; biliary colic not requiring urgent operation: one; acute cholecystitis not requiring urgent operation: two). There were no reports of pancreatitis during the waiting time. Gallstone-related morbidity was not reported in the remaining trials. Forty (18.3%) of the people belonging to the delayed group had either non-resolution of symptoms or recurrence of symptoms before their planned operation and had to undergo emergency laparoscopic cholecystectomy in five trials. The proportion with conversion to open cholecystectomy was 45% (18/40) in this group of people. We found no significant difference between early and late laparoscopic cholecystectomy on our primary outcomes. However, trials with high risk of bias indicate that early laparoscopic cholecystectomy during acute cholecystitis seems safe and may shorten the total hospital stay. The majority of the important outcomes occurred rarely, and hence the confidence intervals are wide. It is unlikely that future randomised clinical trials will be powered to measure differences in bile duct injury and other serious complications since this might involve performing a trial of more than 50,000 people, but several smaller randomised trials may answer the questions through meta-analyses.
Of the three included studies (101 participants), one evaluated continuous arteriovenous haemodialysis and two investigated continuous venovenous haemofiltration; all included conventional therapy as control. We found significant decreases in myoglobin in patients among whom CRRT therapy was initiated on days four, eight, and 10 (day 4: MD -11.00 (μg/L), 95% CI -20.65 to -1.35; Day 8: MD -23.00 (μg/L), 95% CI -30.92 to -15.08; day 10: MD -341.87 (μg/L), 95% CI -626.15 to -57.59) compared with those who underwent conventional therapy. Although CRRT was associated with improved serum creatinine, blood urea nitrogen, and potassium levels; reduced duration of the oliguria phase; and was associated with reduced time in hospital, no significant differences were found in mortality rates compared with conventional therapy (RR 0.17, 95% CI 0.02 to 1.37). The included studies did not report on long-term outcomes or prevention of AKI. Overall, we found that study quality was suboptimal: blinding and randomisation allocation were not reported by any of the included studies, leading to the possibility of selection, performance and detection bias. Although CRRT may provide some benefits for people with rhabdomyolysis, the poor methodological quality of the included studies and lack of data relating to clinically important outcomes limited our findings about the effectiveness of CRRT for people with rhabdomyolysis. There was insufficient evidence to discern any likely benefits of CRRT over conventional therapy for people with rhabdomyolysis and prevention of rhabdomyolysis-induced AKI.
We included seven trials reported in 30 references in the review (354 participants). In all trials, G-CSF was compared with placebo preparations. Dosage of G-CSF varied among studies, ranging from 2.5 to 10 microgram/kg/day. Regarding overall risk of bias, data regarding the generation of randomization sequence and incomplete outcome data were at a low risk of bias; however, data regarding binding of personnel were not conclusive. The rate of mortality was not different between the two groups (RR 0.64, 95% CI 0.15 to 2.80, P = 0.55). Regarding safety, the limited amount of evidence is inadequate to reach any conclusions regarding the safety of G-CSF therapy. Moreover, the results did not show any beneficial effects of G-CSF in patients with AMI regarding left ventricular function parameters, including left ventricular ejection fraction (RR 3.41, 95% CI -0.61 to 7.44, P = 0.1), end systolic volume (RR -1.35, 95% CI -4.68 to 1.99, P = 0.43) and end diastolic volume (RR -4.08, 95% CI -8.28 to 0.12, P = 0.06). It should also be noted that the study was limited since the trials included lacked long enough follow up durations. Limited evidence from small trials suggested a lack of benefit of G-CSF therapy in patients with AMI. Since data of the risk of bias regarding blinding of personnel were not conclusive, larger RCTs with appropriate power calculations and longer follow up durations are required in order to address current uncertainties regarding the clinical efficacy and therapy-related adverse events of G-CSF treatment.
A total of 29 trials were included in this review and 21 trials (17,276 women) provided data that could be included in an analysis. The quality of the trials was variable. 1. Non-closure of visceral and parietal peritoneum versus closure of both parietal layers Sixteen trials involving 15,480 women, were included and analysed, when both parietal peritoneum was left unclosed versus when both peritoneal surfaces were closed. Postoperative adhesion formation was assessed in only four trials with 282 women, and no difference was found between groups (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.76 to 1.29). There was significant reduction in the operative time (mean difference (MD) -5.81 minutes, 95% CI -7.68 to -3.93). The duration of hospital stay in a total of 13 trials involving 14,906 women, was also reduced (MD -0.26, 95% CI -0.47 to -0.05) days. In a trial involving 112 women, reduced chronic pelvic pain was found in the peritoneal non-closure group. 2. Non-closure of visceral peritoneum only versus closure of both peritoneal surfaces Three trials involving 889 women were analysed. There was an increase in adhesion formation (two trials involving 157 women, RR 2.49, 95% CI 1.49 to 4.16) which was limited to one trial with high risk of bias.There was reduction in operative time, postoperative days in hospital and wound infection. There was no significant reduction in postoperative pyrexia. 3. Non-closure of parietal peritoneum only versus closure of both peritoneal layers The two identified trials involved 573 women. Neither study reported on postoperative adhesion formation. There was reduction in operative time and postoperative pain with no difference in the incidence of postoperative pyrexia, endometritis, postoperative duration of hospital stay and wound infection. In only one study, postoperative day one wound pain assessed by the numerical rating scale, (MD -1.60, 95% CI -1.97 to -1.23) and chronic abdominal pain d by the visual analogue score (MD -1.10, 95% CI -1.39 to -0.81) was reduced in the non-closure group. 4. Non-closure versus closure of visceral peritoneum when parietal peritoneum is closed. There was reduction in all the major urinary symptoms of frequency, urgency and stress incontinence when the visceral peritoneum is left unsutured. There was a reduction in operative time across all the subgroups. There was also a reduction in the period of hospitalisation post-caesarean section except in the subgroup where parietal peritoneum only was not sutured where there was no difference in the period of hospitalisation. The evidence on adhesion formation was limited and inconsistent. There is currently insufficient evidence of benefit to justify the additional time and use of suture material necessary for peritoneal closure. More robust evidence on long-term pain, adhesion formation and infertility is needed.
20 double-blind RCTs evaluated the BP lowering efficacy of beta-blockers as second-line drug in 3744 hypertensive patients (baseline BP of 158/102 mmHg; mean duration of 7 weeks). The BP reduction from adding a beta-blocker as the second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. A reduction in BP was seen with adding a beta-blocker to thiazide diuretics or calcium channel blockers at doses as low as 0.25 times the manufacturer's recommended starting dose. The BP lowering efficacy of beta-blockers as a second drug was 6/4 mmHg at 1 times the starting dose and 8/6 mmHg at 2 times the starting dose. Beta-blockers reduced heart rate by 10 beats/min at 1 to 2 times the starting dose. Beta-blockers did not statistically significantly increase withdrawals due to adverse effects but this was likely due to the lack of reporting of this outcome in 35% of the included RCTs. Addition of a beta-blocker to diuretics or calcium-channel blockers reduces BP by 6/4mmHg at 1 times the starting dose and by 8/6 mmHg at 2 times the starting dose. When the blood pressure lowering effect of beta-blockers from this review was compared to that of thiazide diuretics from our previous review (Chen 2009), second-line beta-blockers reduce systolic BP to the same extent as second-line thiazide diuretics, but reduce diastolic BP to a greater degree. The different effect on diastolic BP means that beta-blockers have little or no effect on pulse pressure whereas thiazides cause a significant dose-related decrease in pulse pressure. This difference in the pattern of BP lowering with beta-blockers as compared to thiazides might be the explanation for the fact that beta-blockers appear to be less effective at reducing adverse cardiovascular outcomes than thiazide diuretics, particularly in older individuals.
We included 3684 patients from 53 studies. SEMS insertion was safer and more effective than plastic tube insertion. Thermal and chemical ablative therapy provided comparable dysphagia palliation but had an increased requirement for re-interventions and for adverse effects. Anti-reflux stents provided comparable dysphagia palliation to conventional metal stents. Some anti-reflux stents might have reduced gastro-oesophageal reflux and complications. Newly-designed double-layered nitinol (Niti-S) stents were preferable due to longer survival time and fewer complications compared to simple Niti-S stents. Brachytherapy might be a suitable alternative to SEMS in providing a survival advantage and possibly a better quality of life, and might provide better results when combined with argon plasma coagulation or external beam radiation therapy. Self-expanding metal stent insertion is safe, effective and quicker in palliating dysphagia compared to other modalities. However, high-dose intraluminal brachytherapy is a suitable alternative and might provide additional survival benefit with a better quality of life. Some anti-reflux stents and newly-designed stents lead to longer survival and fewer complications compared to conventional stents. Combinations of brachytherapy with self-expanding metal stent insertion or radiotherapy are preferable due to the reduced requirement for re-interventions. Rigid plastic tube insertion, dilatation alone or in combination with other modalities, and chemotherapy alone are not recommended for palliation of dysphagia due to a high incidence of delayed complications and recurrent dysphagia.
Seven trials met the inclusion criteria and had a total of 4526 women. Five were multi-site studies. Four trials were conducted in the USA, while Nigeria and Zambia were represented by one study each, and one trial was done in both Jamaica and India. Two trials provided multiple sessions for participants. In one study that examined contraceptive choice, women in the expanded program were more likely to choose sterilization (OR 4.26; 95% CI 2.46 to 7.37) or use a modern contraceptive method (OR 2.35; 95% CI 1.82 to 3.03), i.e., sterilization, pills, injectable, intrauterine device or barrier method. For the other study, the groups received educational interventions with differing format and intensity. Both groups reportedly had increases in contraceptive use, but they did not differ significantly by six months in consistent use of an effective contraceptive, i.e., sterilization, IUD, injectable, implant, and consistent use of oral contraceptives, diaphragm, or male condoms. Five trials provided one session and focused on testing educational material or media. In one study, knowledge gain favored a slide-and-sound presentation versus a physician's oral presentation (MD -19.00; 95% CI -27.52 to -10.48). In another trial, a table with contraceptive effectiveness categories led to more correct answers than a table based on pregnancy numbers [ORs were 2.42 (95% CI 1.43 to 4.12) and 2.19 (95% CI 1.21 to 3.97)] or a table with effectiveness categories and pregnancy numbers [ORs were 2.58 (95% CI 1.5 to 4.42) and 2.03 (95% CI 1.13 to 3.64)]. Still another trial provided structured counseling with a flipchart on contraceptive methods. The intervention and usual-care groups did not differ significantly in choice of contraceptive method (by effectiveness category) or in continuation of the chosen method at three months. Lastly, a study with couples used videos to communicate contraceptive information (control, motivational, contraceptive methods, and both motivational and methods videos). The analyses showed no significant difference between the groups in the types of contraceptives chosen. These trials varied greatly in the types of participants and interventions to communicate contraceptive effectiveness. Therefore, we cannot say overall what would help consumers choose an appropriate contraceptive method. For presenting pregnancy risk data, one trial showed that effectiveness categories were better than pregnancy numbers. In another trial, audiovisual aids worked better than the usual oral presentation. Strategies should be tested in clinical settings and measured for their effect on contraceptive choice. More detailed reporting of intervention content would help in interpreting results. Reports could also include whether the instruments used to assess knowledge or attitudes were tested for validity or reliability. Follow-up should be incorporated to assess retention of knowledge over time. The overall quality of evidence was considered to be low for this review, given that five of the seven studies provided low or very low quality evidence.
We included 24 observational cluster studies (359 hospitals) in this review. We did not find any randomised controlled trials or formal economic evaluations. In 22 studies, the people who used the intervention (CSTD plus safe handling) and control (safe handling alone) were pharmacists or pharmacy technicians; in the other two studies, the people who used the intervention and control were nurses, pharmacists, or pharmacy technicians. Therefore, the evidence is mainly applicable to pharmacists or pharmacy technicians. The CSTD used in the studies were PhaSeal (13 studies), Tevadaptor (2 studies), SpikeSwan (1 study), PhaSeal and Tevadaptor (1 study), varied (5 studies), and not stated (2 studies). Therefore, the evidence is mainly applicable for PhaSeal. The studies' descriptions of the control groups were varied. Twenty-two studies provide data on one or more outcomes for this systematic review. All the studies are at serious risk of bias. The quality of evidence is very low for all the outcomes. Very low certainty evidence from small studies is insufficient to determine whether there is any important difference between CSTD and control groups in the proportion of people with positive urine tests for exposure between the CSTD and control groups for any of the drugs: cyclophosphamide alone (RR 0.83, 95% CI 0.46 to 1.52; I² = 12%; 2 studies; 2 hospitals; 20 participants; CSTD: 76.1% versus control: 91.7%); cyclophosphamide or ifosfamide (RR 0.09, 95% CI 0.00 to 2.79; 1 study; 1 hospital; 14 participants; CSTD: 6.4% versus control: 71.4%); and cyclophosphamide, ifosfamide, or gemcitabine (RR not estimable; 1 study; 1 hospital; 36 participants; 0% in both groups). Very low certainty evidence from small studies is insufficient to determine whether there is any important difference between CSTD and control groups in the proportion of surfaces contaminated or the quantity of contamination. Overall, out of 24 comparisons in pharmacy areas or patient-care areas, there was a reduction in the proportion of surfaces contaminated in only one comparison and out of 15 comparisons in pharmacy areas or patient-care areas, there was a reduction in the quantity of contamination in only two comparisons. None of the studies report on atmospheric contamination, blood tests, or other measures of exposure to infusional hazardous drugs such as urine mutagenicity, chromosomal aberrations, sister chromatid exchanges, or micronuclei induction. None of the studies report short-term health outcomes such as reduction in skin rashes, medium-term reproductive health outcomes such as fertility and parity, or long-term health outcomes related to the development of any type of cancer or adverse events. Five studies (six hospitals) report the potential cost savings through the use of CSTD. The studies used different methods of calculating the costs, and the results were not reported in a format that could be pooled via meta-analysis. There is significant variability between the studies in terms of whether CSTD resulted in cost savings (the point estimates of the average potential cost savings ranged from (2017) USD −642,656 to (2017) USD 221,818). The healthcare professionals in the studies that provide data were mostly pharmacists or pharmacy technicians. Therefore, the evidence is mainly applicable to pharmacists and pharmacy technicians. Most of the studies that provide information for this review evaluated the use of PhaSeal; therefore the findings are mostly applicable to PhaSeal. Currently, no firm conclusions can be drawn on the effect of CSTD combined with safe handling versus safe handling alone due to very low certainty evidence available for the main outcomes. Multicentre randomised controlled trials may be feasible depending upon the proportion of people with exposure. The next best study design is interrupted time-series. Future studies should evaluate exposure to a relevant selection of hazardous drugs used in the hospital, and they should measure direct short-term health outcomes.
Four trials (1646 women) were included. The method of randomisation was unclear in all four trials and allocation concealment was reported in only one trial. Two trials used blinding of participants and outcomes. Vitamin B6 as oral capsules or lozenges resulted in decreased risk of dental decay in pregnant women (capsules: risk ratio (RR) 0.84; 95% confidence interval (CI) 0.71 to 0.98; one trial, n = 371, low quality of evidence; lozenges: RR 0.68; 95% CI 0.56 to 0.83; one trial, n = 342, low quality of evidence). A small trial showed reduced mean birthweights with vitamin B6 supplementation (mean difference -0.23 kg; 95% CI -0.42 to -0.04; n = 33; one trial). We did not find any statistically significant differences in the risk of eclampsia (capsules: n = 1242; three trials; lozenges: n = 944; one trial), pre-eclampsia (capsules n = 1197; two trials, low quality of evidence; lozenges: n = 944; one trial, low-quality evidence) or low Apgar scores at one minute (oral pyridoxine: n = 45; one trial), between supplemented and non-supplemented groups. No differences were found in Apgar scores at five minutes, or breastmilk production between controls and women receiving oral (n = 24; one trial) or intramuscular (n = 24; one trial) loading doses of pyridoxine at labour. Overall, the risk of bias was judged as unclear. The quality of the evidence using GRADE was low for both pre-eclampsia and dental decay. The other primary outcomes, preterm birth before 37 weeks and low birthweight, were not reported in the included trials. There were few trials, reporting few clinical outcomes and mostly with unclear trial methodology and inadequate follow-up. There is not enough evidence to detect clinical benefits of vitamin B6 supplementation in pregnancy and/or labour other than one trial suggesting protection against dental decay. Future trials assessing this and other outcomes such as orofacial clefts, cardiovascular malformations, neurological development, preterm birth, pre-eclampsia and adverse events are required.
We included five RCTs (733 women) comparing exercise with no active treatment, exercise with yoga and exercise with HT. The evidence was of low quality: Limitations in study design were noted, along with inconsistency and imprecision. In the comparison of exercise versus no active treatment (three studies, n = 454 women), no evidence was found of a difference between groups in frequency or intensity of vasomotor symptoms (SMD -0.10, 95% CI -0.33 to 0.13, three RCTs, 454 women, I2 = 30%, low-quality evidence). Nor was any evidence found of a difference between groups in the frequency or intensity of vasomotor symptoms when exercise was compared with yoga (SMD -0.03, 95% CI -0.45 to 0.38, two studies, n = 279 women, I2 = 61%, low-quality evidence). It was not possible to include one of the trials in the meta-analyses; this trial compared three groups: exercise plus soy milk, soy milk only and control; results favoured exercise relative to the comparators, but study numbers were small. One trial compared exercise with HT, and the HT group reported significantly fewer flushes in 24 hours than the exercise group (mean difference 5.8, 95% CI 3.17 to 8.43, 14 participants). None of the trials found evidence of a difference between groups with respect to adverse effects, but data were very scanty. Evidence was insufficient to show whether exercise is an effective treatment for vasomotor menopausal symptoms. One small study suggested that HT is more effective than exercise. Evidence was insufficient to show the relative effectiveness of exercise when compared with HT or yoga.
Four trials, in which a total of 1800 infants participated, compared oral/topical non-absorbed antifungal prophylaxis (nystatin or miconazole) with placebo or no drug. These trials had various methodological weaknesses including quasi-randomisation, lack of allocation concealment, and lack of blinding of intervention and outcomes assessment. The incidence of invasive fungal infection was very high in the control groups of three of these trials. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection (typical risk ratio 0.20, 95% confidence interval 0.14 to 0.27; risk difference −0.18, −0.21 to −0.15) but substantial statistical heterogeneity was present. We did not find a statistically significant effect on mortality (typical risk ratio 0.87, 0.72 to 1.05; risk difference −0.03, −0.06 to 0.01). None of the trials assessed posthospital discharge outcomes. Three trials (N = 326) assessed the effect of oral/topical non-absorbed versus systemic antifungal prophylaxis. Meta-analyses did not find any statistically significant differences in the incidences of invasive fungal infection or all-cause mortality. The finding of a reduction in risk of invasive fungal infection in very low birth weight infants treated with oral/topical non-absorbed antifungal prophylaxis should be interpreted cautiously because of methodological weaknesses in the included trials. Further large randomised controlled trials in current neonatal practice settings are needed to resolve this uncertainty. These trials might compare oral/topical non-absorbed antifungal agents with placebo, with each other, or with systemic antifungal agents and should include an assessment of effect on long-term neurodevelopmental outcomes.
We included four trials with 271 patients undergoing open liver resections. The patients were randomised to ischaemic preconditioning (n = 135) and no ischaemic preconditioning (n = 136) prior to continuous vascular occlusion (portal triad clamping in three trials and hepatic vascular exclusion in one trial). All the trials excluded cirrhotic patients. We assessed all the four trials as having high risk of bias. There was no difference in mortality, liver failure, other peri-operative morbidity, hospital stay, intensive therapy unit stay, and operating time between the two groups. The proportion of patients requiring blood transfusion was lower in the ischaemic preconditioning group. There was also a trend towards a lower amount of red cell transfusion favouring ischaemic preconditioning group. There was no difference in the haemodynamic changes, blood loss, bilirubin, or prothrombin activity between the two groups. The enzyme markers of liver injury were lower in the ischaemic preconditioning group on the first post-operative day. Currently, there is no evidence to suggest a protective effect of ischaemic preconditioning in non-cirrhotic patients undergoing liver resection under continuous vascular occlusion. Ischaemic preconditioning reduces the blood transfusion requirements in patients undergoing liver resection.
The review includes a total of 42 trials, and 40 of these trials contributed data on 4240 participants. Twenty studies, involving 1918 women, compared clindamycin plus an aminoglycoside (gentamicin for all studies except for one that used tobramycin) with another regimen. When assessing the individual subgroups of other antibiotic regimens (i.e. cephalosporins, monobactams, penicillins, and quinolones), there were fewer treatment failures in those treated with clindamycin plus an aminoglycoside as compared to those treated with cephalosporins (RR 0.69, 95% CI 0.49 to 0.99; participants = 872; studies = 8; low quality evidence) or penicillins (RR 0.65, 95% CI 0.46 to 0.90; participants = 689; studies = 7, low quality evidence). For the remaining subgroups for the primary analysis, the differences were not significant. There were significantly fewer wound infections in those treated with clindamycin plus aminoglycoside versus cephalosporins (RR 0.53, 95% CI 0.30 to 0.93; participants = 500; studies = 4; low quality evidence). Similarly, there were more treatment failures in those treated with an gentamicin/penicillin when compared to those treated with gentamIcin/clindamycin (RR 2.57, 95% CI 1.48 to 4.46; participants = 200; studies = 1). There were fewer treatment failures when an agent with a longer half-life that is administered less frequently was used (RR 0.61, 95% CI 0.40 to 0.92; participants = 484; studies = 2) as compared to using cefoxitin. There were more treatment failures (RR 1.94, 95% CI 1.38 to 2.72; participants = 774; studies = 7) and wound infections (RR 1.88, 95% CI 1.17 to 3.02; participants = 740; studies = 6) in those treated with a regimen with poor activity against penicillin-resistant anaerobic bacteria as compared to those treated with a regimen with good activity against penicillin-resistant anaerobic bacteria. Once-daily dosing was associated with a shorter length of hospital stay (MD -0.73, 95% CI -1.27 to -0.20; participants = 322; studies = 3). There were no differences between groups with respect to severe complications and no trials reported any maternal deaths. Regarding the secondary outcomes, three studies that compared continued oral antibiotic therapy after intravenous therapy with no oral therapy, found no differences in recurrent endometritis or other outcomes. There were no differences between groups for the outcomes of allergic reactions. The overall risk of bias was unclear in the most of the studies. The quality of the evidence using GRADE comparing clindamycin and an aminoglycoside with another regimen (compared with cephalosporins or penicillins) was low to very low for therapeutic failure, severe complications, wound infection and allergic reaction. The combination of clindamycin and gentamicin is appropriate for the treatment of endometritis. Regimens with good activity against penicillin-resistant anaerobic bacteria are better than those with poor activity against penicillin-resistant anaerobic bacteria. There is no evidence that any one regimen is associated with fewer side-effects. Following clinical improvement of uncomplicated endometritis which has been treated with intravenous therapy, the use of additional oral therapy has not been proven to be beneficial.
We included two studies, with a total of 64 randomised participants (50 and 14 participants) aged 18 years or over, with a perianal abscess. In both studies, participants were enrolled on the first post-operative day and randomised to continued packing by community district nursing teams or to no packing. Participants in the non-packing group managed their own wounds in the community and used absorbant dressings to cover the area. Fortnightly follow-up was undertaken until the cavity closed and the skin re-epithelialised, which constituted healing. For non-attenders, telephone follow-up was conducted. Both studies were at high risk of bias due to risk of attrition, performance and detection bias. It was not possible to pool the two studies for the outcome of time to healing. It is unclear whether continued post-operative packing of the cavity of perianal abscesses affects time to complete healing. One study reported a mean time to wound healing of 26.8 days (95% confidence interval (CI) 22.7 to 30.7) in the packing group and 19.5 days (95% CI 13.6 to 25.4) in the non-packing group (it was not clear if all participants healed). We re-analysed the data and found no clear difference in the time to healing (7.30 days longer in the packing group, 95% CI -2.24 to 16.84; 14 participants). This was assessed as very low quality evidence (downgraded three levels for very serious imprecision and serious risk of bias). The second study reported a median time to complete wound healing of 24.5 days (range 10 to 150 days) in the packing group and 21 days (range 8 to 90 days) in the non-packed group. There was insufficient information to be able to recreate the analysis and the original analysis was inappropriate (did not account for censoring). This second study also provided very low quality evidence (downgraded four levels for serious risk of bias, serious indirectness and very serious imprecision). There was very low quality evidence (downgraded for risk of bias, indirectness and imprecision) of no difference in wound pain scores at the initial dressing change. Both studies also reported patients' retrospective judgement of wound pain over the preceding two weeks (visual analogue scale, VAS) as lower for the non-packed group (2; both studies) compared with the packed group (0; both studies); (very low quality evidence) but we have been unable to reproduce these analyses as no variance data were published. There was no clear evidence of a difference in the number of post-operative fistulae detected between the packed and non-packed groups (risk ratio (RR) 2.31, 95% CIs 0.56 to 9.45, I2 = 0%) (very low quality evidence downgraded three levels for very serious imprecision and serious risk of bias). There was no clear evidence of a difference in the number of abscess recurrences between the packed and non-packed groups over the variable follow-up periods (RR 0.72, 95% CI 0.22 to 2.37, I2 = 0%) (very low quality evidence downgraded three levels for serious risk of bias and very serious imprecision). No study reported participant health-related quality of life/health status, incontinence rates, time to return to work or normal function, resource use in terms of number of dressing changes or visits to a nurse, or change in wound size. It is unclear whether using internal dressings (packing) for the healing of perianal abscess cavities influences time to healing, wound pain, development of fistulae, abscess recurrence or other outcomes. Despite this absence of evidence, the practice of packing abscess cavities is commonplace. Given the lack of high quality evidence, decisions to pack may be based on local practices or patient preferences. Further clinical research is needed to assess the effects and patient experience of packing.
Three small studies evaluating 154 infants were included in this review. One study reported a significant reduction in the risk of hyperbilirubinaemia and rate of treatment with phototherapy associated with enteral supplementation with prebiotics (risk ratio (RR) 0.75, 95% confidence interval (95% CI) 0.58 to 0.97; one study, 50 infants; low-quality evidence). Meta-analyses of two studies showed no significant difference in maximum plasma unconjugated bilirubin levels in infants with prebiotic supplementation (mean difference (MD) 0.14 mg/dL, 95% CI -0.91 to 1.20, I² = 81%, P = 0.79; two studies, 78 infants; low-quality evidence). There was no evidence of a significant difference in duration of phototherapy between the prebiotic and control groups, which was only reported by one study (MD 0.10 days, 95% CI -2.00 to 2.20; one study, 50 infants; low-quality evidence). The meta-analyses of two studies demonstrated a significant reduction in the length of hospital stay (MD -10.57 days, 95% CI -17.81 to -3.33; 2 studies, 78 infants; I² = 0%, P = 0.004; low-quality evidence). Meta-analysis of the three studies showed a significant increase in stool frequency in the prebiotic groups (MD 1.18, 95% CI 0.90 to 1.46, I² = 90%; 3 studies, 154 infants; high-quality evidence). No significant difference in mortality during hospital stay after enteral supplementation with prebiotics was reported (typical RR 0.94, 95% CI 0.14 to 6.19; I² = 6%, P = 0.95; 2 studies; 78 infants; low-quality evidence). There were no reports of the need for exchange transfusion and incidence of acute bilirubin encephalopathy, chronic bilirubin encephalopathy, and major neurodevelopmental disability in the included studies. None of the included studies reported any side effects. Current studies are unable to provide reliable evidence about the effectiveness of prebiotics on hyperbilirubinaemia. Additional large, well-designed RCTs should be undertaken in neonates that compare effects of enteral supplementation with prebiotics on neonatal hyperbilirubinaemia with supplementation of milk with any other placebo (particularly distilled water) or no supplementation.
Two trials with a total of 78 participants met the inclusion criteria. Both the populations and the 'standard' treatments differed in the two studies. Oral steroids as an adjunct to intranasal corticosteroids One trial in adults with nasal polyps included 30 participants. All participants used intranasal corticosteroids and were randomised to either short-course oral steroids (oral methylprednisolone, 1 mg/kg and reduced progressively over a 21-day treatment course) or no additional treatment. None of the primary outcome measures of interest in this review were reported by the study. There may have been an important reduction in the size of the polyps (measured by the nasal polyps score, a secondary outcome measure) in patients receiving oral steroids and intranasal corticosteroids, compared to intranasal corticosteroids alone (mean difference (MD) -0.46, 95% confidence interval (CI) -0.87 to -0.05; 30 participants; scale 1 to 4) at the end of treatment (21 days). This corresponds to a large effect size, but we are very uncertain about this estimate as we judged the study to be at high risk of bias. Moreover, longer-term data were not available and the other outcomes of interest were not reported. Oral steroids as an adjunct to antibiotics One trial in children (mean age of eight years) without nasal polyps included 48 participants. The trial compared oral corticosteroids (oral methylprednisolone, 1 mg/kg and reduced progressively over a 15-day treatment course) with placebo in participants who also received a 30-day course of antibiotics. This study addressed one of the primary outcome measures (disease severity) and one secondary outcome (CT score). For disease severity  the four key symptoms used to define chronic rhinosinusitis in children (nasal blockage, nasal discharge, facial pressure, cough) were combined into one score. There was a greater improvement in symptom severity 30 days after the start of treatment in patients who received oral steroids and antibiotics compared with placebo and antibiotics (MD -7.10, 95% CI -9.59 to -4.61; 45 participants; scale 0 to 40). The observed mean difference corresponds to a large effect size. At the same time point there was a difference in CT scan score (MD -2.90, 95% CI -4.91 to -0.89; 45 participants; scale 0 to 24). We assessed the quality of the evidence to be low. There were no data available for the longer term (three months). There might be an improvement in symptom severity, polyps size and condition of the sinuses when assessed using CT scans in patients taking oral corticosteroids when these are used as an adjunct therapy to antibiotics or intranasal corticosteroids, but the quality of the evidence supporting this is low orvery low (we are uncertain about the effect estimate; the true effect may be substantially different from the estimate of the effect). It is unclear whether the benefits of oral corticosteroids as an adjunct therapy are sustained beyond the short follow-up period reported (up to 30 days), as no longer-term data were available. There were no data in this review about the adverse effects associated with short courses of oral corticosteroids as an adjunct therapy. More research in this area, particularly research evaluating longer-term outcomes and adverse effects, is required.
We included three trials involving a total of 209 participants. The studies were at moderate to high risk of bias. All included studies had differences in participant selection criteria, length of follow-up and outcome measurement, precluding a meta-analysis. The participants were all adults over 18 years with subjective tinnitus, but one study conducted in 2013 (n = 109) included only elderly patients. Improvement in tinnitus severity and disability Only the study in elderly patients used a validated instrument (Tinnitus Handicap Questionnaire) for this primary outcome. The authors of this cross-over study did not report the results of the two phases separately and found no significant differences in the proportion of patients reporting tinnitus improvement at four months of follow-up: 5% (5/93) versus 2% (2/94) in the zinc and placebo groups, respectively (risk ratio (RR) 2.53, 95% confidence interval (CI) 0.50 to 12.70; very low-quality evidence). None of the included studies reported any significant adverse effects. Secondary outcomes For the secondary outcome change in tinnitus loudness, one study reported no significant difference between the zinc and placebo groups after eight weeks: mean difference in tinnitus loudness -9.71 dB (95% CI -25.53 to 6.11; very low-quality evidence). Another study also measured tinnitus loudness but used a 0- to 100-point scale. The authors of this second study reported no significant difference between the zinc and placebo groups after four months: mean difference in tinnitus loudness rating scores 0.50 (95% CI -5.08 to 6.08; very low-quality evidence). Two studies used unvalidated instruments to assess tinnitus severity. One (with 50 participants) reported the severity of tinnitus using a non-validated scale (0 to 7 points) and found no significant difference in subjective tinnitus scores between the zinc and placebo groups at the end of eight weeks of follow-up (mean difference (MD) -1.41, 95% CI -2.97 to 0.15; very low-quality evidence). A third trial (n = 50) also evaluated the improvement of tinnitus using a non-validated instrument (a 0 to 10 scale: 10 = severe and unbearable tinnitus). In this study, after eight weeks there was no difference in the proportion of patients with improvement in their tinnitus, 8.7% (2/23) treated with zinc versus 8% (2/25) of those who received a placebo (RR 1.09, 95% CI 0.17 to 7.10, very low-quality evidence). None of the included studies reported any of our other secondary outcomes (quality of life, change in socioeconomic impact associated with work, change in anxiety and depression disorders, change in psychoacoustic parameters or change in thresholds on pure tone audiometry). We found no evidence that the use of oral zinc supplementation improves symptoms in adults with tinnitus.
A total of 75 trials were included. Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 38% (RR 0.62; 95% CI 0.55 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 21% (95% CI 15% to 26%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.46 (95% CI 0.37 to 0.57) compared to 0.77 (95% CI 0.69 to 0.86) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.68 units of allogeneic RBC per patient (WMD -0.68; 95% CI -0.88 to -0.49). Cell salvage did not appear to impact adversely on clinical outcomes. The results suggest cell salvage is efficacious in reducing the need for allogeneic red cell transfusion in adult elective cardiac and orthopaedic surgery. The use of cell salvage did not appear to impact adversely on clinical outcomes. However, the methodological quality of trials was poor. As the trials were unblinded and lacked adequate concealment of treatment allocation, transfusion practices may have been influenced by knowledge of the patients' treatment status potentially biasing the results in favour of cell salvage.
Fifty-one studies met our inclusion criteria, involving approximately 800,000 participants. The studies included were diverse, including observational studies, between- and within-participant experimental studies, cohort and cross-sectional studies, and time-series analyses. Few studies assessed behavioural outcomes in youth and non-smokers. Five studies assessed the primary outcomes: one observational study assessed smoking prevalence among 700,000 participants until one year after standardised packaging in Australia; four studies assessed consumption in 9394 participants, including a series of Australian national cross-sectional surveys of 8811 current smokers, in addition to three smaller studies. No studies assessed uptake, cessation, or relapse prevention. Two studies assessed quit attempts. Twenty studies examined other behavioural outcomes and 45 studies examined non-behavioural outcomes (e.g. appeal, perceptions of harm). In line with the challenges inherent in evaluating standardised tobacco packaging, a number of methodological imitations were apparent in the included studies and overall we judged most studies to be at high or unclear risk of bias in at least one domain. The one included study assessing the impact of standardised tobacco packaging on smoking prevalence in Australia found a 3.7% reduction in odds when comparing before to after the packaging change, or a 0.5 percentage point drop in smoking prevalence, when adjusting for confounders. Confidence in this finding is limited, due to the nature of the evidence available, and is therefore rated low by GRADE standards. Findings were mixed amongst the four studies assessing consumption, with some studies finding no difference and some studies finding evidence of a decrease; certainty in this outcome was rated very low by GRADE standards due to the limitations in study design. One national study of Australian adult smoker cohorts (5441 participants) found that quit attempts increased from 20.2% prior to the introduction of standardised packaging to 26.6% one year post-implementation. A second study of calls to quitlines provides indirect support for this finding, with a 78% increase observed in the number of calls after the implementation of standardised packaging. Here again, certainty is low. Studies of other behavioural outcomes found evidence of increased avoidance behaviours when using standardised packs, reduced demand for standardised packs and reduced craving. Evidence from studies measuring eye-tracking showed increased visual attention to health warnings on standardised compared to branded packs. Corroborative evidence for the latter finding came from studies assessing non-behavioural outcomes, which in general found greater warning salience when viewing standardised, than branded packs. There was mixed evidence for quitting cognitions, whereas findings with youth generally pointed towards standardised packs being less likely to motivate smoking initiation than branded packs. We found the most consistent evidence for appeal, with standardised packs rating lower than branded packs. Tobacco in standardised packs was also generally perceived as worse-tasting and lower quality than tobacco in branded packs. Standardised packaging also appeared to reduce misperceptions that some cigarettes are less harmful than others, but only when dark colours were used for the uniform colour of the pack. The available evidence suggests that standardised packaging may reduce smoking prevalence. Only one country had implemented standardised packaging at the time of this review, so evidence comes from one large observational study that provides evidence for this effect. A reduction in smoking behaviour is supported by routinely collected data by the Australian government. Data on the effects of standardised packaging on non-behavioural outcomes (e.g. appeal) are clearer and provide plausible mechanisms of effect consistent with the observed decline in prevalence. As standardised packaging is implemented in different countries, research programmes should be initiated to capture long term effects on tobacco use prevalence, behaviour, and uptake. We did not find any evidence suggesting standardised packaging may increase tobacco use.
Four studies involving 971 participants were included. All results were reported using a zero to 10 pain scale. Three studies (four treatment arms) involving 498 participants compared subcutaneous lignocaine with control with no significant difference between pain scores; MD 0.12 (95% confidence interval (CI) -0.46 to 0.69). Two studies (three treatment arms) involving 399 participants compared intravenous pain regimens with control. A significant reduction in pain score was observed with intravenous opioid and anxiolytic; MD -0.90 (95% CI -1.54 to -0.27). One study involving 60 participants compared levobupivacaine with placebo. Longer-acting local anaesthetic significantly lowered the pain score by a MD of -1.10 (95% CI -1.26 to -0.94). The data are insufficient to identify any influence of pain regimens on vascular and procedural complication rates. No studies reported appropriate blinding for all treatment arms. The largest study, comprising 661 participants, was unblinded with a quality score of two out of five. No new studies have been found since the last version of this review and the conclusions therefore remain the same. Intravenous pain regimens and levobupivacaine may have greater efficacy when compared to control for the management of pain related to femoral sheath removal. However, a definitive study is still required because the clinical difference is small. There is no evidence to support the use of subcutaneous lignocaine. There is insufficient evidence to determine if pain relief influences the rate of complications. One new study has been included as a 'study awaiting assessment' as we await further information from the study authors.
Only one quasi-randomized controlled study with 121 study participants comparing two types of IPC devices met the inclusion criteria. The authors found no cases of symptomatic DVT or PE in either the calf-thigh compression group or the plantar compression group during the first three weeks after the THR. The calf-thigh pneumatic compression was more effective than plantar compression for reducing thigh swelling during the early postoperative stage. The strength of the evidence in this review is weak as only one trial was included and it was classified as having a high risk of bias. There is a lack of evidence from randomized controlled trials to make an informed choice of IPC device for preventing venous thromboembolism (VTE) following total hip replacement. More research is urgently required, ideally a multicenter, properly designed RCT including a sufficient number of participants. Clinically relevant outcomes such as mortality, imaging-diagnosed asymptomatic VTE and major complications must be considered.
No additional studies were included or excluded in the updated review. Twenty papers detailing 18 trials were considered. Only three trials were randomised controlled trials and were included in the review. The remaining fifteen studies were excluded for various reasons. All three included trials had a small sample size and reported the trial design, outcome measures and analysis poorly. There were also variations in the outcome measures used between the trials. In addition, there was no consistency on the reporting of mean and medians for blood loss during the operation. It was therefore not possible to pool the data to perform meta-analysis. However, the reported blood loss when using a tourniquet was between 0 and 16 ml compared to between 107 to 133 ml when not using a tourniquet (P < 0.01). Although there were significant quality issues with the available evidence, the use of a tourniquet would appear to reduce blood loss during surgery. There were no reported differences between the use or non-use of a tourniquet in terms of complications and morbidity. However, the available trials were not of sufficient size to detect rarer complications such as nerve damage.
One hundred and twenty one trials with 6700 participants were included. In most trials, PRT was performed two to three times per week and at a high intensity. PRT resulted in a small but significant improvement in physical ability (33 trials, 2172 participants; SMD 0.14, 95% CI 0.05 to 0.22). Functional limitation measures also showed improvements: e.g. there was a modest improvement in gait speed (24 trials, 1179 participants, MD 0.08 m/s, 95% CI 0.04 to 0.12); and a moderate to large effect for getting out of a chair (11 trials, 384 participants, SMD -0.94, 95% CI -1.49 to -0.38). PRT had a large positive effect on muscle strength (73 trials, 3059 participants, SMD 0.84, 95% CI 0.67 to 1.00). Participants with osteoarthritis reported a reduction in pain following PRT(6 trials, 503 participants, SMD -0.30, 95% CI -0.48 to -0.13). There was no evidence from 10 other trials (587 participants) that PRT had an effect on bodily pain. Adverse events were poorly recorded but adverse events related to musculoskeletal complaints, such as joint pain and muscle soreness, were reported in many of the studies that prospectively defined and monitored these events. Serious adverse events were rare, and no serious events were reported to be directly related to the exercise programme. This review provides evidence that PRT is an effective intervention for improving physical functioning in older people, including improving strength and the performance of some simple and complex activities. However, some caution is needed with transferring these exercises for use with clinical populations because adverse events are not adequately reported.
Twenty-three trials with a total of 1821 children and young people were included. Generally, the trials were small, and only one was assessed to have a low risk of bias. Thirteen trials compared exercise alone with no intervention. Eight were included in the meta-analysis, and overall the results were heteregeneous. One study with a low risk of bias showed a standardised mean difference (SMD) of 1.33 (95% CI 0.43 to 2.23), while the SMD's for the three studies with a moderate risk of bias and the four studies with a high risk of bias was 0.21 (95% CI -0.17 to 0.59) and 0.57 (95% CI 0.11 to 1.04), respectively. Twelve trials compared exercise as part of a comprehensive programme with no intervention. Only four provided data sufficient to calculate overall effects, and the results indicate a moderate short-term difference in self-esteem in favour of the intervention [SMD 0.51 (95% CI 0.15 to 0.88)]. The results indicate that exercise has positive short-term effects on self-esteem in children and young people. Since there are no known negative effects of exercise and many positive effects on physical health, exercise may be an important measure in improving children's self-esteem.  These conclusions are based on several small low-quality trials.
We found no RCTs comparing pre-admission antibiotics versus no pre-admission antibiotics or placebo. We included one open-label, non-inferiority RCT with 510 participants, conducted during an epidemic in Niger, evaluating a single dose of intramuscular ceftriaxone versus a single dose of intramuscular long-acting (oily) chloramphenicol. Ceftriaxone was not inferior to chloramphenicol in reducing mortality (RR 1.21, 95% CI 0.57 to 2.56; N = 503; 308 confirmed meningococcal meningitis; 26 deaths; moderate-quality evidence), clinical failures (RR 0.83, 95% CI 0.32 to 2.15; N = 477; 18 clinical failures; moderate-quality evidence), or neurological sequelae (RR 1.29, 95% CI 0.63 to 2.62; N = 477; 29 with sequelae; low-quality evidence). No adverse effects of treatment were reported. Estimated treatment costs were similar. No data were available on disease burden due to sequelae. We found no reliable evidence to support the use pre-admission antibiotics for suspected cases of non-severe meningococcal disease. Moderate-quality evidence from one RCT indicated that single intramuscular injections of ceftriaxone and long-acting chloramphenicol were equally effective, safe, and economical in reducing serious outcomes. The choice between these antibiotics should be based on affordability, availability, and patterns of antibiotic resistance. Further RCTs comparing different pre-admission antibiotics, accompanied by intensive supportive measures, are ethically justified in people with less severe illness, and are needed to provide reliable evidence in different clinical settings.
We included seven studies, which involved 723 participants. We assessed four of the seven studies as being at high risk of bias and three had an unclear risk of bias; the quality of the evidence was difficult to assess as there was often insufficient detail reported to enable any conclusions to be drawn about the methodological rigour of the studies. Four trials involving 285 participants measured cognitive development and we synthesised these data in a meta-analysis. Compared to the control group, there was no statistically significant impact of the intervention on cognitive development (standardised mean difference (SMD) 0.30; 95% confidence interval -0.18 to 0.78). Only three studies reported socioemotional outcomes and there was insufficient data to combine into a meta-analysis. No study reported on adverse effects. This review does not provide evidence of the effectiveness of home-based interventions that are specifically targeted at improving developmental outcomes for preschool children from socially disadvantaged families. Future studies should endeavour to better document and report their methodological processes.
Nine studies, including data of 1228 women, were included in the review evaluating the effect of either LMWH (enoxaparin or nadroparin in varying doses) or aspirin or a combination of both, on the chance of live birth in women with recurrent miscarriage, with or without inherited thrombophilia. Studies were heterogeneous with regard to study design and treatment regimen and three studies were considered to be at high risk of bias. Two of these three studies at high risk of bias showed a benefit of one treatment over the other, but in sensitivity analyses (in which studies at high risk of bias were excluded) anticoagulants did not have a beneficial effect on live birth, regardless of which anticoagulant was evaluated (risk ratio (RR) for live birth in women who received aspirin compared to placebo 0.94, (95% confidence interval (CI) 0.80 to 1.11, n = 256), in women who received LMWH compared to aspirin RR 1.08 (95% CI 0.93 to 1.26, n = 239), and in women who received LMWH and aspirin compared to no-treatment RR 1.01 (95% CI 0.87 to 1.16) n = 322). Obstetric complications such as preterm delivery, pre-eclampsia, intrauterine growth restriction and congenital malformations were not significantly affected by any treatment regimen. In included studies, aspirin did not increase the risk of bleeding, but treatment with LWMH and aspirin increased the risk of bleeding significantly in one study. Local skin reactions (pain, itching, swelling) to injection of LMWH were reported in almost 40% of patients in the same study. There is a limited number of studies on the efficacy and safety of aspirin and heparin in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia. Of the nine reviewed studies quality varied, different treatments were studied and of the studies at low risk of bias only one was placebo-controlled. No beneficial effect of anticoagulants in studies at low risk of bias was found. Therefore, this review does not support the use of anticoagulants in women with unexplained recurrent miscarriage. The effect of anticoagulants in women with unexplained recurrent miscarriage and inherited thrombophilia needs to be assessed in further randomised controlled trials; at present there is no evidence of a beneficial effect.
Twenty-six trials fulfilled the inclusion criteria of the review. All the 26 trials except one trial of 30 participants were at high risk of bias. Nineteen of the trials with 1263 randomised participants provided data for this review. Ten of the 19 trials compared local anaesthetic wound infiltration versus inactive control. One of the 19 trials compared local anaesthetic wound infiltration with two inactive controls, normal saline and no intervention. Two of the 19 trials had four arms comparing local anaesthetic wound infiltration with inactive controls in the presence and absence of co-interventions to decrease pain after laparoscopic cholecystectomy. Four of the 19 trials had three or more arms that could be included for the comparison of local anaesthetic wound infiltration versus inactive control and different methods of local anaesthetic wound infiltration. The remaining two trials compared different methods of local anaesthetic wound infiltration. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Seventeen trials randomised a total of 1095 participants to local anaesthetic wound infiltration (587 participants) versus no local anaesthetic wound infiltration (508 participants). Various anaesthetic agents were used but bupivacaine was the commonest local anaesthetic used. There was no mortality in either group in the seven trials that reported mortality (0/280 (0%) in local anaesthetic infiltration group versus 0/259 (0%) in control group). The effect of local anaesthetic on the proportion of people who developed serious adverse events was imprecise and compatible with increase or no difference in serious adverse events (seven trials; 539 participants; 2/280 (0.8%) in local anaesthetic group versus 1/259 (0.4%) in control; RR 2.00; 95% CI 0.19 to 21.59; very low quality evidence). None of the serious adverse events were related to local anaesthetic wound infiltration. None of the trials reported patient quality of life. The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic infiltration group than in the no local anaesthetic infiltration group (one trial; 97 participants; 33/50 (66.0%) in the local anaesthetic group versus 20/47 (42.6%) in the control group; RR 1.55; 95% CI 1.05 to 2.28; very low quality evidence). The effect of local anaesthetic on the length of hospital stay was compatible with a decrease, increase, or no difference in the length of hospital stay between the two groups (four trials; 327 participants; MD -0.26 days; 95% CI -0.67 to 0.16; very low quality evidence). The pain scores as measured by the visual analogue scale (0 to 10 cm) were lower in the local anaesthetic infiltration group than the control group at 4 to 8 hours (13 trials; 806 participants; MD -1.33 cm on the VAS; 95% CI -1.54 to -1.12; very low quality evidence) and 9 to 24 hours (12 trials; 756 participants; MD -0.36 cm on the VAS; 95% CI -0.53 to -0.20; very low quality evidence). The effect of local anaesthetic on the time taken to return to normal activity between the two groups was imprecise and compatible with a decrease, increase, or no difference in the time taken to return to normal activity (two trials; 195 participants; MD 0.14 days; 95% CI -0.59 to 0.87; very low quality evidence). None of the trials reported on return to work. Four trials randomised a total of 149 participants to local anaesthetic wound infiltration prior to skin incision (74 participants) versus local anaesthetic wound infiltration at the end of surgery (75 participants). Two trials randomised a total of 176 participants to four different local anaesthetics (bupivacaine, levobupivacaine, ropivacaine, neosaxitoxin). Although there were differences between the groups in some outcomes the changes were not consistent. There was no evidence to support the preference of one local anaesthetic over another or to prefer administration of local anaesthetic at a specific time compared with another. Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration (very low quality evidence). There is very low quality evidence that infiltration reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small. Further randomised clinical trials at low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.
Eight studies (225 participants) were included. In general, children included in the studies were young (average age less than two years in the majority of included studies). Severity of croup was described as moderate to severe in all included studies. Six studies took place in the inpatient setting, one in the ED and one setting was not specified. Six of the eight studies were deemed to have a low risk of bias and the risk of bias was unclear in the remaining two studies. Nebulized epinephrine was associated with croup score improvement 30 minutes post-treatment (three RCTs, standardized mean difference (SMD) -0.94; 95% confidence interval (CI) -1.37 to -0.51; I2 statistic = 0%). This effect was not significant two and six hours post-treatment. Nebulized epinephrine was associated with significantly shorter hospital stay than placebo (one RCT, MD -32.0 hours; 95% CI -59.1 to -4.9). Comparing racemic and L-epinephrine, no difference in croup score was found after 30 minutes (SMD 0.33; 95% CI -0.42 to 1.08). After two hours, L-epinephrine showed significant reduction compared with racemic epinephrine (one RCT, SMD 0.87; 95% CI 0.09 to 1.65). There was no significant difference in croup score between administration of nebulized epinephrine via IPPB versus nebulization alone at 30 minutes (one RCT, SMD -0.14; 95% CI -1.24 to 0.95) or two hours (SMD -0.72; 95% CI -1.86 to 0.42). None of the studies sought or reported data on adverse effects. Nebulized epinephrine is associated with clinically and statistically significant transient reduction of symptoms of croup 30 minutes post-treatment. Evidence does not favor racemic epinephrine or L-epinephrine, or IPPB over simple nebulization. The authors note that data and analyses were limited by the small number of relevant studies and total number of participants and thus most outcomes contained data from very few or even single studies.
This review included five studies (with a total of 303 to 305 participants) comparing the effects of betahistine with placebo in adults with subjective idiopathic tinnitus. Four studies were parallel-group RCTs and one had a cross-over design. The risk of bias was unclear in all of the included studies. Due to heterogeneity in the outcomes measured and measurement methods used, very limited data pooling was possible. When we pooled the data from two studies for the primary outcome tinnitus loudness, the mean difference on a 0- to 10-point visual analogue scale at one-month follow-up was not significant between betahistine and placebo (-0.16, 95% confidence interval (CI) -1.01 to 0.70; 81 participants) (very low-quality evidence). There were no reports of upper gastrointestinal discomfort (significant adverse effect) in any study. As a secondary outcome, one study found no difference in the change in the Tinnitus Severity Index between betahistine and placebo (mean difference at 12 weeks 0.02, 95% CI -1.05 to 1.09; 50 participants) (moderate-quality evidence). None of the studies reported the other secondary outcomes of changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health-related quality of life as measured by a validated instrument, nor tinnitus intrusiveness. Other adverse effects that were reported were not treatment-related. There is an absence of evidence to suggest that betahistine has an effect on subjective idiopathic tinnitus when compared to placebo. The evidence suggests that betahistine is generally well tolerated with a similar risk of adverse effects to placebo treatments. The quality of evidence for the reported outcomes, using GRADE, ranged from moderate to very low. If future research into the effectiveness of betahistine in patients with tinnitus is felt to be warranted, it should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the development of validated, patient-centred outcome measures for research in the field of tinnitus.
Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta-analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease-free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between-study heterogeneity (disease-free survival: I² statistic = 16%, Q-test P value = 0.27; overall survival: I² statistic = 6%; Q-test P value = 0.38). Considering that the 5-year overall survival rate for TNM stage II–III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment. Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no-one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation. The results of this meta-analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high-risk (AJCC TNM stage II-III) cutaneous melanoma in terms of both disease-free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.
We included 73 RCTs, with 12,212 participants, comparing GnRH antagonist to long-course GnRH agonist protocols. The quality of the evidence was moderate: limitations were poor reporting of study methods. Live birth There was no evidence of a difference in live birth rate between GnRH antagonist and long course GnRH agonist (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2303, I2= 27%, moderate quality evidence). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%. OHSS GnRH antagonist was associated with lower incidence of any grade of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n = 7944, I2 = 31%, moderate quality evidence). The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%. Other adverse effects There was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.03, 95% CI 0.82 to 1.29; 34 RCTs, n = 7082, I2 = 0%, moderate quality evidence). With respect to cycle cancellation, GnRH antagonist was associated with a lower incidence of cycle cancellation due to high risk of OHSS (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4256, I2 = 0%). However cycle cancellation due to poor ovarian response was higher in women who received GnRH antagonist than those who were treated with GnRH agonist (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5230, I2 = 68%; moderate quality evidence). There is moderate quality evidence that the use of GnRH antagonist compared with long-course GnRH agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth.
We included 15 studies with 498 participants. Ten studies compared physical activity to minimal dietary and behavioural intervention or no intervention. Five studies compared combined dietary, exercise and behavioural intervention to minimal intervention. One study compared behavioural intervention to minimal intervention. Risk of bias varied: eight studies had adequate sequence generation, seven had adequate clinician or outcome assessor blinding, seven had adequate allocation concealment, six had complete outcome data and six were free of selective reporting. No studies assessed the fertility primary outcomes of live birth or miscarriage. No studies reported the secondary reproductive outcome of menstrual regularity, as defined in this review. Lifestyle intervention may improve a secondary (endocrine) reproductive outcome, the free androgen index (FAI) (MD -1.11, 95% confidence interval (CI) -1.96 to -0.26, 6 RCTs, N = 204, I2 = 71%, low-quality evidence). Lifestyle intervention may reduce weight (kg) (MD -1.68 kg, 95% CI -2.66 to -0.70, 9 RCTs, N = 353, I2 = 47%, low-quality evidence). Lifestyle intervention may reduce body mass index (BMI) (kg/m2) (-0.34 kg/m2, 95% CI -0.68 to -0.01, 12 RCTs, N = 434, I2= 0%, low-quality evidence). We are uncertain of the effect of lifestyle intervention on glucose tolerance (glucose outcomes in oral glucose tolerance test) (mmol/L/minute) (SMD -0.02, 95% CI -0.38 to 0.33, 3 RCTs, N = 121, I2 = 0%, low-quality evidence). Lifestyle intervention may improve the free androgen index (FAI), weight and BMI in women with PCOS. We are uncertain of the effect of lifestyle intervention on glucose tolerance. There were no studies that looked at the effect of lifestyle intervention on live birth, miscarriage or menstrual regularity. Most studies in this review were of low quality mainly due to high or unclear risk of bias across most domains and high heterogeneity for the FAI outcome.
We included 10 trials, with a total of 422 participants, that addressed two of the outcomes of interest to this review: swelling (oedema) and bruising (ecchymosis). Nine studies on rhinoplasty used a variety of different types, and doses, of corticosteroids. Overall, the results of the included studies showed that there is some evidence that perioperative administration of corticosteroids decreases formation of oedema over the first two postoperative days. Meta-analysis was only possible for two studies, with a total of 60 participants, and showed that a single perioperative dose of 10 mg dexamethasone decreased oedema formation in the first two days after surgery (SMD = -1.16, 95% CI: -1.71 to -0.61, low quality evidence). The evidence for ecchymosis was less consistent across the studies, with some contradictory results, but overall there was some evidence that perioperatively administered corticosteroids decreased ecchymosis formation over the first two days after surgery (SMD = -1.06, 95% CI:-1.47 to -0.65, two studies, 60 participants, low quality evidence ). The difference was not maintained after this initial period. One study, with 40 participants, showed that high doses of methylprednisolone (over 250 mg) decreased both ecchymosis and oedema between the first and seventh postoperative days. The only study that assessed facelift surgery identified no positive effect on oedema with preoperative administration of corticosteroids. Five trials did not report on harmful (adverse) effects; four trials reported that there were no adverse effects; and one trial reported adverse effects in two participants treated with corticosteroids as well as in four participants treated with placebo. None of the studies reported recovery time, patient satisfaction or quality of life. The studies included were all at an unclear risk of selection bias and at low risk of bias for other domains. There is limited evidence for rhinoplasty that a single perioperative dose of corticosteroids decreases oedema and ecchymosis formation over the first two postoperative days, but the difference is not maintained after this period. There is also limited evidence that high doses of corticosteroids decrease both ecchymosis and oedema between the first and seventh postoperative days. The clinical significance of this decrease is unknown and there is little evidence available regarding the safety of this intervention. More studies are needed because at present the available evidence does not support the use of corticosteroids for prevention of complications following facial plastic surgery.
We found17 studies involving 3212 patients. The methods of 15 studies were at high risk of bias. In only two studies was the risk of bias low. Trials used "positive drugs", of which the efficacy was not known, as controls. Different Chinese herbal preparations were tested in nearly all trials. In only one trial was a Chinese herbal preparation tested twice. In seven trials, six herbal preparations were found to be more effective at enhancing recovery than the control preparations. In the other 10 studies, seven herbal preparations were not shown to be significantly different from the control. One study did not describe the difference between the intervention and control groups. Chinese herbal medicines may shorten the symptomatic phase in patients with the common cold. However, the lack of trials of low enough risk of bias, or using a placebo or a drug clearly identified as a control, means that we are uncertain enough to be unable to recommend any kind of Chinese medicinal herbs for the common cold.
Five studies provided results from adequate parallel-group data. Barnhart 1999 and Dayal 2006 enrolled perimenopausal women with complaints of decreased well being and, using three cognitive measures, found no significant effect of DHEA compared with placebo at 3 months. Wolf 1998b enrolled 75 healthy volunteers (37 women and 38 men aged 59-81) in a study of the effect of DHEA supplements on cognitive impairment induced by stress; after two weeks of treatment, placebo group performance deteriorated significantly on a test of selective attention following a psychosocial stressor (p<0.05), while deterioration was not evident in the DHEA group (p=0.85). However, when compared with placebo, DHEA was associated with significant impairment on a visual memory recall test (p<0.01) following the stressor. No significant effects were found on a third cognitive task. Effects were not found on tasks when administered in the absence of a stressor. van Niekerk 2001 found no effect on cognitive function in 46 men aged 62-76 from three months of DHEA supplementation. Nair 2006, enrolled 57 women and 87 men with low level of sulphated DHEA in a 24-month study, no significant changes in quality of life measures for either sex were found. In Von Muhlen 2008 DHEA for one year showed no benefit on cognition performance in 225 healthy older people. Reduced performance in a visual memory recall test observed in one trial and a significant drop-out rate in favour of placebo emerged in another trial. What little evidence there is from controlled trials does not support a beneficial effect of DHEA supplementation on cognitive function of non-demented middle-aged or elderly people. There is inconsistent evidence from the controlled trials about adverse effects of DHEA. In view of growing public enthusiasm for DHEA supplementation, particularly in the USA, and the theoretical possibility of long-term neuroprotective effects of DHEA there is a need for further high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to provide adequate statistical power. Cognitive outcomes should be assessed in all trials.
Four trials involving 888 participants with previously untreated OAG were included. Surgery was Scheie's procedure in one trial and trabeculectomy in three trials. In three trials, primary medication was usually pilocarpine, in one trial it was a beta-blocker. The most recent trial included participants with on average mild OAG. At five years, the risk of progressive visual field loss, based on a three unit change of a composite visual field score, was not significantly different according to initial medication or initial trabeculectomy (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54 to 1.01). In an analysis based on mean difference (MD) as a single index of visual field loss, the between treatment group difference in MD was -0.20 decibel (dB) (95% CI -1.31 to 0.91). For a subgroup with more severe glaucoma (MD -10 dB), findings from an exploratory analysis suggest that initial trabeculectomy was associated with marginally less visual field loss at five years than initial medication, (mean difference 0.74 dB (95% CI -0.00 to 1.48). Initial trabeculectomy was associated with lower average intraocular pressure (IOP) (mean difference 2.20 mmHg (95% CI 1.63 to 2.77) but more eye symptoms than medication (P = 0.0053). Beyond five years, visual acuity did not differ according to initial treatment (OR 1.48, 95% CI 0.58 to 3.81). From three trials in more severe OAG, there is some evidence that medication was associated with more progressive visual field loss and 3 to 8 mmHg less IOP lowering than surgery. In the longer-term (two trials) the risk of failure of the randomised treatment was greater with medication than trabeculectomy (OR 3.90, 95% CI 1.60 to 9.53; hazard ratio (HR) 7.27, 95% CI 2.23 to 25.71). Medications and surgery have evolved since these trials were undertaken. In three trials the risk of developing cataract was higher with trabeculectomy (OR 2.69, 95% CI 1.64 to 4.42). Evidence from one trial suggests that, beyond five years, the risk of needing cataract surgery did not differ according to initial treatment policy (OR 0.63, 95% CI 0.15 to 2.62). Methodological weaknesses were identified in all the trials. Primary surgery lowers IOP more than primary medication but is associated with more eye discomfort. One trial suggests that visual field restriction at five years is not significantly different whether initial treatment is medication or trabeculectomy. There is some evidence from two small trials in more severe OAG, that initial medication (pilocarpine, now rarely used as first line medication) is associated with more glaucoma progression than surgery. Beyond five years, there is no evidence of a difference in the need for cataract surgery according to initial treatment. The clinical and cost-effectiveness of contemporary medication (prostaglandin analogues, alpha2-agonists and topical carbonic anhydrase inhibitors) compared with primary surgery is not known. Further RCTs of current medical treatments compared with surgery are required, particularly for people with severe glaucoma and in black ethnic groups. Outcomes should include those reported by patients. Economic evaluations are required to inform treatment policy.
Thirteen trials met the inclusion criteria and are included in the review. All studies had at least one domain with unclear risk of bias. Some studies were at high risk of bias for random sequence generation (two trials), allocation concealment (two trials), blinding of outcome assessors (one trial) and incomplete outcome data (one trial). Duration and content of multiple risk factor interventions varied across the trials. Two trials recruited healthy participants and the other 11 trials recruited people with varying risks of CVD, such as participants with known hypertension and type 2 diabetes. Only one study reported CVD outcomes and multiple risk factor interventions did not reduce the incidence of cardiovascular events (RR 0.57, 95% CI 0.11 to 3.07, 232 participants, low-quality evidence); the result is imprecise (a wide confidence interval and small sample size) and makes it difficult to draw a reliable conclusion. None of the included trials reported all-cause mortality. The pooled effect indicated a reduction in systolic blood pressure (MD -6.72 mmHg, 95% CI -9.82 to -3.61, I² = 91%, 4868 participants, low-quality evidence), diastolic blood pressure (MD -4.40 mmHg, 95% CI -6.47 to -2.34, I² = 92%, 4701 participants, low-quality evidence), body mass index (MD -0.76 kg/m², 95% CI -1.29 to -0.22, I² = 80%, 2984 participants, low-quality evidence) and waist circumference (MD -3.31, 95% CI -4.77 to -1.86, I² = 55%, 393 participants, moderate-quality evidence) in favour of multiple risk factor interventions, but there was substantial heterogeneity. There was insufficient evidence to determine the effect of these interventions on consumption of fruit or vegetables, smoking cessation, glycated haemoglobin, fasting blood sugar, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and total cholesterol. None of the included trials reported on adverse events. Due to the limited evidence currently available, we can draw no conclusions as to the effectiveness of multiple risk factor interventions on combined CVD events and mortality. There is some evidence that multiple risk factor interventions may lower blood pressure levels, body mass index and waist circumference in populations in LMIC settings at high risk of hypertension and diabetes. There was considerable heterogeneity between the trials, the trials were small, and at some risk of bias. Larger studies with longer follow-up periods are required to confirm whether multiple risk factor interventions lead to reduced CVD events and mortality in LMIC settings.
Data on 2281 participants from eight RCTs were available from reports of single-agent doxorubicin versus doxorubicin-based combination chemotherapy. Meta-analysis using the fixed effect model detected a higher tumour response rate with combination chemotherapy compared with single-agent chemotherapy (odds ratio [OR= 1.29; 95% confidence interval [CI], 1.03 to 1.60; p = 0.03), but the OR from a pooled analysis using the random effects model and the same data did not achieve statistical significance (OR= 1.26; 95% CI, 0.96 to 1.67; p = 0.10). No significant difference between the two regimens was detected in the pooled one-year mortality rate (OR = 0.87; 95% CI, 0.73 to 1.05; p=0.14) or two-year mortality rate (OR = 0.84; 95% CI, 0.67 to 1.06; p=0.13) (N=2097). Although reporting of adverse effects was limited and inconsistent among trials (making pooling of data for this outcome impossible), adverse effects such as nausea/vomiting and hematologic toxic effects were consistently reported as being worse with combination chemotherapy across the eight eligible studies. Compared to single-agent doxorubicin, the combination chemotherapy regimens evaluated, given in conventional doses, produced only marginal increases in response rates, at the expense of increased toxic effects and with no improvements in overall survival.
Twenty-one trials met the inclusion criteria. A total of 2048 patients were initially enrolled in the trials (1148 received paracetamol, and 892 the placebo) and of these 1968 (96%) were included in the meta-analysis (1133 received paracetamol, and 835 the placebo). Paracetamol provided a statistically significant benefit when compared with placebo for pain relief and pain intensity at both 4 and 6 hours. Most studies were found to have moderate risk of bias, with poorly reported allocation concealment being the main problem. Risk ratio values for pain relief at 4 hours 2.85 (95% confidence interval (CI) 1.89 to 4.29), and at 6 hours 3.32 (95% CI 1.88 to 5.87). A statistically significant benefit was also found between up to 1000 mg and 1000 mg doses, the higher the dose giving greater benefit for each measure at both time points. There was no statistically significant difference between the number of patients who reported adverse events, overall this being 19% in the paracetamol group and 16% in the placebo group. Paracetamol is a safe, effective drug for the treatment of postoperative pain following the surgical removal of lower wisdom teeth.
We included 12 studies (784 participants) in this review; sample sizes ranged from 10 to 187 participants (median 56.5). One study had three arms that were all relevant to this review and all the other studies had two arms. One study was a within-participant comparison. All studies were industry funded. Two studies provided unpublished data for healing. Nine of the included studies compared PMM treatments with other treatments and reported results for the primary outcomes. All treatments were dressings. All studies also gave the participants compression bandaging. Seven of these studies were in participants described as having 'non-responsive' or 'hard-to-heal' ulcers. Results, reported at short, medium and long durations and as time-to-event data, are summarised for the comparison of any dressing regimen incorporating PMM versus any other dressing regimen. The majority of the evidence was of low or very low certainty, and was mainly downgraded for risk of bias and imprecision. It is uncertain whether PMM dressing regimens heal VLUs quicker than non-PMM dressing regimens (low-certainty evidence from 1 trial with 100 participants) (HR 1.21, 95% CI 0.74 to 1.97). In the short term (four to eight weeks) it is unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (very low-certainty evidence, 2 trials involving 207 participants). In the medium term (12 weeks), it is unclear whether PMM dressing regimens increase the probability of healing compared with non-PMM dressing regimens (low-certainty evidence from 4 trials with 192 participants) (RR 1.28, 95% CI 0.95 to 1.71). Over the longer term (6 months), it is also unclear whether there is a difference between PMM dressing regimens and non-PMM dressing regimens in the probability of healing (low certainty evidence, 1 trial, 100 participants) (RR 1.06, 95% CI 0.80 to 1.41). It is uncertain whether there is a difference in adverse events between PMM dressing regimens and non-PMM dressing regimens (low-certainty evidence from 5 trials, 363 participants) (RR 1.03, 95% CI 0.75 to 1.42). It is also unclear whether resource use is lower for PMM dressing regimens (low-certainty evidence, 1 trial involving 73 participants), or whether mean total costs in a German healthcare setting are different (low-certainty evidence, 1 trial in 187 participants). One cost-effectiveness analysis was not included because effectiveness was not based on complete healing. The evidence is generally of low certainty, particularly because of risk of bias and imprecision of effects. Within these limitations, we are unclear whether PMM dressing regimens influence venous ulcer healing relative to dressing regimens without PMM activity. It is also unclear whether there is a difference in rates of adverse events between PMM and non-PMM treatments. It is uncertain whether either resource use (products and staff time) or total costs associated with PMM dressing regimens are different from those for non-PMM dressing regimens. More research is needed to clarify the impact of PMM treatments on venous ulcer healing.
Massage interventions improved daily weight gain by 5.1g (95% CI 3.5, 6.7g). There is no evidence that gentle, still touch is of benefit (increase in daily weight gain 0.2g; 95% CI -1.2, 1.6g). Massage interventions also appeared to reduce length of stay by 4.5 days (95% CI 2.4, 6.5) though there are methodological concerns about the blinding of this outcome. There was also some evidence that massage interventions have a slight, positive effect on postnatal complications and weight at 4 - 6 months. However, serious concerns about the methodological quality of the included studies, particularly with respect to selective reporting of outcomes, weaken credibility in these findings. Evidence that massage for preterm infants is of benefit for developmental outcomes is weak and does not warrant wider use of preterm infant massage. Where massage is currently provided by nurses, consideration should be given as to whether this is a cost-effective use of time. Future research should assess the effects of massage interventions on clinical outcome measures, such as medical complications or length of stay, and on process-of-care outcomes, such as care-giver or parental satisfaction.
We included 53 trials consisting of 1139 participants. Forty-eight studies used a cross-over design, and five were performed in accordance with a parallel-group design. Forty-five studies addressed the effect of a single beta2-agonist administration, and eight focused on long-term treatment. We addressed these two different intervention regimens as different comparisons. Among primary outcomes for short-term administration, data on maximum fall in forced expiratory volume in 1 second (FEV1) showed a significant protective effect for both short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) compared with placebo, with a mean difference of -17.67% (95% confidence interval (CI) -19.51% to -15.84%, P = 0.00001, 799 participants from 72 studies). The subgroup analysis of studies performed in adults compared with those performed in children showed high heterogeneity confined to children, despite the comparable mean bronchoprotective effect. Secondary outcomes on other pulmonary function parameters confirmed a more positive and protective effect of beta2-agonists on EIA compared with placebo. Occurrence of side effects was not significantly different between beta2-agonists and placebo. Overall evaluation of the included long-term studies suggests a beta2-agonist bronchoprotective effect for the first dose of treatment. However, long-term use of both SABA and LABA induced the onset of tolerance and decreased the duration of drug effect, even after a short treatment period. Evidence of low to moderate quality shows that beta2-agonists, both SABA and LABA, when administered in a single dose, are effective and safe in preventing EIA. Long-term regular administration of inhaled beta2-agonists induces tolerance and lacks sufficient safety data. This finding appears to be of particular clinical relevance in view of the potential for prolonged regular use of beta2-agonists as monotherapy in the pretreatment of EIA, despite the warnings of drug agencies (FDA, EMA) regarding LABA.
We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry. None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated. This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.
We included nine randomised controlled trials involving a total of 816 women with PCOS. When metformin was compared with placebo there was no clear evidence of a difference between the groups in live birth rates (OR 1.39, 95% CI 0.81 to 2.40, five RCTs, 551 women, I2 = 52%, low-quality evidence). Our findings suggest that for a woman with a 32 % chance of achieving a live birth using placebo, the corresponding chance using metformin treatment would be between 28% and 53%. When metformin was compared with placebo or no treatment, clinical pregnancy rates were higher in the metformin group (OR 1.52; 95% CI 1.07 to 2.15; eight RCTs, 775 women, I2 = 18%, moderate-quality evidence). This suggests that for a woman with a 31% chance of achieving a clinical pregnancy using placebo or no treatment, the corresponding chance using metformin treatment would be between 32% and 49%. The risk of ovarian hyperstimulation syndrome was lower in the metformin group (OR 0.29; 95% CI 0.18 to 0.49, eight RCTs, 798 women, I2 = 11%, moderate-quality evidence). This suggests that for a woman with a 27% risk of having OHSS without metformin the corresponding chance using metformin treatment would be between 6% and 15%. Side effects (mostly gastrointestinal) were more common in the metformin group (OR 4.49, 95% CI 1.88 to 10.72, for RCTs, 431 women, I2=57%, low quality evidence) The overall quality of the evidence was moderate for the outcomes of clinical pregnancy, OHSS and miscarriage, and low for other outcomes. The main limitations in the evidence were imprecision and inconsistency. This review found no conclusive evidence that metformin treatment before or during ART cycles improved live birth rates in women with PCOS. However, the use of this insulin-sensitising agent increased clinical pregnancy rates and decreased the risk of OHSS.
We included two trials. One study was conducted in the USA in 1981 (250 people randomised and completed trial) and one study conducted in Spain in 2001 (1034 randomised, 935 completed trial). Both trials used extracapsular cataract extraction techniques that are not commonly used in higher income countries now. Most of the data in this review came from the larger trial, which we judged to be at low risk of bias. The mean change in visual acuity (in Snellen lines) of the operated eye four months postoperatively was similar in people given day care surgery (mean 4.1 lines standard deviation (SD) 2.3, 464 participants) compared to people treated as in-patients (mean 4.1 lines, SD 2.2, 471 participants) (P value = 0.74). No data were available from either study on intra-operative complications. Wound leakage, intraocular pressure (IOP) and corneal oedema were reported in the first day postoperatively and at four months after surgery. There was an increased risk of high IOP in the day care group in the first day after surgery (risk ratio (RR) 3.33, 95% confidence intervals (CI) 1.21 to 9.16, 935 participants) but not at four months (RR 0.61, 95% CI 0.14 to 2.55, 935 participants). The findings for the other outcomes were inconclusive with wide CIs. There were two cases of endophthalmitis observed at four months in the day care group and none in the in-patient group. The smaller study stated that there were no infections or severe hyphaemas. In a subset of participants evaluated for quality of life (VF14 questionnaire) similar change in quality of life before and four months after surgery was observed (mean change in VF14 score: day care group 25.2, SD 21.2, 150 participants; in-patient group: 23.5, SD 25.7, 155 participants; P value = 0.30). Subjective assessment of patient satisfaction in the smaller study suggested that participants preferred to recuperate at home, were more comfortable in their familiar surroundings and enjoyed the family support that they received at home. Costs were 20% more for the in-patient group and this was attributed to higher costs for overnight stay. This review provides evidence that there is cost saving with day care cataract surgery compared to in-patient cataract surgery. Although effects on visual acuity and quality of life appeared similar, the evidence with respect to postoperative complications was inconclusive because the effect estimates were imprecise. Given the wide-spread adoption of day care cataract surgery, future research in cataract clinical pathways should focus on evidence provided by high quality clinical databases (registers), which would enable clinicians and healthcare planners to agree clinical and social indications for in-patient care and so make better use of resources.
We identified three new studies in this update of the review. In total seven studies were eligible for inclusion, three were ongoing RCTs and four were completed studies. The four completed studies were included in the original review and the three ongoing studies were included in this update. We did not identify any RCTs that compared TXA with EACA. Of the four completed studies, one cross-over TXA study (eight participants) was excluded from the outcome analysis because it had very flawed study methodology. Data from the other three studies were all at unclear risk of bias due to lack of reporting of study methodology. Three studies (two TXA (12 to 56 participants), one EACA (18 participants) reported in four articles (published 1983 to 1995) were included in the narrative review. All three studies compared the drug with placebo. All three studies included adults with acute leukaemia receiving chemotherapy. One study (12 participants) only included participants with acute promyelocytic leukaemia. None of the studies included children. One of the three studies reported funding sources and this study was funded by a charity. We are uncertain whether antifibrinolytics reduce the risk of bleeding (three studies; 86 participants; very low-quality evidence). Only one study reported the number of bleeding events per participant and there was no difference in the number of bleeding events seen during induction or consolidation chemotherapy between TXA and placebo (induction; 38 participants; mean difference (MD) 1.70 bleeding events, 95% confidence interval (CI) -0.37 to 3.77: consolidation; 18 participants; MD -1.50 bleeding events, 95% CI -3.25 to 0.25; very low-quality evidence). The two other studies suggested bleeding was reduced in the antifibrinolytic study arm, but this was statistically significant in only one of these two studies. Two studies reported thromboembolism and no events occurred (68 participants, very low-quality evidence). All three studies reported a reduction in platelet transfusion usage (three studies, 86 participants; very low-quality evidence), but this was reported in different ways and no meta-analysis could be performed. No trials reported the number of platelet transfusions per participant. Only one study reported the number of platelet components per participant and there was a reduction in the number of platelet components per participant during consolidation chemotherapy but not during induction chemotherapy (consolidation; 18 participants; MD -5.60 platelet units, 95% CI -9.02 to -2.18: induction; 38 participants, MD -1.00 platelet units, 95% CI -9.11 to 7.11; very low-quality evidence). Only one study reported adverse events of TXA as an outcome measure and none occurred. One study stated side effects of EACA were minimal but no further information was provided (two studies, 74 participants, very low-quality evidence). None of the studies reported on the following pre-specified outcomes: overall mortality, adverse events of transfusion, disseminated intravascular coagulation (DIC) or quality of life (QoL). Our results indicate that the evidence available for the use of antifibrinolytics in haematology patients is very limited. The trials were too small to assess whether or not antifibrinolytics decrease bleeding. No trials reported the number of platelet transfusions per participant. The trials were too small to assess whether or not antifibrinolytics increased the risk of thromboembolic events or other adverse events. There are three ongoing RCTs (1276 participants) due to be completed in 2017 and 2020.
We included 22 randomised controlled trials (2858 women), most of which had high risk of bias in several domains. We performed 13 comparisons. Many comparisons are based on a small number of studies with small sample sizes. No analysis of our primary outcomes contained more than two studies. Intravenous iron was compared to oral iron in 10 studies (1553 women). Fatigue was reported in two studies and improved significantly favouring the intravenously treated group in one of the studies. Other anaemia symptoms were not reported. One woman died from cardiomyopathy (risk ratio (RR) 2.95; 95% confidence interval (CI) 0.12 to 71.96; two studies; one event; 374 women; low quality evidence). One woman developed arrhythmia. Both cardiac complications occurred in the intravenously treated group. Allergic reactions occurred in three women treated with intravenous iron, not statistically significant (average RR 2.78; 95% CI 0.31 to 24.92; eight studies; 1454 women; I² = 0%; low quality evidence). Gastrointestinal events were less frequent in the intravenously treated group (average RR 0.31; 95% CI 0.20 to 0.47; eight studies; 169 events; 1307 women; I² = 0%; very low quality evidence). One study evaluated red blood cell transfusion versus non-intervention. General fatigue improved significantly more in the transfusion group at three days (MD -0.80; 95% CI -1.53 to -0.07; women 388; low quality evidence), but no difference between groups was seen at six weeks. Maternal mortality was not reported. The remaining comparisons evaluated oral iron (with or without other food substances) versus placebo (three studies), intravenous iron with oral iron versus oral iron (two studies) and erythropoietin (alone or combined with iron) versus placebo or iron (seven studies). These studies did not investigate fatigue. Maternal mortality was rarely reported. The body of evidence did not allow us to reach a clear conclusion regarding the efficacy of the interventions on postpartum iron deficiency anaemia. The quality of evidence was low. Clinical outcomes were rarely reported. Laboratory values may not be reliable indicators for efficacy, as they do not always correlate with clinical treatment effects. It remains unclear which treatment modality is most effective in alleviating symptoms of postpartum anaemia. Intravenous iron was superior regarding gastrointestinal harms, however anaphylaxis and cardiac events occurred and more data are needed to establish whether this was caused by intravenous iron. The clinical significance of some temporarily improved fatigue scores in women treated with blood transfusion is uncertain and this modest effect should be balanced against known risks, e.g. maternal mortality (not reported) and maternal immunological sensitisation, which can potentially harm future pregnancies. When comparing oral iron to placebo it remains unknown whether efficacy (relief of anaemia symptoms) outweighs the documented gastrointestinal harms. We could not draw conclusions regarding erythropoietin treatment due to lack of evidence. Further research should evaluate treatment effect through clinical outcomes, i.e. presence and severity of anaemia symptoms balanced against harms, i.e. survival and severe morbidity.
From 6168 studies identified in the searches, 41 RCTs with a total of 6858 participants were included. Methodological quality ratings ranged from 1 to 9 out 12, and 13 of the 41 included studies were assessed as low risk of bias. Pooled estimates from 16 RCTs provided moderate to low quality evidence that MBR is more effective than usual care in reducing pain and disability, with standardised mean differences (SMDs) in the long term of 0.21 (95% CI 0.04 to 0.37) and 0.23 (95% CI 0.06 to 0.4) respectively. The range across all time points equated to approximately 0.5 to 1.4 units on a 0 to 10 numerical rating scale for pain and 1.4 to 2.5 points on the Roland Morris disability scale (0 to 24). There was moderate to low quality evidence of no difference on work outcomes (odds ratio (OR) at long term 1.04, 95% CI 0.73 to 1.47). Pooled estimates from 19 RCTs provided moderate to low quality evidence that MBR was more effective than physical treatment for pain and disability with SMDs in the long term of 0.51 (95% CI -0.01 to 1.04) and 0.68 (95% CI 0.16 to 1.19) respectively. Across all time points this translated to approximately 0.6 to 1.2 units on the pain scale and 1.2 to 4.0 points on the Roland Morris scale. There was moderate to low quality evidence of an effect on work outcomes (OR at long term 1.87, 95% CI 1.39 to 2.53). There was insufficient evidence to assess whether MBR interventions were associated with more adverse events than usual care or physical interventions. Sensitivity analyses did not suggest that the pooled estimates were unduly influenced by the results from low quality studies. Subgroup analyses were inconclusive regarding the influence of baseline symptom severity and intervention intensity. Patients with chronic LBP receiving MBR are likely to experience less pain and disability than those receiving usual care or a physical treatment. MBR also has a positive influence on work status compared to physical treatment. Effects are of a modest magnitude and should be balanced against the time and resource requirements of MBR programs. More intensive interventions were not responsible for effects that were substantially different to those of less intensive interventions. While we were not able to determine if symptom intensity at presentation influenced the likelihood of success, it seems appropriate that only those people with indicators of significant psychosocial impact are referred to MBR.
We included in this review 19 trials involving 516 participants. Seven of the included studies (N = 222) had not been evaluated in the previous review. Investigators compared several positions: prone versus supine, prone alternant versus supine, prone versus lateral right, lateral right versus supine, lateral left versus supine, lateral alternant versus supine, lateral right versus lateral left, quarter turn from prone versus supine, quarter turn from prone versus prone and good lung dependent versus good lung uppermost. Apart from two studies that compared lateral alternant versus supine, one comparing lateral right versus supine and two comparing prone or prone alternant versus the supine position, all included studies had a cross-over design. In five studies, infants were ventilated with continuous positive airway pressure (CPAP); in the other studies, infants were treated with conventional ventilation (CV). Risks of bias did not differ substantially for different comparisons and outcomes. This update detects a moderate to high grade of inconsistency, similar to previous versions. However, for the analysed outcomes, the direction of effect was the same in all studies. Therefore, we consider that this inconsistency had little effect on the conclusions of the meta-analysis. When comparing prone versus supine position, we observed an increase in arterial oxygen tension (PO2) in the prone position (mean difference (MD) 5.49 mmHg, 95% confidence interval (CI) 2.92 to 8.05 mmHg; three trials; 116 participants; I2= 0). When percent haemoglobin oxygen saturation was measured with pulse oximetry (SpO2), improvement in the prone position was between 1.13% and 3.24% (typical effect based on nine trials with 154 participants; I2= 89%). The subgroup ventilated with CPAP (three trials; 59 participants) showed a trend towards improving SpO2 in the prone position compared with the supine position, although the mean difference (1.91%) was not significant (95% CI -1.14 to 4.97) and heterogeneity was extreme (I2= 95%). Sensitivity analyses restricted to studies with low risk of selection bias showed homogeneous results and verified a small but significant effect (MD 0.64, 95% CI 0.26 to 1.02; four trials; 92 participants; I2= 0). We also noted a slight improvement in the number of episodes of desaturation; it was not possible to establish whether this effect continued once the intervention was stopped. Investigators studied few adverse effects from the interventions in sufficient detail. Two studies analysed tracheal cultures of neonates after five days on MV, reporting lower bacterial colonisation in the alternating lateral position than in the supine posture. Other effects - positive or negative - cannot be excluded in light of the relatively small numbers of neonates studied. This update of our last review in 2013 supports previous conclusions. Evidence of low to moderate quality favours the prone position for slightly improved oxygenation in neonates undergoing mechanical ventilation. However, we found no evidence to suggest that particular body positions during mechanical ventilation of the neonate are effective in producing sustained and clinically relevant improvement.
We included 20 trials with 3791 participants. Studies were heterogenous in study design, population, antibiotic regimens, and outcomes. We grouped the sixteen different antibiotic agents studied into six categories: 1) anti-pseudomonal penicillins (three trials); 2) broad-spectrum penicillins (one trial); 3) cephalosporins (two trials); 4) carbapenems (four trials); 5) fluoroquinolones (six trials); 6) other antibiotics (four trials). Only 9 of the 20 trials protected against detection bias with blinded outcome assessment. Only one-third of the trials provided enough information to enable a judgement about whether the randomisation sequence was adequately concealed. Eighteen out of 20 trials received funding from pharmaceutical industry-sponsors. The included studies reported the following findings for clinical resolution of infection: there is evidence from one large trial at low risk of bias that patients receiving ertapenem with or without vancomycin are more likely to have resolution of their foot infection than those receiving tigecycline (RR 0.92, 95% confidence interval (CI) 0.85 to 0.99; 955 participants). It is unclear if there is a difference in rates of clinical resolution of infection between: 1) two alternative anti-pseudomonal penicillins (one trial); 2) an anti-pseudomonal penicillin and a broad-spectrum penicillin (one trial) or a carbapenem (one trial); 3) a broad-spectrum penicillin and a second-generation cephalosporin (one trial); 4) cephalosporins and other beta-lactam antibiotics (two trials); 5) carbapenems and anti-pseudomonal penicillins or broad-spectrum penicillins (four trials); 6) fluoroquinolones and anti-pseudomonal penicillins (four trials) or broad-spectrum penicillins (two trials); 7) daptomycin and vancomycin (one trial); 8) linezolid and a combination of aminopenicillins and beta-lactamase inhibitors (one trial); and 9) clindamycin and cephalexin (one trial). Carbapenems combined with anti-pseudomonal agents produced fewer adverse effects than anti-pseudomonal penicillins (RR 0.27, 95% CI 0.09 to 0.84; 1 trial). An additional trial did not find significant differences in the rate of adverse events between a carbapenem alone and an anti-pseudomonal penicillin, but the rate of diarrhoea was lower for participants treated with a carbapenem (RR 0.58, 95% CI 0.36 to 0.93; 1 trial). Daptomycin produced fewer adverse effects than vancomycin or other semi-synthetic penicillins (RR 0.61, 95%CI 0.39 to 0.94; 1 trial). Linezolid produced more adverse effects than ampicillin-sulbactam (RR 2.66; 95% CI 1.49 to 4.73; 1 trial), as did tigecycline compared to ertapenem with or without vancomycin (RR 1.47, 95% CI 1.34 to 1.60; 1 trial). There was no evidence of a difference in safety for the other comparisons. The evidence for the relative effects of different systemic antibiotics for the treatment of foot infections in diabetes is very heterogeneous and generally at unclear or high risk of bias. Consequently it is not clear if any one systemic antibiotic treatment is better than others in resolving infection or in terms of safety. One non-inferiority trial suggested that ertapenem with or without vancomycin is more effective in achieving clinical resolution of infection than tigecycline. Otherwise the relative effects of different antibiotics are unclear. The quality of the evidence is low due to limitations in the design of the included trials and important differences between them in terms of the diversity of antibiotics assessed, duration of treatments, and time points at which outcomes were assessed. Any further studies in this area should have a blinded assessment of outcomes, use standardised criteria to classify severity of infection, define clear outcome measures, and establish the duration of treatment.
Six studies met our inclusion criteria and included a total of 5143 women. Of three studies with self-reported pregnancy data, two showed pregnancy to be less likely in the experimental group than in the comparison group (OR 0.48, 95% CI 0.27 to 0.87) (OR 0.60, 95% CI 0.41 to 0.87). The interventions included a clinic-based counseling program and a community-based communication project. All studies showed some association of the intervention with contraceptive use. Two showed that treatment-group women were more likely to use a modern method than the control group: ORs were 1.77 (95% CI 1.08 to 2.89) and 3.08 (95% CI 2.36 to 4.02). In another study, treatment-group women were more likely than control-group women to use pills (OR 1.78, 95% CI 1.26 to 2.50) or an intrauterine device (IUD) (OR 3.72, 95% CI 1.27 to 10.86) but less likely to use and injectable method (OR 0.23, 95% CI 0.05 to 1.00). One study used a score for method effectiveness. The methods of the special-intervention group scored higher than those of the comparison group at three months (MD 13.26, 95% CI 3.16 to 23.36). A study emphasizing IUDs showed women in the intervention group were more likely to use an IUD (OR 1.79, 95% CI 1.20 to 2.69) and less likely to use no method (OR 0.48, 95% CI 0.31 to 0.75). In another study, contraceptive use was more likely among women in a health service intervention compared to women in a community awareness program at four months (OR 1.79, 95% CI 1.40 to 2.30) or women receiving standard care at 10 to 12 months (OR 2.08, 95% CI 1.58 to 2.74). That study was the only one with a specific component on the lactational amenorrhea method (LAM) that had sufficient data on LAM use. Women in the health service group were more likely than those in the community awareness group to use LAM (OR 41.36, 95% CI 10.11 to 169.20). We considered the quality of evidence to be very low. The studies had limitations in design, analysis, or reporting. Three did not adjust for potential confounding and only two had sufficient information on intervention fidelity. Outcomes were self reported and definitions varied for contraceptive use. All studies had adequate follow-up periods but most had high losses, as often occurs in contraception studies.
We included five studies conducted in Europe and North America. Four separate trials compared grid laser to no treatment, sham treatment, intravitreal bevacizumab and intravitreal triamcinolone. One further trial compared subthreshold to threshold laser. Two of these trials were judged to be at high risk of bias in one or more domains. In one trial of grid laser versus observation, people receiving grid laser were more likely to gain visual acuity (VA) (10 or more ETDRS letters) at 36 months (RR 1.75, 95% confidence interval (CI) 1.08 to 2.84, 78 participants, moderate-quality evidence). The effect of grid laser on loss of VA (10 or more letters) was uncertain as the results were imprecise (RR 0.68, 95% CI 0.23 to 2.04, 78 participants, moderate-quality evidence). On average, people receiving grid laser had better improvement in VA (mean difference (MD) 0.11 logMAR, 95% CI 0.05 to 0.17, high-quality evidence). In a trial of early and delayed grid laser treatment versus sham laser (n = 108, data available for 99 participants), no participant gained or lost VA (15 or more ETDRS letters). At 12 months, there was no evidence for a difference in change in VA (from baseline) between early grid laser and sham laser (MD -0.03 logMAR, 95% confidence interval (CI) -0.07 to 0.01, 68 participants, low-quality evidence) or between delayed grid laser and sham laser (MD 0.00, 95% CI -0.04 to 0.04, 66 participants, low-quality evidence). The relative effects of subthreshold and threshold laser were uncertain. In one trial, the RR for gain of VA (15 or more letters) at 12 months was 1.68 (95% CI 0.57 to 4.95, 36 participants, moderate-quality evidence); the RR for loss of VA (15 or more letters) was 0.56 (95% CI 0.06 to 5.63, moderate-quality evidence); and at 24 months the change in VA from baseline was MD 0.07 (95% CI -0.10 to 0.24, moderate-quality evidence). The relative effects of macular grid laser and intravitreal bevacizumab were uncertain. In one trial, the RR for gain of 15 or more letters at 12 months was 0.67 (95% CI 0.39 to 1.14, 30 participants, low-quality evidence). Loss of 15 or more letters was not reported. Change in VA at 12 months was MD 0.11 logMAR (95% CI -0.36 to 0.14, low-quality evidence). The relative effects of grid laser and 1mg triamcinolone were uncertain at 12 months. RR for gain of VA (15 or more letters) was 1.13 (95% CI 0.75 to 1.71, 1 RCT, 242 participants, moderate-quality evidence); RR for loss of VA (15 or more letters) was 1.20 (95% CI 0.63 to 2.27, moderate-quality evidence); MD for change in VA was -0.03 letters (95% CI -0.12 to 0.06, moderate-quality evidence). Similar results were seen for the comparison with 4mg triamcinolone. Beyond 12 months, the visual outcomes were in favour of grid laser at 24 months and 36 months with people in the macular grid group gaining more VA. Four studies reported on adverse effects. Laser photocoagulation appeared to be well tolerated in the studies. One participant (out of 71) suffered a perforation of Bruch's membrane, but this did not affect visual acuity. Moderate-quality evidence from one RCT supports the use of grid laser photocoagulation to treat macular oedema following BRVO. There was insufficient evidence to support the use of early grid laser or subthreshold laser. There was insufficient evidence to show a benefit of intravitreal triamcinolone or anti-vascular endothelial growth factor (VEGF) over macular grid laser photocoagulation in BRVO. With recent interest in the use of intravitreal anti-VEGF or steroid therapy, assessment of treatment efficacy (change in visual acuity and foveal or central macular thickness using optical coherence tomography (OCT)) and the number of treatments needed for maintenance and long-term safety will be important for future studies.
Tiotropium plus LABA/ICS versus tiotropium We included six studies (1902 participants) with low risk of bias that compared tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy versus tiotropium alone. We found no statistically significant differences in mortality between treatments (odds ratio (OR) 1.80, 95% confidence interval (CI) 0.55 to 5.91; two studies; 961 participants) as well as in the all-cause hospitalisations (OR 0.84, 95% CI 0.53 to 1.33; two studies; 961 participants). The effect on exacerbations was heterogeneous among trials and was not meta-analysed. Health-related quality of life measured by St. George’s Respiratory Questionnaire (SGRQ) showed a statistically significant improvement in total scores with use of tiotropium + LABA/ICS compared with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1446 participants). Lung function was significantly different in the combined therapy (tiotropium + LABA/ICS) group, although average benefit with this therapy was small. None of the included studies included exercise tolerance as an outcome. A pooled estimate of these studies did not show a statistically significant difference in adverse events (OR 1.16, 95% CI 0.92 to 1.47; four studies; 1363 participants), serious adverse events (OR 0.86, 95% CI 0.57 to 1.30; four studies; 1758 participants) and pneumonia (Peto OR 1.62, 95% CI 0.54 to 4.82; four studies; 1758 participants). Tiotropium plus LABA/ICS versus LABA/ICS One of the six studies (60 participants) also compared combined therapy (tiotropium + LABA/ICS) versus LABA/ICS therapy alone. This study was affected by lack of power; therefore results did not allow us to draw conclusions for this comparison. This review update includes three additional studies and provides new low quality evidence supporting the finding that tiotropium + LABA/ICS-based therapy improves the disease-specific quality of life. The current evidence is insufficient to support the benefit of tiotropium + LABA/ICS-based therapy for mortality, hospital admission or exacerbations (moderate and low quality evidence). Compared with use of tiotropium alone, tiotropium + LABA/ICS-based therapy does not seem to increase undesirable effects nor serious non-fatal adverse events.
We included 29 trials (n = 2431) in this review. The study sample sizes ranged from 20 to 323 participants. We considered a total of 76.6% of the included trials to have a low risk of bias, representing 86% of all participants. There is low to high quality evidence that MCE is not clinically more effective than other exercises for all follow-up periods and outcomes tested. When compared with minimal intervention, there is low to moderate quality evidence that MCE is effective for improving pain at short, intermediate and long-term follow-up with medium effect sizes (long-term, MD –12.97; 95% CI –18.51 to –7.42). There was also a clinically important difference for the outcomes function and global impression of recovery compared with minimal intervention. There is moderate to high quality evidence that there is no clinically important difference between MCE and manual therapy for all follow-up periods and outcomes tested. Finally, there is very low to low quality evidence that MCE is clinically more effective than exercise and electrophysical agents (EPA) for pain, disability, global impression of recovery and quality of life with medium to large effect sizes (pain at short term, MD –30.18; 95% CI –35.32 to –25.05). Minor or no adverse events were reported in the included trials. There is very low to moderate quality evidence that MCE has a clinically important effect compared with a minimal intervention for chronic low back pain. There is very low to low quality evidence that MCE has a clinically important effect compared with exercise plus EPA. There is moderate to high quality evidence that MCE provides similar outcomes to manual therapies and low to moderate quality evidence that it provides similar outcomes to other forms of exercises. Given the evidence that MCE is not superior to other forms of exercise, the choice of exercise for chronic LBP should probably depend on patient or therapist preferences, therapist training, costs and safety.
Ten prospective, parallel-group design, randomised controlled trials, involving a total of 577 participants with type 1 and type 2 diabetes mellitus, were identified. Risk of bias was high or unclear in all but two trials, which were assessed as having moderate risk of bias. Risk of bias in some domains was high in 50% of trials. Oral monopreparations of cinnamon (predominantly Cinnamomum cassia) were administered at a mean dose of 2 g daily, for a period ranging from 4 to 16 weeks. The effect of cinnamon on fasting blood glucose level was inconclusive. No statistically significant difference in glycosylated haemoglobin A1c (HbA1c), serum insulin or postprandial glucose was found between cinnamon and control groups. There were insufficient data to pool results for insulin sensitivity. No trials reported health-related quality of life, morbidity, mortality or costs. Adverse reactions to oral cinnamon were infrequent and generally mild in nature. There is insufficient evidence to support the use of cinnamon for type 1 or type 2 diabetes mellitus. Further trials, which address the issues of allocation concealment and blinding, are now required. The inclusion of other important endpoints, such as health-related quality of life, diabetes complications and costs, is also needed.
Thirty studies (2047 participants) were included. We categorised studies by intervention type: supportive interventions during follow-up, educational interventions and behavioural therapy. Across all three intervention classes, most studies incorporated elements of more than one intervention. For the purposes of this systematic review, we categorised them by the prevailing type of intervention, which we expected would have the greatest impact on the study outcome. Baseline Epworth Sleepiness Scale (ESS) scores indicated that most participants experienced daytime sleepiness, and CPAP was indicated on the basis of sleep disturbance indices. A vast majority of recruited participants had not used CPAP previously. Most of the studies were at an unclear risk of bias overall, although because of the nature of the intervention, blinding of both study personnel and participants was not feasible, and this affected a number of key outcomes. Adverse events were not reported in these studies. Low- to moderate-quality evidence showed that all three types of interventions led to increased machine usage in CPAP-naive participants with moderate to severe OSA syndrome. Compared with usual care, supportive ongoing interventions increased machine usage by about 50 minutes per night (0.82 hours, 95% confidence interval (CI) 0.36 to 1.27, N = 803, 13 studies; low-quality evidence), increased the number of participants who used their machines for longer than four hours per night from 59 to 75 per 100 (odds ratio (OR) 2.06, 95% CI 1.22 to 3.47, N = 268, four studies; low-quality evidence) and reduced the likelihood of study withdrawal (OR 0.65, 95% CI 0.44 to 0.97, N = 903, 12 studies; moderate-quality evidence). With the exception of study withdrawal, considerable variation was evident between the results of individual studies across these outcomes. Evidence of an effect on symptoms and quality of life was statistically imprecise (ESS score -0.60 points, 95% CI -1.81 to 0.62, N = 501, eight studies; very low-quality evidence; Functional Outcomes of Sleep Questionnaire 0.98 units, 95% CI -0.84 to 2.79, N = 70, two studies; low-quality evidence, respectively). Educational interventions increased machine usage by about 35 minutes per night (0.60 hours, 95% CI 0.27 to 0.93, N = 508, seven studies; moderate-quality evidence), increased the number of participants who used their machines for longer than four hours per night from 57 to 70 per 100 (OR 1.80, 95% CI 1.09 to 2.95, N = 285, three studies; low-quality evidence) and reduced the likelihood of withdrawal from the study (OR 0.67, 95% CI 0.45 to 0.98, N = 683, eight studies; low-quality evidence). Participants experienced a small improvement in symptoms, the size of which may not be clinically significant (ESS score -1.17 points, 95% CI -2.07 to -0.26, N = 336, five studies). Behavioural therapy led to substantial improvement in average machine usage of 1.44 hours per night (95% CI 0.43 to 2.45, N = 584, six studies; low-quality evidence) and increased the number of participants who used their machines for longer than four hours per night from 28 to 47 per 100 (OR 2.23, 95% CI 1.45 to 3.45, N = 358, three studies; low-quality evidence) but with high levels of statistical heterogeneity. The estimated lower rate of withdrawal with behavioural interventions was imprecise and did not reach statistical significance (OR 0.85, 95% CI 0.57 to 1.25, N = 609, five studies, very low-quality evidence). In CPAP-naive people with severe sleep apnoea, low-quality evidence indicates that supportive interventions that encourage people to continue to use their CPAP machines increase usage compared with usual care. Moderate-quality evidence shows that a short-term educational intervention results in a modest increase in CPAP usage. Low-quality evidence indicates that behavioural therapy leads to a large increase in CPAP machine usage. The impact of improved CPAP usage on daytime sleepiness, quality of life and long-term cardiovascular risks remains unclear. For outcomes reflecting machine usage, we downgraded for risk of bias and inconsistency. An additional limitation for daytime sleepiness and quality of life measures was imprecision. Trials in people who have struggled to persist with treatment are needed, as currently little evidence is available for this population. Optimal timing and duration and long-term effectiveness of interventions remain uncertain. The relationship between improved machine usage and effect on symptoms and quality of life requires further assessment. Studies addressing the choice of interventions that best match individual patient needs and therefore result in the most successful and cost-effective therapy are needed.
We included 12 studies involving 1954 participants. We identified ten studies as being of methodologically poor quality and two studies as being of medium quality. We did not perform a meta-analysis but reported the results separately. Six formulations were shown to be superior to the control in improving recovery: Ertong Qingyan Jiere Koufuye was more effective than Fufang Shuanghua Koufuye for acute pharyngitis (odds ratio (OR) 2.52; 95% confidence interval (Cl) 1.11 to 5.74); Yanhouling mixture  was more effective than gentamicin atomised inhalation for acute pharyngitis (OR 5.39; 95% CI 2.69 to 10.81); Qinganlan Liyan Hanpian was more effective than Fufang Caoshanhu Hanpian for acute pharyngitis (OR 2.25; 95% CI 1.08 to 4.67); sore throat capsules were more effective than antibiotics (intravenous cefalexin) for acute pharyngitis or acute tonsillitis (OR 2.36; 95% CI 1.01 to 5.51); compound dandelion soup was more effective than sodium penicillin for acute purulent tonsillitis (OR 5.06; 95% CI 1.70 to 15.05); and eliminating heat by nourishing yin and relieving sore-throat methods combined with Dikuiluqan Hanpian was more effective than Dikuiluqan Hanpian alone for children with chronic pharyngitis (OR 2.63; 95% CI 1.02 to 6.79). Another six formulations were shown to be equally efficacious as the control. Based on the existing evidence in this review, some Chinese herbal medicines for treating sore throat appeared efficacious. However, due to the lack of high quality clinical trials, the efficacy of Chinese herbal medicine for treating sore throat is controversial and questionable. Therefore we cannot recommend any kind of Chinese medical herbal formulation as an effective remedy for sore throat.
We included three trials with 330 participants. We judged the quality of the evidence as very low for all the outcomes. The quality of the data was limited by the lack of complete outcome reporting, unclear risk of bias in the methods in which the studies were conducted, and the age of the studies (> 20 years). The methods of cancer staging and types of surgical procedures, which do not reflect current practice, reduced our confidence in the estimation of the effect. Two studies compared surgery to radiation therapy, and in one study chemotherapy was administered to both arms. One study administered initial chemotherapy, then responders were randomised to surgery versus control; following, both groups underwent chest and whole brain irradiation. Due to the clinical heterogeneity of the trials, we were unable to pool results for meta-analysis. All three studies reported overall survival. One study reported a mean overall survival of 199 days in the surgical arm, compared to 300 days in the radiotherapy arm (P = 0.04). One study reported overall survival as 4% in the surgical arm, compared to 10% in the radiotherapy arm at two years. Conversely, one study reported overall survival at two years as 52% in the surgical arm, compared to 18% in the radiotherapy arm. However this difference was not statistically significant (P = 0.12). One study reported early postoperative mortality as 7% for the surgical arm, compared to 0% mortality in the radiotherapy arm. One study reported the difference in mean degree of dyspnoea as −1.2 comparing surgical intervention to radiotherapy, indicating that participants undergoing radiotherapy are likely to experience more dyspnoea. This was measured using a non-validated scale. Evidence from currently available RCTs does not support a role for surgical resection in the management of limited-stage small-cell lung cancer; however our conclusions are limited by the quality of the available evidence and the lack of contemporary data. The results of the trials included in this review may not be generalisable to patients with clinical stage 1 small-cell lung cancer carefully staged using contemporary staging methods. Although some guidelines currently recommend surgical resection in clinical stage 1 small-cell lung cancer, prospective randomised controlled trials are needed to determine if there is any benefit in terms of short- and long-term mortality and quality of life compared with chemo-radiotherapy alone.
Thirty six trials were included in the review, reporting on 5908 participants randomly allocated to azapirones and/or placebo, benzodiazepines, antidepressants, psychotherapy or kava kava. Azapirones, including buspirone, were superior to placebo in treating GAD. The calculated number needed to treat for azapirones using the Clinical Global Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4). Azapirones may be less effective than benzodiazepines and we were unable to conclude if azapirones were superior to antidepressants, kava kava or psychotherapy. Azapirones appeared to be well tolerated. Fewer participants stopped taking benzodiazepines compared to azapirones. The length of studies ranged from four to nine weeks, with one study lasting 14 weeks. Azapirones appeared to be useful in the treatment of GAD, particularly for those participants who had not been on a benzodiazepine. Azapirones may not be superior to benzodiazepines and do not appear as acceptable as benzodiazepines. Side effects appeared mild and non serious in the azapirone treated group. Longer term studies are needed to show that azapirones are effective in treating GAD, which is a chronic long-term illness.
This update includes 15 new eligible treatment-comparisons from 12 studies. In total, 28 treatment-comparisons, involving 4418 women, from 24 studies are now included in one or more meta-analyses. Of the 28 treatment-comparisons, 19 and 16 had published or provided extractable time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively. All 28 treatment-comparisons provided OTRR data that could be included in meta-analyses. Most women recruited to the studies were not selected on the basis of mTNBC status. In a subgroup of three treatment-comparisons assessing women with mTNBC, platinum-containing regimens may have provided a survival benefit (HR 0.75, 95% CI 0.57 to 1.00; low-quality evidence). In women unselected for intrinsic subtypes such as mTNBC, there was little or no effect on survival (HR 1.01, 95% CI 0.92 to 1.12; high-quality evidence). This effect was similar to the combined analysis of survival data for both populations (HR 0.98, 95% CI 0.89 to 1.07; I2 =39%, 1868 deaths, 2922 women; 19 trials). The difference in treatment effects between mTNBC women compared with unselected women was of borderline statistical significance (P = 0.05). Data from three treatment-comparisons with mTNBC participants showed that platinum regimens may improve PFS/TTP (HR 0.59, 95% CI 0.49 to 0.72; low-quality evidence). Thirteen treatment-comparisons of unselected metastatic participants showed that there was probably a small PFS/TTP benefit for platinum recipients, although the confidence interval included no difference (HR 0.92, 95% CI 0.84 to 1.01; moderate-quality evidence). Combined analysis of data from an estimated 1772 women who progressed or died out of 2136 women selected or unselected for mTNBC indicated that platinum-containing regimens improved PFS/TTP (HR 0.85, 95% CI 0.78 to 0.93). There was marked evidence of heterogeneity (P = 0.0004; I2 = 63%). The larger treatment benefit in mTNBC women compared with unselected women was statistically significant (P < 0.0001). There was low-quality evidence of better tumour response in both subgroups of women with mTNBC and unselected women (RR 1.33, 95% CI 1.13 to 1.56; RR 1.11, 95% CI 1.04 to 1.19, respectively). Combined analysis of both populations was closer to the effect in unselected women (RR 1.15, 95% CI 1.08 to 1.22; 4130 women). There was considerable evidence of heterogeneity (P < 0.0001; I2 = 64%), which may reflect between-study differences and general difficulties in assessing response, as well as the varying potencies of the comparators. Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were probably higher among women receiving cisplatin- (RR 2.65, 95% CI 2.10 to 3.34; 1731 women; moderate-quality evidence) but the effect from carboplatin-containing regimens was less certain (RR 0.77, 95% CI 0.47 to 1.26; 1441 women; moderate-quality evidence); rates of grade 3 and 4 anaemia were higher among women receiving cisplatin- (RR 3.72, 95% CI 2.36 to 5.88; 1644 women; high-quality evidence) and carboplatin-containing regimens (RR 1.72, 95% CI 1.10 to 2.70; 1441 women; high-quality evidence); rates of grade 3 and 4 hair loss (RR 1.41, 95% CI 1.26 to 1.58; 1452 women; high-quality evidence) and leukopenia (RR 1.38, 95% CI 1.21 to 1.57; 3176 women; moderate-quality evidence) were higher among women receiving platinum-containing regimens (regardless of platinum agent). In women with metastatic breast cancer who do not have triple-negative disease, there is high-quality evidence of little or no survival benefit and excess toxicity from platinum-based regimens. There is preliminary low-quality evidence of a moderate survival benefit from platinum-based regimens for women with mTNBC. Further randomised trials of platinum-based regimens in this subpopulation of women with metastatic breast cancer are required.
A total of 12 studies with a combined total of 12,168 patients were included in this review. Antiplatelet agents reduced all cause (RR 0.76, 95% CI 0.60 to 0.98) and cardiovascular mortality (RR 0.54, 95% CI 0.32 to 0.93) in patients with IC compared with placebo. A reduction in total cardiovascular events was not statistically significant (RR 0.80, 95% CI 0.63 to 1.01). Data from two trials (which tested clopidogrel and picotamide respectively against aspirin) showed a significantly lower risk of all cause mortality (RR 0.73, 95% CI 0.58 to 0.93) and cardiovascular events (RR 0.81, 95% CI 0.67 to 0.98) with antiplatelets other than aspirin compared with aspirin. Antiplatelet therapy was associated with a higher risk of adverse events, including gastrointestinal symptoms (dyspepsia) (RR 2.11, 95% CI 1.23 to 3.61) and adverse events leading to cessation of therapy (RR 2.05, 95% CI 1.53 to 2.75) compared with placebo; data on major bleeding (RR 1.73, 95% CI 0.51, 5.83) and on adverse events in trials of aspirin versus alternative antiplatelet were limited. Risk of limb deterioration leading to revascularisation was significantly reduced by antiplatelet treatment compared with placebo (RR 0.65, 95% CI 0.43 to 0.97). Antiplatelet agents have a beneficial effect in reducing all cause mortality and fatal cardiovascular events in patients with IC. Treatment with antiplatelet agents in this patient group however is associated with an increase in adverse effects, including GI symptoms, and healthcare professionals and patients need to be aware of the potential harm as well as the benefit of therapy; more data are required on the effect of antiplatelets on major bleeding. Evidence on the effectiveness of aspirin versus either placebo or an alternative antiplatelet agent is lacking. Evidence for thienopyridine antiplatelet agents was particularly compelling and there is an urgent need for multicentre trials to compare the effects of aspirin against thienopyridines.
This review included 10 RCTs (reported in 12 articles) consisting of 2326 participants The methodological quality of the studies varied. The type of intervention was separated into three categories; AED versus placebo or standard care, alternative neuroprotective agent versus placebo or standard care and AED versus other AED. Treatment with an AED (phenytoin or carbamazepine) decreased the risk of early seizure compared with placebo or standard care (RR 0.42, 95% CI 0.23 to 0.73; very low quality evidence). There was no evidence of a difference in the risk of late seizure occurrence between AEDs and placebo or standard care (RR 0.91, 95% CI 0.57 to 1.46; very low quality evidence). There was no evidence of a significant difference in all-cause mortality between AEDs and placebo or standard care (RR 1.08 95% CI 0.79 to 1.46,very low quality of evidence). Only one study looked at other potentially neuroprotective agents (magnesium sulfate) compared with placebo. The risk ratios were: late seizure 1.07 (95% CI 0.53 to 2.17) and all-cause mortality 1.20 (95% CI 0.80 to 1.81). The risk ratio for occurrence of early seizure was not estimable. Two studies looked at comparison of two AEDs (levetiracetam, valproate) with phenytoin used as the main comparator in each study. The risk ratio for all-cause mortality was 0.53 (95% CI 0.30 to 0.94). There was no evidence of treatment benefit of phenytoin compared with another AED for early seizures (RR 0.66, 95% 0.20 to 2.12) or late seizures(RR 0.77, 95% CI 0.46 to 1.30). Only two studies reported adverse events. The RR of any adverse event with AED compared with placebo was 1.65 (95% CI 0.73 to 3.66; low quality evidence). There were insufficient data on adverse events in the other treatment comparisons. This review found low-quality evidence that early treatment with an AED compared with placebo or standard care reduced the risk of early post-traumatic seizures. There was no evidence to support a reduction in the risk of late seizures or mortality. There was insufficient evidence to make any conclusions regarding the effectiveness or safety of other neuroprotective agents compared with placebo or for the comparison of phenytoin, a traditional AED, with another AED.
Four studies enrolled approximately 1700 participants. Trials lasted between nine months to two years. Three studies were randomised controlled trials, two of which showed a cluster randomised design; one trial probably was a controlled trial with researcher controlled group assignment. In children up to three years of age in Turkey, Vitamin D compared to no intervention showed a relative risk of 0.04 (95% confidence interval (CI) 0 to 0.71). Despite a marked non-compliance, a Chinese trial in children up to three years of age comparing a combined intervention of supplementation of vitamin D, calcium and nutritional counselling showed a relative risk of 0.76 (95% CI 0.61 to 0.95) compared to no intervention. In two studies conducted in older children in China and in France no rickets occurred in both the intervention and control group. There a only few studies on the prevention of nutritional rickets in term born children. Until new data become available, it appears sound to offer preventive measures (vitamin D or calcium) to groups of high risk, like infants and toddlers; children living in Africa, Asia or the Middle East or migrated children from these regions into areas where rickets is not frequent. Due to a marked clinical heterogeneity and the scarcity of data, the main and adverse effects of preventive measures against nutritional rickets should be investigated in different countries, different age groups and in children of different ethnic origin.
Twenty studies comprising 667 participants were included in the 2006 review. In that review, there was insufficient evidence of treatment effects on major clinical outcomes to draw clinically meaningful conclusions. Searching to February 2015 identified 40 eligible studies comprising 3483 participants overall. In total, 35 studies (4039 participants) compared HF, HDF or AFB with HD, three studies (54 participants) compared AFB with HDF, and three studies (129 participants) compared HDF with HF. Risks of bias in all studies were generally high resulting in low confidence in estimated treatment effects. Convective dialysis had no significant effect on all-cause mortality (11 studies, 3396 participants: RR 0.87, 95% CI 0.72 to 1.05; I2 = 34%), but significantly reduced cardiovascular mortality (6 studies, 2889 participants: RR 0.75, 95% CI 0.61 to 0.92; I2 = 0%). One study reported no significant effect on rates of nonfatal cardiovascular events (714 participants: RR 1.14, 95% CI 0.86 to 1.50) and two studies showed no significant difference in hospitalisation (2 studies, 1688 participants: RR 1.23, 95% CI 0.93 to 1.63; I2 = 0%). One study reported rates of hypotension during dialysis were significantly reduced with convective therapy (906 participants: RR 0.72, 95% CI 0.66 to 0.80). Adverse events were not systematically evaluated in most studies and data for health-related quality of life were sparse. Convective therapies significantly reduced predialysis levels of B2 microglobulin (12 studies, 1813 participants: MD -5.55 mg/dL, 95% CI -9.11 to -1.98; I2 = 94%) and increased dialysis dose (Kt/V urea) (14 studies, 2022 participants: MD 0.07, 95% CI -0.00 to 0.14; I2 = 90%) compared to diffusive therapy, but results across studies were very heterogeneous. Sensitivity analyses limited to studies comparing HDF with HD showed very similar results. Directly comparative data for differing types of convective dialysis were insufficient to draw conclusions. Studies had important risks of bias leading to low confidence in the summary estimates and were generally limited to patients who had adequate dialysis vascular access. Convective dialysis may reduce cardiovascular but not all-cause mortality and effects on nonfatal cardiovascular events and hospitalisation are inconclusive. However, any treatment benefits of convective dialysis on all patient outcomes including cardiovascular death are unreliable due to limitations in study methods and reporting. Future studies which assess treatment effects of convection dose on patient outcomes including mortality and cardiovascular events would be informative.
We included eight studies (seven RCTs, one quasi-RCT, 315 adults (299 women), aged 18 to 75 years): six used a parallel-group design and two used a cross-over design. Sample sizes of intervention arms were five to 43 participants. Two studies, one of which was a cross-over design, compared TENS with placebo TENS (82 participants), one study compared TENS with no treatment (43 participants), and four studies compared TENS with other treatments (medication (two studies, 74 participants), electroacupuncture (one study, 44 participants), superficial warmth (one cross-over study, 32 participants), and hydrotherapy (one study, 10 participants)). Two studies compared TENS plus exercise with exercise alone (98 participants, 49 per treatment arm). None of the studies measured participant-reported pain relief of 50% or greater or PGIC. Overall, the studies were at unclear or high risk of bias, and in particular all were at high risk of bias for sample size. Only one study (14 participants) measured the primary outcome participant-reported pain relief of 30% or greater. Thirty percent achieved 30% or greater reduction in pain with TENS and exercise compared with 13% with exercise alone. One study found 10/28 participants reported pain relief of 25% or greater with TENS compared with 10/24 participants using superficial warmth (42 °C). We judged that statistical pooling was not possible because there were insufficient data and outcomes were not homogeneous. There were no data for the primary outcomes participant-reported pain relief from baseline of 50% or greater and PGIC. There was a paucity of data for secondary outcomes. One pilot cross-over study of 43 participants found that the mean (95% confidence intervals (CI)) decrease in pain intensity on movement (100-mm visual analogue scale (VAS)) during one 30-minute treatment was 11.1 mm (95% CI 5.9 to 16.3) for TENS and 2.3 mm (95% CI 2.4 to 7.7) for placebo TENS. There were no significant differences between TENS and placebo for pain at rest. One parallel group study of 39 participants found that mean ± standard deviation (SD) pain intensity (100-mm VAS) decreased from 85 ± 20 mm at baseline to 43 ± 20 mm after one week of dual-site TENS; decreased from 85 ± 10 mm at baseline to 60 ± 10 mm after single-site TENS; and decreased from 82 ± 20 mm at baseline to 80 ± 20 mm after one week of placebo TENS. The authors of seven studies concluded that TENS relieved pain but the findings of single small studies are unlikely to be correct. One study found clinically important improvements in Fibromyalgia Impact Questionnaire (FIQ) subscales for work performance, fatigue, stiffness, anxiety, and depression for TENS with exercise compared with exercise alone. One study found no additional improvements in FIQ scores when TENS was added to the first three weeks of a 12-week supervised exercise programme. No serious adverse events were reported in any of the studies although there were reports of TENS causing minor discomfort in a total of 3 participants. The quality of evidence was very low. We downgraded the GRADE rating mostly due to a lack of data; therefore, we have little confidence in the effect estimates where available. There was insufficient high-quality evidence to support or refute the use of TENS for fibromyalgia. We found a small number of inadequately powered studies with incomplete reporting of methodologies and treatment interventions.
Our systematic review included seven studies with a total of 492 participants. We included 422 participants in our analysis. Thirteen studies are awaiting classification. For the comparison dexmedetomidine versus placebo (six studies, 402 participants), most studies found a reduction in 'rescue' opioid consumption in the first 24 hours after surgery, together with in general no clinically important differences in postoperative pain (visual analogue scale (VAS) 0 to 100 mm, where 0 = no pain and 100 = worst imaginable pain) in the first 24 hours after surgery - except for one study (80 participants) with a reduction in VAS pain at two hours after surgery in favour of dexmedetomidine, with a mean difference of -30.00 mm (95% confidence interval (CI) -38.25 to -21.75). As the result of substantial heterogeneity, pooling of data in statistical meta-analyses was not appropriate. The quality of evidence was very low for our primary outcomes because of imprecision of results and risk of bias. Regarding our secondary aims, evidence was too scant in general to allow robust conclusions, or the estimates too imprecise or of poor methodological quality. Regarding adverse effects, low quality data (one study, 80 participants) suggest that the proportion of participants with hypotension requiring intervention was slightly higher in the high-dose dexmedetomidine group with a risk ratio of 2.50 (95% CI 0.94 to 6.66), but lower doses of dexmedetomidine led to no differences compared with control. Evidence for the comparison dexmedetomidine versus fentanyl was insufficient to permit robust conclusions (one study, 20 participants). Dexmedetomidine, when administered perioperatively for acute pain after abdominal surgery in adults, seemed to have some opioid-sparing effect together with in general no important differences in postoperative pain when compared with placebo. However the quality of the evidence was very low as the result of imprecision, methodological limitations and substantial heterogeneity among the seven included studies. The clinical importance for patients is uncertain, in as much as the influence of dexmedetomidine on patient-important outcomes such as gastrointestinal function, mobilization and adverse effects could not be satisfactorily determined. All included studies were relatively small, and publication bias could not be ruled out. Applicability of evidence was limited to middle-aged participants who were relatively free of co-morbidity and were undergoing elective abdominal surgery. A potential bias was a considerable quantity of unobtainable data from studies with mixed surgery. To detect and investigate patient-important outcomes, larger studies with longer periods of follow-up are needed.
The review included eight randomised controlled trials. Approximately 4300 women were recruited to detect the effect of prophylactic antibiotic administration on pregnancy outcomes. Primary outcomes Antibiotic prophylaxis did not reduce the risk of preterm prelabour rupture of membranes (risk ratio (RR) 0.31; 95% confidence interval (CI) 0.06 to 1.49 (one trial, 229 women), low quality evidence) or preterm delivery (RR 0.88; 95% CI 0.72 to 1.09 (six trials, 3663 women), highquality evidence). However, preterm delivery was reduced in the subgroup of pregnant women with a previous preterm birth who had bacterial vaginosis (BV) during the current pregnancy (RR 0.64; 95% CI 0.47 to 0.88 (one trial, 258 women)), but there was no reduction in the subgroup of pregnant women with previous preterm birth without BV during the pregnancy (RR 1.08; 95% CI 0.66 to 1.77 (two trials, 500 women)). A reduction in the risk of postpartum endometritis (RR 0.55; 95% CI 0.33 to 0.92 (one trial, 196 women)) was observed in high-risk pregnant women (women with a history of preterm birth, low birthweight, stillbirth or early perinatal death) and in all women (RR 0.53; 95% CI 0.35 to 0.82 (three trials, 627 women), moderate quality evidence). There was no difference in low birthweight (RR 0.86; 95% CI 0.53 to 1.39 (four trials; 978 women)) or neonatal sepsis (RR 11.31; 95% CI 0.64 to 200.79) (one trial, 142 women)); and blood culture confirming sepsis was not reported in any of the studies. Secondary outcomes Antibiotic prophylaxis reduced the risk of prelabour rupture of membranes (RR 0.34; 95% CI 0.15 to 0.78 (one trial, 229 women), low quality evidence) and gonococcal infection (RR 0.35; 95% CI 0.13 to 0.94 (one trial, 204 women)). There were no differences observed in other secondary outcomes (congenital abnormality; small-for-gestational age; perinatal mortality), whilst many other secondary outcomes (e.g. intrapartum fever needing treatment with antibiotics) were not reported in included trials. Regarding the route of antibiotic administration, vaginal antibiotic prophylaxis during pregnancy did not prevent infectious pregnancy outcomes. The overall risk of bias was low, except that incomplete outcome data produced high risk of bias in some studies. The quality of the evidence using GRADE was assessed as low for preterm prelabour rupture of membranes, high for preterm delivery, moderate for postpartum endometritis, low for prelabour rupture of membranes, and very low for chorioamnionitis. Intrapartum fever needing treatment with antibiotics was not reported in any of the included studies. Antibiotic prophylaxis did not reduce the risk of preterm prelabour rupture of membranes or preterm delivery (apart from in the subgroup of women with a previous preterm birth who had bacterial vaginosis). Antibiotic prophylaxis given during the second or third trimester of pregnancy reduced the risk of postpartum endometritis, term pregnancy with pre-labour rupture of membranes and gonococcal infection when given routinely to all pregnant women. Substantial bias possibly exists in the review's results because of a high rate of loss to follow-up and the small numbers of studies included in each of our analyses. There is also insufficient evidence on possible harmful effects on the baby. Therefore, we conclude that there is not enough evidence to support the use of routine antibiotics during pregnancy to prevent infectious adverse effects on pregnancy outcomes.
Six RCTs compared the effect of oral ascorbic acid (1 to 4 grams) and placebo treatment in CMT1A. In five trials involving adults with CMT1A, a total of 622 participants received ascorbic acid or placebo. Trials were largely at low risk of bias. There is high-quality evidence that ascorbic acid does not improve the course of CMT1A in adults as measured by the CMT neuropathy score (0 to 36 scale) at 12 months (mean difference (MD) -0.37; 95% confidence intervals (CI) -0.83 to 0.09; five studies; N = 533), or at 24 months (MD -0.21; 95% CI -0.81 to 0.39; three studies; N = 388). Ascorbic acid treatment showed a positive effect on the nine-hole peg test versus placebo (MD -1.16 seconds; 95% CI -1.96 to -0.37), but the clinical significance of this result is probably small. Meta-analyses of other secondary outcome parameters showed no relevant benefit of ascorbic acid. In one trial, 80 children with CMT1A received ascorbic acid or placebo. The trial showed no clinical benefit of ascorbic acid treatment. Adverse effects did not differ in their nature or abundance between ascorbic acid and placebo. High-quality evidence indicates that ascorbic acid does not improve the course of CMT1A in adults in terms of the outcome parameters used. According to low-quality evidence, ascorbic acid does not improve the course of CMT1A in children. However, CMT1A is slowly progressive and the outcome parameters show only small change over time. Longer study durations should be considered, and outcome parameters more sensitive to change over time should be designed and validated for future studies.
Eleven studies with 1053 patients (550 on dipyrone) met the inclusion criteria. Unfortunately, few data were available for analysis; most analyses were based on the results of single, small trials and statistical pooling of the results was inappropriate. Efficacy estimates were calculated as the weighted mean percent of patients achieving at least 50% pain relief with the range of values from trials contributing to the analysis. However, these estimates were not robust. Commonly reported adverse effects with intravenous dipyrone were dry mouth and somnolence, and one study reported pain at the injection site. Insufficient information was available for safety analyses. Limited available data indicated that single dose dipyrone was of similar efficacy to other analgesics used in renal colic pain, although intramuscular dipyrone was less effective than diclofenac 75 mg. Combining dipyrone with antispasmolytic agents did not appear to improve its efficacy. Intravenous dipyrone was more effective than intramuscular dipyrone. Dry mouth and somnolence were commonly reported with intravenous dipyrone. None of the studies reported agranulocytosis.
We found three trials (involving 1915 babies) for inclusion in the review, but have included only two trials (involving 1302 healthy full-term breastfeeding infants) in the analysis. Meta-analysis of the two combined studies showed that pacifier use in healthy breastfeeding infants had no significant effect on the proportion of infants exclusively breastfed at three months (risk ratio (RR) 1.01; 95% confidence interval (CI) 0.96 to 1.07, two studies, 1228 infants), and at four months of age (RR 1.01; 95% CI 0.94 to 1.09, one study, 970 infants, moderate-quality evidence), and also had no effect on the proportion of infants partially breastfed at three months (RR 1.00; 95% CI 0.98 to 1.02, two studies, 1228 infants), and at four months of age (RR 0.99; 95% CI 0.97 to 1.02, one study, 970 infants). None of the included trials reported data on the other primary outcomes, i.e. duration of partial or exclusive breastfeeding, or secondary outcomes: breastfeeding difficulties (mastitis, cracked nipples, breast engorgement); infant's health (dental malocclusion, otitis media, oral candidiasis; sudden infant death syndrome (SIDS)); maternal satisfaction and level of confidence in parenting. One study reported that avoidance of pacifiers had no effect on cry/fuss behavior at ages four, six, or nine weeks and also reported no effect on the risk of weaning before age three months, however the data were incomplete and so could not be included for analysis. Pacifier use in healthy term breastfeeding infants, started from birth or after lactation is established, did not significantly affect the prevalence or duration of exclusive and partial breastfeeding up to four months of age. Evidence to assess the short-term breastfeeding difficulties faced by mothers and long-term effect of pacifiers on infants' health is lacking.
Five studies met the inclusion criteria. Three included studies compared extended-field RT versus pelvic RT, one included study compared extended-field RT with pelvic CRT, and one study compared extended-field CRT versus pelvic CRT. Extended-field radiotherapy versus pelvic radiotherapy alone Compared to pelvic RT, extended-field RT probably reduces the risk of death (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.48 to 0.94; 1 study; 337 participants; moderate-certainty evidence) and para-aortic lymph node recurrence (risk ratio (RR) 0.36, 95% CI 0.18 to 0.70; 2 studies; 477 participants; moderate-certainty evidence), although there may or may not have been improvement in the risk of disease progression (HR 0.92, 95% CI 0.69 to 1.22; 1 study; 337 participants; moderate-certainty evidence) and severe adverse events (RR 1.05, 95% CI 0.79 to 1.41; 2 studies; 776 participants; moderate-certainty evidence). Extended-field radiotherapy versus pelvic chemoradiotherapy In a comparison of extended-field RT versus pelvic CRT, women given pelvic CRT probably had a lower risk of death (HR 0.50, 95% CI 0.39 to 0.64; 1 study; 389 participants; moderate-certainty evidence) and disease progression (HR 0.52, 95% CI 0.37 to 0.72; 1 study; 389 participants; moderate-certainty evidence). Participants given extended-field RT may or may not have had a lower risk of para-aortic lymph node recurrence (HR 0.44, 95% CI 0.20 to 0.99; 1 study; 389 participants; low-certainty evidence) and acute severe adverse events (RR 0.05, 95% CI 0.02 to 0.11; 1 study; 388 participants; moderate-certainty evidence). There were no clear differences in terms of late severe adverse events among the comparison groups (RR 1.06, 95% CI 0.69 to 1.62; 1 study; 386 participants; moderate-certainty evidence). Extended-field chemoradiotherapy versus pelvic chemoradiotherapy Very low-certainty evidence obtained from one small study (74 participants) showed that, compared to pelvic CRT, extended-field CRT may or may not have reduced risk of death (HR 0.37, 95% CI 0.14 to 0.96) and disease progression (HR 0.25, 95% CI 0.07 to 0.87). There were no clear differences between the groups in the risks of para-aortic lymph node recurrence (RR 0.19, 95% CI 0.02 to 1.54; very low-certainty evidence) and severe adverse events (acute: RR 0.95, 95% CI 0.20 to 4.39; late: RR 0.95, 95% CI 0.06 to 14.59; very low-certainty evidence). Moderate-certainty evidence shows that, compared with pelvic RT alone, extended-field RT probably improves overall survival and reduces risk of para-aortic lymph node recurrence. However, pelvic RT alone would now be considered substandard treatment, so this result cannot be extrapolated to modern standards of care. Low- to moderate-certainty evidence suggests that pelvic CRT may increase overall and progression-free survival compared to extended-field RT, although there may or may not be a higher rate of para-aortic recurrence and acute adverse events. Extended-field CRT versus pelvic CRT may improve overall or progression-free survival, but these findings should be interpreted with caution due to very low-certainty evidence. High-quality RCTs, comparing modern treatment techniques in CRT, are needed to more fully inform treatment for locally advanced cervical cancer without obvious para-aortic node involvement.
Eleven trials met the inclusion criteria. Ten trials (1460 infants) compared vitamin A supplementation with a control and one (120 infants) compared different regimens of vitamin A supplementation. Compared to the control group, vitamin A appeared to have a small benefit in reducing the risk of death or oxygen requirement at one month of age (typical RR 0.93, 95% CI 0.88 to 0.99; typical RD −0.05, 95% CI −0.10 to −0.01; NNTB 20, 95% CI 10 to 100; 6 studies, 1165 infants) and the risk of chronic lung disease (oxygen requirement) at 36 weeks' postmenstrual age (typical RR 0.87, 95% CI 0.77 to 0.99; typical RD −0.07, 95% CI −0.13 to −0.01; NNTB 11, 95% CI 6 to 100; 5 studies, 986 infants) (moderate-quality evidence). There was a marginal reduction of the combined outcome of death or chronic lung disease (typical RR 0.92, 95% CI 0.84 to 1.01; typical RD −0.05, 95% CI −0.11 to 0.01; 4 studies, 1089 infants). Neurodevelopmental assessment of 88% of the surviving infants in the largest trial showed no difference between the groups at 18 to 22 months of age, corrected for prematurity (low-quality evidence). There is no evidence to support different vitamin A dosing regimens. No adverse effects of vitamin A supplementation were reported, but it was noted that intramuscular injections of vitamin A were painful. Whether clinicians decide to utilise repeat intramuscular doses of vitamin A to prevent chronic lung disease may depend upon the local incidence of this outcome and the value attached to achieving a modest reduction in the outcome balanced against the lack of other proven benefits and the acceptability of the treatment. Information on long-term neurodevelopmental status suggests no evidence of either benefit or harm from the intervention.
We identified 23 studies (16 RCTs, 6 of high quality), including 37,561 participants and 4042 family caregivers, largely with advanced cancer but also congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), HIV/AIDS and multiple sclerosis (MS), among other conditions. Meta-analysis showed increased odds of dying at home (odds ratio (OR) 2.21, 95% CI 1.31 to 3.71; Z = 2.98, P value = 0.003; Chi2 = 20.57, degrees of freedom (df) = 6, P value = 0.002; I2 = 71%; NNTB 5, 95% CI 3 to 14 (seven trials with 1222 participants, three of high quality)). In addition, narrative synthesis showed evidence of small but statistically significant beneficial effects of home palliative care services compared to usual care on reducing symptom burden for patients (three trials, two of high quality, and one CBA with 2107 participants) and of no effect on caregiver grief (three RCTs, two of high quality, and one CBA with 2113 caregivers). Evidence on cost-effectiveness (six studies) is inconclusive. The results provide clear and reliable evidence that home palliative care increases the chance of dying at home and reduces symptom burden in particular for patients with cancer, without impacting on caregiver grief. This justifies providing home palliative care for patients who wish to die at home. More work is needed to study cost-effectiveness especially for people with non-malignant conditions, assessing place of death and appropriate outcomes that are sensitive to change and valid in these populations, and to compare different models of home palliative care, in powered studies.
We identified two eligible studies with small numbers of infants enrolled (64 infants). Prophylaxis with cromolyn sodium did not result in a statistically significant effect on the combined outcome of mortality and CLD at 28 days (typical RR 1.05, 95% CI 0.73 to 1.52; typical RD 0.03, 95% CI -0.20 to 0.27; 2 trials, 64 infants; I2 = 0% for both RR and RD); mortality at 28 days (typical RR 1.31, 95% CI 0.52 to 3.29; I2 = 73% typical RD 0.06, 95% CI -0.13 to 0.26; I2 = 87%; 2 trials, 64 infants) (very low quality evidence); CLD at 28 days (typical RR 0.93, 95% CI 0.53 to 1.64; I2 = 40%; typical RD -0.03, 95% CI -0.27 to 0.20; I2 = 38%; 2 trials, 64 infants) or at 36 weeks' PMA (RR 1.25, 95% CI 0.43 to 3.63; RD 0.08, 95% CI -0.29 to 0.44; 1 trial, 26 infants). There was no significant difference in CLD in survivors at 28 days (typical RR 0.97, 95% CI 0.58 to 1.63; typical RD -0.02, 95% CI -0.29 to 0.26; I2 = 0% for both RR and RD; 2 trials, 50 infants) or at 36 weeks' PMA (RR 1.04, 95% CI 0.38 to 2.87; RD 0.02, 95% CI -0.40 to 0.43; 1 trial, 22 infants). Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall neonatal mortality, incidence of air leaks, necrotising enterocolitis, intraventricular haemorrhage, sepsis, and days of mechanical ventilation. There were no adverse effects noted. The quality of evidence according to GRADE was very low for one outcome (mortality to 28 days) and low for all other outcomes. The reasons for downgrading the evidence was due to design (risk of bias in one study), inconsistency between the two studies (high I2 values for mortality at 28 days for both RR and RD), and lack of precision of estimates (small sample sizes). Further research does not seem to be justified. There is currently no evidence from randomised trials that cromolyn sodium has a role in the prevention of CLD. Cromolyn sodium cannot be recommended for the prevention of CLD in preterm infants.
We obtained data from 18 trials and 2074 patients for the first comparison. Considering these trials together there was a high level of statistical heterogeneity, a substantial amount of which was explained by analyses of trial groups. Trials using chemotherapy cycle lengths shorter than 14 days (HR = 0.83, 95% CI = 0.69 to 1.00, p = 0.046) or cisplatin dose intensities greater than 25 mg/m2 per week (HR = 0.91, 95% CI = 0.78 to 1.05, p = 0.20) tended to show an advantage of neoadjuvant chemotherapy on survival. In contrast, trials using cycle lengths longer than 14 days (HR = 1.25, 95% CI = 1.07 to 1.46, p = 0.005) or cisplatin dose intensities lower than 25 mg/m2 per week (HR = 1.35, 95% CI = 1.11 to 1.14, p = 0.002) showed a detrimental effect of neoadjuvant chemotherapy on survival. In the second comparison, data from 5 trials and 872 patients were obtained. The combined results (HR = 0.65, 95% CI = 0.53 to 0.80, p = 0.0004) indicated a highly significant reduction in the risk of death with neoadjuvant chemotherapy, but with heterogeneity in both the design and results. The timing and dose intensity of cisplatin-based neoadjuvant chemotherapy appears to have an important impact on whether or not it benefits women with locally advanced cervical cancer and warrants further exploration. Obtaining additional IPD may improve the strength of these conclusions.
Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or dose-adjusted warfarin. Four studies used a central, interactive, automated response system for allocation concealment while the other did not specify concealment methods. Four studies were blinded while the other was partially open-label. However, given that all studies involved blinded evaluation of outcome events, we considered the risk of bias to be low. We were unable to create funnel plots due to the small number of studies, thwarting assessment of publication bias. Study duration ranged from 1.8 to 2.8 years. The large majority of participants included in this study were CKD stage G3 (12,155), and a small number were stage G4 (390). Of 12,545 participants from five studies, a total of 321 cases (2.56%) of the primary efficacy outcome occurred per year. Further, of 12,521 participants from five studies, a total of 617 cases (4.93%) of the primary safety outcome occurred per year. DOAC appeared to probably reduce the incidence of stroke and systemic embolism events (5 studies, 12,545 participants: RR 0.81, 95% CI 0.65 to 1.00; moderate certainty evidence) and to slightly reduce the incidence of major bleeding events (5 studies, 12,521 participants: RR 0.79, 95% CI 0.59 to 1.04; low certainty evidence) in comparison with warfarin. Our findings indicate that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. These findings should encourage physicians to prescribe DOAC in AF patients with CKD without fear of bleeding. The major limitation is that the results of this study chiefly reflect CKD stage G3. Application of the results to CKD stage G4 patients requires additional investigation. Furthermore, we could not assess CKD stage G5 patients. Future reviews should assess participants at more advanced CKD stages. Additionally, we could not conduct detailed analyses of subgroups and sensitivity analyses due to lack of data.
Eight studies were identified but only seven trials enrolling 1410 preterm infants were located. There was no significant difference detected in neonatal mortality or neurodevelopmental outcome at two years between infants treated with ethamsylate and controls. Infants treated with ethamsylate had significantly less intraventricular haemorrhage than controls at < 31 weeks (typical RR 0.63, 95% CI 0.47 to 0.86) and < 35 weeks gestation (typical RR 0.77, 0.65 to 0.92). There was also a significant reduction in grade 3 and 4 intraventricular haemorrhage when all infants < 35 weeks gestation (typical RR 0.67, 95% CI 0.49 to 0.94) were analysed as a single group, but not for the group of infants < 32 weeks alone. There was a reduction in symptomatic patent ductus arteriosus at < 31 weeks gestation (typical RR 0.32, 95% CI 0.12 to 0.87). There were no adverse effects of ethamsylate identified from this systematic review. Preterm infants treated with ethamsylate showed no reductions in mortality or neurodevelopmental impairment despite the reduction in any grade of intraventricular haemorrhage seen in infants < 35 weeks gestation.
We included 22 RCTs (2902 women). Participants were from different ethnic backgrounds with the majority of Chinese origin. When CHM was compared with placebo (eight RCTs), there was little or no evidence of a difference between the groups for the following pooled outcomes: hot flushes per day (MD 0.00, 95% CI -0.88 to 0.89; 2 trials, 199 women; moderate quality evidence); hot flushes per day assessed by an overall hot flush score in which a difference of one point equates to one mild hot flush per day (MD -0.81 points, 95% CI -2.08 to 0.45; 3 RCTs, 263 women; low quality evidence); and overall vasomotor symptoms per month measured by the Menopause-Specific Quality of Life questionnaire (MENQOL, scale 0 to 6) (MD -0.42 points; 95% CI -1.52 to 0.68; 3 RCTs, 256 women; low quality evidence). In addition, results from individual studies suggested there was no evidence of a difference between the groups for daily hot flushes assessed by severity (MD -0.70 points, 95% CI -1.00, -0.40; 1 RCT, 108 women; moderate quality evidence); or overall monthly hot flushes scores (MD -2.80 points, 95% CI -8.93 to 3.33; 1 RCT, 84 women; very low quality evidence); or overall daily night sweats scores (MD 0.07 points, 95% CI -0.19 to 0.33, 1 RCT, 64 women; low quality evidence); or overall monthly night sweats scores (MD 1.30 points, 95% CI -1.76 to 4.36, 1 RCT, 84 women; very low quality evidence). However one study using the Kupperman Index reported that overall monthly vasomotor symptom scores were lower in the CHM group (MD -4.79 points, 95% CI -5.52 to -4.06; 1 RCT, 69 women; low quality evidence). When CHM was compared with hormone therapy (HT) (10 RCTs), only two RCTs reported monthly vasomotor symptoms using MENQOL. It was uncertain whether CHM reduces vasomotor symptoms (MD 0.47 points, 95% CI -0.50 to 1.44; 2 RCTs, 127 women; very low quality evidence). Adverse effects were not fully reported in the included studies. Adverse events reported by women taking CHM included mild diarrhoea, breast tenderness, gastric discomfort and an unpleasant taste. Effects were inconclusive because of imprecise estimates of effects: CHM versus placebo (RR 1.51; 95% CI 0.69 to 3.33; 7 trials, 705 women; I² = 40%); CHM versus HT (RR 0.96; 95% CI 0.66 to 1.39; 2 RCTs, 864 women; I² = 0%); and CHM versus specific conventional medications (such as Fluoxetine and Estazolam) (RR 0.20; 95% CI 0.03 to 1.17; 2 RCTs, 139 women; I² = 61%). We found insufficient evidence that Chinese herbal medicines were any more or less effective than placebo or HT for the relief of vasomotor symptoms. Effects on safety were inconclusive. The quality of the evidence ranged from very low to moderate; there is a need for well-designed randomised controlled studies.
This updated review includes 30 studies (one RCT with two arms and 29 observational studies) with a total of 99,224 participants. We included 19 studies in the original review (n = 3459), all of which were observational, with 13 studies included in the meta-analysis for mortality. We included 12 new studies in this update (one RCT and 11 observational studies), and excluded one study in the original review as it has been superceded by a more recent analysis. Twenty-one studies were included in the meta-analysis (9536 individuals), of which 15 studied people infected with 2009 influenza A H1N1 virus (H1N1pdm09). Data specific to mortality were of very low quality, based predominantly on observational studies, with inconsistent reporting of variables potentially associated with the outcomes of interest, differences between studies in the way in which they were conducted, and with the likelihood of potential confounding by indication. Reported doses of corticosteroids used were high, and indications for their use were not well reported. On meta-analysis, corticosteroid therapy was associated with increased mortality (odds ratio (OR) 3.90, 95% confidence interval (CI) 2.31 to 6.60; I2 = 68%; 15 studies). A similar increase in risk of mortality was seen in a stratified analysis of studies reporting adjusted estimates (OR 2.23, 95% CI 1.54 to 3.24; I2 = 0%; 5 studies). An association between corticosteroid therapy and increased mortality was also seen on pooled analysis of six studies which reported adjusted hazard ratios (HRs) (HR 1.49, 95% CI 1.09 to 2.02; I2 = 69%). Increased odds of hospital-acquired infection related to corticosteroid therapy were found on pooled analysis of seven studies (pooled OR 2.74, 95% CI 1.51 to 4.95; I2 = 90%); all were unadjusted estimates, and we graded the data as of very low certainty. We found one RCT of adjunctive corticosteroid therapy for treating people with community-acquired pneumonia, but the number of people with laboratory-confirmed influenza in the treatment and placebo arms was too small to draw conclusions regarding the effect of corticosteroids in this group, and we did not include it in our meta-analyses of observational studies. The certainty of the available evidence from observational studies was very low, with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy is associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high-quality research is needed (both RCTs and observational studies that adjust for confounding by indication). The currently available evidence is insufficient to determine the effectiveness of corticosteroids for people with influenza.
Thirty one studies (contributing 33 data sets), randomising 534 participants met the inclusion criteria of the review. Oxygen improved all pooled outcomes relating to endurance exercise capacity (distance, time, number of steps) and maximal exercise capacity (exercise time and work rate). Data relating to VO2 max could not be pooled and results from the original studies were not consistent. For the secondary outcomes of breathlessness, SaO2 and VE, comparisons were made at isotime. In all studies except two the isotime is defined as the time at which the placebo test ended. Oxygen improved breathlessness, SaO2/PaO2 and VE at isotime with endurance exercise testing. There was no data on breathlessness at isotime with maximal exercise testing. Oxygen improved SaO2/PaO2 and reduced VE at Isotime. This review provides some evidence from small, single assessment studies that ambulatory oxygen improves exercise performance in people with moderate to severe COPD. The results of the review may be affected by publication bias, and the small sample sizes in the studies. Although positive, the findings of the review require replication in larger trials with more distinct subgroups of participants. Maximal or endurance tests can be used in ambulatory oxygen assessment. Consideration should be given to the measurement of SaO2 and breathlessness at isotime as these provide important additional information. We recommend that these outcomes are included in the assessment for ambulatory oxygen. Future research needs to establish the level of benefit of ambulatory oxygen in specific subgroups of people with COPD.
We found two studies that met our inclusion criteria but they were of unclear quality. One study, involving 307 women, compared vaginal examinations with rectal examinations, and the other study, involving 150 women, compared two-hourly with four-hourly vaginal examinations. Both studies were of unclear quality in terms of risk of selection bias, and the study comparing the timing of the vaginal examinations excluded 27% (two hourly) to 28% (four hourly) of women after randomisation because they no longer met the inclusion criteria. When comparing routine vaginal examinations with routine rectal examinations to assess the progress of labour, we identified no difference in neonatal infections requiring antibiotics (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 8.07, one study, 307 infants). There were no data on the other primary outcomes of length of labour, maternal infections requiring antibiotics and women's overall views of labour. The study did show that significantly fewer women reported that vaginal examination was very uncomfortable compared with rectal examinations (RR 0.42, 95% CI 0.25 to 0.70, one study, 303 women). We identified no difference in the secondary outcomes of augmentation, caesarean section, spontaneous vaginal birth, operative vaginal birth, perinatal mortality and admission to neonatal intensive care. Comparing two-hourly vaginal examinations with four-hourly vaginal examinations in labour, we found no difference in length of labour (mean difference in minutes (MD) -6.00, 95% CI -88.70 to 76.70, one study, 109 women). There were no data on the other primary outcomes of maternal or neonatal infections requiring antibiotics, and women's overall views of labour. We identified no difference in the secondary outcomes of augmentation, epidural for pain relief, caesarean section, spontaneous vaginal birth and operative vaginal birth. On the basis of women's preferences, vaginal examination seems to be preferred to rectal examination. For all other outcomes, we found no evidence to support or reject the use of routine vaginal examinations in labour to improve outcomes for women and babies. The two studies included in the review were both small, and carried out in high-income countries in the 1990s.  It is surprising that there is such a widespread use of this intervention without good evidence of effectiveness, particularly considering the sensitivity of the procedure for the women receiving it, and the potential for adverse consequences in some settings. The effectiveness of the use and timing of routine vaginal examinations in labour, and other ways of assessing progress in labour, including maternal behavioural cues, should be the focus of new research as a matter of urgency. Women's views of ways of assessing labour progress should be given high priority in any future research in this area.
Eight trials comprising 468 participants were included. For the primary outcome of subjective tinnitus loudness we found no evidence of a difference between CBT and no treatment or another intervention (yoga, education and 'minimal contact - education'). In the secondary outcomes we found evidence that quality of life scores were improved in participants who had tinnitus when comparing CBT to no treatment or another intervention (education and 'minimal contact education'). We also found evidence that depression scores improved when comparing CBT to no treatment. We found no evidence of benefit in depression scores when comparing CBT to other treatments (yoga, education and 'minimal contact - education'). There were no adverse/side effects reported in any trial. In six studies we found no evidence of a significant difference in the subjective loudness of tinnitus. However, we found a significant improvement in depression score (in six studies) and quality of life (decrease of global tinnitus severity) in another five studies, suggesting that CBT has a positive effect on the management of tinnitus.
We included four cross-over RCTs with a total of 209 participants, ranging in age from 23 to 85 and with a preponderance of men. All the studies allowed the use of hearing aids for a total period of at least eight weeks before questions on preference were asked. All studies recruited patients with bilateral hearing loss but there was considerable variation in the types and degree of sensorineural hearing loss that the participants were experiencing. Three of the studies were published before the mid-1990s whereas the fourth study was published in 2011. Therefore, only the most recent study used hearing aids incorporating technology comparable to that currently readily available in high-income settings. Of the four studies, two were conducted in the UK in National Health Service (NHS – public sector) patients: one recruited patients from primary care with hearing loss detected by a screening programme whereas the other recruited patients who had been referred by their primary care practitioner to an otolaryngology department for hearing aids. The other two studies were conducted in the United States: one study recruited only military personnel or veterans with noise-induced hearing loss whereas about half of the participants in the other study were veterans. Only one primary outcome (patient preference) was reported in all studies. The percentage of patients who preferred bilateral hearing aids varied between studies: this was 54% (51 out of 94 participants), 39% (22 out of 56), 55% (16 out of 29) and 77% (23 out of 30), respectively. We have not combined the data from these four studies. The evidence for this outcome is of very low quality. The other outcomes of interest were not reported in the included studies. This review identified only four studies comparing the use of one hearing aid with two. The studies were small and included participants of widely varying ages. There was also considerable variation in the types and degree of sensorineural hearing loss that the participants were experiencing. For the most part, the types of hearing aid evaluated would now be regarded, in high-income settings, as 'old technology', with only one study looking at 'modern' digital aids. However, the relevance of this is uncertain, as this review did not evaluate the differences in outcomes between the different types of technology. We were unable to pool data from the four studies and the very low quality of the evidence leads us to conclude that we do not know if people with hearing loss have a preference for one aid or two. Similarly, we do not know if hearing-specific health-related quality of life, or any of our other outcomes, are better with bilateral or unilateral aids.
We included 17 relevant trials (with 556 review-relevant participants) which we categorised into three types of interventions: (1) various exposures to bright light (n = 10); (2) various opportunities for napping (n = 4); and (3) other interventions, such as physical exercise or sleep education (n = 3). In most instances, the studies were too heterogeneous to pool. Most of the comparisons yielded low to very low quality evidence. Only one comparison provided moderate quality evidence. Overall, the included studies’ results were inconclusive. We present the results regarding sleepiness below. Bright light Combining two comparable studies (with 184 participants altogether) that investigated the effect of bright light during the night on sleepiness during a shift, revealed a mean reduction 0.83 score points of sleepiness (measured via the Stanford Sleepiness Scale (SSS) (95% confidence interval (CI) -1.3 to -0.36, very low quality evidence). Another trial did not find a significant difference in overall sleepiness on another sleepiness scale (16 participants, low quality evidence). Bright light during the night plus sunglasses at dawn did not significantly influence sleepiness compared to normal light (1 study, 17 participants, assessment via reaction time, very low quality evidence). Bright light during the day shift did not significantly reduce sleepiness during the day compared to normal light (1 trial, 61 participants, subjective assessment, low quality evidence) or compared to normal light plus placebo capsule (1 trial, 12 participants, assessment via reaction time, very low quality evidence). Napping during the night shift A meta-analysis on a single nap opportunity and the effect on the mean reaction time as a surrogate for sleepiness, resulted in a 11.87 ms reduction (95% CI 31.94 to -8.2, very low quality evidence). Two other studies also reported statistically non-significant decreases in reaction time (1 study seven participants; 1 study 49 participants, very low quality evidence). A two-nap opportunity resulted in a statistically non-significant increase of sleepiness (subjective assessment) in one study (mean difference (MD) 2.32, 95% CI -24.74 to 29.38, 1 study, 15 participants, low quality evidence). Other interventions Physical exercise and sleep education interventions showed promise, but sufficient data to draw conclusions are lacking. Given the methodological diversity of the included studies, in terms of interventions, settings, and assessment tools, their limited reporting and the very low to low quality of the evidence they present, it is not possible to determine whether shift workers' sleepiness can be reduced or if their sleep length or quality can be improved with these interventions. We need better and adequately powered RCTs of the effect of bright light, and naps, either on their own or together and other non-pharmacological interventions that also consider shift workers’ chronobiology on the investigated sleep parameters.
Twenty-nine trial comparisons involving 11,306 participants contributed to the meta-analysis on the risk ratio (RR) of developing a cold whilst taking vitamin C regularly over the study period. In the general community trials involving 10,708 participants, the pooled RR was 0.97 (95% confidence interval (CI) 0.94 to 1.00). Five trials involving a total of 598 marathon runners, skiers and soldiers on subarctic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64). Thirty-one comparisons examined the effect of regular vitamin C on common cold duration (9745 episodes). In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration. Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the duration or severity of colds in the therapeutic trials. The majority of included trials were randomised, double-blind trials. The exclusion of trials that were either not randomised or not double-blind had no effect on the conclusions. The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted.
In this review, we included 22 RCTs that investigated the use of T-cell antibody induction, with a total of 1427 heart-transplant recipients. All trials were judged to be at a high risk of bias. Five trials, with a total of 606 participants, compared any kind of T-cell antibody induction versus no antibody induction; four trials, with a total of 576 participants, compared interleukin-2 receptor antagonist (IL-2 RA) versus no induction; one trial, with 30 participants, compared monoclonal antibody (other than IL-2 RA) versus no antibody induction; two trials, with a total of 159 participants, compared IL-2 RA versus monoclonal antibody (other than IL-2 RA) induction; four trials, with a total of 185 participants, compared IL-2 RA versus polyclonal antibody induction; seven trials, with a total of 315 participants, compared monoclonal antibody (other than IL-2 RA) versus polyclonal antibody induction; and four trials, with a total of 162 participants, compared polyclonal antibody induction versus another kind, or dose of polyclonal antibodies. No significant differences were found for any of the comparisons for the outcomes of mortality, infection, CMV infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, or hyperlipidaemia. Acute rejection occurred significantly less frequently when IL-2 RA induction was compared with no induction (93/284 (33%) versus 132/292 (45%); RR 0.73; 95% CI 0.59 to 0.90; I2 57%) applying the fixed-effect model. No significant difference was found when the random-effects model was applied (RR 0.73; 95% CI 0.46 to 1.17; I2 57%). In addition, acute rejection occurred more often statistically when IL-2 RA induction was compared with polyclonal antibody induction (24/90 (27%) versus 10/95 (11%); RR 2.43; 95% CI 1.01 to 5.86; I2 28%). For all of these differences in acute rejection, trial sequential alpha-spending boundaries were not crossed and the required information sizes were not reached when trial sequential analysis was performed, indicating that we cannot exclude random errors. We observed some occasional significant differences in adverse events in some of the comparisons, however definitions of adverse events varied between trials, and numbers of participants and events in these outcomes were too small to allow definitive conclusions to be drawn. This review shows that acute rejection might be reduced by IL-2 RA compared with no induction, and by polyclonal antibody induction compared with IL-2 RA, though trial sequential analyses cannot exclude random errors, and the significance of our observations depended on the statistical model used. Furthermore, this review does not show other clear benefits or harms associated with the use of any kind of T-cell antibody induction compared with no induction, or when one type of T-cell antibody is compared with another type of antibody. The number of trials investigating the use of antibodies against T-cells for induction after heart transplantation is small, and the number of participants and outcomes in these RCTs is limited. Furthermore, the included trials are at a high risk of bias. Hence, more RCTs are needed to assess the benefits and harms of T-cell antibody induction for heart-transplant recipients. Such trials ought to be conducted with low risks of systematic and random error.
We included 71 trials in the review with 26 studies (1398 participants) comparing a bleaching agent to placebo and 51 studies (2382 participants) comparing a bleaching agent to another bleaching agent. Two studies were at low overall risk of bias; two at high overall risk of bias; and the remaining 67 at unclear overall risk of bias. The bleaching agents (carbamide peroxide (CP) gel in tray, hydrogen peroxide (HP) gel in tray, HP strips, CP paint-on gel, HP paint-on gel, sodium hexametaphosphate (SHMP) chewing gum, sodium tripolyphosphate (STPP) chewing gum, and HP mouthwash) at different concentrations with varying application times whitened teeth compared to placebo over a short time period (from 2 weeks to 6 months), however the certainty of the evidence is low to very low. In trials comparing one bleaching agent to another, concentrations, application method and application times, and duration of use varied widely. Most of the comparisons were reported in single trials with small sample sizes and event rates and certainty of the evidence was assessed as low to very low. Therefore the evidence currently available is insufficient to draw reliable conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use. Tooth sensitivity and oral irritation were the most common side effects which were more prevalent with higher concentrations of active agents though the effects were mild and transient. Tooth whitening did not have any effect on oral health-related quality of life. We found low to very low-certainty evidence over short time periods to support the effectiveness of home-based chemically-induced bleaching methods compared to placebo for all the outcomes tested. We were unable to draw any conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use, as the overall evidence generated was of very low certainty. Well-planned RCTs need to be conducted by standardising methods of application, concentrations, application times, and duration of treatment.
In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89,  I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence). The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.
We included three trials (429 participants) with differences regarding their design (two trials compared bronchial thermoplasty vs medical management and the other compared bronchial thermoplasty vs a sham intervention) and participant characteristics; one of the studies included participants with more symptomatic asthma compared with the others. The pooled analysis showed improvement in quality of life at 12 months in participants who received bronchial thermoplasty that did not reach the threshold for clinical significance (3 trials, 429 participants; mean difference (MD) in Asthma Quality of Life Questionnaire (AQLQ) scores 0.28, 95% confidence interval (CI) 0.07 to 0.50; moderate-quality evidence). Measures of symptom control showed no significant differences (3 trials, 429 participants; MD in Asthma Control Questionnaire (ACQ) scores -0.15, 95% CI -0.40 to 0.10; moderate-quality evidence). The risk of bias for these outcomes was high because two of the studies did not have a sham intervention for the control group. The results from two trials showed a lower rate of exacerbation after 12 months of treatment for participants who underwent bronchial thermoplasty. The trial with sham intervention showed a significant reduction in the proportion of participants visiting the emergency department for respiratory symptoms, from 15.3% on sham treatment to 8.4% over 12 months following thermoplasty. The trials showed no significant improvement in pulmonary function parameters (with the exception of a greater increase in morning peak expiratory flow (PEF) in one trial). Treated participants who underwent bronchial thermoplasty had a greater risk of hospitalisation for respiratory adverse events during the treatment period (3 trials, 429 participants; risk ratio 3.50, 95% CI 1.26 to 9.68; high-quality evidence), which represents an absolute increase from 2% to 8% (95% CI 3% to 23%) over the treatment period. This means that six of 100 participants treated with thermoplasty (95% CI 1 to 21) would require an additional hospitalisation over the treatment period. No significant difference in the risk of hospitalisation was noted at the end of the treatment period. Bronchial thermoplasty was associated with an increase in respiratory adverse events, mainly during the treatment period. Most of these events were mild or moderate, appeared in the 24-hour post-treatment period, and were resolved within a week. Bronchial thermoplasty for patients with moderate to severe asthma provides a modest clinical benefit in quality of life and lower rates of asthma exacerbation, but no significant difference in asthma control scores. The quality of life findings are at risk of bias, as the main benefits were seen in the two studies that did not include a sham treatment arm. This procedure increases the risk of adverse events during treatment but has a reasonable safety profile after completion of the bronchoscopies. The overall quality of evidence regarding this procedure is moderate. For clinical practice, it would be advisable to collect data from patients systematically in independent clinical registries. Further research should provide better understanding of the mechanisms of action of bronchial thermoplasty, as well as its effect in different asthma phenotypes or in patients with worse lung function.
We identified and included 10 studies (428 total participants, followed for 2-16 weeks) in this review. Our primary outcome was restlessness or uncomfortable leg sensations, which was quantified using the International Restless Legs Scale (IRLS) (range, 0 to 40) in eight trials and a different RLS symptom scale in a ninth trial. Nine studies compared iron to placebo and one study compared iron to a dopamine agonist (pramipexole). The possibility for bias among the trials was variable. Three studies had a single element with high risk of bias, which was lack of blinding in two and incomplete outcome data in one. All studies had at least one feature resulting in unclear risk of bias. Combining data from the seven trials using the IRLS to compare iron and placebo, use of iron resulted in greater improvement in IRLS scores (MD -3.78, 95% CI -6.25 to -1.31; I2= 66%, 7 studies, 345 participants) measured 2 to 12 weeks after treatment. Including an eighth study, which measured restlessness using a different scale, use of iron remained beneficial compared to placebo (SMD -0.74, 95% CI -1.26 to -0.23; I2 = 80%, 8 studies, 370 participants). The GRADE assessment of certainty for this outcome was moderate. The single study comparing iron to a dopamine agonist (pramipexole) found a similar reduction in RLS severity in the two groups (MD -0.40, 95% CI -5.93 to 5.13, 30 participants). Assessment of secondary outcomes was limited by small numbers of trials assessing each outcome. Iron did not improve quality of life as a dichotomous measure (RR 2.01, 95% CI 0.54 to 7.45; I2=54%, 2 studies, 39 participants), but did improve quality of life measured on continuous scales (SMD 0.51, 95% CI 0.15 to 0.87; I2= 0%, 3 studies, 128 participants), compared to placebo. Subjective sleep quality was no different between iron and placebo groups (SMD 0.19, 95% CI -0.18 to 0.56; I2 = 9%, 3 studies, 128 participants), nor was objective sleep quality, as measured by change in sleep efficiency in a single study (-35.5 +/- 92.0 versus -41.4 +/- 98.2, 18 participants). Periodic limb movements of sleep were not significantly reduced with iron compared to placebo ( SMD -0.19, 95% CI -0.70 to 0.32; I2 = 0%, 2 studies, 60 participants). Iron did not improve sleepiness compared to placebo, as measured on the Epworth Sleepiness Scale (data not provided, 1 study, 60 participants) but did improve the daytime tiredness item of the RLS-6 compared to placebo (least squares mean difference -1.5, 95% CI -2.5 to -0.6; 1 study, 110 participants). The GRADE rating for secondary outcomes ranged from low to very low. Prespecified subgroup analyses showed more improvement with iron in those trials studying participants on dialysis. The use of low serum ferritin levels as an inclusion criteria and the use or oral versus intravenous iron did not show significant subgroup differences. Iron did not result in significantly more adverse events than placebo (RR 1.48, 95% CI 0.97 to 2.25; I2=45%, 6 studies, 298 participants). A single study reported that people treated with iron therapy experienced fewer adverse events than the active comparator pramipexole. Iron therapy probably improves restlessness and RLS severity in comparison to placebo. Iron therapy may not increase the risk of side effects in comparison to placebo. We are uncertain whether iron therapy improves quality of life in comparison to placebo. Iron therapy may make little or no difference to pramipexole in restlessness and RLS severity, as well as in the risk of adverse events. The effect on secondary outcomes such as quality of life, daytime functioning, and sleep quality, the optimal timing and formulation of administration, and patient characteristics predicting response require additional study.
Twenty-two RCTs (1744 people) met our inclusion criteria. The RCTs were of variable methodological quality (most at high risk of bias because of lack of blinding). There was no evidence for a sustained BP lowering effect of acupuncture; only one trial investigated a sustained effect and found no BP lowering effect at three and six months after acupuncture. Four sham acupuncture controlled trials provided very low quality evidence that acupuncture had a short-term (one to 24 hours) effect on SBP (change) -3.4 mmHg (-6.0 to -0.9) and DBP -1.9 mmHg (95% CI -3.6 to -0.3). Pooled analysis of eight trials comparing acupuncture with angiotensin-converting enzyme inhibitors and seven trials comparing acupuncture to calcium antagonists suggested that acupuncture lowered short-term BP better than the antihypertensive drugs. However, because of the very high risk of bias in these trials, we think that this is most likely a reflection of bias and not a true effect. As a result, we did not report these results in the 'Summary of findings' table. Safety of acupuncture could not be assessed as only eight trials reported adverse events. At present, there is no evidence for the sustained BP lowering effect of acupuncture that is required for the management of chronically elevated BP. The short-term effects of acupuncture are uncertain due to the very low quality of evidence. The larger effect shown in non-sham acupuncture controlled trials most likely reflects bias and is not a true effect. Future RCTs must use sham acupuncture controls and assess whether there is a BP lowering effect of acupuncture that lasts at least seven days.
In this substantive review update, 30 RCTs (49 papers) (12,461 participants randomised) and seven ongoing trials met our inclusion criteria. The majority of trials contributed to primary prevention: comparisons 1 (nine trials) and 2 (13 trials). Secondary prevention trials were included for comparison 3 (two trials) and comparison 4 (four trials plus an additional two trials that were excluded from the main analyses due to published concerns regarding the reliability of the data). Two trials reported on adverse events where these were absent or minor (low- to moderate-quality evidence). No trials reported on costs or health-related quality of life. Primary prevention The included studies for comparison 1 did not report on clinical endpoints (CVD mortality, total mortality or non-fatal endpoints such as myocardial infarction or stroke). The PREDIMED trial (included in comparison 2) was retracted and re-analysed following concerns regarding randomisation at two of 11 sites. Low-quality evidence shows little or no effect of the PREDIMED (7747 randomised) intervention (advice to follow a Mediterranean diet plus supplemental extra-virgin olive oil or tree nuts) compared to a low-fat diet on CVD mortality (hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.50 to 1.32) or total mortality (HR 1.0, 95% CI 0.81 to 1.24) over 4.8 years. There was, however, a reduction in the number of strokes with the PREDIMED intervention (HR 0.60, 95% CI 0.45 to 0.80), a decrease from 24/1000 to 14/1000 (95% CI 11 to 19), moderate-quality evidence). For CVD risk factors for comparison 1 there was low-quality evidence for a possible small reduction in total cholesterol (-0.16 mmol/L, 95% CI -0.32 to 0.00) and moderate-quality evidence for a reduction in systolic (-2.99 mmHg (95% CI -3.45 to -2.53) and diastolic blood pressure (-2.0 mmHg, 95% CI -2.29 to -1.71), with low or very low-quality evidence of little or no effect on LDL or HDL cholesterol or triglycerides. For comparison 2 there was moderate-quality evidence of a possible small reduction in LDL cholesterol (-0.15 mmol/L, 95% CI -0.27 to -0.02) and triglycerides (-0.09 mmol/L, 95% CI -0.16 to -0.01) with moderate or low-quality evidence of little or no effect on total or HDL cholesterol or blood pressure. Secondary prevention For secondary prevention, the Lyon Diet Heart Study (comparison 3) examined the effect of advice to follow a Mediterranean diet and supplemental canola margarine compared to usual care in 605 CHD patients over 46 months and there was low-quality evidence of a reduction in adjusted estimates for CVD mortality (HR 0.35, 95% CI 0.15 to 0.82) and total mortality (HR 0.44, 95% CI 0.21 to 0.92) with the intervention. Only one small trial (101 participants) provided unadjusted estimates for composite clinical endpoints for comparison 4 (very low-quality evidence of uncertain effect). For comparison 3 there was low-quality evidence of little or no effect of a Mediterranean-style diet on lipid levels and very low-quality evidence for blood pressure. Similarly, for comparison 4 where only two trials contributed to the analyses there was low or very low-quality evidence of little or no effect of the intervention on lipid levels or blood pressure. Despite the relatively large number of studies included in this review, there is still some uncertainty regarding the effects of a Mediterranean-style diet on clinical endpoints and CVD risk factors for both primary and secondary prevention. The quality of evidence for the modest benefits on CVD risk factors in primary prevention is low or moderate, with a small number of studies reporting minimal harms. There is a paucity of evidence for secondary prevention. The ongoing studies may provide more certainty in the future.
Twelve included studies in 11 publications (1511 participants), all with chronic neuropathic pain: central post-stroke pain (1), chemotherapy-induced neuropathic pain (1), diabetic neuropathy (4), HIV-related neuropathy (2), mixed neuropathic pain (2), spinal cord injury-related pain (1), and trigeminal neuralgia (1). We did not identify any additional studies. Participants were aged between 26 and 77 years. Study duration was two weeks in one study and at least six weeks in the remainder; eight were of eight-week duration or longer. No study provided first-tier evidence for an efficacy outcome. There was no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of 200 mg to 400 mg daily. Almost 10% of participants taking lamotrigine reported a skin rash. Large, high-quality, long-duration studies reporting clinically useful levels of pain relief for individual participants provided no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of about 200 to 400 mg daily. Given the availability of more effective treatments including antiepileptics and antidepressant medicines, lamotrigine does not have a significant place in therapy based on the available evidence. The adverse effect profile of lamotrigine is also of concern.
We included three small trials (total 397 women) of average quality in the review. Magnesium sulphate was associated with fewer maternal deaths (risk ratio (RR) 0.14, 95% confidence interval (CI) 0.03 to 0.59; 3 trials, 397 women) and was better at preventing further seizures (RR 0.06, 95% CI 0.03 to 0.12; 3 trials, 397 women) than lytic cocktail. Magnesium sulphate was also associated with less respiratory depression (RR 0.12, 95% CI 0.02 to 0.91; 2 trials, 198 women), less coma (RR 0.04, 95% CI 0.00 to 0.74; 1 trial, 108 women), and less pneumonia (RR 0.20, 95% CI 0.06 to 0.67; 2 trials, 307 women). There was no clear difference in the RR for any death of the baby (RR 0.35, 95% CI 0.05 to 2.38, random effects; 2 trials, 177 babies). Magnesium sulphate, rather than lytic cocktail, for women with eclampsia reduces the RR of maternal death, of further seizures and of serious maternal morbidity (respiratory depression, coma, pneumonia). Magnesium sulphate is the anticonvulsant of choice for women with eclampsia; the use of lytic cocktail should be abandoned.
We included six trials with 596 participants in this review. All studies had a randomised controlled parallel group design, with two conducted in the UK, three in the US and one in Israel. Meta-analyses were performed to pool data on response and remission from studies comparing antidepressants with placebo. No meta-analyses could be conducted for other comparisons due to the small number of trials identified. Four studies compared selective serotonin reuptake inhibitors (SSRIs) with placebo (two using sertraline, one using paroxetine and one using fluoxetine; 233 participants in total). In two of these studies both the experimental and placebo groups also received psychological therapy. Pooled risk ratios based on data from three of these studies (146 participants) showed that women randomised to SSRIs had higher rates of response and remission than those randomised to placebo (response: RR 1.43, 95% CI 1.01 to 2.03; remission: RR 1.79, 95% CI 1.08 to 2.98); the fourth study did not report data on response or remission. One study (254 participants) compared antidepressant treatment with treatment as usual (for the first four weeks) followed by listening visits. The study found significantly higher rates of improvement in the antidepressant group than treatment-as-usual group after the first four weeks, but no difference between antidepressants and listening visits at the later follow-up. In addition, one study comparing sertraline with nortriptyline (a tricyclic antidepressant) found no difference in effectiveness (109 participants). Side effects were experienced by a substantial proportion of women, but there was no evidence of a meaningful difference in the number of adverse effects between treatment arms in any study. There were very limited data on adverse effects experienced by breastfed infants, with no long-term follow-up. All but one of the studies were assessed as being at high or uncertain risk of attrition bias and selective outcome reporting. In particular, one of the placebo-controlled studies had over 50% drop-out. The evidence base for this review was very limited, with a small number of studies and little information on a number of important outcomes, particularly regarding potential effects on the child. Risk of bias, for example from high attrition rates, as well as low representativeness of participants (e.g. exclusion of women with severe or chronic depression in several trials) also limit the conclusions that can be drawn. Pooled estimates for response and remission found that SSRIs were significantly more effective than placebo for women with postnatal depression. However the quality of evidence contributing to this comparison was assessed as very low owing to the small sample size for this comparison (146 participants from three studies), the risk of bias in included studes and the inclusion of one study where all participants in both study arms additionally received psychological therapy. There was insufficient evidence to conclude whether, and for whom, antidepressant or psychological/psychosocial treatments are more effective, or whether some antidepressants are more effective or better tolerated than others. There is also inadequate evidence on whether the benefits of antidepressants persist beyond eight weeks or whether they have short- or long-term adverse effects on breastfeeding infants. Professionals treating women with severe depression in the postnatal period will need to draw on other evidence, including trials among general adult populations and observational studies of antidepressant safety when breastfeeding (although the potential for confounding in non-randomised studies must be considered). More RCTs are needed with larger sample sizes and longer follow-up, including assessment of the impact on the child and safety of breastfeeding. Further larger-scale trials comparing antidepressants with alternative treatment modalities are also required.
Twenty-six RCTs met the inclusion criteria, randomly assigning 14,939 people with COPD to receive twice-daily LABA or placebo. Study duration ranged from three months to three years; the median duration was six months. Participants were more often male with moderate to severe symptoms at randomisation; mean forced expiratory volume in 1 second (FEV1) was between 33% and 55% predicted normal in the studies, and mean St George's Respiratory Questionnaire score (SGRQ) ranged from 44 to 55 when reported. Moderate-quality evidence showed that LABA treatment improved quality of life on the SGRQ (mean difference (MD) -2.32, 95% confidence interval (CI) -3.09 to -1.54; I2 = 50%; 17 trials including 11,397 people) and reduced the number of exacerbations requiring hospitalisation (odds ratio (OR) 0.73, 95% CI 0.56 to 0.95; I2 = 10%; seven trials including 3804 people). In absolute terms, 18 fewer people per 1000 were hospitalised as the result of an exacerbation while receiving LABA therapy over a weighted mean of 7 months (95% CI 3 to 31 fewer). Scores were also improved on the Chronic Respiratory Disease Questionnaire (CRQ), and more people receiving LABA treatment showed clinically important improvement of at least four points on the SGRQ. The number of people who had exacerbations requiring a course of oral steroids or antibiotics was also lower among those taking LABA (52 fewer per 1000 treated over 8 months; 95% CI 24 to 78 fewer, moderate quality evidence). Mortality was low, and combined findings of all studies showed that LABA therapy did not significantly affect mortality (OR 0.90, 95% CI 0.75 to 1.08; I2 = 21%; 23 trials including 14,079 people, moderate quality evidence). LABA therapy did not affect the rate of serious adverse events (OR 0.97, 95% CI 0.83 to 1.14; I2 = 34%, moderate quality evidence), although there was significant unexplained heterogeneity, especially between the two formoterol doses. LABA therapy improved predose FEV1 by 73 mL more than placebo (95% CI 48 to 98; I2 = 71%, low quality evidence), and people were more likely to withdraw from placebo than from LABA therapy (OR 0.74, 95% CI 0.69 to 0.80; I2 = 0%). Higher rates of withdrawal in the placebo arm may reduce our confidence in some results, but the disparity is more likely to reduce the magnitude of difference between LABA and placebo than inflate the true effect; removing studies at highest risk of bias on the basis of high and unbalanced attrition did not change conclusions for the primary outcomes. Moderate-quality evidence from 26 studies showed that inhaled long-acting beta2-agonists are effective over the medium and long term for patients with moderate to severe COPD. Their use is associated with improved quality of life and reduced exacerbations, including those requiring hospitalisation. Overall, findings showed that inhaled LABAs did not significantly reduce mortality or serious adverse events.
We found 33 trials that met our inclusion criteria. The proportion of men who reportedly achieved azoospermia or had no detectable sperm varied widely. A few important differences emerged. 1) Levonorgestrel implants (160 μg daily) combined with injectable testosterone enanthate (TE) were more effective than levonorgestrel 125 µg daily combined with testosterone patches. 2) Levonorgestrel 500 μg daily improved the effectiveness of TE 100 mg injected weekly. 3) Levonorgestrel 250 μg daily improved the effectiveness of testosterone undecanoate (TU) 1000 mg injection plus TU 500 mg injected at 6 and 12 weeks. 4) Desogestrel 150 μg was less effective than desogestrel 300 μg (with testosterone pellets). 5) TU 500 mg was less likely to produce azoospermia than TU 1000 mg (with levonorgestrel implants). 6) Norethisterone enanthate 200 mg with TU 1000 mg led to more azoospermia when given every 8 weeks versus 12 weeks. 7) Four implants of 7-alpha-methyl-19-nortestosterone (MENT) were more effective than two MENT implants. We did not conduct any meta-analysis due to intervention differences. Several trials showed promising efficacy in percentages with azoospermia. Three examined desogestrel and testosterone preparations or etonogestrel and testosterone, and two examined levonorgestrel and testosterone. No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. In addition, assessment of azoospermia can vary by sensitivity of the method used. Future trials need more attention to the methodological requirements for RCTs. More trials with adequate power would also be helpful.
We included 80 randomised controlled trials with 205,401 eligible participants. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes were affected by risk of bias. The risk ratio (RR) for all-cause mortality was compatible with a reduction and a small increased risk of death with zinc supplementation (RR 0.95, 95% confidence interval (CI) 0.86 to 1.05, 14 studies, high-quality evidence), and also for cause-specific mortality due to diarrhoea (RR 0.95, 95% CI 0.69 to 1.31, four studies, moderate-quality evidence), lower respiratory tract infection (LRTI) (RR 0.86, 95% CI 0.64 to 1.15, three studies, moderate-quality evidence), or malaria (RR 0.90, 95% CI 0.77 to 1.06, two studies, moderate-quality evidence). Supplementation reduced diarrhoea morbidity, including the incidence of all-cause diarrhoea (RR 0.87, 95% CI 0.85 to 0.89, 26 studies, moderate-quality evidence), but the results for LRTI and malaria were imprecise: LRTI (RR 1, 95% CI 0.94 to 1.07, 12 studies, moderate-quality evidence); malaria (RR 1.05, 95% 0.95 to 1.15, four studies, moderate-quality evidence). There was moderate-quality evidence of a very small improvement in height with supplementation (standardised mean difference (SMD) -0.09, 95% CI -0.13 to -0.06; 50 studies), but the size of this effect might not be clinically important. There was a medium to large positive effect on zinc status. Supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46, five studies, high-quality evidence). We found no clear evidence of benefit or harm of supplementation with regard to haemoglobin or iron status. Supplementation had a negative effect on copper status. In our opinion, the benefits of preventive zinc supplementation outweigh the harms in areas where the risk of zinc deficiency is relatively high. Further research should determine optimal intervention characteristics such as supplement dose.
Twenty-four studies containing information about five index tests (rK39 immunochromatographic test (ICT), KAtex latex agglutination test in urine, FAST agglutination test, rK26 ICT, and rKE16 ICT) recruiting 4271 participants (2605 with VL) were included. We carried out a meta-analysis for the rK39 ICT (including 18 studies; 3622 participants) and the latex agglutination test (six studies; 1374 participants). The results showed considerable heterogeneity. For the rK39 ICT, the overall sensitivity was 91.9% (95% confidence interval (95% CI) 84.8 to 96.5) and the specificity 92.4% (95% CI 85.6 to 96.8). The sensitivity was lower in East Africa (85.3%; 95% CI 74.5 to 93.2) than in the Indian subcontinent (97.0%; 95% CI 90.0 to 99.5). For the latex agglutination test, overall sensitivity was 63.6% (95% CI 40.9 to 85.6) and specificity 92.9% (95% CI 76.7 to 99.2). The rK39 ICT shows high sensitivity and specificity for the diagnosis of visceral leishmaniasis in patients with febrile splenomegaly and no previous history of the disease, but the sensitivity is notably lower in east Africa than in the Indian subcontinent. Other rapid tests lack accuracy, validation, or both.
We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes. We identified no completed non-RCTs or CBAs. We identified no ongoing RCTs, non-RCTs, or CBAs. We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.
Nine trials involving 117,272 individuals of age 35 years or older are included in this review. The trials were conducted in Australia, Finland, India, Italy, the United Kingdom and the United States, with duration of follow-up ranging from 2.1 to 12 years. The doses of antioxidant vitamins were higher than the recommended daily allowance. There was no evidence of effect of antioxidant vitamin supplementation in reducing the risk of cataract, cataract extraction, progression of cataract or in slowing the loss of visual acuity. In the pooled analyses, there was no evidence of effect of beta-carotene supplementation in reducing the risk of cataract (two trials) (relative risk (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08; n = 57,703) or in reducing the risk of cataract extraction (three trials) (RR 1.00, 95% CI 0.91 to 1.10; n = 86,836) or of vitamin E supplementation in reducing the risk of cataract (three trials) (RR 0.97, 95% CI 0.91 to 1.04; n = 50,059) or of cataract extraction (five trials) (RR 0.98, 95% CI 0.91 to 1.05; n = 83,956). The proportion of participants developing hypercarotenodermia (yellowing of skin) while on beta-carotene ranged from 7.4% to 15.8%. There is no evidence from RCTs that supplementation with antioxidant vitamins (beta-carotene, vitamin C or vitamin E) prevents or slows the progression of age-related cataract. We do not recommend any further studies to examine the role of antioxidant vitamins beta-carotene, vitamin C and vitamin E in preventing or slowing the progression of age-related cataract. Costs and adverse effects should be weighed carefully with unproven benefits before recommending their intake above recommended daily allowances.
Sixty trials involving 66,689 patients were included. During PCI (48 trials with 33,513 participants) glycoprotein IIb/IIIa blockers decreased all-cause mortality at 30 days (OR 0.79, 95% CI 0.64 to 0.97) but not at six months (OR 0.90, 95% CI 0.77 to 1.05). All-cause death or myocardial infarction was decreased both at 30 days (OR 0.66, 95% CI 0.60 to 0.72) and at six months (OR 0.75, 95% CI 0.64 to 0.86), although severe bleeding was increased (OR 1.39, 95% CI 1.21 to 1.61; absolute risk increase (ARI) 8.0 per 1000). The efficacy results were homogeneous for every endpoint according to the clinical condition of the patients, but were less marked for patients pre-treated with clopidogrel, especially in patients without acute coronary syndromes. As initial medical treatment of NSTEACS (12 trials with 33,176 participants), IIb/IIIa blockers did not decrease mortality at 30 days (OR 0.90, 95% CI 0.79 to 1.02) or at six months (OR 1.00, 95% CI 0.87 to 1.15), but slightly decreased death or myocardial infarction at 30 days (OR 0.91, 95% CI 0.85 to 0.98) and at six months (OR 0.88, 95% CI 0.81 to 0.96), although severe bleeding was increased (OR 1.29, 95% CI 1.14 to 1.45; ARI 1.4 per 1000). When administered during PCI, intravenous glycoprotein IIb/IIIa blockers reduce the risk of all-cause death at 30 days but not at six months, and reduce the risk of death or myocardial infarction at 30 days and at six months, at a price of an increase in the risk of severe bleeding. The efficacy effects are homogeneous but are less marked in patients pre-treated with clopidogrel where they seem to be effective only in patients with acute coronary syndromes. When administered as initial medical treatment in patients with NSTEACS, these agents do not reduce mortality although they slightly reduce the risk of death or myocardial infarction.
Three trials involving a total of 161 preterm infants were included in this review, but only two trials (131 infants) contributed data for meta-analysis. There was no evidence of a clear effect of exposure to the smell and taste of milk with tube feedings on time taken to reach full sucking feeds (MD -2.57 days, 95% CI -5.15 to 0.02; I2 = 17%; 2 trials, 131 infants; very low-quality evidence). One trial reported no adverse effects. There was no evidence of a clear effect of exposure to the smell and taste of milk on the following outcomes: time taken to reach full enteral feeds (MD -1.57 days, 95% CI -6.25 to 3.11; 1 trial, 51 infants; very low-quality evidence), duration of parenteral nutrition (MD -2.20 days, 95% CI -9.49 to 5.09; 1 trial, 51 infants; very low-quality evidence), incidence of necrotising enterocolitis (RR 0.62, 95% CI 0.15 to 2.48; 1 trial, 51 infants; low-quality evidence), and late infection (RR 2.46, 95% CI 0.27 to 22.13; 1 trial, 51 infants; low-quality evidence). There was very low-quality evidence demonstrating that exposure to the smell and taste of milk decreased duration of hospitalisation by almost four days (MD -3.89 days, 95% CI -7.03 to -0.75; I2 = 51%; 2 trials, 131 infants). In two trials, an increased growth velocity was noted in infants exposed to the intervention, but we were unable to combine data to perform meta-analysis. No data were available to assess feed intolerance and rates of exclusive breastfeeding at discharge. Included trials were small and had methodological limitations including lack of randomisation (one trial), lack of blinding, and different inclusion criteria and administration of the interventions. Evidence from two trials suggests that exposure to the smell and taste of milk with tube feedings has no clear effect on time taken to reach full sucking feeds, but it may decrease length of hospitalisation. However, these results are uncertain due to the very low quality of the evidence. There is also limited evidence about the impact on other important clinical outcomes and on safety. Future research should examine the effect of exposure to the smell and taste of milk with tube feedings on clinical outcomes during hospitalisation, such as attainment of full enteral and sucking feeds, safety, feed tolerance, incidence of infection, and infant growth. Additionally, future research should be sufficiently powered to evaluate the effect of the intervention in infants of different gestational ages, on each sex separately, and on the optimal frequency and duration of exposure.
We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05). There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.
This review includes eight studies with a total of 250 participants comparing nebuliser versus pMDI plus spacer treatment. We identified no studies comparing DPI with nebulisers. We found two studies assessing the primary outcome of 'change in forced expiratory volume in one second (FEV1) one hour after dosing'. We could not pool these studies, but both showed a non-significant difference in favour of the nebuliser group, with similar frequencies of serious adverse events. For the secondary outcome, 'change in FEV1 closest to one hour after dosing': we found a significant difference of 83 ml (95% CI 10 to 156, P = 0.03) in favour of nebuliser treatment. For the secondary outcome of adverse events, we found a non-significant odds ratio of 1.65 (95% CI 0.42 to 6.48) in favour of the pMDI plus spacer group. There is a lack of evidence in favour of one mode of delivery over another for bronchodilators during exacerbations of COPD. We found no difference between nebulisers versus pMDI plus spacer regarding the primary outcomes of FEV1 at one hour and safety. For the secondary outcome 'change in FEV1 closest to one hour after dosing' during an exacerbation of COPD, we found a greater improvement in FEV1 when treating with nebulisers than with pMDI plus spacers. A limited amount of data are available (eight studies involving 250 participants). These studies were difficult to pool, of low quality and did not provide enough evidence to favour one mode of delivery over another. No data of sufficient quality have been published comparing nebulisers versus DPIs in this setting. More studies are required to assess the optimal mode of delivery during exacerbations of COPD.
Five studies met the inclusion criteria. The pooled estimates of MMSE cognitive and ADAS-cognitive change scores from three of these studies revealed non-significant cognitive effects for melatonin treatment. In two of these studies, significant improvements in psychopathological behaviours (e.g., decreased mood symptoms of depression, anxiety and apathy and decreased behavior symptoms of hallucinations, delusions, agitation, irritability, and appetite disturbances), were found from meta-analysis of the change scores from the NPI (7 weeks, 2.5 mg melatonin), and ADAS non-cognitive (4 weeks, 3 mg melatonin) scales. Sensitivity analyses found similar results to those of the original meta-analyses, and thus, supported the effect estimates for non-significant cognitive outcomes. Individual study estimates for treatment effect of 2.5 mg melatonin at one year demonstrated a significant worsening of mood (e.g. decrease in positive affect) as measured by the Philadelphia Geriatric Centre Affect Rating Scale (positive). The remainder of the treatment effects for mood, behavior, and function of daily living were non-significant. There were no reported adverse effects associated with melatonin use. The analyses did not support the use of melatonin for treatment of cognitive impairment associated with dementia. Meta-analysis of psychopathologic behavior scale scores suggested that melatonin may be effective in treating these dementia-related disturbances.
Nine studies (162 participants) are included in this review. No significant difference was noted between NCS and SCG with respect to the maximum percent decrease in FEV1 (WMD = -0.88; 95% CI: -4.50, 2.74), complete protection (i.e. maximum % fall FEV1 still =>10%); OR = 0.95; 95% CI: 0.50 to 1.8, clinical protection (i.e. < 50% improvement over placebo); OR = 0.71; 95% CI: 0.36 to 1.39; unpleasant taste (OR = 6.85; 95% CI: 0.77, 60.73), or sore throat (OR = 3.46; 95% CI: 0.32, 37.48). For these pooled comparisons, no statistically significant heterogeneity was identified. Subgroup analyses based on age, dosage of medications and timing of exercise post-inhalation were consistent with the overall pooled analyses. No significant differences were evident between the effect of NCS and SCG during the immediate post-exercise period in adults and children with EIB with regards to pulmonary function - specifically maximum percent decrease in FEV1, complete protection, clinical protection, or side effects.
We included in this review a total of 12 RCTs. Ten studies assessed fibrinolytic agents versus placebo (993 participants); one study compared streptokinase with urokinase (50 participants); and one compared alteplase versus urokinase (99 participants). The primary outcomes were death, requirement for surgical intervention, overall treatment failure and serious adverse effects. All studies were in the inpatient setting. Outcomes were measured at varying time points from hospital discharge to three months. Seven trials were at low or unclear risk of bias and two at high risk of bias due to inadequate randomisation and inappropriate study design respectively. We found no evidence of difference in overall mortality with fibrinolytic versus placebo (OR 1.16, 95% CI 0.71 to 1.91; 8 studies, 867 participants; I² = 0%; moderate certainty of evidence). We found evidence of a reduction in surgical intervention with fibrinolysis in the same studies (OR 0.37, 95% CI 0.21 to 0.68; 8 studies, 897 participants; I² = 51%; low certainty of evidence); and overall treatment failure (OR 0.16, 95% CI 0.05 to 0.58; 7 studies, 769 participants; I² = 88%; very low certainty of evidence, with evidence of significant heterogeneity). We found no clear evidence of an increase in adverse effects with intrapleural fibrinolysis, although this cannot be excluded (OR 1.28, 95% CI 0.36 to 4.57; low certainty of evidence). In a sensitivity analysis, the reduction in referrals for surgery and overall treatment failure with fibrinolysis disappeared when the analysis was confined to studies at low or unclear risk of bias. In a moderate-risk population (baseline 14% risk of death, 20% risk of surgery, 27% risk of treatment failure), intra-pleural fibrinolysis leads to 19 more deaths (36 fewer to 59 more), 115 fewer surgical interventions (150 fewer to 55 fewer) and 214 fewer overall treatment failures (252 fewer to 93 fewer) per 1000 people. A single study of streptokinase versus urokinase found no clear difference between the treatments for requirement for surgery (OR 1.00, 95% CI 0.13 to 7.72; 50 participants; low-certainty evidence). A single study of alteplase versus urokinase showed no clear difference in requirement for surgery (OR alteplase versus urokinase 0.46, 95% CI 0.04 to 5.24) but an increased rate of adverse effects, primarily bleeding, with alteplase (OR 5.61, 95% CI 1.16 to 27.11; 99 participants; low-certainty evidence). This translated into 154 (6 to 499 more) serious adverse events with alteplase compared with urokinase per 1000 people treated. In patients with complicated infective pleural effusion or empyema, intrapleural fibrinolytic therapy was associated with a reduction in the requirement for surgical intervention and overall treatment failure but with no evidence of change in mortality. Discordance between the negative largest trial of this therapy and other studies is of concern, however, as is an absence of significant effect when analysing low risk of bias trials only. The reasons for this difference are uncertain but may include publication bias. Intrapleural fibrinolytics may increase the rate of serious adverse events, but the evidence is insufficient to confirm or exclude this possibility.
We included a total of 39 studies (36 randomised controlled trials (RCTs) and 3 quasi-RCTs) that involved a total of 2492 adults. Most studies were small (median = 59 participants). Participants' mean ages ranged from 34 years to 59 years. When reported, most participants had heel pain for several months. The trials were usually conducted in outpatient specialty clinics of tertiary care hospitals in 17 countries. Steroid injection was given with a local anaesthetic agent in 34 trials. Follow-up was from one month to over two years. With one exception, trials were assessed at high risk of bias in one or more domains, mostly relating to lack of blinding, including lack of confirmation of allocation concealment. With two exceptions, we rated the available evidence as very low quality, implying in each case that we are 'very uncertain about the estimate'. The 39 trials covered 18 comparisons, with six of the seven trials with three or four groups providing evidence towards two comparisons. Eight trials (724 participants) compared steroid injection versus placebo or no treatment. Steroid injection may lead to lower heel pain visual analogue scores (VAS) (0 to 100; higher scores = worse pain) in the short-term (< 1 month) (MD -6.38, 95% CI -11.13 to -1.64; 350 participants; 5 studies; I² = 65%; low quality evidence). Based on a minimal clinically significant difference (MCID) of 8 for average heel pain, the 95% CI includes a marginal clinical benefit. This potential benefit was diminished when data were restricted to three placebo-controlled trials. Steroid injection made no difference to average heel pain in the medium-term (1 to 6 months follow-up) (MD -3.47, 95% CI -8.43 to 1.48; 382 participants; 6 studies; I² = 40%; low quality evidence). There was very low quality evidence for no effect on function in the medium-term and for an absence of serious adverse events (219 participants, 4 studies). No studies reported on other adverse events, such as post-injection pain, and on return to previous activity. There was very low quality evidence for fewer treatment failures (defined variously as persistent heel pain at 8 weeks, steroid injection at 12 weeks, and unrelieved pain at 6 months) after steroid injection. The available evidence for other comparisons was rated as very low quality. We are therefore very uncertain of the estimates for the relative effects on people with heel pain of steroids compared with other interventions in: 1. Tibial nerve block with anaesthetic (2 trials); orthoses (4 trials); oral NSAIDs (2 trials); and intensive physiotherapy (1 trial). 2. Physical modalities: ESWT (5 trials); laser (2 trials); and radiation therapy (1 trial). 3. Other invasive procedures: locally injectable NSAID (1 trial); platelet-rich plasma injections (5 trials); autologous blood injections (2 trials); botulinum toxin injections (2 trials); cryopreserved human amniotic membrane injection (1 trial); localised peppering with a needle (1 trial); dry needling (1 trial); and mini scalpel needle release (1 trial). We are also uncertain about the estimates from trials testing different techniques of local steroid injection: ultrasonography-guided versus palpation-guided (5 trials); and scintigraphy-guided versus palpation-guided (1 trial). An exploratory analysis involving pooling data from 21 trials reporting on adverse events revealed two ruptures of plantar fascia (reported in 1 trial) and three injection site infections (reported in 2 trials) in 699 participants allocated to steroid injection study arms. Five trials reported a total of 27 participants with less serious short-term adverse events in the 699 participants allocated steroid injection study arms. Reported treatments were analgesia, ice or both. Given the high risk of selective reporting for these outcomes and imprecision, this evidence was rated at very low quality. We found low quality evidence that local steroid injections compared with placebo or no treatment may slightly reduce heel pain up to one month but not subsequently. The available evidence for other outcomes of this comparison was very low quality. Where available, the evidence from comparisons of steroid injections with other interventions used to treat heel pain and of different methods of guiding the injection was also very low quality. Although serious adverse events relating to steroid injection were rare, these were under-reported and a higher risk cannot be ruled out. Further research should focus on establishing the effects (benefits and harms) of injected steroids compared with placebo in typical clinical settings, subsequent to a course of unsuccessful conservative therapy. Ideally, this should be preceded by research, including patient involvement, aimed to obtain consensus on the priority questions for treating plantar heel pain.
Three studies, involving a total of 354 participants, met our inclusion criteria for the primary outcome. Compared with intermittent monitoring, continuous monitoring significantly reduced death and disability at three months or discharge (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.13 to 0.56) and was associated with a non-significant reduction in deaths from any cause at discharge (OR 0.72, 95% CI 0.28 to 1.85). These significant results depend on one study that has a high risk of bias. Continuous monitoring was associated with a non-significant reduction of dependency (OR 0.79, 95% CI 0.30 to 2.06), death from vascular causes (OR 0.48, 95% CI 0.10 to 2.39), neurological complications (OR 0.81, 95% CI 0.46 to 1.43), length of stay (mean difference (MD) -5.24, 95% CI -10.51 to 0.03) and institutionalisation (OR 0.83, 95% CI 0.04 to 15.72) (secondary outcomes). For the last two outcomes we detected consistent heterogeneity across trials. Cardiac complications (OR 8.65, 95% CI 2.52 to 29.66), fever (OR 2.17, 95% CI 1.22 to 3.84) and hypotension (OR 4.32, 95% CI 1.68 to 14.38) were detected significantly more often in participants who received continuous monitoring (surrogate outcomes). We detected no significant increase in adverse events due to immobility (pneumonia, other infections or deep vein thrombosis) in participants who were continuously monitored compared with those allocated to intermittent monitoring. Continuous monitoring of physiological variables for the first two to three days may improve outcomes and prevent complications. Attention to the changes in physiological variables is a key feature of a stroke unit, and can most likely be aided by continuous monitoring without complications related to immobility or to treatments triggered by the relief of abnormal physiological variables. Well-designed, high-quality studies are needed because many questions remain open and deserve further research. These include when to start continuous monitoring, when to interrupt it, which people should be given priority, and which treatments are most appropriate after the identification of abnormalities in physiological variables.
Four high-quality RCTs (585 patients) met the selection criteria. Clinical heterogeneity prevented the use of meta-analysis. Therefore, a qualitative synthesis was completed. There was conflicting evidence about whether TENS was beneficial in reducing back pain intensity and consistent evidence in two trials (410 patients) that it did not improve back-specific functional status. There was moderate evidence that work status and the use of medical services did not change with treatment. Conflicting results were obtained from two studies regarding generic health status, with one study showing no improvement on the modified Sickness Impact Profile and another study showing significant improvements on several, but not all subsections of the SF-36 questionnaire. Multiple physical outcome measures lacked statistically significant improvement relative to placebo. In general, patients treated with acupuncture-like TENS responded similarly to those treated with conventional TENS. However, in two of the trials, an inadequate stimulation intensity was used for acupuncture-like TENS, given that muscle twitching was not induced. Optimal treatment schedules could not be reliably determined based on the available data. Adverse effects included minor skin irritation at the site of electrode placement. At this time, the evidence from the small number of placebo-controlled trials does not support the use of TENS in the routine management of chronic LBP. Further research is encouraged.
We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting. Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male. There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication. Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.
We identified two RCTs (N=89) eligible for inclusion. These RCTs addressed oral or sublingual immunotherapy, both in adults, with an allergy to apple or peach respectively. Both studies enrolled a small number of participants and used different methods to provide these differing types of immunotherapy. Both studies were judged to be at high risk of bias in at least one domain. Overall, the quality of evidence was judged to be very low due to the small number of studies and participants and possible bias. The studies were clinically heterogeneous and hence we did not pool the results. A study comparing SLIT with placebo for allergy to peach did not detect a significant difference between the number of patients desensitised at six months following a double-blind placebo-controlled food challenge (RR 1.16, 95% confidence interval (CI) 0.49 to 2.74). The second study, comparing OIT versus no treatment for apple allergy, found an effect on desensitisation in favour of the intervention using an oral provocation test at eight months, but results were imprecise (RR 17.50, 95% CI 1.13 to 270.19). Neither study reported data on evidence of immunologic tolerance. In both studies, the incidence of mild and moderate adverse events was higher in the intervention groups than in the controls. In the study comparing SLIT with placebo, patients in the intervention group experienced significantly more local adverse reactions than participants in the control group (RR 3.21, 95% CI 1.51 to 6.82), though there was not a significant difference in the number of participants experiencing systemic adverse reactions (RR 0.81, 95% CI 0.22 to 3.02). In the study of OIT, two of the 25 participants in the intervention group reported relevant side effects, whereas no participants in the control group reported relevant side effects. There is insufficient evidence for using OIT or SLIT to treat allergy to fruit, specifically related to peach and apple. Mild or moderate adverse reactions were reported more frequently in people receiving OIT or SLIT. However, these reactions could be treated successfully with medications.
Three RCTs enrolling 144 participants met our inclusion criteria. Two compared steroid avoidance versus late steroid withdrawal and one compared late steroid withdrawal versus steroid maintenance. All studies included SPK and only one also included PTA. All studies had an overall moderate risk of bias and presented only short-term results (six to 12 months). Two studies (89 participants) compared steroid avoidance or early steroid withdrawal versus late steroid withdrawal. There was no clear evidence of an impact on mortality (2 studies, 89 participants: RR 1.64, 95% CI 0.21 to 12.75), risk of kidney loss censored for death (2 studies, 89 participants: RR 0.35, 95% CI 0.04 to 3.09), risk of pancreas loss censored for death (2 studies, 89 participants: RR 1.05, 95% CI 0.36 to 3.04), or acute kidney rejection (1 study, 49 participants: RR 2.08, 95% CI 0.20 to 21.50), however results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. The study that compared late steroid withdrawal versus steroid maintenance observed no deaths, no graft loss or acute kidney rejection at six months in either group and reported uncertain effects on acute pancreas rejection (RR 0.88, 95% CI 0.06 to 13.35). Of the possible adverse effects only infection was reported by one study. There were significantly more UTIs reported in the late withdrawal group compared to the steroid avoidance group (1 study, 25 patients: RR 0.41, 95% CI 0.26 to 0.66). We also identified 13 cohort studies and one RCT which randomised tacrolimus versus cyclosporin. These studies in general showed that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of infections (BK virus and CMV disease) and improved blood pressure control without increasing the risk of rejection. However, two studies found an increased incidence of acute pancreas rejection (HR 2.8, 95% CI 0.89 to 8.81, P = 0.066 in one study and 43.3% in the steroid withdrawal group versus 9.3% in the steroid maintenance, P < 0.05 at three years in the other) and one study found an increased incidence of acute kidney rejection (18.7% in the steroid withdrawal group versus 2.8% in the steroid maintenance, P < 0.05) at three years. There is currently insufficient evidence for the benefits and harms of steroid withdrawal in pancreas transplantation in the three RCTs (144 patients) identified. The results showed uncertain results for short-term risk of rejection, mortality, or graft survival in steroid-sparing strategies in a very small number of patients over a short period of follow-up. Overall the data was sparse, so no firm conclusions are possible. Moreover, the 13 observational studies findings generally concur with the evidence found in the RCTs.
This review includes a total of 5142 participants (mostly inpatients) from 44 trials conducted between 1988 and 2009 (median study duration ˜ 12 weeks, risk of bias - moderate). We found that incidences of non-compliance were lower in the psychoeducation group in the short term (n = 1400, RR 0.52 CI 0.40 to 0.67, NNT 11 CI 9 to 16). This finding holds for the medium and long term. Relapse appeared to be lower in psychoeducation group (n = 1214, RR 0.70 CI 0.61 to 0.81, NNT 9 CI 7 to 14) and this also applied to readmission (n = 206, RR 0.71 CI 0.56 to 0.89, NNT 5 CI 4 to 13). Scale-derived data also suggested that psychoeducation promotes better social and global functioning. In the medium term, treating four people with schizophrenia with psychoeducation instead of standard care resulted in one additional person showing a clinical improvement. Evidence suggests that participants receiving psychoeducation are more likely to be satisfied with mental health services (n = 236, RR 0.24 CI 0.12 to 0.50, NNT 5 CI 5 to 8) and have improved quality of life. Psychoeducation does seem to reduce relapse, readmission and encourage medication compliance, as well as reduce the length of hospital stay in these hospital-based studies of limited quality. The true size of effect is likely to be less than demonstrated in this review - but, nevertheless, some sort of psychoeducation could be clinically effective and potentially cost beneficial. It is not difficult to justify better, more applicable, research in this area aimed at fully investigating the effects of this promising approach. Note: the 27 new citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.
We include 57 studies (61 comparisons) in this updated review. We found 31 studies of workplace interventions aimed at individual workers, covering group therapy, individual counselling, self-help materials, nicotine replacement therapy, and social support, and 30 studies testing interventions applied to the workplace as a whole, i.e. environmental cues, incentives, and comprehensive programmes. The trials were generally of moderate to high quality, with results that were consistent with those found in other settings. Group therapy programmes (odds ratio (OR) for cessation 1.71, 95% confidence interval (CI) 1.05 to 2.80; eight trials, 1309 participants), individual counselling (OR 1.96, 95% CI 1.51 to 2.54; eight trials, 3516 participants), pharmacotherapies (OR 1.98, 95% CI 1.26 to 3.11; five trials, 1092 participants), and multiple intervention programmes aimed mainly or solely at smoking cessation (OR 1.55, 95% CI 1.13 to 2.13; six trials, 5018 participants) all increased cessation rates in comparison to no treatment or minimal intervention controls. Self-help materials were less effective (OR 1.16, 95% CI 0.74 to 1.82; six trials, 1906 participants), and two relapse prevention programmes (484 participants) did not help to sustain long-term abstinence. Incentives did not appear to improve the odds of quitting, apart from one study which found a sustained positive benefit. There was a lack of evidence that comprehensive programmes targeting multiple risk factors reduced the prevalence of smoking. 1. We found strong evidence that some interventions directed towards individual smokers increase the likelihood of quitting smoking. These include individual and group counselling, pharmacological treatment to overcome nicotine addiction, and multiple interventions targeting smoking cessation as the primary or only outcome. All these interventions show similar effects whether offered in the workplace or elsewhere. Self-help interventions and social support are less effective. Although people taking up these interventions are more likely to stop, the absolute numbers who quit are low. 2. We failed to detect an effect of comprehensive programmes targeting multiple risk factors in reducing the prevalence of smoking, although this finding was not based on meta-analysed data.  3. There was limited evidence that participation in programmes can be increased by competitions and incentives organized by the employer, although one trial demonstrated a sustained effect of financial rewards for attending a smoking cessation course and for long-term quitting. Further research is needed to establish which components of this trial contributed to the improvement in success rates. 4. Further research would be valuable in low-income and developing countries, where high rates of smoking prevail and smoke-free legislation is not widely accepted or enforced.
We included six studies involving 119 participants. We combined studies that evaluated MP in addition to another treatment versus the other treatment alone. Mental practice in combination with other treatment appears more effective in improving upper extremity function than the other treatment alone (Z = 3.48, P = 0.0005; standardised mean difference (SMD) 1.37; 95% confidence interval (CI) 0.60 to 2.15). We attempted subgroup analyses, based on time since stroke and dosage of MP; however, numbers in each group were small. We evaluated the quality of the evidence with the PEDro scale, ranging from 6 to 9 out of 10; we determined the GRADE score to be moderate. There is limited evidence to suggest that MP in combination with other rehabilitation treatment appears to be beneficial in improving upper extremity function after stroke, as compared with other rehabilitation treatment without MP. Evidence regarding improvement in motor recovery and quality of movement is less clear. There is no clear pattern regarding the ideal dosage of MP required to improve outcomes. Further studies are required to evaluate the effect of MP on time post stroke, volume of MP that is required to affect the outcomes and whether improvement is maintained long-term. Numerous large ongoing studies will soon improve the evidence base.
Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years. Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials.
Twenty-two trials (3142 episodes in 2372 patients) were included in the analyses. The mortality rate was similar when comparing oral to intravenous antibiotic treatment (RR 0.95, 95% CI 0.54 to 1.68, 9 trials, 1392 patients, median mortality 0, range 0% to 8.8%). Treatment failure rates were also similar (RR 0.96, 95% CI 0.86 to 1.06, all trials). No significant heterogeneity was shown for all comparisons but adverse events. The effect was stable in a wide range of patients. Quinolones alone or combined with another antibiotic were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics. Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, and do not have pneumonia, infection of a central line or a severe soft-tissue infection. The wide CI for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.
Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). There is no evidence to support the use of adjuvant progestagen therapy in the primary treatment of endometrial cancer. There have now been several RCTs which have failed to establish a role for adjuvant progestagen therapy after primary treatment for endometrial cancer and therefore, further trials in this field are probably not justified.
Of the 1888 records identified, 62 randomised trials, including a total of 3428 patients, were eligible for inclusion. All studies were at high or uncertain risk of bias for at least one domain. Network meta-analysis evaluating the rate of pleurodesis failure, suggested talc poudrage to be a highly effective method (ranked second of 16 (95% credible interval (Cr-I) 1 to 5)) and provided evidence that it resulted in fewer pleurodesis failures than eight other methods. The estimated ranks of other commonly used agents were: talc slurry (fourth; 95% Cr-I 2 to 8), mepacrine (fourth; 95% Cr-I 1 to 10), iodine (fifth; 95% Cr-I 1 to 12), bleomycin (eighth; 95% Cr-I 5 to 11) and doxycyline (tenth; 95% Cr-I 4 to 15). The estimates were imprecise as evidenced by the wide credible intervals and both high statistical and clinical heterogeneity. Most of the secondary outcomes, including adverse events, were inconsistently reported by the included studies and the methods used to describe them varied widely. Hence the majority of the secondary outcomes were reported descriptively in this review. We obtained sufficient data to perform network meta-analysis for the most commonly reported adverse events: pain, fever and mortality. The fever network was imprecise and showed substantial heterogeneity, but suggested placebo caused the least fever (ranked first of 11 (95% Cr-I 1 to 7)) and mepacrine and Corynebacterium parvum (C. parvum) appeared to be associated with the most fever (ranked tenth (95% Cr-I 6 to 11) and eleventh (95% Cr-I 7 to 11) respectively). No differences between interventions were revealed by the network meta-analysis of the pain data. The only potential difference in mortality identified in the mortality network was that those receiving tetracycline appeared to have a longer survival than those receiving mitoxantrone (OR 0.16 (95% Confidence Interval (CI) 0.03 to 0.72)). Indwelling pleural catheters were examined in two randomised studies, both of which reported improved breathlessness when compared to talc slurry pleurodesis, despite lower pleurodesis success rates. The risk of bias in a number of the included studies was substantial, for example the vast majority of studies were unblinded, and the methods used for sequence generation and allocation concealment were often unclear. Overall, however, the risk of bias for all studies was moderate. We have not reported the GRADE quality of evidence for the outcomes, as the role of GRADE is not well established in the context of Network Meta-analysis (NMA). Based on the available evidence, talc poudrage is a more effective pleurodesis method in MPE than a number of other frequently used methods, including tetracycline and bleomycin. However further data are required to definitively confirm whether it is more effective than certain other commonly used interventions such as talc slurry and doxycycline, particularly in view of the high statistical and clinical heterogeneity within the network and the high risk of bias of many of the included studies. Based on the strength of the evidence from both direct and indirect comparisons of randomised data of sclerosants administered at the bedside, there is no evidence to suggest large differences between the other highly effective methods (talc slurry, mepacrine, iodine and C. parvum). However, local availability, global experience of these agents and their adverse events, which may not be identified in randomised trials, must also be considered when selecting a sclerosant. Further research is required to delineate the roles of different treatments according to patient characteristics (e.g. according to their prognosis or presence of trapped lung) and to explore patient-centred outcomes, such as breathlessness and quality of life, in more detail. Careful consideration to minimise the risk of bias and standardise outcome measures is essential for future trial design.
Eleven reports (relating to five possible trials) were found. We included one study (six trial reports) involving 256 women. Four other studies are ongoing. The included trial consisted of three treatment arms: probiotic with dietary intervention, placebo and dietary intervention, and dietary intervention alone; it was at a low risk of bias. The study reported primary outcomes of a reduction in the rate of gestational diabetes mellitus (risk ratio (RR) 0.38, 95% confidence interval (CI) 0.20 to 0.70), with no statistical difference in the rates of miscarriage/intrauterine fetal death (IUFD)/stillbirth/neonatal death (RR 2.00, 95% CI 0.35 to 11.35). Secondary outcomes reported were a reduction in infant birthweight (mean difference (MD) -127.71 g, 95% CI -251.37 to -4.06) in the probiotic group and no clear evidence of increased risk of preterm delivery (RR 3.27, 95% CI 0.44 to 24.43), or caesarean section rate (RR 1.23, 95% CI 0.65 to 2.32). The primary infant outcomes of rates of macrosomia and large-for-gestational age infants were not reported. The following secondary outcomes were not reported: maternal gestational weight gain, pre-eclampsia, and the long-term diagnosis of diabetes mellitus; infant body composition, shoulder dystocia, admission to neonatal intensive care, jaundice, hypoglycaemia and long-term rates of obesity and diabetes mellitus. One trial has shown a reduction in the rate of GDM when women are randomised to probiotics early in pregnancy but more uncertain evidence of any effect on miscarriage/IUFD/stillbirth/neonatal death. There are no data on macrosomia. At this time, there are insufficient studies to perform a quantitative meta-analysis. Further results are awaited from four ongoing studies.
We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601 of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran 36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of bias and statistical heterogeneity of the studies included were low. The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01). DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected no difference in death from all causes.
Twelve RCTs with a total of 585 participants were included. Six trials were double-blinded, placebo-controlled studies, and the other six trials were of less adequate methodology. Most trials were small and had high rates of dropout. Eleven of the 12 included trials described the effects of antioxidants on chronic abdominal pain in chronic pancreatitis. Pain as measured on a visual analogue scale (VAS, scale range 0 to 10) after one to six months was less in the antioxidant group than in the control group (mean difference (MD) -0.33, 95% confidence interval (CI) -0.64 to -0.02, P value 0.04, moderate-quality evidence). The number of pain-free participants was not statistically significantly different (risk ratio (RR) 1.73, 95% CI 0.95 to 3.15, P value 0.07, low-quality evidence). More adverse events were observed in the antioxidant group, both in the parallel trials (RR 4.43, 95% CI 1.60 to 12.29, P value 0.0004, moderate-quality evidence) and in the cross-over trials (RR 5.80, 95% CI 1.56 to 21.53, P value 0.0009, moderate-quality evidence). Adverse events occurred in 16% of participants and were mostly mild (e.g. headache, gastrointestinal complaints), but were sufficient to make participants stop antioxidant use. Other important outcomes such as use of analgesics, exacerbation of pancreatitis and quality of life were rarely reported. One trial from 1991 evaluated the effects of antioxidants on acute pain during exacerbation of chronic pancreatitis and found that a significantly higher proportion of participants in the antioxidant group experienced pain relief. This trial was conducted more than 25 years ago and has not been reproduced since that time. Therefore, additional trials are needed before reliable conclusions can be drawn. Current evidence shows that antioxidants can reduce pain slightly in patients with chronic pancreatitis. The clinical relevance of this small reduction is uncertain, and more evidence is needed. Adverse events in one of six patients may prevent the use of antioxidants. Effects of antioxidants on other outcome measures, such as use of analgesics, exacerbation of pancreatitis and quality of life remain uncertain because reliable data are not available.
There were 8203 citations identified from database searches and reference lists. We included 12 trials with 2605 consumer participants and more than 905 primary care practitioner participants. Eleven trials compared consultation liaison to standard care and one compared consultation liaison to collaborative care, with a case manager co-ordinating mental health care. People with depression were included in eight trials; and one trial each included people with a variety of disorders: depression, anxiety and somatoform disorders; medically unexplained symptoms; and drinking problems. None of the included trials reported separate data for children or older people. There was some evidence that consultation liaison improved mental health up to three months following the start of treatment (two trials, n = 445, NNTB 8, 95% CI 5 to 25) but there was no evidence of its effectiveness between three and 12 months. Consultation liaison also appeared to improve consumer satisfaction (up to three months: one trial, n = 228, NNTB 3, 95% CI 3 to 5; 3 to 12 months: two trials, n = 445, NNTB 8, 95% CI 5 to 17) and adherence (3 to 12 months: seven trials, n = 1251, NNTB 6, 95% CI 4 to 13) up to 12 months. There was also an improvement in the primary care provider outcomes of providing adequate treatment between three to 12 months (three trials, n = 797, NNTB 7, 95% CI 4 to 17) and prescribing pharmacological treatment up to 12 months (four trials, n = 796, NNTB 13, 95% CI 7 to 50). There was also some evidence that consultation liaison may not be as effective as collaborative care in regards to symptoms of mental disorder, disability, general health status, and provision of treatment. The quality of these findings were low for all outcomes however, apart from consumer adherence from three to 12 months, which was of moderate quality. Eight trials were rated a high risk of performance bias because consumer participants were likely to have known whether or not they were allocated to the intervention group and most outcomes were self reported. Bias due to attrition was rated high in eight trials and reporting bias was rated high in six. There is evidence that consultation liaison improves mental health for up to three months; and satisfaction and adherence for up to 12 months in people with mental disorders, particularly those who are depressed. Primary care providers were also more likely to provide adequate treatment and prescribe pharmacological therapy for up to 12 months. There was also some evidence that consultation liaison may not be as effective as collaborative care in terms of mental disorder symptoms, disability, general health status, and provision of treatment. However, the overall quality of trials was low particularly in regards to performance and attrition bias and may have resulted in an overestimation of effectiveness. More evidence is needed to determine the effectiveness of consultation liaison for people with mental disorders particularly for those with mental disorders other than depression.
Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. A further updated search conducted in June 2005 did not yield any new studies. There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.
We identified one randomized controlled trial of high quality, involving 300 patients , comparing SmartCare™ to a written protocol. In this trial, SmartCare™ had no effect on discontinuation time. While SmartCare™ significantly reduced the time to the first SBT (mean difference (MD) -0.34 days, 95% CI -0.60 to -0.08; P = 0.01) it did not reduce the time to the first successful SBT (MD -0.25 days, 95% CI -0.55 to 0.05; P = 0.10) and other clinically important outcomes. SmartCare™ did not demonstrate beneficial effects on most clinically important outcomes including time to successful extubation, total duration of mechanical ventilation, ICU and hospital lengths of stay, and the requirement for tracheostomy. Moreover, SmartCare™ did not favourably impact reintubation, mortality, self-extubation, and the proportion of patients undergoing protracted mechanical ventilation, with a small numbers of events in this single trial. There is a paucity of evidence from randomized controlled trials to support or refute use of automated weaning and SBT systems in discontinuing invasive mechanical ventilation in adult postoperative patients. In a single large trial of high methodologic quality, while the use of SmartCare™ to adjust ventilator settings and conduct SBTs shortened the time to undergoing the first SBT, it did not reduce the time to the first successful SBT or the rate of tracheostomy compared to a written protocol implemented by physicians. SmartCare™ did not demonstrate beneficial effects on clinically important outcomes including time to mechanical ventilation discontinuation, time to successful discontinuation, total duration of mechanical ventilation, and ICU and hospital lengths of stay. Additional well-designed, adequately powered randomized controlled trials are needed to clarify the role for SmartCare™ on important outcomes in patients who predominantly require short term ventilation and in specific postoperative patient populations.
We identified four RCTs with 148 participants in total. In the first one, of 14 participants with moderate or severe myasthenia gravis, improvement after one month was not significantly greater for participants treated with plasma exchange and prednisone than for those treated with prednisone alone. A randomised controlled cross-over trial of 12 participants with moderate to severe myasthenia gravis found no statistically significant difference in the efficacy of plasma exchange or intravenous immunoglobulins after four weeks. A trial including 87 participants with myasthenia gravis exacerbation found no statistically significant difference between plasma exchange and immunoglobulin after two weeks. The fourth RCT, with 35 participants, showed a statistically significant difference in favour of plasma exchange before thymectomy. However these trials, except the third, are at high risk of bias and have a weak statistical power. No adequate RCTs have been performed to determine whether plasma exchange improves the short- or long-term outcome for chronic myasthenia gravis or myasthenia gravis exacerbation. However, many studies with case series report short-term benefit from plasma exchange in myasthenia gravis, especially in myasthenic crisis. In severe exacerbations of myasthenia gravis one RCT did not show a significant difference between plasma exchange and intravenous immunoglobulin. Further research is need to compare plasma exchange with alternative short-term treatments for myasthenic crisis or before thymectomy and to determine the value of long-term plasma exchange for treating myasthenia gravis.
There were three randomized controlled trials that met our inclusion criteria recruited HIV-negative participants with chancroid (two trials with 143 participants) and primary syphilis (one trial with 30 participants). The syphilis study, carried out in the US between 1995 and 1997, randomized participants to receive a single 2.0 g oral dose of azithromycin (11 participants); two 2.0 g oral doses of azithromycin administered six to eight days apart (eight participants); or benzathine penicillin G administered as either 2.4 million units intramuscular injection once or twice seven days apart (11 participants). No participant in the trial seroconverted during 12 months of follow-up. The chancroid trials, conducted in Kenya by 1990, found no significant differences in HIV seroconversion rates during four to 12 weeks of follow-up between 400 and 200 mg single oral doses of fleroxacin (one trial, 45 participants; RR 3.00; 95% CI 0.29 to 30.69), or between 400 mg fleroxacin and 800 mg sulfamethoxazole plus 160 mg trimethoprim (one trial, 98 participants; RR 0.33; 95% CI 0.04 to 3.09). Adverse events reported were mild to moderate in severity, and included Jarisch-Herxheimer reactions and gastrointestinal symptoms. The differences between the treatment arms in the incidence of adverse events were not significant. The quality of this evidence on the effectiveness of genital ulcer disease treatment in reducing sexual acquisition of HIV, according to GRADE methodology, is of very low quality. At present, there is insufficient evidence to determine whether curative treatment of genital ulcer disease would reduce the risk of HIV acquisition. The very low quality of the evidence implies that the true effect of genital ulcer disease treatment on sexual acquisition of HIV may be substantially different from the effect estimated from currently available data. However, genital ulcer diseases are public health problems in their own right and patients with these conditions should be treated appropriately; whether the treatment reduces the risk of HIV infection or not.
We included one RCT with 34 participants who were randomly assigned to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. There were no significant differences between adjuvant IVIg and adjuvant placebo in mortality, serious adverse events, time to relapse, open-label rescue therapy, and infection rates. The fall in disease activity score, derived from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95% Confidence interval (CI) 1.12 to 3.48, P < 0.01) and three months (MD 1.80; 95% CI 0.35 to 3.25, P = 0.01). There was a significant increase in total adverse events in the IVIg group (relative risk (RR) 3.50; 95% CI 1.44 to 8.48, P < 0.01). There is insufficient evidence from one RCT that IVIg adjuvant therapy provides a therapeutic advantage compared with the combination of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2 g/kg for a 70 kg patient = $8,400), it should be limited to treat WG in the context of a well conducted RCT powered to detect patient-relevant outcomes.
Previous versions of this review included no trials. From the 2015 search, we identified three cross-over trials that could be included. The 2017 search found no new studies relevant to this review. The included trials randomised 47 inpatients with chronic mental illnesses in the USA and China. Trials were published in the 1990s and were of short duration (six to 10 weeks). Overall, the risk of bias was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, and attrition and outcome data were not fully reported. Findings were sparse, no study reported on the primary outcome 'no clinically important improvement in tardive dyskinesia symptoms,' but two small studies (37 participants) found no difference on the tardive dyskinesia symptoms scale Abnormal Involuntary Movement Scale (AIMS) scores between diltiazem or flunarizine and placebo after three to four weeks' treatment (MD -0.71, 95% CI -2.68 to 1.26, very low quality evidence). Only one study randomising 20 participants reported on adverse events, and reported that there were no adverse events with flunarizine or with placebo (very low quality evidence). One study with 18 participants reported no events of deterioration in mental state with diltiazem or with placebo (very low quality evidence). No studies reported on acceptability of treatment or on social confidence, social inclusion, social networks or personalised quality of life outcomes designated important to patients. Available evidence from randomised controlled trials is extremely limited and very low quality, conclusions cannot be drawn. The effects of calcium channel blockers for antipsychotic-induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well-designed randomised trials.
We identified three eligible studies; two describing ICU patients (N = 358), and one describing relatives of ICU patients (N = 30). The study involving relatives of ICU patients was a substudy of family members from one of the ICU patient studies. There was a mixed risk of bias within the included studies. Blinding of participants to allocation was not possible and blinding of the outcome assessment was not adequately achieved or reported. Overall the quality of the evidence was low to very low. The patient diary intervention was not identical between studies. However, each provided a prospectively prepared, day-to-day description of the participants' ICU admission. No study adequately reported on risk of PTSD as described using a clinical interview, family or caregiver anxiety or depression, health-related quality of life or costs. Within a single study there was no clear evidence of a difference in risk for developing anxiety (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.07 to 1.19) or depression (RR 0.38, 95% CI 0.12 to 1.19) in participants who received ICU diaries, in comparison to those that did not receive a patient diary. However, the results were imprecise and consistent with benefit in either group, or no difference. Within a single study there was no evidence of difference in median post-traumatic stress symptomatology scores (diaries 24, SD 11.6; no diary 24, SD 11.6) and delusional ICU memory recall (RR 1.04, 95% CI 0.84 to 1.28) between the patients recovering from ICU admission who received patient diaries, and those who did not. One study reported reduced post-traumatic stress symptomatology in family members of patients recovering from admission to ICU who received patient diaries (median 19; range 14 to 28), in comparison to no diary (median 28; range 14 to 38). Currently there is minimal evidence from RCTs of the benefits or harms of patient diaries for patients and their caregivers or family members. A small study has described their potential to reduce post-traumatic stress symptomatology in family members. However, there is currently inadequate evidence to support their effectiveness in improving psychological recovery after critical illness for patients and their family members.
We included nine RCTs with a total of 534 participants with cirrhosis and ascites. One RCT had a low risk of bias for mortality and a high risk of bias for the remaining outcomes. All included trials had a high risk of bias for non-mortality outcomes. In total, 473 participants had type 1 hepatorenal syndrome. Seven RCTs specifically evaluated terlipressin and albumin. Terlipressin was associated with a beneficial effect on mortality when including all RCTs (RR 0.85, 95% CI 0.73 to 0.98; 534 participants; number needed to treat for an additional beneficial outcome (NNTB) 10.3 people; low-quality evidence). Trial Sequential Analysis including all RCTs also found a beneficial effect of terlipressin. Additional analyses showed a beneficial effect of terlipressin and albumin on reversal of hepatorenal syndrome (RR 0.63, 95% CI 0.48 to 0.82; 510 participants; 8 RCTs; NNTB 4 people; low-quality evidence). Terlipressin increased the risk of serious cardiovascular adverse events (RR 7.26, 95% CI 1.70 to 31.05; 234 participants; 4 RCTs), but it had no effect on the risk of serious adverse events when analysed as a composite outcome (RR 0.91, 95% CI 0.68 to 1.21; 534 participants; 9 RCTs; number needed to treat for an additional harmful outcome 24.5 people; low-quality evidence). Non-serious adverse events were mainly gastrointestinal, including diarrhoea (RR 5.76, 95% CI 2.19 to 15.15; 240 participants; low-quality evidence) and abdominal pain (RR 1.54, 95% CI 0.97 to 2.43; 294 participants; low-quality evidence). We identified one ongoing trial on terlipressin versus placebo in participants with cirrhosis, ascites, and hepatorenal syndrome type 1. Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies. This review suggests that terlipressin may be associated with beneficial effects on mortality and renal function in people with cirrhosis and type 1 hepatorenal syndrome, but it is also associated with serious adverse effects. We downgraded the strength of the evidence due to methodological issues including bias control, clinical heterogeneity, and imprecision. Consequently, additional evidence is needed.
We included 14 trials that included 1063 women in the intervention groups and 1065 women in the control groups. Thirteen studies compared endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle versus no injury, and one study compared endometrial injury on the day of oocyte retrieval versus no injury. Overall, eight of the 14 included studies were deemed to be at high risk of bias in at least one domain. In studies comparing endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle versus no intervention or a sham procedure, endometrial injury was associated with an increase in live birth or ongoing pregnancy rate: RR 1.42, 95% confidence interval (CI) 1.08 to 1.85; P value 0.01; nine RCTs; 1496 women; I² = 53%; moderate-quality evidence. In other words, moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with endometrial injury. A sensitivity analysis removing the studies at high risk of bias showed no difference in effect. There was no evidence of an effect on miscarriage, however the evidence is of low-quality: RR 0.99, 95% CI 0.63 to 1.53; P value 0.06; eight RCTs; 500 clinical pregnancies; I² = 10%; low-quality evidence. Endometrial injury was also associated with an increased clinical pregnancy rate: RR 1.34, 95% CI 1.21 to 1.61; P value 0.002; 13 RCTs; 1972 women; I² = 45%; moderate-quality evidence. This suggests that if 30% of women achieve clinical pregnancy without endometrial injury, between 33% and 48% will achieve clinical pregnancy with this intervention. Endometrial injury was associated with increased pain, however the evidence was of very low quality. One study reported pain on a VAS scale: MD 4.60, 95% CI 3.98 to 5.22; P value < 0.00001; one RCT; 158 women. Two studies reported the number of pain complaints after the procedure; one recorded no events in either group, and the other reported that endometrial injury increased pain complaints: OR 8.65, 95% CI 2.49 to 30.10; P value 0.0007; one RCT; 101 women. Results from the only randomised controlled trial (RCT) comparing endometrial injury on the day of oocyte retrieval versus no injury, reported that this endometrial injury markedly decreased live birth (RR 0.31, 95% CI 0.14 to 0.69; P value 0.004; 156 women; low-quality evidence) and clinical pregnancy (RR 0.36, 95% CI 0.18 to 0.71; P value 0.003; one RCT; 156 women; low-quality evidence). Moderate-quality evidence indicates that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle is associated with an improvement in live birth and clinical pregnancy rates in women with more than two previous embryo transfers. There is no evidence of an effect on miscarriage, multiple pregnancy or bleeding. The procedure is mildly painful. Endometrial injury on the day of oocyte retrieval is associated with a reduction of clinical and ongoing pregnancy rates. Although current evidence suggests some benefit of endometrial injury, we need evidence from well-designed trials that avoid instrumentation of the uterus in the preceding three months, do not cause endometrial damage in the control group, stratify the results for women with and without recurrent implantation failure (RIF) and report live birth.
Six trials were included. Based on similar designs, trials clustered in three categories. (1) MLD + standard physiotherapy versus standard physiotherapy (one trial) showed significant improvements in both groups from baseline but no significant between-groups differences for per cent reduction. (2) MLD + compression bandaging versus compression bandaging (two trials) showed significant per cent reductions of 30% to 38.6% for compression bandaging alone, and an additional 7.11% reduction for MLD (MD 7.11%, 95% CI 1.75% to 12.47%; two RCTs; 83 participants). Volume reduction was borderline significant (P = 0.06). LE volume was not significant. Subgroup analyses was significant showing that participants with mild-to-moderate BCRL were better responders to MLD than were moderate-to-severe participants. (3) MLD + compression therapy versus nonMLD treatment + compression therapy (three trials) were too varied to pool. One of the trials compared compression sleeve plus MLD to compression sleeve plus pneumatic pump. Volume reduction was statistically significant favoring MLD (MD 47.00 mL, 95% CI 15.25 mL to 78.75 mL; 1 RCT; 24 participants), per cent reduction was borderline significant (P=0.07), and LE volume was not significant. A second trial compared compression sleeve plus MLD to compression sleeve plus self-administered simple lymphatic drainage (SLD), and was significant for MLD for LE volume (MD -230.00 mL, 95% CI -450.84 mL to -9.16 mL; 1 RCT; 31 participants) but not for volume reduction or per cent reduction. A third trial of MLD + compression bandaging versus SLD + compression bandaging was not significant (P = 0.10) for per cent reduction, the only outcome measured (MD 11.80%, 95% CI -2.47% to 26.07%, 28 participants). MLD was well tolerated and safe in all trials. Two trials measured function as range of motion with conflicting results. One trial reported significant within-groups gains for both groups, but no between-groups differences. The other trial reported there were no significant within-groups gains and did not report between-groups results. One trial measured strength and reported no significant changes in either group. Two trials measured QoL, but results were not usable because one trial did not report any results, and the other trial did not report between-groups results. Four trials measured sensations such as pain and heaviness. Overall, the sensations were significantly reduced in both groups over baseline, but with no between-groups differences. No trials reported cost of care. Trials were small ranging from 24 to 45 participants. Most trials appeared to randomize participants adequately. However, in four trials the person measuring the swelling knew what treatment the participants were receiving, and this could have biased results. MLD is safe and may offer additional benefit to compression bandaging for swelling reduction. Compared to individuals with moderate-to-severe BCRL, those with mild-to-moderate BCRL may be the ones who benefit from adding MLD to an intensive course of treatment with compression bandaging. This finding, however, needs to be confirmed by randomized data. In trials where MLD and sleeve were compared with a nonMLD treatment and sleeve, volumetric outcomes were inconsistent within the same trial. Research is needed to identify the most clinically meaningful volumetric measurement, to incorporate newer technologies in LE assessment, and to assess other clinically relevant outcomes such as fibrotic tissue formation. Findings were contradictory for function (range of motion), and inconclusive for quality of life. For symptoms such as pain and heaviness, 60% to 80% of participants reported feeling better regardless of which treatment they received. One-year follow-up suggests that once swelling had been reduced, participants were likely to keep their swelling down if they continued to use a custom-made sleeve.
This review includes 26 studies (33,849 participants). Overall, we judged 13 studies to be at low risk of bias, three at high risk, and the remainder at unclear risk. Settings and recruitment procedures varied across studies, but most studies were conducted in high-income countries. There was moderate-certainty evidence, limited by inconsistency, that automated text messaging interventions were more effective than minimal smoking cessation support (RR 1.54, 95% CI 1.19 to 2.00; I2 = 71%; 13 studies, 14,133 participants). There was also moderate-certainty evidence, limited by imprecision, that text messaging added to other smoking cessation interventions was more effective than the other smoking cessation interventions alone (RR 1.59, 95% CI 1.09 to 2.33; I2 = 0%, 4 studies, 997 participants). Two studies comparing text messaging with other smoking cessation interventions, and three studies comparing high- and low-intensity messaging, did not show significant differences between groups (RR 0.92 95% CI 0.61 to 1.40; I2 = 27%; 2 studies, 2238 participants; and RR 1.00, 95% CI 0.95 to 1.06; I2 = 0%, 3 studies, 12,985 participants, respectively) but confidence intervals were wide in the former comparison. Five studies compared a smoking cessation smartphone app with lower-intensity smoking cessation support (either a lower-intensity app or non-app minimal support). We pooled the evidence and deemed it to be of very low certainty due to inconsistency and serious imprecision. It provided no evidence that smartphone apps improved the likelihood of smoking cessation (RR 1.00, 95% CI 0.66 to 1.52; I2 = 59%; 5 studies, 3079 participants). Other smartphone apps tested differed from the apps included in the analysis, as two used contingency management and one combined text messaging with an app, and so we did not pool them. Using complete case data as opposed to using data from all participants randomised did not substantially alter the findings. There is moderate-certainty evidence that automated text message-based smoking cessation interventions result in greater quit rates than minimal smoking cessation support. There is moderate-certainty evidence of the benefit of text messaging interventions in addition to other smoking cessation support in comparison with that smoking cessation support alone. The evidence comparing smartphone apps with less intensive support was of very low certainty, and more randomised controlled trials are needed to test these interventions.
Three RCTs were identified. A qualitative approach with no meta analysis was performed because of variety in interventions between included studies. Interventions compared were antibiotics to no antibiotics, single to double compound antibiotic therapy and short to long IV administration. None of the studies found significant difference between the tested interventions. Risk of bias varied from low to high. The newest RCT overall had the best quality and statistical power. The newest evidence from one RCT says there is no significant difference between antibiotics versus no antibiotics in the treatment of uncomplicated diverticulitis. Previous RCTs have only suggested a non-inferiority between different antibiotic regimes and treatment lengths. This new evidence needs confirmation from more RCTs before it can be implicated safely in clinical guidelines. Ongoing RCTs will be published in the years to come and more are needed. The role of antibiotics in the treatment of complicated diverticulitis has not been investigated yet.
Three randomised controlled trials (1039 women) published between 1922 and 2005 fulfilled the prespecified criteria. In the earliest trial, 389 women were alternately allocated to receive either skin preparation and perineal shaving or clipping of vulval hair only. In the second trial, which included 150 participants, perineal shaving was compared with the cutting of long hairs for procedures only. In the third and most recent trial, 500 women were randomly allocated to shaving of perineal area or cutting of perineal hair. The primary outcome for all three trials was maternal febrile morbidity; no differences were found (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.73 to 1.76). No differences were found in terms of perineal wound infection (RR 1.47, 95% CI 0.80 to 2.70) and perineal wound dehiscence (RR 0.33, 95% CI 0.01 to 8.00) in the most recent trial involving 500 women, which was the only trial to assess these outcomes. In the smallest trial, fewer women who had not been shaved had Gram-negative bacterial colonisation compared with women who had been shaved (RR 0.83, 95% CI 0.70 to 0.98). There were no instances of neonatal infection in either group in the one trial that reported this outcome. There were no differences in maternal satisfaction between groups in the larger trial reporting this outcome (mean difference (MD) 0.00, 95% CI -0.13 to 0.13). No trial reported on perineal trauma. One trial reported on side-effects and these included irritation, redness, burning and itching. The overall quality of evidence ranged from very low (for the outcomes postpartum maternal febrile morbidity and neonatal infection) to low (for the outcome maternal satisfaction and wound infection). There is insufficient evidence to recommend perineal shaving for women on admission in labour.
We added seven studies during this update, bringing the total to 15 studies, involving 989 participants. The interventions involved various memory retraining techniques, such as computerised programmes and training on internal and external memory aids. Control groups varied in format from assessment-only groups, discussion and games, non-specific cognitive retraining, and attention or visuospatial training. The risk of bias of the included studies was generally low, but we found eight studies to have high risk of bias related to certain aspects of their methodology. We found significant effect of intervention on objective assessments of memory in both the immediate and long-term follow-ups: standardised mean difference (SMD) 0.23 (95% confidence interval (CI) 0.05 to 0.41) and SMD 0.26 (95% CI 0.03 to 0.49), respectively. We also found significant effect of intervention for quality of life in the immediate follow-up (SMD 0.23 (95% CI 0.05 to 0.41)). These findings showed that the intervention group performed significantly better than the control group. We also found a significant difference for activities of daily living (ADL) in the long-term follow-up (SMD -0.33 (95% CI -0.63 to -0.03)), showing that the control groups had significantly less difficulty completing ADLs than the intervention groups. We found no significant effects, either immediate or long-term, on subjective reports of memory problems (SMD 0.04 (95% CI -0.19 to 0.27) and SMD 0.04 (95% CI -0.19 to 0.27)); on mood (SMD 0.02 (95% CI -0.16 to 0.20) and SMD -0.01 (95% CI -0.21 to 0.20)); and on immediate follow-up for ADL (SMD -0.13 (95% CI -0.60 to 0.33)) and in the long term for quality of life (SMD 0.16 (95% CI -0.03 to 0.36)). We could not complete a sensitivity analysis of intention-to-treat in comparison with per-protocol analysis, due to insufficient information from the included papers. However, a sensitivity analysis of high- versus low-risk studies suggested that while quality of the trials did not affect most outcomes, differences were seen in the objective memory outcomes (both at immediate and long term) and quality of life (immediate) outcome, with studies with higher risk of bias inflating the overall effect size estimates for these outcomes, and the test of overall effect changing from being statistically significant to not significant when studies at high risk of bias were excluded. This suggests that lower-quality studies may have positively influenced the outcomes. There is some evidence to support the effectiveness of memory rehabilitation on memory function, as well as on quality of life. However, the evidence is limited and does not extend to subjective reports of memory functioning or mood. Furthermore, the objective measures used are not ecologically valid measures, and thus potentially limit generalisability of these findings into daily life. Further robust RCTs of high methodological quality and better quality of reporting, using ecologically valid outcome assessments, are still needed.
Twenty-three published and unpublished studies (6061 participants) were included in the review. There was a significant change in forced expiratory volume in 1 second (FEV1) in favour of salmeterol 50 mcg twice daily (BID) of 51 mls (95% confidence intervals (CI) 32 to 70), end of study morning peak expiratory flow (PEF) 14.89 L/min (95% CI 10.86 to 18.91). Supplemental short-acting bronchodilator usage was reduced by just under one puff per day. There were significant differences in the total, activity and impact domain scores of the St George's respiratory questionnaire in favour of salmeterol 50 mcg BID. Findings from other health status measurements and symptom scores were conflicting. There was no significant difference in exercise tolerance. The number of participants experiencing exacerbations was significantly reduced with salmeterol 50 mcg treatment compared with placebo (numbers needed to treat to benefit 24). This review shows that the treatment of patients with COPD with salmeterol 50 mcg produces modest increases in lung function. There were varying effects for other important outcomes such as health related quality of life or reduction in symptoms. However, there was a consistent reduction in exacerbations which may help people with COPD who suffer frequent deterioration of symptoms prompting healthcare utilisation. The strength of evidence for the use of salmeterol 100 mcg, formoterol 12 mcg, 18 mcg, 24 mcg was insufficient to provide clear indications for practice.
We included six trials involving 359,078 adult women and men. One trial was at low risk of bias in all six specific domains assessed. Two trials examined the effect of multiple rounds of chlamydia screening on C. trachomatis transmission. A cluster-controlled trial in women and men in the general population in the Netherlands found no change in chlamydia test positivity after three yearly invitations (intervention 4.1% vs control 4.3%, RR 0.96, 95% CI 0.84 to 1.09, 1 trial, 317,304 participants at first screening invitation, low quality evidence). Uptake of the intervention was low (maximum 16%). A cluster-randomised trial in female sex workers in Peru found a reduction in chlamydia prevalence after four years (adjusted RR 0.72, 95% CI 0.54 to 0.98, 1 trial, 4465 participants, low quality evidence). Four RCTs examined the effect of chlamydia screening on PID in women 12 months after a single screening offer. In analysis of four trials according to the intention-to-treat principle, the risk of PID was lower in women in intervention than control groups, with little evidence of between-trial heterogeneity (RR 0.68, 95% CI 0.49 to 0.94, I2 7%, 4 trials, 21,686 participants, moderate quality evidence). In a sensitivity analysis, the estimated effect of chlamydia screening in two RCTs at low risk of detection bias (RR 0.80, 95% CI 0.55 to 1.17) was compatible with no effect and was lower than in two RCTs at high or unclear risk of detection bias (RR 0.42, 95% CI 0.22 to 0.83). The risk of epididymitis in men invited for screening, 12 months after a single screening offer, was 20% lower risk for epididymitis than in those not invited; the confidence interval was wide and compatible with no effect (RR 0.80, 95% CI 0.45 to 1.42, 1 trial, 14,980 participants, very low quality evidence). We found no RCTs of the effects of chlamydia screening in pregnancy and no trials that measured the harms of chlamydia screening. Evidence about the effects of screening on C. trachomatis transmission is of low quality because of directness and risk of bias. There is moderate quality evidence that detection and treatment of chlamydia infection can reduce the risk of PID in women at individual level. There is an absence of RCT evidence about the effects of chlamydia screening in pregnancy. Future RCTs of chlamydia screening interventions should determine the effects of chlamydia screening in pregnancy, of repeated rounds of screening on the incidence of chlamydia-associated PID and chlamydia reinfection in general and high risk populations.
We included 39 randomised controlled trials involving 2599 randomised participants. We included participants of either gender, aged from the first year of life through to 55 years (only six studies assessed adults), who had mild to severe eczema. Trials were undertaken in primary and secondary healthcare settings, mainly in Europe or Asia. Duration of treatment ranged from four weeks to six months, and duration of follow-up after end of treatment ranged from zero to 36 months. We selected no standard dose: researchers used a variety of doses and concentrations of probiotics. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species, which were taken alone or combined with other probiotics, and were given with or without prebiotics. Comparators were no treatment, placebo, and other treatments with no probiotics. For all results described in this abstract, the comparator was no probiotics. Active treatment ranged from six weeks to three months for all of the following results, apart from the investigator-rated eczema severity outcome, for which the upper limit of active treatment was 16 weeks. With regard to score, the higher the score, the more severe were the symptoms. All key results reported in this abstract were measured at the end of active treatment, except for adverse events, which were measured during the active treatment period. Probiotics probably make little or no difference in participant- or parent-rated symptoms of eczema (13 trials; 754 participants): symptom severity on a scale from 0 to 20 was 0.44 points lower after probiotic treatment (95% confidence interval (CI) -1.22 to 0.33; moderate-quality evidence). Trial sequential analysis shows that target sample sizes of 258 and 456, which are necessary to demonstrate a minimum mean difference of -2 and -1.5, respectively, with 90% power, have been exceeded, suggesting that further trials with similar probiotic strains for this outcome at the end of active treatment may be futile. We found no evidence suggesting that probiotics make a difference in QoL for patients with eczema (six studies; 552 participants; standardised mean difference (SMD) 0.03, 95% CI -0.36 to 0.42; low-quality evidence) when measured by the participant or the parent using validated disease-specific QoL instruments. Probiotics may slightly reduce investigator-rated eczema severity scores (24 trials; 1596 participants). On a scale of 0 to 103 for total Severity Scoring of Atopic Dermatitis (SCORAD), a score combining investigator-rated eczema severity score and participant scoring for eczema symptoms of itch and sleep loss was 3.91 points lower after probiotic treatment than after no probiotic treatment (95% CI -5.86 to -1.96; low-quality evidence). The minimum clinically important difference for SCORAD has been estimated to be 8.7 points. We noted significant to extreme levels of unexplainable heterogeneity between the results of individual studies. We judged most studies to be at unclear risk of bias; six studies had high attrition bias, and nine were at low risk of bias overall. We found no evidence to show that probiotics make a difference in the risk of adverse events during active treatment (risk ratio (RR) 1.54, 95% CI 0.90 to 2.63; seven trials; 402 participants; low-quality evidence). Studies in our review that reported adverse effects described gastrointestinal symptoms. Evidence suggests that, compared with no probiotic, currently available probiotic strains probably make little or no difference in improving patient-rated eczema symptoms. Probiotics may make little or no difference in QoL for people with eczema nor in investigator-rated eczema severity score (combined with participant scoring for eczema symptoms of itch and sleep loss); for the latter, the observed effect was small and of uncertain clinical significance. Therefore, use of probiotics for the treatment of eczema is currently not evidence-based. This update found no evidence of increased adverse effects with probiotic use during studies, but a separate adverse events search from the first review revealed that probiotic treatment carries a small risk of adverse events. Results show significant, unexplainable heterogeneity between individual trial results. Only a small number of studies measured some outcomes. Future studies should better measure QoL scores and adverse events, and should report on new probiotics. Researchers should also consider studying subgroups of patients (e.g. patients with atopy or food allergies, adults) and standardising doses/concentrations of probiotics given.
From an initial 1388 citations, we identified 43 studies in 40 papers. Of those, 29 studies with 10,044 participants compared six prokinetics with placebo for the outcome of absence of symptoms or symptom improvement. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR of remaining dyspeptic = 0.81, 95% CI 0.74 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) =7, very low-quality evidence) with considerable heterogeneity; I2 = 91% (P < 0.00001). After removing cisapride from the analysis, the effect of prokinetics in global symptom improvement still persisted, compared to placebo (RR 0.87, 95% CI 0.80 to 0.94), but was still based on very low-quality evidence. The result showed persistence of significant improvement in subgroups of studies at unclear or at low risk of bias (RR 0.86, 95% CI 0.80-0.92), and in subgroups by molecules of cisapride (RR 0.71, 95% CI 0.54 to 0.93; NNTB = 4), acotiamide (RR 0.94, 95% CI 0.91 to 0.98; NNTB = 20) and tegaserod(RR 0.89, 95% CI 0.82 to 0.96; NNTB = 14). Ten studies compared different types of prokinetics with each other and the most commonly used comparator was domperidone, 10 mg three times a day (eight of the 10 studies). There was a significantly better post-treatment symptom score in other prokinetics, compared to domperidone (SMD -0.19, 95% CI -0.35 to -0.03, very low-quality evidence), but no difference in reducing global symptom (RR 0.94, 95% CI 0.83 to 1.07), and mean difference symptom scores (SMD -0.13, 95% CI -0.31 to 0.05). We found five studies that assessed quality of life, but there was no benefit in improving quality of life with prokinetic treatment (SMD 0.11, 95% CI -0.10 to 0.33; participants = 1774). The adverse events in individual prokinetics was not different from placebo (RR 1.09, 95% CI 0.95 to 1.25; participants = 3811; studies = 17). However, when we looked at the adverse effects by each prokinetic, there were overall greater adverse effects in the active treatment group with cisapride (RR 1.31, 95% CI 1.03 to 1.65; P = 0.03). The most common side effects were diarrhoea, abdominal discomfort and nausea. The funnel plot was asymmetric (Egger's test, P = 0.02) implying reporting bias or other small-study effects may be, in part, driving the benefit of prokinetics compared to placebo in this meta-analysis. The GRADE assessment of the quality of the evidence in each outcome are mostly low or very low due to concerns around risk of bias in study design, unexplained heterogeneity and possible publication bias. Due to low, or very low, quality of evidence, we are unable to say whether prokinetics are effective for the treatment of functional dyspepsia . We are uncertain which of the individual prokinetic drugs is the most effective as well as whether prokinetics can improve quality of life. Apart from cisapride, prokinetics are well-tolerated. Good quality RCTs are needed to verify the efficacy of prokinetics.
We found only two RCTs that compared oral L-acetylcarnitine (LAC) with oral placebo in children with FXS. The studies included a total of 83 participants, all of them male, who were treated and followed for one year. The age of participants at the start of treatment ranged from 6 to 13 years, with a mean age of 9 years. Neither study provided information on randomisation, allocation concealment procedures, or blinding of outcome assessment, and we received no responses from the authors we emailed for clarification. We therefore rated studies as being at unclear risk of bias on these domains. We judged both studies to be at low risk of bias for blinding of participants and personnel, incomplete outcome data, and selective reporting, but to be at high risk of other bias, as at least one study was funded by a drug company, and in both studies people working for the company were part of the research team. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of the available evidence. Overall, the quality of the evidence was low due to the imprecision of results and high risk of other bias. Regarding the primary outcome of psychological and learning capabilities, both studies assessed the effect of interventions on children's verbal and non-verbal intellectual functioning using the Wechsler Intelligence Scale for Children - Revised. The authors did not provide detailed data on those results but said that they found no important differences between treatment and placebo. Both studies evaluated the impact of the treatment on hyperactive behaviour using the Conners' Abbreviated Parent-Teacher Questionnaire. In one study, teachers' assessments of the children found no clear evidence of a difference (mean difference (MD) 0.50, 95% confidence interval (CI) -5.08 to 6.08, n = 51; low-quality evidence). The other study stated that there were no differences between treated and untreated participants, but did not provide detailed data for inclusion in the meta-analysis. Parents' assessments favoured LAC in one study (MD -0.57, 95% CI -0.94 to -0.19, n = 17; low-quality evidence), but not in the other (MD -2.80, 95% CI -7.61 to 2.01, n = 51; low-quality evidence), though changes were not large enough to be considered clinically relevant. Regarding social skills, one study reported no clear evidence of a difference in Vineland Adaptive Behavior composite scores (MD 8.20, 95% CI -0.02 to 16.42, n = 51; low-quality evidence), yet results in the socialisation domain favoured LAC (MD 11.30, 95% CI 2.52 to 20.08, n = 51; low-quality evidence). Both studies assessed the safety of the active treatment and recorded no side effects. Neither of the included studies assessed the secondary outcome of caregiver burden. Low-quality evidence from two small trials showed that when compared to placebo, LAC may not improve intellectual functioning or hyperactive behaviour in children with FXS.
We included 17 trials (with 2434 patients) in this updated review. The original review included 11 trials. The total geometric mean duration of mechanical ventilation in the protocolized weaning group was on average reduced by 26% compared with the usual care group (N = 14 trials, 95% confidence interval (CI) 13% to 37%, P = 0.0002). Reductions were most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. Weaning duration was reduced by 70% (N = 8 trials, 95% CI 27% to 88%, P = 0.009); and ICU length of stay by 11% (N = 9 trials, 95% CI 3% to 19%, P = 0.01). There was significant heterogeneity among studies for total duration of mechanical ventilation (I2 = 67%, P < 0.0001) and weaning duration (I2 = 97%, P < 0.00001), which could not be explained by subgroup analyses based on type of unit or type of approach. There is evidence of reduced duration of mechanical ventilation, weaning duration and ICU length of stay with use of standardized weaning protocols. Reductions are most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. However, significant heterogeneity among studies indicates caution in generalizing results. Some study authors suggest that organizational context may influence outcomes, however these factors were not considered in all included studies and could not be evaluated. Future trials should consider an evaluation of the process of intervention delivery to distinguish between intervention and implementation effects. There is an important need for further development and research in the neurosurgical population.
We included six RCTs with a total of 750 participants. Each trial was conducted in a different country: Denmark, Germany, India, Japan, UK, and United States. Additionally, we identified two ongoing trials not due to be completed until 2016. Among the six trials included in this review, we judged one to be at high risk of bias. The remaining five trials were judged to be at either low or uncertain risk of biases. Five trials compared only two intervention groups and one trial had a three-arm comparison of oral corticosteroids or intravenous corticosteroids with placebo. Of the five trials with only two intervention groups, two trials compared oral corticosteroids versus placebo, two trials compared intravenous corticosteroids with placebo, and one trial compared intravenous dexamethasone with intravenous methylprednisolone plus oral prednisolone. Three trials evaluating oral corticosteroids used varying doses of corticosteroids versus placebo. In the meta-analyses to assess visual acuity, the risk ratio (RR) was 1.00 (95% confidence interval (CI) 0.82 to 1.23; participants = 398) at one month; 0.92 (95% CI 0.77 to 1.11; participants = 355) at six months; and 0.93 (95% CI 0.70 to 1.24; participants = 368) at one year. In the meta-analyses of two trials evaluating corticosteroids with total dose greater than 3000 mg administered intravenously, the RR of normal visual acuity (defined as 20/20 Snellen fraction or equivalent) in the intravenous corticosteroids group compared with the placebo group was 1.05 (95% CI 0.88 to 1.26; participants = 346) at six months. The RR of contrast sensitivity in the normal range for the same comparison was 1.11 (95% CI 0.92 to 1.33; participants = 346) at six months follow-up. The RR of normal visual field for this comparison was 1.08 (95% CI 0.96 to 1.21; 346 participants) at six months; and 1.01 (95% CI 0.86 to 1.19; participants = 316) at one year. Four trials reported adverse events primarily related to gastrointestinal symptoms and sleep disturbance; one trial reported minor adverse event of acne. There is no conclusive evidence of benefit in terms of recovery to normal visual acuity, visual field or contrast sensitivity six months after initiation with either intravenous or oral corticosteroids at the doses evaluated in trials included in this review.
Two RCTs with a total of 144 participants met the selection criteria. Both trials compared simvastatin versus placebo in older people (older than 50 or 60 years) with high risk of developing AMD (drusen present on examination). Overall, we judged the quality of the evidence to be low, as we downgraded all outcomes due to limitations in the designs of the trials and insufficient outcome reporting. The larger trial, with 114 participants, was conducted in Australia and used a higher dose (40 mg daily) of simvastatin for three years. Participants and study personnel in this trial were adequately masked, however data were missing for 30% of participants at three years' follow-up. The smaller trial, with 30 participants, was conducted in Italy and used a lower dose (20 mg) of simvastatin for three months. This trial reported insufficient details to assess the risk of bias. Neither trial reported data for change in visual acuity. Low-quality evidence from the smaller trial, with 30 participants, did not show a statistically significant difference between the simvastatin and placebo groups in visual acuity values at three months of treatment (decimal visual acuity 0.21 ± 0.56 in simvastatin group and 0.19 ± 0.40 in placebo group) or 45 days after the completion of treatment (decimal visual acuity 0.20 ± 0.50 in simvastatin group and 0.19 ± 0.48 in placebo group). The lack of a difference in visual acuity was not explained by lens or retina status, which remained unchanged during and after the treatment period for both groups. Preliminary analyses of 42 participants who had completed 12 months' follow-up in the larger trial did not show a statistically significant difference between simvastatin and the placebo groups for visual acuity, drusen score, or visual function (effect estimates and confidence intervals were not available). Complete data for these outcomes at three years' follow-up were not reported. At three years, low-quality evidence showed an effect of simvastatin in slowing progression of AMD compared with placebo to be uncertain (odds ratio 0.51, 95% confidence interval 0.23 to 1.09). One trial did not report adverse outcomes. The second trial reported no difference between groups in terms of adverse events such as death, muscle aches, and acute hepatitis. Evidence from currently available RCTs is insufficient to conclude that statins have a role in preventing or delaying the onset or progression of AMD.
The original review included 10 studies with 996 participants. This updated review included 15 studies (1509 participants); 11 assessed naproxen sodium and four naproxen. In nine studies (784 participants) using 500/550 mg naproxen or naproxen sodium the NNT for at least 50% pain relief over four to six hours was 2.7 (95% CI 2.3 to 3.2). No dose response was demonstrated over the range 200/220 mg to 500/550 mg, but limited data was identified. Median time to use of rescue medication was 8.9 hours for naproxen 500/550 mg and 2.0 hours for placebo. Use of rescue medication was significantly less common with naproxen than placebo. Associated adverse events were generally of mild to moderate severity and rarely led to withdrawal. Doses equivalent to 500 mg and 400 mg naproxen administered orally provided effective analgesia to adults with moderate to severe acute postoperative pain. About half of participants treated with these doses experienced clinically useful levels of pain relief, compared to 15% with placebo, and half required additional medication within nine hours, compared to two hours with placebo. Associated adverse events did not differ from placebo.
A total of six RCTs (326 patients) evaluating therapeutic discontinuation in patients with quiescent CD were eligible for inclusion. In four RCTs azathioprine monotherapy was discontinued, and in two RCTs azathioprine was discontinued from a combination therapy regimen consisting of azathioprine with infliximab. No studies of biologic monotherapy withdrawal were eligible for inclusion. The majority of studies received unclear or low risk of bias ratings, with the exception of three open-label RCTs, which were rated as high risk of bias for blinding. Four RCTs (215 participants) compared discontinuation to continuation of azathioprine monotherapy, while two studies (125 participants) compared discontinuation of azathioprine from a combination regimen to continuation of combination therapy. Continuation of azathioprine monotherapy was shown to be superior to withdrawal for risk of clinical relapse. Thirty-two per cent (36/111) of azathioprine withdrawal participants relapsed compared to 14% (14/104) of participants who continued with azathioprine therapy (RR 0.42, 95% CI 0.24 to 0.72, GRADE low quality evidence). However, it is uncertain if there are any between-group differences in new CD-related complications (RR 0.34, 95% CI 0.06 to 2.08, GRADE low quality evidence), adverse events (RR 0.88, 95% CI 0.67 to 1.17, GRADE low quality evidence), serious adverse events (RR 3.29, 95% CI 0.35 to 30.80, GRADE low quality evidence) or withdrawal due to adverse events (RR 2.59, 95% CI 0.35 to 19.04, GRADE low quality evidence). Common adverse events included infections, mild leukopenia, abdominal symptoms, arthralgias, headache and elevated liver enzymes. No differences between azathioprine withdrawal from combination therapy versus continuation of combination therapy were observed for clinical relapse. Among patients who continued combination therapy with azathioprine and infliximab, 48% (27/56) had a clinical relapse compared to 49% (27/55) of patients discontinued azathioprine but remained on infliximab (RR 1.02, 95% CI 0.68 to 1.52, P = 0.32; GRADE low quality evidence). The effects on adverse events (RR 1.11, 95% CI 0.44 to 2.81, GRADE low quality of evidence) or serious adverse events are uncertain (RR 1.00, 95% CI 0.21 to 4.66; GRADE very low quality of evidence). Common adverse events in the combination therapy studies included infections, liver test elevations, arthralgias and infusion reactions. The effects of withdrawal of immunosuppressant therapy in people with quiescent Crohn's disease are uncertain. Low quality evidence suggests that continuing azathioprine monotherapy may be superior to withdrawal for avoiding clinical relapse, while very low quality evidence suggests that there may be no difference in clinical relapse rates between discontinuing azathioprine from a combination therapy regimen, compared to continuing combination therapy. It is unclear whether withdrawal of azathioprine, initially administered alone or in combination, impacts on the development of CD-related complications, adverse events, serious adverse events or withdrawal due to adverse events. Further high-quality research is needed in this area, particularly double-blind RCTs in which biologic therapy or an immunosuppressant other than azathioprine is withdrawn.
We included eight studies examining the blood pressure lowering efficacy of carvedilol and labetalol in 1493 hypertensive patients. Five of the included studies were parallel design; three were cross-over design. The two largest included studies were unpublished carvedilol studies. The estimates of BP lowering effect (systolic BP/diastolic BP millimeters of mercury; SPB/DBP mm Hg) were -4 mm Hg (95% confidence intervals (CI) -6 to -2)/-3 mm Hg (95% CI -4 to -2) for carvedilol (>1000 subjects) and -10 mm Hg (95% CI -14 to -7)/-7 mm Hg (95% CI -9 to -5) for labetalol (110 subjects). The effect of labetalol is likely to be exaggerated due to high risk of bias. Carvedilol, within the recommended dose range, did not show a significant dose response effect for SBP or DBP. Carvedilol had little or no effect on pulse pressure (-1 mm Hg) and did not change BP variability. Overall, once and twice the starting dose of carvedilol and labetalol lowered BP by -6 mm Hg (95% CI -7 to -4) /-4 mm Hg (95% CI -4 to -3) (low quality evidence) and lowered heart rate by five beats per minute (95% CI -6 to -4) (low quality evidence). Five studies (N = 1412) reported withdrawal due to adverse effects; the risk ratio was 0.88 (95% CI 0.54 to 1.42) (moderate quality evidence). This review provides low quality evidence that in patients with mild to moderate hypertension, dual receptor blockers lowered trough BP by an average of -6/-4 mm Hg and reduced heart rate by five beats per minute. Due to the larger sample size from the two unpublished studies, carvedilol provided a better estimate of BP lowering effect than labetalol. The BP lowering estimate from combining carvedilol once and twice the starting doses is -4/-3 mm Hg. Doses higher than the recommended starting dose did not provide additional BP reduction. Higher doses of dual receptor blockers caused more bradycardia than lower doses. Based on indirect comparison with other classes of drugs, the blood pressure lowering effect of dual alpha- and beta-receptor blockers is less than non-selective, beta1 selective and partial agonist beta blockers, as well as thiazides and drugs inhibiting the renin angiotensin system. Dual blockers also had little or no effect on reducing pulse pressure, which is similar to the other beta-blocker classes, but less than the average reduction of pulse pressure seen with thiazides and drugs inhibiting the renin angiotensin system. Patients taking dual receptor blockers were not more likely to withdraw from the study compared to patients taking placebo.
We included eight studies (24 reports, 258 participants). Because duration of the included studies was too short (1 to 26 weeks) to test the effect of salt restriction on endpoints such as mortality, cardiovascular events or CKD progression, changes in salt intake on blood pressure and other secondary risk factors were applied. Three studies were parallel RCTs and five were cross-over studies. Selection bias was low in five studies and unclear in three. Performance and detection biases were low in two studies and unclear in six. Attrition and reporting biases were low in four studies and unclear in four. One study had the potential for high carryover effect; three had high risk of bias from baseline characteristics (change of medication or diet) and two studies were industry funded. There was a significant reduction in 24 hour sodium excretion associated with low salt interventions (range 52 to 141 mmol) (8 studies, 258 participants: MD -105.86 mmol/d, 95% CI -119.20 to -92.51; I2 = 51%). Reducing salt intake significantly reduced systolic blood pressure (8 studies, 258 participants: MD -8.75 mm Hg, 95% CI -11.33 to -6.16; I2 = 0%) and diastolic blood pressure (8 studies, 258 participants: MD -3.70 mm Hg, 95% CI -5.09 to -2.30; I2 = 0%). One study reported restricting salt intake reduced the risk of oedema by 56%. Salt restriction significantly increased plasma renin activity (2 studies, 71 participants: MD 1.08 ng/mL/h, 95% CI 0.51 to 1.65; I2 = 0%) and serum aldosterone (2 studies, 71 participants: 6.20 ng/dL (95% CI 3.82 to 8.58; I2 = 0%). Antihypertensive medication dosage was significantly reduced with a low salt diet (2 studies, 52 participants): RR 5.48, 95% CI 1.27 to 23.66; I2 = 0%). There was no significant difference in eGFR (2 studies, 68 participants: MD -1.14 mL/min/1.73 m2, 95% CI -4.38 to 2.11; I2 = 0%), creatinine clearance (3 studies, 85 participants): MD -4.60 mL/min, 95% CI -11.78 to 2.57; I2 = 0%), serum creatinine (5 studies, 151 participants: MD 5.14 µmol/L, 95% CI -8.98 to 19.26; I2 = 59%) or body weight (5 studies, 139 participants: MD -1.46 kg; 95% CI -4.55 to 1.64; I2 = 0%). There was no significant change in total cholesterol in relation to salt restriction (3 studies, 105 participants: MD -0.23 mmol/L, 95% CI -0.57 to 0.10; I2 = 0%) or symptomatic hypotension (2 studies, 72 participants: RR 6.60, 95% CI 0.77 to 56.55; I2 = 0%). Salt restriction significantly reduced urinary protein excretion in all studies that reported proteinuria as an outcome, however data could not be meta-analysed. We found a critical evidence gap in long-term effects of salt restriction in people with CKD that meant we were unable to determine the direct effects of sodium restriction on primary endpoints such as mortality and progression to end-stage kidney disease (ESKD). We found that salt reduction in people with CKD reduced blood pressure considerably and consistently reduced proteinuria. If such reductions could be maintained long-term, this effect may translate to clinically significant reductions in ESKD incidence and cardiovascular events. Research into the long-term effects of sodium-restricted diet for people with CKD is warranted, as is investigation into adherence to a low salt diet.
Rates of developing postoperative ileus were comparable between study groups (RR 0.47, 95% CI 0.17 to 1.29, P = 0.14, 3 RCTs, 279 women, I² = 0%, moderate-quality evidence). When we considered the rates of nausea or vomiting or both, there was no evidence of a difference between the study groups (RR 1.03, 95% CI 0.64 to 1.67, P = 0.90, 4 RCTs, 484 women, I² = 73%, moderate-quality evidence). There was no evidence of a difference between the study groups in abdominal distension (RR 1.07, 95% CI 0.77 to 1.47, 2 RCTs, 301 women, I² = 0%) or a need for postoperative nasogastric tube placement (RR 0.48, 95% CI 0.13 to 1.80, 1 RCT, 195 women). Early feeding was associated with shorter time to the presence of bowel sound (MD -0.32 days, 95% CI -0.61 to -0.03, P = 0.03, 2 RCTs, 338 women, I² = 52%, moderate-quality evidence) and faster onset of flatus (MD -0.21 days, 95% CI -0.40 to -0.01, P = 0.04, 3 RCTs, 444 women, I² = 23%, moderate-quality evidence). In addition, women in the early feeding group resumed a solid diet sooner (MD -1.47 days, 95% CI -2.26 to -0.68, P = 0.0003, 2 RCTs, 301 women, I² = 92%, moderate-quality evidence). There was no evidence of a difference in time to the first passage of stool between the two study groups (MD -0.25 days, 95% CI -0.58 to 0.09, P = 0.15, 2 RCTs, 249 women, I² = 0%, moderate-quality evidence). Hospital stay was shorter in the early feeding group (MD -0.92 days, 95% CI -1.53 to -0.31, P = 0.003, 4 RCTs, 484 women, I² = 68%, moderate-quality evidence). Infectious complications were less common in the early feeding group (RR 0.20, 95% CI 0.05 to 0.73, P = 0.02, 2 RCTs, 183 women, I² = 0%, high-quality evidence). In one study, the satisfaction score was significantly higher in the early feeding group (MD 11.10, 95% CI 6.68 to 15.52, P < 0.00001, 143 women, moderate-quality evidence). Early postoperative feeding after major abdominal gynaecologic surgery for either benign or malignant conditions appeared to be safe without increased gastrointestinal morbidities or other postoperative complications. The benefits of this approach include faster recovery of bowel function, lower rates of infectious complications, shorter hospital stay, and higher satisfaction.
We included only one non-randomised study published 30 years ago in the review. This study included 77 participants who had gastric ulcer and in whom medical therapy (histamine H2 receptor blockers, antacids, and diet) had failed after an average duration of treatment of 29 months. The authors do not state whether these were recurrent or refractory ulcers. It appears that the participants did not have previous complications such as bleeding or perforation. Of the 77 included participants, 37 participants continued to have medical therapy while 40 participants received surgical therapy (antrectomy with or without vagotomy; subtotal gastrectomy with or without vagotomy; vagotomy; pyloroplasty and suture of the ulcer; suture or closure of ulcer without vagotomy or excision of the ulcer; proximal gastric or parietal cell vagotomy alone; suture or closure of the ulcer with proximal gastric or parietal cell vagotomy). Whether to use medical or surgical treatment was determined by participant's or treating physician's preference. The study authors reported that two participants in the medical treatment group (2 out of 37; 5.4%) had gastric cancer, which was identified by repeated biopsy. They did not report the proportion of participants who had gastric cancer in the surgical treatment group. They also did not report the implications of the delayed diagnosis of gastric cancer in the medical treatment group. They did not report any other outcomes of interest for this review (that is health-related quality of life (using any validated scale), adverse events and serious adverse events, peptic ulcer bleeding, peptic ulcer perforation, abdominal pain, and long-term mortality). We found no studies that provide the relative benefits and harms of medical versus surgical treatment for recurrent or refractory peptic ulcers. Studies that evaluate the natural history of recurrent and refractory peptic ulcers are urgently required to determine whether randomised controlled trials comparing medical versus surgical management in patients with recurrent or refractory peptic ulcers or both are necessary. Such studies will also provide information for the design of such randomised controlled trials. A minimum follow-up of two to three years will allow the calculation of the incidence of complications and gastric cancer (in gastric ulcers only) in recurrent and refractory peptic ulcers. In addition to complications related to treatment and disease, health-related quality of life and loss of productivity should also be measured.
Three trials with a total of 81 patients were included in the analysis. Forty patients were randomized to azathioprine and forty-one to placebo. A pooled estimate was calculated for two outcomes. A statistically significant benefit was observed for azathioprine when compared to placebo for tender joint scores. The standardized weighted mean difference between treatment and placebo was -0.98 (95% CI -1.45, -0.50). Withdrawals from adverse reactions were significantly higher in the azathioprine group OR=4.56 (95% CI 1.16, 17.85). Azathioprine appears to have a statistically significant benefit on the disease activity in joints of patients with RA. This evidence however is based on a small number of patients, included in older trials. Its effects on long-term functional status and radiological progression were not assessed due to lack of data. Toxicity is shown to be higher and more serious than that observed with other disease-modifying anti-rheumatic drugs (DMARDs). Given this high risk to benefit ratio, there is no evidence to recommend the use of azathioprine over other DMARDs.
Six trials were included, involving 606 participants. Five trials included comparisons of ultrasound therapy with sham ultrasound; and three trials included single comparisons of ultrasound with three other treatments. The assessment of risk of bias was hampered by poor reporting of trial methods and results. None of the five placebo-controlled trials (sham ultrasound) demonstrated statistically significant differences between true and sham ultrasound therapy for any outcome measure at one to four weeks of follow-up. The pooled risk ratio for general improvement at one week was 1.04 (random-effects model, 95% confidence interval 0.92 to 1.17) for active versus sham ultrasound. The differences between intervention groups were generally small, between zero and six per cent, for most dichotomous outcomes. The evidence from the five small placebo-controlled trials included in this review does not support the use of ultrasound in the treatment of acute ankle sprains. The potential treatment effects of ultrasound appear to be generally small and of probably of limited clinical importance, especially in the context of the usually short-term recovery period for these injuries. However, the available evidence is insufficient to rule out the possibility that there is an optimal dosage schedule for ultrasound therapy that may be of benefit.
Eleven trials (550 women) compared corticosteroids with placebo or no treatment. There was no difference in the risk of maternal death (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.28 to 3.21), maternal death or severe maternal morbidity (RR 0.27, 95% CI 0.03 to 2.12), or perinatal/infant death (RR 0.64, 95% CI 0.21 to 1.97). The only clear effect of treatment on individual outcomes was improved platelet count (standardized mean difference (SMD) 0.67, 95% CI 0.24 to 1.10). The effect on platelet count was strongest for women who commenced treatment antenatally (SMD 0.80, 95% CI 0.25 to 1.35). Two trials (76 women) compared dexamethasone with betamethasone. There was no clear evidence of a difference between groups in respect to perinatal/infant death (RR 0.95, 95% CI 0.15 to 6.17) or severe perinatal/infant morbidity or death (RR 0.64, 95% CI 0.27 to 1.48). Maternal death and severe maternal morbidity were not reported. In respect to platelet count, dexamethasone was superior to betamethasone (MD 6.02, 95% CI 1.71 to 10.33), both when treatment was commenced antenatally (MD 8.10, 95% CI 6.23 to 9.97) and postnatally (MD 3.70, 95% CI 0.96 to 6.44). There was no clear evidence of any effect of corticosteroids on substantive clinical outcomes. Those receiving steroids showed significantly greater improvement in platelet counts which was greater for those receiving dexamethasone than those receiving betamethasone. There is to date insufficient evidence of benefits in terms of substantive clinical outcomes to support the routine use of steroids for the management of HELLP. The use of corticosteroids may be justified in clinical situations in which increased rate of recovery in platelet count is considered clinically worthwhile.
We included 23 trials involving 1886 people in this updated review. Twenty-two of these trials investigated the addition of medication to treat the identified dysfunction, with most agents studied in only single studies. One study investigated switching to an alternative antidepressant. In men, data for the phosphodiesterase inhibitors sildenafil (three studies, 255 participants) and tadalafil (one study, 54 participants) indicated they led to a greater improvement in erectile function than placebo. Combined data from three sildenafil studies found benefit over placebo on International Index of Erectile Function ratings of ability to achieve (MD 1.04, 95% CI 0.65 to 1.44), and maintain erections (MD 1.18, 95% CI 0.78 to 1.59). A single point improvement on these ratings is equivalent to an improvement in frequency from 'sometimes' to 'most times'. Men receiving tadalafil were more likely to report improved erectile function (RR 11.50, 95% CI 3.03 to 43.67). For women it remains uncertain whether sildenafil is more effective than placebo. Unpublished data could reduce this uncertainty. Data from three studies in men and women of bupropion 150 mg twice daily indicate a benefit over placebo on rating scale scores (SMD 1.60, 95% CI 1.40 to 1.81), but response rates in two studies of bupropion 150 mg once daily demonstrated no statistically significant difference in effect (RR 0.62, 95% CI 0.09 to 4.41). Other augmentation strategies failed to demonstrate significant improvements in sexual dysfunction compared with placebo. One trial involving 75 people with sexual dysfunction due to sertraline assessed the effect of changing antidepressant. Switching to nefazodone was significantly less likely to result in the re-emergence of sexual dysfunction than restarting sertraline (RR 0.34, 95% CI 0.19 to 0.60), however, nefazodone is no longer available for clinical use. There is an absence of randomised trials assessing the effects of switching to currently-available antidepressant agents with lower rates of adverse sexual effects, the role of psychological or mechanical interventions, or of techniques such as drug holidays. We identified no data for any of the strategies included in the trials assessed that indicated that they led to a worsening of psychiatric symptoms. However, the relatively small numbers assessed for many of the interventions studied means that the possibility of such an effect cannot confidently be excluded in all cases. Given the small numbers of studies assessing most of the strategies assessed, the presence of any unpublished trials could have substantial effects on estimates of effect. In some cases, only results from particular items or subscales within ratings scales are available. It is likely that this could act to bias estimates of effect obtained, increasing apparent effectiveness. The evidence currently available is rather limited. For men with antidepressant-induced erectile dysfunction, the addition of sildenafil or tadalafil appears to be an effective strategy. For women with antidepressant-induced sexual dysfunction the addition of bupropion at higher doses appears to be the most promising approach studied so far.
Twelve trials were eligible for inclusion. Three of these trials, involving a total of 909 patients, compared ICS plus systemic corticosteroids versus oral corticosteroid therapy alone. There was no demonstrated benefit of ICS therapy when used in addition to oral corticosteroid therapy in the trials. Relapses were reduced; however, this was not statistically significant with the addition of ICS therapy (OR 0.68; 95% CI 0.46 to 1.02; 3 studies; N = 909). In addition, no statistically significant differences were demonstrated between the two groups for relapses requiring admission, quality of life, symptom scores or adverse effects. Nine trials, involving a total of 1296 patients compared high-dose ICS therapy alone versus oral corticosteroid therapy alone after ED discharge. There were no significant differences demonstrated between ICS therapy alone versus oral corticosteroid therapy alone for relapse rates (OR 1.00; 95% CI 0.66 to 1.52; 4 studies; N = 684), admissions to hospital, or in the secondary outcomes of beta2-agonist use, symptoms or adverse events. However, the sample size was not adequate to exclude the possibility of either treatment being significantly inferior and people with severe asthma were excluded from these trials. There is insufficient evidence that ICS therapy provides additional benefit when used in combination with standard systemic corticosteroid therapy upon ED discharge for acute asthma. There is some evidence that high-dose ICS therapy alone may be as effective as oral corticosteroid therapy when used in mild asthmatics upon ED discharge; however, the confidence intervals were too wide to be confident of equal effectiveness. Further research is needed to clarify whether ICS therapy should be employed in acute asthma treatment following ED discharge. The review does not suggest any reason to stop usual treatment with ICS following ED discharge, even if a course of oral corticosteroids are prescribed.
We included 15 trials. Seven studies reported from 2010 to 2014 were added to eight from the original 2001 review. Newer trials compared immediate postplacental insertion versus early (10 minutes to 48 hours) or standard insertion (during the postpartum visit). Of four with full reports, three were small trials. The other three studies had conference abstracts. The eight early trials examined immediate insertion of different devices or insertion techniques. Most studies were published in the 1980s, some with limited reporting. Our sensitivity analysis included trials with sufficient outcome data and moderate or high quality evidence. Four newer trials comparing insertion times met the inclusion criteria. Two studies used the levonorgestrel-releasing intrauterine system (LNG-IUS) after vaginal delivery. The other two trials placed IUC after cesarean section; one used the CuT 380A intrauterine device (IUD) and the other used the LNG-IUS. A pilot trial compared immediate insertion versus early or standard insertion. In groups comparing immediate versus early insertion (N = 30), all women had the LNG-IUS inserted. By six months, the groups had the same expulsion rate and did not differ significantly in IUC use. For immediate versus standard insertion, we conducted meta-analyses of four trials. Insertion rates did not differ significantly between study arms. However, the trial from Uganda showed insertion was more likely for the immediate group, although the estimate was imprecise. In the meta-analysis, expulsion by six months was more likely for the immediate group, but the confidence interval was wide (OR 4.89, 95% CI 1.47 to 16.32; participants = 210; studies = 4). IUC use at six months was more likely with immediate insertion than with standard insertion (OR 2.04, 95% CI 1.01 to 4.09; participants = 243; studies = 4). Study arms did not differ in use at 3 or 12 months in individual small trials. Recent trials compared different insertion times after vaginal or cesarean delivery. Evidence was limited because studies with full reports generally had small sample sizes. Overall, the quality of evidence was moderate; abstracts and older studies had limited reporting. Ongoing trials will add to the evidence, although some are small. Trials of adequate power are needed to estimate expulsion rates and side effects. The benefit of effective contraception immediately after delivery may outweigh the disadvantage of increased risk for expulsion. Frequent prenatal visits during the third trimester provide the opportunity to discuss effective contraceptive methods and desired timing for initiation. Clinical follow-up can help detect early expulsion, as can educating women about expulsion signs and symptoms.
After conducting initial searches and screening the titles and abstracts of the identified literature, 77 full text papers were retrieved and read. Ultimately three studies were included. Two controlled before-after studies were conducted in hospital settings (one in the UK and one in the Netherlands) and one cluster randomised controlled trial was conducted in a primary care setting (in the USA). The study conducted in primary care reported that physicians were receptive to the screening intervention, but the intervention did not result in any improvements in the malnutrition detection rate or nutritional intervention rate. The two studies conducted in hospitals had important methodological limitations. One study reported that as a result of the intervention, the recording of patients' weight increased in the intervention wards. No significant changes were observed in the referral rates to dietitians or care at meal time. The third study reported weight gains and a reduction in hospital acquired infection rate in the intervention hospital. They found no significant differences in length of stay, pressure sores, malnutrition and treatment costs per patient between the two hospitals. Current evidence is insufficient to support the effectiveness of nutritional screening, although equally there is no evidence of no effect. Therefore, more high quality studies should be conducted to assess the effectiveness of nutritional screening in different settings.
We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low. According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.
We included 38 randomised controlled trials involving 1907 participants (1114 cell therapy, 793 controls) in this review update. Twenty-three trials were at high or unclear risk of selection bias. Other sources of potential bias included lack of blinding of participants (12 trials) and full or partial commercial sponsorship (13 trials). Cell therapy reduced the incidence of long-term mortality (≥ 12 months) (risk ratio (RR) 0.42, 95% confidence interval (CI) 0.21 to 0.87; participants = 491; studies = 9; I2 = 0%; low-quality evidence). Periprocedural adverse events associated with the mapping or cell/placebo injection procedure were infrequent. Cell therapy was also associated with a long-term reduction in the incidence of non-fatal myocardial infarction (RR 0.38, 95% CI 0.15 to 0.97; participants = 345; studies = 5; I2 = 0%; low-quality evidence) and incidence of arrhythmias (RR 0.42, 95% CI 0.18 to 0.99; participants = 82; studies = 1; low-quality evidence). However, we found no evidence that cell therapy affects the risk of rehospitalisation for heart failure (RR 0.63, 95% CI 0.36 to 1.09; participants = 375; studies = 6; I2 = 0%; low-quality evidence) or composite incidence of mortality, non-fatal myocardial infarction, and/or rehospitalisation for heart failure (RR 0.64, 95% CI 0.38 to 1.08; participants = 141; studies = 3; I2 = 0%; low-quality evidence), or long-term left ventricular ejection fraction when measured by magnetic resonance imaging (mean difference -1.60, 95% CI -8.70 to 5.50; participants = 25; studies = 1; low-quality evidence). This systematic review and meta-analysis found low-quality evidence that treatment with bone marrow-derived stem/progenitor cells reduces mortality and improves left ventricular ejection fraction over short- and long-term follow-up and may reduce the incidence of non-fatal myocardial infarction and improve New York Heart Association (NYHA) Functional Classification in people with chronic ischaemic heart disease and congestive heart failure. These findings should be interpreted with caution, as event rates were generally low, leading to a lack of precision.
Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias. In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.
We found four randomised clinical trials including 496 adult participants diagnosed with variceal haemorrhage due to cirrhotic portal hypertension. The overall risk of bias in all the trials was judged at high risk. All the trials were conducted in the United States of America (USA). Two of the trials randomised participants to selective surgical shunts versus TIPS. The other two trials randomised participants to non-selective surgical shunts versus TIPS. The diagnosis of liver cirrhosis was by clinical and laboratory findings. We are uncertain whether there is a difference in all-cause mortality at 30 days between surgical portosystemic shunts compared with TIPS (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.44 to 1.99; participants = 496; studies = 4). We are uncertain whether there is a difference in encephalopathy between surgical shunts compared with TIPS (RR 0.56, 95% CI 0.27 to 1.16; participants = 496; studies = 4). We found evidence suggesting an increase in the occurrence of the following harms in the TIPS group compared with surgical shunts: all-cause mortality at five years (RR 0.61, 95% CI 0.42 to 0.90; participants = 496; studies = 4); variceal rebleeding (RR 0.18, 95% CI 0.07 to 0.49; participants = 496; studies = 4); reinterventions (RR 0.13, 95% CI 0.06 to 0.28; participants = 496; studies = 4); and shunt occlusion (RR 0.14, 95% CI 0.04 to 0.51; participants = 496; studies = 4). We could not perform an analysis of health-related quality of life but available evidence appear to suggest improved health-related quality of life in people who received surgical shunt compared with TIPS. We downgraded the certainty of the evidence for all-cause mortality at 30 days and five years, irreversible shunt occlusion, and encephalopathy to very low because of high risk of bias (due to lack of blinding); inconsistency (due to heterogeneity); imprecision (due to small sample sizes of the individual trials and few events); and publication bias (few trials reporting outcomes). We downgraded the certainty of the evidence for variceal rebleeding and reintervention to very low because of high risk of bias (due to lack of blinding); imprecision (due to small sample sizes of the individual trials and few events); and publication bias (few trials reporting outcomes). The small sample sizes and few events did not allow us to produce meaningful trial sequential monitoring boundaries, suggesting plausible random errors in our estimates. We found evidence suggesting that surgical portosystemic shunts may have benefit over TIPS for treatment of refractory or recurrent variceal haemorrhage in people with cirrhotic portal hypertension. Given the very low-certainty of the available evidence and risks of random errors in our analyses, we have very little confidence in our review findings.
We included nine trials, with 316 participants in total, that compared the effects of naloxone versus placebo or no drug in newborn infants exposed to maternal opioid analgesia prior to delivery. None of the included trials investigated infants born to mothers who had used a prescribed or non-prescribed opioid during pregnancy. None of these trials specifically recruited infants with cardiorespiratory or neurological depression. The main outcomes reported were measures of respiratory function in the first six hours after birth. There is some evidence that naloxone increases alveolar ventilation. The trials did not assess the effect on the primary outcomes of this review (admission to a neonatal unit and failure to establish breastfeeding). The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opioid. Given concerns about the safety of naloxone in this context, it may be appropriate to limit its use to randomised controlled trials that aim to resolve these uncertainties.
We found no RCT and thus no available data for evaluation of the primary outcome (mortality) nor secondary outcomes or adverse effects. Therefore, we conducted no statistical analysis. A total of 73 observational studies reported on various clinically relevant outcomes following catheter removal or catheter retention. Most of these excluded, observational studies reported a beneficial effect of catheter removal in patients with candidaemia. None of the observational studies reported results in favour of retaining a catheter. However, the observational studies were very heterogeneous with regards to population, pathogens and interventions. Furthermore, they suffered from confounding by indication and an overall high risk of bias. As a consequence, we are not able to provide recommendations or to draw firm conclusions because of the difficulties involved in interpreting the results of these observational studies (very low quality of evidence, GRADE - Grades of Recommendation, Assessment, Development and Evaluation Working Group). Despite indications from observational studies in favour of early catheter removal, we found no eligible RCTs or quasi-RCTs to support these practices and therefore could draw no firm conclusions. At this stage, RCTs have provided no evidence to support the benefit of early or late catheter removal for survival or other important outcomes among patients with candidaemia; no evidence with regards to assessment of harm or benefit with prompt central venous catheter removal and subsequent re-insertion of new catheters to continue treatment; and no evidence on optimal timing of insertion of a new central venous catheter.
We included three RCTs (n=277) with 24-28 weeks follow-up. Three combinations of minerals were investigated: potassium-magnesium, calcium-magnesium, and calcium-potassium. One trial investigated combinations of calcium-magnesium and of calcium-potassium, and for each found a statistically non-significant increase in both SBP and DBP. All three trials investigated the potassium-magnesium combination. None of the trials provided mortality or morbidity data. The potassium-magnesium combination compared to control resulted in statistically non-significant reductions in both SBP (mean difference = -4.6 mmHg, 95% CI: -9.9 to 0.7) and DBP (mean difference = -3.8 mmHg, 95% CI: -9.5 to 1.8), although the results were heterogeneous (I2=68% and 85% for SBP and DBP respectively). A sensitivity analysis using alternative reported values which accounted for missing data had very little effect on DBP but resulted in a larger, statistically significant reduction in SBP (mean difference = -5.8 mmHg, 95% CI: -10.5 to -1.0). The quality of the trials was not well reported. We found no robust evidence that supplements of any combination of potassium, magnesium or calcium reduce mortality, morbidity or BP in adults. More trials are needed to investigate whether the combination of potassium & magnesium is effective.
Two small RCTs (total 42 patients) met the inclusion criteria and were included in the review. One study (18 patients) compared four weeks of treatment with a glutamine-enriched polymeric diet (42% amino acid composition) to a standard polymeric diet (4% amino acid composition) with low glutamine content in paediatric patients (< 18 years of age) with active Crohn's disease. The other study (24 patients) compared glutamine-supplemented total parenteral nutrition to non-supplemented total parenteral nutrition in adult patients (> 18 years of age) with acute exacerbation of inflammatory bowel disease. The paediatric study was rated as low risk of bias. The study in adult patients was rated as unclear risk of bias for blinding and low risk of bias for all other items. It was not possible to pool data for meta-analysis because of significant differences in study populations, nature of interventions, and the way outcomes were assessed. Data from one study showed no statistically significant difference in clinical remission rates at four weeks. Forty-four per cent (4/9) of patients who received a glutamine-enriched polymeric diet achieved remission compared to 56% (5/9) of patients who received a standard low-glutamine polymeric diet (RR 0.80, 95% CI 0.31 to 2.04). A GRADE analysis indicated that the overall quality of evidence for this outcome was low due to serious imprecision (9 events). In both included studies, no statistically significant changes in intestinal permeability were found between patients who received glutamine supplementation and those who did not. Neither study reported on clinical response, quality of life or growth in children. Adverse event data were not well documented. There were no serious adverse events in the paediatric study. The study in adult patients reported three central catheter infections with positive blood cultures in the glutamine group compared to none in the control group (RR 7.00, 95% CI 0.40 to 122.44). Currently there is insufficient evidence to allow firm conclusions regarding the efficacy and safety of glutamine for induction of remission in Crohn's disease. Data from two small studies suggest that glutamine supplementation may not be beneficial in active Crohn's disease but these results need to be interpreted with caution as they are based on small numbers of patients. This review highlights the need for adequately powered randomised controlled trials to investigate the efficacy and safety of glutamine for induction of remission in Crohn's disease.
We included 18 RCTs involving 1014 infants. All studies were small and at high risk of bias, often presenting major shortcomings across multiple design factors (e.g. selection, performance, attrition, lack of washout period). Three studies compared simethicone with placebo, and one with Mentha piperita; four studies compared herbal agents with placebo; two compared sucrose or glucose with placebo; five compared dicyclomine with placebo; and two compared cimetropium - one against placebo and the other at two different dosages. One multiple-arm study compared sucrose and herbal tea versus no treatment. Simethicone. Comparison with placebo revealed no difference in daily hours of crying reported for simethicone at the end of treatment in one small, low-quality study involving 27 infants. A meta-analysis of data from two cross-over studies comparing simethicone with placebo showed no difference in the number of of infants who responded positively to treatment (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.73 to 1.23; 110 infants, low-quality evidence). One small study (30 participants) compared simethicone with Mentha piperita and found no difference in crying duration, number of crying episodes or number of responders. Herbal agents. We found low-quality evidence suggesting that herbal agents reduce the duration of crying compared with placebo (mean difference (MD) 1.33, 95% CI 0.71 to 1.96; three studies, 279 infants), with different magnitude of benefit noted across studies (I² = 96%). We found moderate-quality evidence indicating that herbal agents increase response over placebo (RR 2.05, 95% CI 1.56 to 2.70; three studies, 277 infants). Sucrose. One very low-quality study involving 35 infants reported that sucrose reduced hours spent crying compared with placebo (MD 1.72, 95% CI 1.38 to 2.06). Dicyclomine. We could consider only one of the five studies of dicyclomine (48 infants) for the primary comparison. In this study, more of the infants given dicyclomine responded than than those given placebo (RR 2.50, 95% CI 1.17 to 5.34). Cimetropium bromide. Data from one very low-quality study comparing cimetropium bromide with placebo showed reduced crying duration among infants treated with cimetropium bromide (MD -30.20 minutes per crisis, 95% CI -39.51 to -20.89; 86 infants). The same study reported that cimetropium increased the number of responders (RR 2.29, 95% CI 1.44 to 3.64). No serious adverse events were reported for all of the agents considered, with the exception of dicyclomine, for which two of five studies reported relevant adverse effects (longer sleep 4%, wide-eyed state 4%, drowsiness 13%). At the present time, evidence of the effectiveness of pain-relieving agents for the treatment of infantile colic is sparse and prone to bias. The few available studies included small sample sizes, and most had serious limitations. Benefits, when reported, were inconsistent. We found no evidence to support the use of simethicone as a pain-relieving agent for infantile colic. Available evidence shows that herbal agents, sugar, dicyclomine and cimetropium bromide cannot be recommended for infants with colic. Investigators must conduct RCTs using standardised measures that allow comparisons among pain-relieving agents and pooling of results across studies. Parents, who most often provide the intervention and assess the outcome, should always be blinded.
We included one randomized controlled trial on pharmacological interventions with 95 participants. No studies were found for non-pharmacological interventions. Concerning the proportion of participants with seizure freedom, no significant differences were found for the comparisons of levetiracetam (LEV) versus lamotrigine (LTG) (risk ratio (RR) 1.20, 95% confidence interval (CI) 0.53 to 2.71), LEV versus phenobarbital (PB) (RR 1.01, 95% CI 0.47 to 2.19), or LTG versus PB (RR 0.84, 95% CI 0.35 to 2.02). It seemed that LEV could improve cognition and LTG could relieve depression, while PB and LTG could worsen cognition, and LEV and PB could worsen mood. Unclear risk of bias was found in allocation, blinding and selective reporting. We judged the quality of the evidence to be very low. This review does not provide sufficient evidence to support LEV, PB or LTG for the treatment of epilepsy in people with AD. Regarding efficacy and tolerability, no significant differences were found between LEV, PB and LTG. Large randomized controlled trials with a double-blind, parallel-group design are required to determine the efficacy and tolerability of treatment for epilepsy in people with AD.
Eight studies involving 290 participants were included. Two trials examined the effects of captopril, the rest were single trials on single drugs. All comparisons were with placebo. The methodological quality of most trials was poor. Enalapril was associated with a small increase in the frequency of attacks per week (difference in means 0.8; 95% CI 0.43 to 1.17). The difference between the intervention groups on a subjective improvement score was non-significant.  There was a significant effect of buflomedil on the frequency of attacks per week (weighted mean difference (WMD) -8.8; 95% CI -17.55 to -0.09), but there was no evidence of effect on the severity score.  The proportion with fewer attacks was significantly higher on moxisylyte than on placebo (relative risk (RR) 4.33; 95% CI 1.36 to 13.81).  For captopril, beraprost, dazoxiben and ketanserin there was no evidence of an effect on the frequency, severity or duration of attacks.  Beraprost and moxisylyte gave significantly more adverse effects than placebo. Poor methodological quality, small sample sizes and the limited data available resulted in low precision of the statistical results and limited value of the overall results .The overall results show that there is no evidence for an effect of vasodilator drugs on primary Raynaud's phenomenon.
We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence). Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.
This review includes 18 randomised controlled trials (14 new to this version), reported in 26 papers, involving 928 children and adolescents with RAP between the ages of 6 and 18 years. The interventions were classified into four types of psychosocial therapy: cognitive behavioural therapy (CBT), hypnotherapy (including guided imagery), yoga, and written self-disclosure. The studies were carried out in the USA, Australia, Canada, the Netherlands, Germany, and Brazil. The majority of the studies were small and short term; only two studies included more than 100 participants, and only five studies had follow-up assessments beyond six months. Small sample sizes and the degree of assessed risk of performance and detection bias in many studies led to the overall quality of the evidence being rated as low to very low for all outcomes. For CBT compared to control, we found evidence of treatment success postintervention (odds ratio (OR) 5.67, 95% confidence interval (CI) 1.18 to 27.32; Z = 2.16; P = 0.03; 4 studies; 175 children; very low-quality evidence), but no evidence of treatment success at medium-term follow-up (OR 3.08, 95% CI 0.93 to 10.16; Z = 1.85; P = 0.06; 3 studies; 139 children; low-quality evidence) or long-term follow-up (OR 1.29, 95% CI 0.50 to 3.33; Z = 0.53; P = 0.60; 2 studies; 120 children; low-quality evidence). We found no evidence of effects of intervention on pain intensity scores measured postintervention (standardised mean difference (SMD) -0.33, 95% CI -0.74 to 0.08; 7 studies; 405 children; low-quality evidence), or at medium-term follow-up (SMD -0.32, 95% CI -0.85 to 0.20; 4 studies; 301 children; low-quality evidence). For hypnotherapy (including studies of guided imagery) compared to control, we found evidence of greater treatment success postintervention (OR 6.78, 95% CI 2.41 to 19.07; Z = 3.63; P = 0.0003; 4 studies; 146 children; low-quality evidence) as well as reductions in pain intensity (SMD -1.01, 95% CI -1.41 to -0.61; Z = 4.97; P < 0.00001; 4 studies; 146 children; low-quality evidence) and pain frequency (SMD -1.28, 95% CI -1.84 to -0.72; Z = 4.48; P < 0.00001; 4 studies; 146 children; low-quality evidence). The only study of long-term effect reported continued benefit of hypnotherapy compared to usual care after five years, with 68% reporting treatment success compared to 20% of controls (P = 0.005). For yoga therapy compared to control, we found no evidence of effectiveness on pain intensity reduction postintervention (SMD -0.31, 95% CI -0.67 to 0.05; Z = 1.69; P = 0.09; 3 studies; 122 children; low-quality evidence). The single study of written self-disclosure therapy reported no benefit for pain. There was no evidence of effect from the pooled analyses for any type of intervention on the secondary outcomes of school performance, social or psychological functioning, and quality of daily life. There were no adverse effects for any of the interventions reported. The data from trials to date provide some evidence for beneficial effects of CBT and hypnotherapy in reducing pain in the short term in children and adolescents presenting with RAP. There was no evidence for the effectiveness of yoga therapy or written self-disclosure therapy. There were insufficient data to explore effects of treatment by RAP subtype. Higher-quality, longer-duration trials are needed to fully investigate the effectiveness of psychosocial interventions. Identifying the active components of the interventions and establishing whether benefits are sustained in the long term are areas of priority. Future research studies would benefit from employing active control groups to help minimise potential bias from wait-list control designs and to help account for therapist and intervention time.
We included 5 RCTs involving a total of 103 participants; all of the trials used a within-participant design. The interventions and outcomes were too varied to be combined statistically. All trials used the pulsed dye laser for comparisons. None of the studies focused on participant satisfaction, which was one of our primary outcomes, but participant preference was evaluated in three of five studies. Participants preferred the pulsed dye laser to intense pulsed light based on the clinical effect. They marginally preferred the Neodymium:YAG (yttrium-aluminium-garnet) (Nd:YAG) laser to the pulsed dye laser due to shorter lasting purpura, and pulsed dye laser in conjunction with cooling was preferred to treatment with pulsed dye laser alone. All trials examined short-term efficacy of less than six months after treatments with the pulsed dye laser, intense pulsed light, and Nd:YAG laser. The pulsed dye laser was evaluated in all five trials. Depending upon the setting of the pulsed dye laser, this resulted in more than 25% reduction in redness. This was after 1 to 3 treatments for up to 4 to 6 months postoperatively in 50% to 100% of the participants. There was only one study each of intense pulsed light and Nd:YAG laser. Two trials had no occurrence of long-term adverse effects, i.e. six months after treatment. Three trials reported pigmentary alterations in 3% to 24% of the participants, with the highest percentage occurring in Chinese participants with darker skin types. In one study one participant experienced scarring of the skin caused by a too-high dose of the laser used. Short-term side-effects included pain, crusting, and blistering in the first two weeks after treatment. The pulsed dye laser leads to clinically relevant clearance of port-wine stains. A limited number of RCTs evaluated the efficacy from intense pulsed light and other laser types. High-quality RCTs are needed to assess individual efficacy from different lasers and light sources, as well as participant satisfaction.
Twenty four studies, including 2147 participants, met the inclusion criteria. Comparing any dopamine agonist versus placebo, we found no differences for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). This was also observed when single dopamine agonists were compared against placebo. Comparing amantadine versus antidepressants, we found low quality of evidence that antidepressants performed better for abstinence (RR 0.25, 95% CI 0.12 to 0.53) based on two studies with 44 participants. No differences were found for dropout or adverse events, for both moderate quality of evidence. The major flaws of the included studies concerned selection bias because most studies did not report information about sequence generation (80%) and allocation concealment methods (86%): half of the included studies were judged at unclear risk of performance bias and 62.5% at unclear risk of detection bias for what concerns subjective outcomes. Current evidence from RCTs does not support the use of dopamine agonists for treating cocaine misuse. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Even the potential benefit of combining a dopamine agonist with a more potent psychosocial intervention, which was suggested by the previous Cochrane Review (Soares 2003), is not supported by the results of this Cochrane Review update.
We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias. The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia. We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.
Nine randomized, double-blind, placebo controlled trials meeting the inclusion criteria were identified. Eight trials enrolled healthy participants, and one was of subjects with age-associated memory impairment (AAMI). Only five of the identified trials had extractable information and were included in the analysis. Four studies investigated the effects of ginseng extract and one assessed the efficacy of ginseng compound HT008-1. All of these trials investigated the effects of ginseng on healthy participants. Pooling the data was impossible owing to heterogeneity in outcome measures, trial duration, and ginseng dosage. Results of the analysis suggested improvement of some aspects of cognitive function, behavior and quality of life. No serious adverse events associated with ginseng were found. Currently, there is a lack of convincing evidence to show a cognitive enhancing effect of Panax ginseng in healthy participants and no high quality evidence about its efficacy in patients with dementia. Randomized, double-blind, placebo-controlled, parallel group trials with large sample sizes are needed to further investigate the effect of ginseng on cognition in different populations, including dementia patients.
The review currently includes two short-term low-quality randomised trials (total n=508) both comparing sertindole with risperidone. One third of participants left the studies early (2 RCTs, n=504, RR 1.23 CI 0.94 to 1.60). There was no difference in efficacy (2 RCTs, n=493, WMD PANSS total change from baseline 1.98 CI -8.24 to 12.20). Compared with relatively high doses of risperidone (between 4 and 12 mg/day), sertindole produced significantly less akathisia and parkinsonism (1 RCT, n=321, RR 0.24 CI 0.09 to 0.69, NNT 14, CI 8 to 100). Sertindole produced more cardiac effects (2 RCTs, n=508, RR QTc prolongation 4.86 CI 1.94 to 12.18), weight change (2 RCTs, n=328, WMD 0.99 CI 0.12 to 1.86) and male sexual dysfunction (2 RCTs, n=437, RR 2.90 CI 1.32 to 6.35, NNH 13 CI 8 to 33). Sertindole may induce fewer movement disorders, but more cardiac effects, weight change and male sexual dysfunction than risperidone. However these data are based on only two studies and are too limited to allow firm conclusions. Nothing can be said about the effects of sertindole compared with second generation antipsychotics other than risperidone. There are several relevant trials underway or completed and about to report.
This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose. Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.
We identified four studies that met the inclusion criteria: three randomized controlled trials and a pilot study for one of the included trials. The interventions differed markedly: computer-delivered, individually tailored sessions; phone counseling added to clinic counseling; and case management plus a peer-leadership program. The latter study, which addressed multiple risks, showed an effect on contraceptive use. Compared to the control group, the intervention group was more likely to report consistent dual-method use, i.e., oral contraceptives and condoms. The reported relative risk was 1.58 at 12 months (95% CI 1.03 to 2.43) and 1.36 at 24 months (95% CI 1.01 to 1.85). The related pilot study showed more reporting of consistent dual-method use for the intervention group compared to the control group (reported P value = 0.06); the investigators used a higher alpha (P < 0.10) for this pilot study. The other two trials did not show any significant difference between the study groups in reported dual-method use or in test results for pregnancy or STIs at 12 or 24 months. We found few behavioral interventions for improving dual-method contraceptive use and little evidence of effectiveness. A multifaceted program showed some effect but only had self-reported outcomes. Two trials were more applicable to clinical settings and had objective outcomes measures, but neither showed any effect. The included studies had adequate information on intervention fidelity and sufficient follow-up periods for change to occur. However, the overall quality of evidence was considered low. Two trials had design limitations and two had high losses to follow up, as often occurs in contraceptive trials. Good quality studies are still needed of carefully designed and implemented programs or services.
Six RCTs involving 439 participants with dementia were included in the review, but no studies of participants with MCI were identified. The studies included people with dementia living in the community or in nursing home care and were carried out in several countries. Only one of the studies was classified as low risk of bias. Five studies were at unclear or high risk of bias due to uncertainties around randomisation, blinding and selective reporting of results. The studies used the different psychological approaches of cognitive behavioural therapy (CBT), interpersonal therapy and counselling. Two studies were of multimodal interventions including a specific psychological therapy. The comparison groups received either usual care, attention-control educational programs, diagnostic feedback or services slightly above usual care. Meta-analysis showed a positive effect of psychological treatments on depression (6 trials, 439 participants, standardised mean difference (SMD) -0.22; 95% confidence interval (CI) -0.41 to -0.03, moderate quality evidence) and on clinician-rated anxiety (2 trials, 65 participants, mean difference (MD) -4.57; 95% CI -7.81 to -1.32, low quality evidence), but not on self-rated anxiety (2 trials, SMD 0.05; 95% CI -0.44 to 0.54) or carer-rated anxiety (1 trial, MD -2.40; 95% CI -4.96 to 0.16). Results were compatible with both benefit and harm on the secondary outcomes of patient quality of life, activities of daily living (ADLs), neuropsychiatric symptoms and cognition, or on carers' self-rated depressive symptoms, but most of the studies did not measure these outcomes. There were no reports of adverse events. We found evidence that psychological interventions added to usual care can reduce symptoms of depression and clinician-rated anxiety for people with dementia. We conclude that psychological interventions have the potential to improve patient well-being. Further high quality studies are needed to investigate which treatments are most effective and to evaluate the effect of psychological interventions in people with MCI.
We included one study involving 15 participants from the UK. The included participants were diagnosed with delirium based on the Confusion Assessment Method (CAM) criteria. Eight males and seven females were included, with a mean age of 82.5 years. Seven of the 15 participants had comorbid dementia at baseline. The risk of bias was low in all domains. The study compared rivastigmine with placebo. We did not find any clear differences between the two groups in terms of duration of delirium (MD -3.6, 95% CI -15.6 to 8.4), adverse events (nausea, RR 0.30, 95% CI 0.01 to 6.29), use of rescue medications (RR 0.13, 95% CI 0.01 to 2.1), mortality (RR 0.10, 95% CI 0.01 to 1.56), and leaving the study early (RR 0.88, 95% CI 0.07 to 11.54). Evidence was not available regarding the severity of delirium, persistent cognitive impairment, length of hospitalisation, cost of intervention, or other predefined secondary outcomes. The quality of evidence is low due to the very small sample size. There is insufficient evidence to support or refute the use of cholinesterase inhibitors for the treatment of delirium in non-ICU settings. No clear benefits or harms associated with cholinesterase inhibitors were observed when compared with placebo due to the lack of data. More trials are required.
Four trials including a total of 1447 young offenders were included in the review. Results failed to find a significant effect for restorative justice conferencing over normal court procedures for any of the main analyses, including number re-arrested (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.59 to 1.71; P = 0.99), monthly rate of reoffending (standardised mean difference (SMD) -0.06, 95% CI -0.28 to 0.16; P = 0.61), young person’s remorse following conference (OR 1.73, 95% CI 0.97 to 3.10; P = 0.06), young person's recognition of wrongdoing following conference (OR 1.97, 95% CI 0.81 to 4.80; P = 0.14), young person's self-perception following conference (OR 0.95, 95% CI 0.55 to 1.63; P = 0.85), young person's satisfaction following conference (OR 0.42, 95% CI 0.04 to 4.07; P = 0.45) and victim's satisfaction following conference (OR 4.05, 95% CI 0.56 to 29.04; P = 0.16). A small number of sensitivity analyses did indicate significant effects, although all are to be interpreted with caution. There is currently a lack of high quality evidence regarding the effectiveness of restorative justice conferencing for young offenders. Caution is urged in interpreting the results of this review considering the small number of included studies, subsequent low power and high risk of bias. The effects may potentially be more evident for victims than offenders. The need for further research in this area is highlighted.
We included a total of 20 heterogeneous studies (2012 participants with acute ankle sprains); three of which included more than one comparison. Seventeen trials were conducted in China. All of the studies had a high risk of bias due to lack of blinding. The results may also have been affected by selection bias, particularly as five studies were quasi-randomised controlled trials and 12 studies gave no information on their method of randomisation. Of our three prespecified primary outcomes, only cure rate was reported by the majority of studies. No study reported on patient-reported assessment of function and only one reported on adverse events (in which three participants receiving a control intervention experienced skin problems from over-the-counter Chinese herbal patches). The other 19 studies did not record or report on adverse events. We assessed the quality of evidence for cure rates as very low for all comparisons, which means we are very uncertain about the reliability of any of the estimates. The single study comparing acupuncture treatment with no treatment found acupuncture to be more effective with regard to cure rate at five days (31/31 versus 1/30; RR 20.34, 95% CI 4.27 to 96.68). Acupuncture plus another standard treatment versus that standard treatment alone was tested in eight studies; with cure rate data available for seven. Most of these studies reported higher cure rates in the acupuncture plus another standard treatment group than in the standard treatment alone group. However, while the results of an exploratory meta-analysis of cure rate data from eight trials testing acupuncture versus no acupuncture tended to favour acupuncture, the results were very inconsistent across the studies and the estimated effect was very imprecise (383/396 versus 272/355; RR 1.32, 95% CI 0.95 to 1.84; P value = 0.1; I2 = 98%). Fourteen studies compared acupuncture with a variety of other non-surgical treatments, such as Chinese drug patches, hot and cold water, ice packs, oral Chinese herbal medicine and elastic bandage. Some studies found in favour of acupuncture, some in favour of the other treatment and some found a lack of evidence for a difference between the two interventions under test. The results of an exploratory meta-analysis of cure rate data from 11 trials testing acupuncture versus another non-surgical intervention tended to slightly favour acupuncture, but these were not statistically significant and the data were very heterogeneous (404/509 versus 416/497; RR 1.07, 95% CI 0.94 to 1.22; P value = 0.30; I2 = 92%). The currently available evidence from a very heterogeneous group of randomised and quasi-randomised controlled trials evaluating the effects of acupuncture for the treatment of acute ankle sprains does not provide reliable support for either the effectiveness or safety of acupuncture treatments, alone or in combination with other non-surgical interventions; or in comparison with other non-surgical interventions. Future rigorous randomised clinical trials with larger sample sizes will be necessary to establish robust clinical evidence concerning the effectiveness and safety of acupuncture treatment for acute ankle sprains.
We identified one RCT, with 18 participants, that fulfilled the predetermined inclusion criteria. The trial compared plasma exchange to sham plasma exchange in participants with IgG or IgA paraproteinaemic neuropathy over a three-week follow-up period. We identified four other studies but these were not RCTs or quasi-RCTs. The included RCT did not report our predefined primary outcome measure, change in disability six months after randomisation. The trial revealed a modest benefit of plasma exchange in the weakness component of the Neuropathy Disability Score (NDS, now the Neuropathy Impairment Score); the mean improvement with plasma exchange was 17 points (95% confidence interval (CI) 5.2 to 28.8 points) versus 1 point (95% CI -7.7 to 9.7 points) in the sham exchange group at three weeks' follow-up (mean difference (MD) 16.00; 95% CI 1.37 to 30.63, low quality evidence). There was no statistically significant difference in the overall NDS (MD 18.00; 95% CI -2.03 to 38.03, low quality evidence), vibration thresholds or neurophysiological indices. Adverse events were not reported. The trial was at low risk of bias overall, although limitations of trial size and duration reduce the quality of the evidence in support of its conclusions. The evidence from RCTs for the treatment of IgG or IgA paraproteinaemic neuropathy is currently inadequate. More RCTs of treatments are required. These should have adequate follow-up periods and contain larger numbers of participants, perhaps through multicentre collaboration, considering the relative infrequency of this condition. Observational or open trial data provide limited support for the use of treatments such as plasma exchange, cyclophosphamide combined with prednisolone, intravenous immunoglobulin, and corticosteroids. These interventions show potential therapeutic promise but the potential benefits must be weighed against adverse effects. Their optimal use and the long-term benefits need to be considered and validated with well-designed RCTs.
The review includes 22 studies (8032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline. Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease-specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Peto odds ratio (OR) 1.57; 95% CI 1.06 to 2.31). One extra serious adverse event occurred over 16 weeks for every 149 people treated with regular formoterol (95% CI 66 to 1407 people). The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicate that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids. No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline. In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age groups was not significant. Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all severities of adverse events or limited to those events that are thought by the investigator to be drug-related.
We inspected over 1100 electronic records. The review currently includes 315 excluded studies and 55 included studies. The quality of the evidence is very low. We found chlorpromazine reduced the number of participants experiencing a relapse compared with placebo during six months to two years follow-up (n=512, 3 RCTs, RR 0.65 CI 0.47 to 0.90), but data were heterogeneous. No difference was found in relapse rates in the short, medium or long term over two years, although data were also heterogeneous. We found chlorpromazine provided a global improvement in a person's symptoms and functioning (n=1164, 14 RCTs, RR 0.71 CI 0.58 to 0.86). Fewer people allocated to chlorpromazine left trials early ( n=1831, 27 RCTs, RR 0.64 CI 0.53 to 0.78) compared with placebo. There are many adverse effects. Chlorpromazine is clearly sedating (n=1627, 23 RCTs, RR 2.79 CI 2.25 to 3.45), it increases a person's chances of experiencing acute movement disorders (n=942, 5 RCTs, RR 3.47 CI 1.50 to 8.03) and parkinsonism (n=1468, 15 RCTs, RR 2.11 CI 1.59 to 2.80). Akathisia did not occur more often in the chlorpromazine group than placebo. Chlorpromazine clearly causes a lowering of blood pressure with accompanying dizziness (n=1488, 18 RCTs, RR 2.38 CI 1.74 to 3.25) and considerable weight gain (n=165, 5 RCTs, RR 4.92 CI 2.32 to 10.43). The results of this review confirm much that clinicians and recipients of care already know but aim to provide quantification to support clinical impression. Chlorpromazine's global position as a 'benchmark' treatment for psychoses is not threatened by the findings of this review. Chlorpromazine, in common use for half a century, is a well-established but imperfect treatment. Judicious use of this best available evidence should lead to improved evidence-based decision making by clinicians, carers and patients.
Cognitive training was not associated with positive or negative effects in relation to any reported outcomes. The overall quality of the trials was low to moderate. The single RCT of cognitive rehabilitation found promising results in relation to a number of participant and caregiver outcomes, and was generally of high quality. Available evidence regarding cognitive training remains limited, and the quality of the evidence needs to improve. However, there is still no indication of any significant benefit derived from cognitive training. Trial reports indicate that some gains resulting from intervention may not be captured adequately by available standardised outcome measures. The results of the single RCT of cognitive rehabilitation show promise but are preliminary in nature. Further, well-designed studies of cognitive training and cognitive rehabilitation are required to obtain more definitive evidence. Researchers should describe and classify their interventions appropriately using available terminology.
One study with a total of 24 participants was available for review. This study was a small, single-blind, multicentre trial studying adults with RSE receiving either propofol or thiopental sodium for the control of seizure activity. This study was terminated early due to recruitment problems. For our primary outcome of total control of seizures after the first course of study drug, there were 6/14 patients versus 2/7 patients in the propofol and thiopental sodium groups, respectively (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.40 to 5.61, low quality evidence). Mortality was seen in 3/14 patients versus 1/7 patients in the propofol and thiopental sodium groups, respectively (RR 1.50, 95% CI 0.19 to 11.93, low quality evidence). Our third primary outcome of length of ICU stay was not reported. For our secondary outcomes of adverse events, infection was seen in 7/14 patients versus 5/7 patients in the propofol and thiopental sodium groups, respectively (RR 0.70; 95% CI 0.35 to 1.41). Hypotension during administration of study drugs and requiring use of vasopressors was seen in 7/14 patients versus 4/7 patients in the propofol and thiopental sodium groups, respectively (RR 0.87; 95% CI 0.38 to 2.00). The other severe complication noted was non-fatal propofol infusion syndrome in one patient. Patients receiving thiopental sodium required more days of mechanical ventilation when compared with patients receiving propofol: (median (range) 17 days (5 to 70 days) with thiopental sodium versus four days (2 to 28 days) with propofol). At three months there was no evidence of a difference between the drugs with respect to outcome measures such as control of seizure activity and functional outcome. Since the last version of this review we have found no new studies. There is a lack of robust, randomised, controlled evidence to clarify the efficacy of propofol and thiopental sodium compared to each other in the treatment of RSE. There is a need for large RCTs for this serious condition.
A total of four studies were included that involved 823 participants, 412 in the exercise group and 411 in the control group. Follow-up of participants ranged from 16 weeks to 6 months. Overall, the included studies had a high risk of selection, detection, and attrition bias. Meta-analysis was not possible because the interventions (setting, type and intensity of exercise) and outcome measurements were not comparable, and the risk of bias in the identified studies was high. No study assessed cardiovascular or all‑cause mortality or cardiovascular events as individual outcomes. One or more of the studies reported on total cardiovascular risk, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, blood pressure, body mass index, exercise capacity, and health-related quality of life but the available evidence was not sufficient to determine the effectiveness of exercise. Adverse events and smoking cessation were not assessed in the included studies. Evidence to date is entirely limited to small studies with regard to sample size, short-term follow-up, and high risk of methodological bias, which makes it difficult to derive any conclusions on the efficacy or safety of aerobic or resistance exercise on groups with increased cardiovascular risk or in individuals with two or more coexisting risk factors. Further randomized clinical trials assessing controlled exercise programmes on total cardiovascular risk in individuals are warranted.
We included 19 studies (2256 participants). Epinephrine versus placebo among outpatients showed a significant reduction in admissions at Day 1 (risk ratio (RR) 0.67; 95% confidence interval (CI) 0.50 to 0.89) but not at Day 7 post-emergency department visit. There was no difference in LOS for inpatients. Epinephrine versus salbutamol showed no differences among outpatients for admissions at Day 1 or 7. Inpatients receiving epinephrine had a significantly shorter LOS compared to salbutamol (mean difference -0.28; 95% CI -0.46 to -0.09). One large RCT showed a significantly shorter admission rate at Day 7 for epinephrine and steroid combined versus placebo (RR 0.65; 95% CI 0.44 to 0.95). There were no important differences in adverse events. This review demonstrates the superiority of epinephrine compared to placebo for short-term outcomes for outpatients, particularly in the first 24 hours of care. Exploratory evidence from a single study suggests benefits of epinephrine and steroid combined for later time points. More research is required to confirm the benefits of combined epinephrine and steroids among outpatients. There is no evidence of effectiveness for repeated dose or prolonged use of epinephrine or epinephrine and dexamethasone combined among inpatients.
We did not identify any new trials for inclusion in this fifth update. Seven trials involving a total of 10,157 participants were included. Four of the included trials had three comparison groups. The antiseptic used in all trials was 4% chlorhexidine gluconate (Hibiscrub/Riohex). Three trials involving 7791 participants compared chlorhexidine with a placebo. Bathing with chlorhexidine compared with placebo did not result in a statistically significant reduction in SSIs; the relative risk of SSI (RR) was 0.91 (95% confidence interval (CI) 0.80 to 1.04). When only trials of high quality were included in this comparison, the RR of SSI was 0.95 (95%CI 0.82 to 1.10). Three trials of 1443 participants compared bar soap with chlorhexidine; when combined there was no difference in the risk of SSIs (RR 1.02, 95% CI 0.57 to 1.84). Three trials of 1192 patients compared bathing with chlorhexidine with no washing, one large study found a statistically significant difference in favour of bathing with chlorhexidine (RR 0.36, 95%CI 0.17 to 0.79). The smaller studies found no difference between patients who washed with chlorhexidine and those who did not wash preoperatively. This review provides no clear evidence of benefit for preoperative showering or bathing with chlorhexidine over other wash products, to reduce surgical site infection. Efforts to reduce the incidence of nosocomial surgical site infection should focus on interventions where effect has been demonstrated.
We included eight randomised controlled trials with a total of 391 participants. Six trials focused on children and two on adults. Trials compared tube thoracostomy drainage (non-surgical), with or without intrapleural fibrinolytics, to either VATS or thoracotomy (surgical) for the management of pleural empyema. Assessment of risk of bias for the included studies was generally unclear for selection and blinding but low for attrition and reporting bias. Data analyses compared thoracotomy versus tube thoracostomy and VATS versus tube thoracostomy. We pooled data for meta-analysis where appropriate. We performed a subgroup analysis for children along with a sensitivity analysis for studies that used fibrinolysis in non-surgical treatment arms. The comparison of open thoracotomy versus thoracostomy drainage included only one study in children, which reported no deaths in either treatment arm. However, the trial showed a statistically significant reduction in mean hospital stay of 5.90 days for those treated with primary thoracotomy. It also showed a statistically significant reduction in procedural complications for those treated with thoracotomy compared to thoracostomy drainage. We downgraded the quality of the evidence for length of hospital stay and procedural complications outcomes to moderate due to the small sample size. The comparison of VATS versus thoracostomy drainage included seven studies, which we pooled in a meta-analysis. There was no statistically significant difference in mortality or procedural complications between groups. This was true for both adults and children with or without fibrinolysis. However, mortality data were limited: one study reported one death in each treatment arm, and seven studies reported no deaths. There was a statistically significant reduction in mean length of hospital stay for those treated with VATS. The subgroup analysis showed the same result in adults, but there was insufficient evidence to estimate an effect for children. We could not perform a separate analysis for fibrinolysis for this outcome because all included studies used fibrinolysis in the non-surgical arms. We downgraded the quality of the evidence to low for mortality (due to wide confidence intervals and indirectness), and moderate for other outcomes in this comparison due to either high heterogeneity or wide confidence intervals. Our findings suggest there is no statistically significant difference in mortality between primary surgical and non-surgical management of pleural empyema for all age groups. Video-assisted thoracoscopic surgery may reduce length of hospital stay compared to thoracostomy drainage alone. There was insufficient evidence to assess the impact of fibrinolytic therapy. A number of common outcomes were reported in the included studies that were not directly examined in our primary and secondary outcomes. These included duration of chest tube drainage, duration of fever, analgesia requirement, and total cost of treatment. Future studies focusing on patient-centred outcomes, such as patient functional scores, and other clinically relevant outcomes, such as radiographic improvement, treatment failure rates, and amount of fluid drainage, are needed to inform clinical decisions.
One randomized controlled trial comparing high target serum concentration and low target serum concentration tacrolimus versus placebo was identified and included in the review. Clinical remission was observed in 19% (4/21) of patients in the high target serum concentration group, in 9% (2/22) in the low target serum concentration group and in 5% (1/20) in the placebo group (OR 2.27; 95% CI 0.35 to 14.75). A statistically significant benefit for clinical improvement at two weeks was observed. Clinical improvement was observed in 62% (13/21) of patients in the high target serum concentration group, in 36% (8/22) in the low target serum concentration group and in 10% (2/20) in the placebo group (OR 8.66; 95% CI 1.79 to 42.00; RD 0.39; 95% CI 0.20 to 0.59; NNT = 3). Patients in the high serum target concentration group were significantly more likely than placebo patients to experience adverse events related to treatment (P = 0.043). Finger tremor (n = 6) was the most common adverse event in the tacrolimus group. Other adverse events included: gastroenteritis, sepsis, sleepiness, hot flush, headache, queasiness and stomach discomfort. Tacrolimus may be effective for short-term clinical improvement in patients with refractory ulcerative colitis. However, these results should be interpreted with caution due to the small number of patients enrolled in the trial and other study limitations. Insufficient treatment and follow-up intervals prevent any conclusions with regard to long term safety and efficacy. The use of tacrolimus in the clinical setting requires careful consideration of risks versus benefits as well as close monitoring for adverse events. More data from well designed and controlled studies are needed to determine the long-term efficacy and safety of tacrolimus.
We identified 85 studies involving 9765 participants. Seventy-five trials included 8520 adults and 10 trials included 1245 children. Most studies had risk of bias issues, with attrition bias being the largest source across studies due to incomplete outcome data. In adults, pain intensity on day one was reduced by 0.75 cm on a 10 cm VAS after LA (MD -0.75, 95% CI -1.04 to -0.45; 20 RCTs; 2421 participants; low-quality evidence). Wound infections were less likely after LA (Peto OR 0.42, 95% CI 0.35 to 0.51; 63 RCTs; 7612 participants; moderate-quality evidence), but the incidence of intra-abdominal abscesses was increased following LA (Peto OR 1.65, 95% CI 1.12 to 2.43; 53 RCTs; 6677 participants; moderate-quality evidence). The length of hospital stay was shortened by one day after LA (MD -0.96, 95% CI -1.23 to -0.70; 46 RCTs; 5127 participant; low-quality evidence). The time until return to normal activity occurred five days earlier after LA than after OA (MD -4.97, 95% CI -6.77 to -3.16; 17 RCTs; 1653 participants; low-quality evidence). Two studies showed better quality of life scores following LA, but used different scales, and therefore no pooled estimates were presented. One used the SF-36 questionnaire two weeks after surgery and the other used the Gastro-intestinal Quality of Life Index six weeks and six months after surgery (both low-quality evidence). In children, we found no differences in pain intensity on day one (MD -0.80, 95% CI -1.65 to 0.05; 1 RCT; 61 participants; low-quality evidence), intra-abdominal abscesses after LA (Peto OR 0.54, 95% CI 0.24 to 1.22; 9 RCTs; 1185 participants; low-quality evidence) or time until return to normal activity (MD -0.50, 95% CI -1.30 to 0.30; 1 RCT; 383 participants; moderate-quality evidence). However, wound infections were less likely after LA (Peto OR 0.25, 95% CI 0.15 to 0.42; 10 RCTs; 1245 participants; moderate-quality evidence) and the length of hospital stay was shortened by 0.8 days after LA (MD -0.81, 95% CI -1.01 to -0.62; 6 RCTs; 316 participants; low-quality evidence). Quality of life was not reported in any of the included studies. Except for a higher rate of intra-abdominal abscesses after LA in adults, LA showed advantages over OA in pain intensity on day one, wound infections, length of hospital stay and time until return to normal activity in adults. In contrast, LA showed advantages over OA in wound infections and length of hospital stay in children. Two studies reported better quality of life scores in adults. No study reported this outcome in children. However, the quality of evidence ranged from very low to moderate and some of the clinical effects of LA were small and of limited clinical relevance. Future studies with low risk of bias should investigate, in particular, the quality of life in children.
Five trial reports were retrieved using the search strategies. Four trials were excluded. We did not identify any randomised controlled trials for inclusion but we included one quasi-randomised study (involving 210 women) that evaluated the effect of extra fluid for breastfeeding mothers on breastfeeding outcomes. The study was considered to be at a high risk of bias. Only one of this review's primary outcomes was reported (breast milk production (as defined by the trialist)) but data were not in a suitable format for analysis (no standard deviations or standard errors were reported). The trialist reported that advising women to drink extra fluids did not improve breast milk production. No data were reported for the review's other primary outcomes: satisfactory weight gain in the infant (as defined by the trialists) and duration of exclusive breastfeeding (months). Similarly, no data were reported for any of this review's secondary outcomes: duration of any breastfeeding; mother's satisfaction with breastfeeding; hydration in mother; dehydration in the infant; or episodes of gastrointestinal illness. This review only identified one small quasi-randomised controlled trial of low quality and high risk of bias. The study provided limited data on only one of this review's primary outcomes, breast milk production, but the data were not reported in a format that permitted further analysis. The trialist reported that extra fluids did not improve breast milk production. However, this outcome was measured by using test feeds (also known as test weighing). In the 1950s, when the study was conducted, it was common for babies in developed countries to be weighed before and after a feed, known as test weighing or test feeding. However, this practice is not now routinely practiced for term infants due to concerns about lack of precision as a measure of breast milk production. The included study did not report on this review's other primary outcomes (satisfactory weight gain in the infant or duration of exclusive breastfeeding) nor any of the review's secondary outcomes. The effect of additional fluids for breastfeeding mothers remains unknown, due to a lack of well-conducted trials. However, because the physiological basis for any such improvement remains unclear, the conduct of further clinical trials may not be a priority. There is not enough evidence to support an increased fluid intake beyond what breastfeeding mothers are likely to require to meet their physiological needs.
We included 27 RCTs based on data from 1251 participants. Three trials compared early treatment with a functional appliance versus late treatment for overjet, ANB and incisal trauma. After phase one of early treatment (i.e. before the other group had received any intervention), there was a reduction in overjet and ANB reduction favouring treatment with a functional appliance; however, when both groups had completed treatment, there was no difference between groups in final overjet (MD 0.21, 95% CI −0.10 to 0.51, P = 0.18; 343 participants) (low-quality evidence) or ANB (MD −0.02, 95% CI −0.47 to 0.43; 347 participants) (moderate-quality evidence). Early treatment with functional appliances reduced the incidence of incisal trauma compared to late treatment (OR 0.56, 95% CI 0.33 to 0.95; 332 participants) (moderate-quality evidence). The difference in the incidence of incisal trauma was clinically important with 30% (51/171) of participants reporting new trauma in the late treatment group compared to only 19% (31/161) of participants who had received early treatment. Two trials compared early treatment using headgear versus late treatment. After phase one of early treatment, headgear had reduced overjet and ANB; however, when both groups had completed treatment, there was no evidence of a difference between groups in overjet (MD −0.22, 95% CI −0.56 to 0.12; 238 participants) (low-quality evidence) or ANB (MD −0.27, 95% CI −0.80 to 0.26; 231 participants) (low-quality evidence). Early (two-phase) treatment with headgear reduced the incidence of incisal trauma (OR 0.45, 95% CI 0.25 to 0.80; 237 participants) (low-quality evidence), with almost half the incidence of new incisal trauma (24/117) compared to the late treatment group (44/120). Seven trials compared late treatment with functional appliances versus no treatment. There was a reduction in final overjet with both fixed functional appliances (MD −5.46 mm, 95% CI −6.63 to −4.28; 2 trials, 61 participants) and removable functional appliances (MD −4.62, 95% CI -5.33 to -3.92; 3 trials, 122 participants) (low-quality evidence). There was no evidence of a difference in final ANB between fixed functional appliances and no treatment (MD −0.53°, 95% CI −1.27 to −0.22; 3 trials, 89 participants) (low-quality evidence), but removable functional appliances seemed to reduce ANB compared to no treatment (MD −2.37°, 95% CI -3.01 to -1.74; 2 trials, 99 participants) (low-quality evidence). Six trials compared orthodontic treatment for adolescents with Twin Block versus other appliances and found no difference in overjet (0.08 mm, 95% CI −0.60 to 0.76; 4 trials, 259 participants) (low-quality evidence). The reduction in ANB favoured treatment with a Twin Block (−0.56°, 95% CI −0.96 to −0.16; 6 trials, 320 participants) (low-quality evidence). Three trials compared orthodontic treatment for adolescents with removable functional appliances versus fixed functional appliances and found a reduction in overjet in favour of fixed appliances (0.74, 95% CI 0.15 to 1.33; two trials, 154 participants) (low-quality evidence), and a reduction in ANB in favour of removable appliances (−1.04°, 95% CI −1.60 to −0.49; 3 trials, 185 participants) (low-quality evidence). Evidence of low to moderate quality suggests that providing early orthodontic treatment for children with prominent upper front teeth is more effective for reducing the incidence of incisal trauma than providing one course of orthodontic treatment in adolescence. There appear to be no other advantages of providing early treatment when compared to late treatment. Low-quality evidence suggests that, compared to no treatment, late treatment in adolescence with functional appliances, is effective for reducing the prominence of upper front teeth.
We included two trials that randomised 4523 women and their infants. Both trials were conducted in Ireland. One trial (which quasi-randomised 3742 women, and analysed 3152 women) compared universal screening versus risk factor-based screening, and one trial (which randomised 781 women, and analysed 690 women) compared primary care screening versus secondary care screening. We were not able to perform meta-analyses due to the different interventions and comparisons assessed. Overall, there was moderate to high risk of bias due to one trial being quasi-randomised, inadequate blinding, and incomplete outcome data in both trials. We used GRADEpro GDT software to assess the quality of the evidence for selected outcomes for the mother and her child. Evidence was downgraded for study design limitations and imprecision of effect estimates. Universal screening versus risk-factor screening (one trial) Mother More women were diagnosed with GDM in the universal screening group than in the risk-factor screening group (risk ratio (RR) 1.85, 95% confidence interval (CI) 1.12 to 3.04; participants = 3152; low-quality evidence). There were no data reported under this comparison for other maternal outcomes including hypertensive disorders of pregnancy, caesarean birth, perineal trauma, gestational weight gain, postnatal depression, and type 2 diabetes. Child Neonatal outcomes: large-for-gestational age, perinatal mortality, mortality or morbidity composite, hypoglycaemia; and childhood/adulthood outcomes: adiposity, type 2 diabetes, and neurosensory disability, were not reported under this comparison. Primary care screening versus secondary care screening (one trial) Mother There was no clear difference between the primary care and secondary care screening groups for GDM (RR 0.91, 95% CI 0.50 to 1.66; participants = 690; low-quality evidence), hypertension (RR 1.41, 95% CI 0.77 to 2.59; participants = 690; low-quality evidence), pre-eclampsia (RR 0.80, 95% CI 0.36 to 1.78; participants = 690;low-quality evidence), or caesarean section birth (RR 1.00, 95% CI 0.80 to 1.27; participants = 690; low-quality evidence). There were no data reported for perineal trauma, gestational weight gain, postnatal depression, or type 2 diabetes. Child There was no clear difference between the primary care and secondary care screening groups for large-for-gestational age (RR 1.37, 95% CI 0.96 to 1.96; participants = 690; low-quality evidence), neonatal complications: composite outcome, including: hypoglycaemia, respiratory distress, need for phototherapy, birth trauma, shoulder dystocia, five minute Apgar less than seven at one or five minutes, prematurity (RR 0.99, 95% CI 0.57 to 1.71; participants = 690; low-quality evidence), or neonatal hypoglycaemia (RR 1.10, 95% CI 0.28 to 4.38; participants = 690; very low-quality evidence). There was one perinatal death in the primary care screening group and two in the secondary care screening group (RR 1.10, 95% CI 0.10 to 12.12; participants = 690; very low-quality evidence). There were no data for neurosensory disability, or childhood/adulthood adiposity or type 2 diabetes. There are insufficient randomised controlled trial data evaluating the effects of screening for GDM based on different risk profiles and settings on maternal and infant outcomes. Low-quality evidence suggests universal screening compared with risk factor-based screening leads to more women being diagnosed with GDM. Low to very low-quality evidence suggests no clear differences between primary care and secondary care screening, for outcomes: GDM, hypertension, pre-eclampsia, caesarean birth, large-for-gestational age, neonatal complications composite, and hypoglycaemia. Further, high-quality randomised controlled trials are needed to assess the value of screening for GDM, which may compare different protocols, guidelines or programmes for screening (based on different risk profiles and settings), with the absence of screening, or with other protocols, guidelines or programmes. There is a need for future trials to be sufficiently powered to detect important differences in short- and long-term maternal and infant outcomes, such as those important outcomes pre-specified in this review. As only a proportion of women will be diagnosed with GDM in these trials, large sample sizes may be required.
The search identified nine trials of cognitive behavioural and psychodynamic therapy approaches, together with a small group of 'active control' interventions. No trials relating to other psychotherapeutic approaches and techniques were found. A total of seven trials provided sufficient data for inclusion in the comparison between CBT and controls. No trials compared psychodynamic psychotherapy with controls. Based on five trials (153 participants), cognitive behavioural therapy was more effective than waiting list controls (WMD -9.85, 95% CI -11.97 to -7.73). Only three small trials compared psychodynamic therapy with CBT, with no significant difference in treatment effect indicated between the two types of psychotherapeutic treatment. Based on three trials with usable data, CBT was superior to active control interventions when using the Hamilton Depression Rating Scale (WMD -5.69, 95% CI -11.04 to -0.35), but equivalent when using the Geriatric Depression Scale (WMD -2.00, 95% CI -5.31 to 1.32). Only a small number of studies and patients were included in the meta-analysis. If taken on their own merit, the findings do not provide strong support for psychotherapeutic treatments in the management of depression in older people. However, the findings do reflect those of a larger meta-analysis that included patients with broader age ranges, suggesting that CBT may be of potential benefit.
We included 13 studies randomizing 417 participants with 7184 teeth/brackets. We assessed two studies (15%) as being at low risk of bias, 10 studies (77%) as being at high risk of bias and one study (8%) as being at unclear risk of bias. Self etching primers (SEPs) versus conventional etchants Eleven studies compared the effects of SEPs with conventional etchants. Only five of these studies (three of split-mouth design and two of parallel design) reported data at the participant level, with the remaining studies reporting at the tooth level, thus ignoring clustering/the paired nature of the data. A meta-analysis of these five studies, with follow-up ranging from 5 to 37 months, provided low-quality evidence that was insufficient to determine whether or not there is a difference in bond failure rate between SEPs and convention etchants (risk ratio 1.14; 95% confidence interval (CI) 0.75 to 1.73; 221 participants). The uncertainty in the CI includes both no effect and appreciable benefit and harm. Subgroup analysis did not show a difference between split-mouth and parallel studies. There were no data available to allow assessment of the outcomes: decalcification, participant satisfaction and cost-effectiveness. One study reported decalcification, but only at the tooth level. SEPs versus SEPs Two studies compared two different SEPs. Both studies reported bond failure rate, with one of the studies also reporting decalcification. However, as both studies reported outcomes only at the tooth level, there were no data available to evaluate the superiority of any of the SEPs over the others investigated with regards to any of the outcomes of this review. We did not find any eligible studies evaluating different etching materials (e.g. phosphoric acid, polyacrylic acid, maleic acid), concentrations or etching times. We found low-quality evidence that was insufficient to conclude whether or not there is a difference in bond failure rate between SEPs and conventional etching systems when bonding fixed orthodontic appliances over a 5- to 37-month follow-up. Insufficient data were also available to allow any conclusions to be formed regarding the superiority of SEPs or conventional etching for the outcomes: decalcification, participant satisfaction and cost-effectiveness, or regarding the superiority of different etching materials, concentrations or etching times, or of any one SEP over another. Further well-designed RCTs on this topic are needed to provide more evidence in order to answer these clinical questions.
We included six RCTs and were able to extract data from five studies. The total number of included participants was 206. The majority of participants were Group I pulmonary artery hypertension (PAH). Study duration ranged from three to 15 weeks. Exercise programmes included both inpatient- and outpatient-based rehabilitation that incorporated both upper and lower limb exercise. The mean six-minute walk distance following exercise training was 60.12 metres higher than control (30.17 to 90.07 metres, n = 165, 5 RCTs, low-quality evidence; minimal important difference was 30 metres), the mean peak oxygen uptake was 2.4 ml/kg/minute higher (1.4 to 3.4 ml/kg/min, n = 145, 4 RCTs, low-quality evidence) and the mean peak power in the intervention groups was 16.4 W higher (10.9 to 22.0 higher, n = 145, 4 RCTs, low-quality evidence). The mean change in HRQoL for the SF-36 physical component score was 4.63 points higher (0.80 to 8.47 points, n = 33, 2 RCTs, low-quality evidence) and for the SF-36 mental component score was 4.17 points higher (0.01 to 8.34 points; n = 33; 2 RCTs, low-quality evidence). One study reported a single adverse event, where a participant stopped exercise training due to lightheadedness. In people with PH, exercise-based rehabilitation results in clinically relevant improvements in exercise capacity. Exercise training was not associated with any serious adverse events. Whilst most studies reported improvements in HRQoL, these may not be clinically important. Overall, we assessed the quality of the evidence to be low. The small number of studies and lack of information on participant selection makes it difficult to generalise these results across the spectrum of people with PH.
From a total of 502 references, we retrieved 47 papers for more detailed evaluation. We selected 20 papers, reporting data from seven studies, which included 1137 participants, of which 559 were randomized to TMLR. Participants and professionals were not blinded, which suggests high risk of performance bias. Overall, 43.8% of participants in the treatment group decreased two angina classes, as compared with 14.8% in the control group: odds ratio (OR) 4.63, 95% confidence interval (CI) 3.43 to 6.25), and heterogeneity was present. Mortality by intention-to-treat analysis was similar in both groups at 30 days (4.0% in the TMLR group and 3.5% in the control group), and one year (12.2% in the TMLR group and 11.9% in the control group). However, the 30-day mortality as-treated was 6.8% in the TMLR group and 0.8% in the control group (pooled OR was 3.76, 95% CI 1.63 to 8.66), mainly due to a higher mortality in participants crossing from standard treatment to TMLR. The assessment of subjective outcomes, such as improvement in angina, was affected by a high risk of bias and this may explain the differences found. Other adverse events such as myocardial infarction, arrhythmias or heart failure, were not considered in this review, as they were not predefined outcomes in trials design and they show a high inconsistency across studies. No new trials on transmyocardial laser revascularization have been published in the last ten years and it is very unlikely that new research will be undertaken in this field. This review shows that risks associated with TMLR outweigh the potential clinical benefits. Subjective outcomes are subject to high risk of bias and no differences were found in survival, but a significant increase in postoperative mortality and other safety outcomes suggests that the procedure may pose unacceptable risks.
Eighteen studies (20 reports) involving a total of 933 participants with COPD, chronic respiratory disease, chronic heart failure, and/or thoracic cancer met the inclusion criteria for this update, an additional seven studies since the previous version of this review. All but one study that compared NMES to resistance training compared a programme of NMES to no treatment or placebo NMES. Most studies were conducted in a single centre and had a risk of bias arising from a lack of participant or assessor blinding and small study size. The quality of the evidence using GRADE comparing NMES to control was low for quadriceps muscle strength, moderate for occurrence of adverse events, and very low to low for all other secondary outcomes. We downgraded the quality of evidence ratings predominantly due to inconsistency among study findings and imprecision regarding estimates of effect. The included studies reported no serious adverse events and a low incidence of muscle soreness following NMES. NMES led to a statistically significant improvement in quadriceps muscle strength as compared to the control (12 studies; 781 participants; SMD 0.53, 95% confidence interval (CI) 0.19 to 0.87), equating to a difference of approximately 1.1 kg. An increase in muscle mass was also observed following NMES, though the observable effect appeared dependent on the assessment modality used (eight studies, 314 participants). Across tests of exercise performance, mean differences compared to control were statistically significant for the 6-minute walk test (seven studies; 317 participants; 35 m, 95% CI 14 to 56), but not for the incremental shuttle walk test (three studies; 434 participants; 9 m, 95% CI -35 to 52), endurance shuttle walk test (four studies; 452 participants; 64 m, 95% CI -18 to 146), or for cardiopulmonary exercise testing with cycle ergometry (six studies; 141 participants; 45 mL/minute, 95% CI -7 to 97). Limited data were available for other secondary outcomes, and we could not determine the most beneficial type of NMES programme. The overall conclusions have not changed from the last publication of this review, although we have included more data, new analyses, and an assessment of the quality of the evidence using the GRADE approach. NMES may be an effective treatment for muscle weakness in adults with advanced progressive disease, and could be considered as an exercise treatment for use within rehabilitation programmes. Further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate. We recommend further research to understand the role of NMES as a component of, and in relation to, existing rehabilitation approaches. For example, studies may consider examining NMES as an adjuvant treatment to enhance the strengthening effect of programmes, or support patients with muscle weakness who have difficulty engaging with existing services.
Our search strategies led to 149 potentially relevant references, but only a single small study met our inclusion criteria. The included study was published as a full text article and investigated the feasibility and effect of Tibetan Yoga additional to standard care (N = 20; 1 person dropped out before attending any classes and no data were collected) compared to standard care only (N = 19). The study included people with all stages of Hodgkin and non-Hodgkin's lymphoma, with and without current cancer treatment. The mean age was 51 years. We judged the overall risk of bias as high as we found a high risk for performance, detection and attrition bias. Additionally, potential outcome reporting bias could not be completely ruled out. Following the recommendations of GRADE, we judged the overall quality of the body of evidence for all predefined outcomes as 'very low', due to the methodical limitations and the very small sample size. The influence of yoga on HRQoL and OS was not reported. There is no evidence that yoga in addition to standard care compared with standard care only can improve distress in people with haematological malignancies (mean difference (MD) -0.30, 95% confidence interval (CI) -5.55 to 4.95; P = 0.91). Similarly, there is no evidence of a difference between either group for fatigue (MD 0.00, 95% CI -0.94 to 0.94; P = 1.00), anxiety (MD 0.30, 95% CI -5.01 to 5.61; P = 0.91) or depression (MD -0.70, 95% CI -3.21 to 1.81; P = 0.58). There is very low quality evidence that yoga improves the overall quality of sleep (MD -2.30, 95% CI -3.78 to -0.82; P = 0.002). The yoga groups' total score for the Pittsburgh Sleep Quality Index (PSQI) was 5.8 (± 2.3 SD) and better than the total score (8.1 (± 2.4 SD)) of the control group. A PSQI total score of 0 to 5 indicates good sleep whereas PSQI total score 6 to 21 points towards significant sleep disturbances. The occurrence of AEs was not reported. The currently available data provide little information about the effectiveness of yoga interventions for people suffering from haematological malignancies. The finding that yoga may be beneficial for the patients' quality of sleep is based on a very small body of evidence. Therefore, the role of yoga as an additional therapy for haematological malignancies remains unclear. Further high-quality randomised controlled trials with larger numbers of participants are needed to make a definitive statement.
Seven randomised controlled trials, involving 582 women undergoing caesarean section were included in this review. The risk of bias of included trials was variable, with some trials not adequately describing allocation or randomisation. Three comparisons were included. 1. Tocolysis versus no tocolysis A single randomised trial involving 97 women was identified and included in the review. Birth trauma was not reported. There were no cases of any maternal side-effect reported in either the nitroglycerin or the placebo group. No other maternal and infant health outcomes were reported. 2. Reverse breech extraction versus head push for the deeply impacted head at full dilation at caesarean section Four randomised trials involving 357 women were identified and included in the review. The primary outcome of birth trauma was reported by three trials and there was no difference between reverse breech extraction and head push for this rare outcome (three studies, 239 women, risk ratio (RR) 1.55, 95% confidence interval (CI) 0.42 to 5.73). Secondary outcomes including endometritis rate (three studies, 285 women, average RR 0.52, 95% CI 0.26 to 1.05, Tau I² = 0.22, I² = 56%), extension of uterine incision (four studies, 357 women, average RR 0.23, 95% CI 0.13 to 0.40), mean blood loss (three studies, 298 women, mean difference (MD) -294.92, 95% CI -493.25 to -96.59; I² = 98%) and neonatal intensive care unit (NICU)/special care nursery (SCN) admission (two studies, 226 babies, average RR 0.53, 95% CI 0.23 to 1.22, Tau I² = 0.27, I² = 74%) were decreased with reverse breech extraction. No differences were observed between groups for many of the other secondary outcomes reported (blood loss > 500 mL; blood transfusion; wound infection; mean hospital stay; average Apgar score). There was significant heterogeneity between the trials for the outcomes mean blood loss, operative time and mean hospital stay, making comparison difficult. However the operation duration was significantly shorter for reverse breech extraction, which may correspond with ease of delivery and therefore, the amount of tissue trauma and therefore, significantly less blood loss. Given the heterogeneity, we cannot define the amount of difference in blood loss, operative time or hospital stay however. 3. Instrument (vacuum or forceps) versus manual extraction at elective caesarean section Two randomised trials involving 128 women were identified and included in the review. Only one trial reported maternal and infant health outcomes as prespecified in this review. This trial reported birth trauma as an outcome but there were no instances of birth trauma in either comparison group. There were no differences found in mean fall in haemoglobin (Hb) between groups (one study, 44 women, MD 0.03, 95% CI -0.53 to 0.59), or in uterine incision extension (one study, 44 women, RR 0.70, 95% CI 0.13 to 3.73). There is currently insufficient information available from randomised trials to support or refute the routine or selective use of tocolytic agents or instrument to facilitate infant birth at the time of difficult caesarean section. There is limited evidence that reverse breech extraction may improve maternal and fetal outcomes, though there was no difference in primary outcome of infant birth trauma. Further randomised controlled trials are needed to answer these questions.
Thirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included. In the comparison of vitamin B with placebo, two small trials showed no significant short-term benefit in pain intensity while one of the trials showed a small significant benefit in vibration detection from oral benfotiamine, a derivative of thiamine. In the larger of two trials comparing different doses of vitamin B complex, there was some evidence that higher doses resulted in a significant short-term reduction in pain and improvement in paraesthesiae, in a composite outcome combining pain, temperature and vibration, and in a composite outcome combining pain, numbness and paraesthesiae. There was some evidence that vitamin B is less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in the short-term improvement of clinical and nerve conduction study outcomes but the trials were small. There were few minor adverse effects reported. There are only limited data in randomised trials testing the efficacy of vitamin B for treating peripheral neuropathy and the evidence is insufficient to determine whether vitamin B is beneficial or harmful. One small trial in alcoholic peripheral neuropathy reported slightly greater improvement in vibration perception threshold with oral benfotiamine for eight weeks than placebo. In another small study, a higher dose of oral vitamin B complex for four weeks was more efficacious than a lower dose in reducing symptoms and signs. Vitamin B administered by various routes for two to eight weeks was less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in short-term improvement of clinical and nerve conduction study outcomes. Vitamin B is generally well-tolerated.
We only found one study eligible for this review (22 participants). We assessed the risk of bias for most domains as unclear. We graded the overall quality of evidence as very low. Compared to placebo, patients treated with pregabalin showed no significant improvement of motor tasks on the 36-point subscale of the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) (MD −2.15 points; 95% CI −9.16 to 4.86) or on the 32-point functional abilities subscale of the TRS (MD −0.66 points; 95% CI −2.90 to 1.58).The limited evidence showed no difference in study withdrawal (Mantel-Haenszel RD −0.09; 95% CI −0.48 to 0.30) and presentation of adverse events between pregabalin and placebo (Mantel-Haenszel RD 0.18; 95% CI −0.13 to 0.50). The effects of pregabalin for treating essential tremor are uncertain because the quality of the evidence is very low. One small study did not highlight any effect of this treatment; however, the high risk of bias and the lack of other studies on this topic limit further conclusion.
Only one small trial of the seven included studies truly evaluated TCM for schizophrenia. The other trials evaluated Chinese herbs for schizophrenia. We found one study comparing Chinese herbal medicine with antipsychotic drugs. Data for the global state outcome 'no change/worse' favoured people allocated to antipsychotic medication (n=90, RR 1.88 CI 1.2 to 2.9, NNH 4 CI 2 to 12). Six trials compared Chinese herbal medicine in combination with antipsychotic with antipsychotic drugs alone. One trial found global state 'not improved/worse' favoured the herbal medicine/antipsychotic combination (n=123, RR 0.19 CI 0.1 to 0.6, NNT 6 CI 5 to 11). Two studies (n=103) also found short-term data from the Clinical Global Impression scale favoured the herbal medicine plus antipsychotic group (WMD -0.46 CI -0.9 to -0.1) compared with those given only antipsychotics. Significantly fewer people in the experimental group left the study early compared with those given antipsychotics alone (n=1004, 6 RCTs, RR 0.30 CI 0.16 to 0.58, NNT 21 CI 18 to 35). Reports of constipation were significantly lower in the treatment group compared to those receiving antipsychotics (n=67, 1 RCT, RR 0.03 CI 0.0 to 0.5, NNH 2 CI 2 to 4). Chinese herbal medicines, given in a Western biomedical context, may be beneficial for people with schizophrenia when combined with antipsychotics. Traditional Chinese medicine is also under-evaluated, but results from one pioneering study that attempted to evaluate TCM should encourage further trials. Note: the 45 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.
We included 42 trials with a total of 9606 couples. Comparing rFSH to all other gonadotrophins combined, irrespective of the down-regulation protocol used, did not result in any evidence of a statistically significant difference in live birth rate (28 trials, 7339 couples, odds ratio (OR) 0.97, 95% CI 0.87 to 1.08). This suggests that for a group with a 25% live birth rate using urinary gonadotrophins the rate would be between 22.5% and 26.5% using rFSH. There was also no evidence of a difference in the OHSS rate (32 trials, 7740 couples, OR 1.18, 95% CI 0.86 to 1.61). This means that for a group with 2% risk of OHSS using urinary gonadotrophins, the risk would be between 1.7% and 3.2% using rFSH. When different urinary gonadotrophins were considered separately, there were significantly fewer live births after rFSH than HMG (11 trials, N=3197, OR 0.84, 95% CI 0.72 to 0.99). This means that for a live birth rate of 25% using HMG, use of rFSH instead would be expected to result in a rate between 19% and 25%. There was no evidence of a difference in live births when rFSH was compared with FSH-P (5 trials, N=1430, OR 1.26, 95% CI 0.96 to 1.64) or when rFSH was compared with FSH-HP (13 trials, N=2712; OR 1.03, 95% CI 0.86 to 1.22). Clinical choice of gonadotrophin should depend on availability, convenience and costs. Differences between urinary gonadotrophins were considered unlikely to be clinically significant. Further research on these comparisons is unlikely to identify substantive differences in effectiveness or safety.
Seven trials are included but few reported the outcomes selected for this review. A meta-analysis of ciclosporin versus placebo from two trials (59 participants) - one as monotherapy (20 participants) and the other with corticosteroids (39 participants) - showed that it resulted in improvement of participants in the ciclosporin group compared with those in the placebo group, with a relative rate of improvement of 2.44 (95% confidence interval (CI) 1.13 to 5.27). In addition the weighted mean difference in QMG score between the ciclosporin and placebo groups was -0.34 (95% CI -0.52 to -0.17). Azathioprine (plus prednisolone for first month) had no significant benefit over prednisolone alone (41 participants). The effects of azathioprine plus prednisolone versus prednisolone plus placebo were similar (34 participants). Cyclophosphamide was reported to be statistically more efficacious than placebo at 12 months in corticosteroid-dependent participants (23 participants), but no raw data were available. Trials of mycophenolate mofetil and tacrolimus did not provide relevant endpoint data for this review. All trials had low numbers of participants. Adverse event reporting was variable. Trial protocol heterogeneity prevented comparison of the different immunosuppressants. In generalised MG, limited evidence from small RCTs suggests that ciclosporin, as monotherapy or with corticosteroids, or cyclophosphamide with corticosteroids, significantly improve MG.  Limited evidence from RCTs shows no significant benefit from azathioprine (as monotherapy or with steroids), mycophenolate mofetil (as monotherapy or with either corticosteroids or ciclosporin) or tacrolimus (with corticosteroids or plasma exchange). Bigger, better-designed, longer trials are needed.
We identified 10,488 unique records, with 323 screened as full text. Five studies were included for the main analysis: one RCT with a low risk, two CBAs with a moderate risk and two CBAs with a high risk of bias. Three CBAs evaluated multicomponent slum upgrading strategies. Road paving only was evaluated in one RCT and water supply in one CBA. A total of 3453 households or observations were included within the four studies reporting sample sizes. Most health outcomes in the main studies related to communicable diseases, for which the body of evidence was judged to be low quality. One CBA with a moderate risk of bias found that diarrhoeal incidence was reduced in households which received water connections from a private water company (risk ratio (RR) 0.53; 95% confidence interval (CI) 0.27 to 1.04) and the severity of diarrhoeal episodes (RR 0.48; 95% CI 0.19  to 1.22). There was no effect for duration of diarrhoea. Road paving did not result in changes in parasitic infections or sickness in one RCT. After multicomponent slum upgrading, claims for a waterborne disease as opposed to a non-waterborne disease reduced (RR 0.64; 95% CI 0.27 to 0.98) in one CBA with a high risk of bias but there was no change in sanitation-related mortality in a CBA with a moderate risk of bias. The majority of socio-economic outcomes reported within the main studies related to financial poverty, for which the body of evidence was of very low quality. Results were mixed amongst the main studies; one RCT and two CBAs reported no effect on the income of slum dwellers following slum upgrading. One further CBA found significant reduction in monthly water expenditure (mean difference (MD) -17.11 pesos; 95% CI -32.6 to -1.62). One RCT also showed mixed results for employment variables, finding no effect on unemployment levels but increased weekly worked hours (MD 4.68; 95% CI -0.46 to 9.82) and lower risk of residents intending to migrate for work (RR 0.78; 95% CI 0.60 to 1.01). There was no evidence available to assess the impact of slum upgrading on non-communicable diseases or social capital. Maternal and perinatal conditions, infant mortality, nutritional deficiencies, injuries, self-reported quality of life, education and crime were evaluated in one study each. Nine supporting studies were included that measured varying outcomes (6794 households or observations within eight studies reporting sample sizes). One CPI evaluated cement flooring only while three UBAs and five CPIs evaluated multicomponent slum upgrading strategies. All studies but one had a high risk of bias. The studies reinforced main study findings for diarrhoea incidence and water-related expenditure. Findings for parasitic infections and financial poverty were inconsistent with the main studies. In addition, supporting studies reported a number of disparate outcomes that were not evaluated in the main studies. Five supporting studies included some limited information on slum dweller perspectives. They indicated the importance of appropriate siting of facilities, preference for private facilities, delivering synergistic interventions together, and ensuring that infrastructure was fit for purpose and systems were provided for cleaning, maintenance and repair. A high risk of bias within the included studies, heterogeneity and evidence gaps prevent firm conclusions on the effect of slum upgrading strategies on health and socio-economic wellbeing. The most common health and socio-economic outcomes reported were communicable diseases and indicators of financial poverty. There was a limited but consistent body of evidence to suggest that slum upgrading may reduce the incidence of diarrhoeal diseases and water-related expenditure. The information available on slum dwellers’ perspectives provided some insight to barriers and facilitators for successful implementation and maintenance of interventions. The availability and use of reliable, comparable outcome measures to determine the effect of slum upgrading on health, quality of life and socio-economic wellbeing would make a useful contribution to new research in this important area. Given the complexity in delivering slum upgrading, evaluations should look to incorporate process and qualitative information alongside quantitative effectiveness data to determine which particular interventions work (or don’t work) and for whom.
We identified six trials that met our inclusion criteria. The trials compared 3, 24 and 96 hour infusions and one trial examined different schedules (1 versus 3 day). From the included RCTs we found no evidence of a difference between short and long infusions in terms of overall and progression-free survival and tumour non-response. In most cases a greater proportion of adverse events and severe toxicity occurred in the 24 hour infusion group compared to the 3 hour group with many of the analyses being highly statistically significant (RR = 0.32, 95% CI 0.22, 0.47, RR = 0.06, 95% CI 0.02, 0.17, RR = 0.59, 95% CI 0.40, 0.88, RR = 0.52, 95% CI 0.28, 0.97 for severe hypersensitivity, febrile neutropenia, sore mouth and diarrhoea outcomes respectively). Although a meta analysis of three trials found that 3 hour infusions were associated with a statistically significant increase in the risk of neurosensory changes compared with 24 hour infusions (RR = 1.26, 95% CI 1.09 to 1.46). Adverses events were not comprehensively reported for any of the other comparisons. Outcomes were incompletely documented and QoL outcomes were not reported in any of the trials. The strength of the evidence is weak in this review as it is based on meta analyses of very few trials or single trial analyses and all trials were at moderate risk of bias and two were published in abstract form only. Ideally, large, multi-centre supporting trials are needed as outcomes were incompletely reported in included trials in this review. It may be beneficial to design a multi-arm trial comparing 3, 24 and 96 hour infusions or maybe looking at different schedules. In the absence of such trials, the decision to offer short or long infusions in advanced adenocarcinoma may need to be individualised, although it certainly appears that women have less toxicity, apart from sensory nerve damage, with a shorter infusion. Efficacy appearing similar regardless of infusion duration.
Five studies were identified through the searches, only one met our inclusion criteria. The included study randomized 22 participants (seven males and 15 females) having proteinuria or microalbuminuria with sickle cell disease and treated the participants for six months (median length of follow up of three months) with captopril or placebo. The overall quality of the outcomes reported was high, since most aspects that may contribute to bias were regarded to be of low risk, although allocation concealment was not reported. At six months, the study reported no significant difference in urinary albumin excretion between the captopril group and the placebo group, although the mean urinary albumin excretion in the captopril group was lower by a mean difference of -49.00 (95% confidence interval -124.10 to 26.10) compared to that of placebo. However, our analysis on the absolute change score showed significant changes between the two groups by a mean difference of -63.00 (95% confidence interval -93.78 to -32.22). At six months albumin excretion in the captopril group was noted to decrease from baseline by a mean of 45 ± 23 mg/day and the placebo group was noted to increase by 18 ± 45 mg/day. Serum creatinine and potassium levels were reported constant throughout the study. The potential for inducing hypotension should be highlighted; the study reported a decrease of 8 mmHg in systolic pressure and 5 mmHg in diastolic and mean blood pressure. There is not enough evidence to show that the administration of ACE inhibitors is associated with a reduction of microalbuminuria and proteinuria in people with sickle cell disease, although a potential for this was seen. More long-term studies involving multiple centers and larger cohorts using a randomized-controlled design are warranted, especially among the pediatric age group. Detailed reporting of each outcome measure is necessary to allow a clear cut interpretation in a systematic review. One of the difficulties encountered in this review was the lack of detailed data reported in the included study.
We included 15 trials (1376 participants) in this review. We downgraded the quality of evidence for many of our outcomes on the basis of high risk of bias. Low-quality evidence suggests that immunonutrition decreases all-cause mortality (RR 0.49, 95% CI 0.29 to 0.80). The effect of immunonutrition on other outcomes from a subset of the included trials was uncertain. Subgrouping trials by type of enteral nutrition did not explain any variation in effect. We found mainly very low-quality evidence for the effects of probiotics on the main outcomes. One eligible trial in this comparison reported a higher rate of serious adverse events leading to increased organ failure and mortality due to low numbers of events and low risk of bias. When we excluded this study as a post hoc sensitivity analysis, risks of mortality (RR 0.30, 95% CI 0.10 to 0.84), organ failure (RR 0.74, 95% CI 0.59 to 0.92) and local septic complications (RR 0.40, 95% CI 0.22 to 0.72) were lower with probiotics. In one trial assessing immunonutrition with probiotics and fibres, no deaths occurred, but hospital stay was shorter with immunonutrition (MD -5.20 days, 95% CI -8.73 to -1.67). No deaths were reported following semi-elemental enteral nutrition (EN), and the effect on length of hospital stay was small (MD 0.30 days, 95% CI -0.82 to 1.42). Fibre-enriched formulations reduced the number of other local complications (RR 0.52, 95% CI 0.32 to 0.87) and length of hospital stay (MD -9.28 days, 95% CI -13.21 to -5.35) but did not significantly affect all-cause mortality (RR 0.23, 95% CI 0.03 to 1.84) and other outcomes. Very low-quality evidence from the subgroup of trials comparing EN versus no intervention showed a decrease in all-cause mortality with EN (RR 0.50, 95% CI 0.29 to 0.86). We found evidence of low or very low quality for the effects of immunonutrition on efficacy and safety outcomes. The role of supplementation of enteral nutrition with potential immunomodulatory agents remains in question, and further research is required in this area. Studies assessing probiotics yielded inconsistent and almost contrary results, especially regarding safety and adverse events, and their findings do not support the routine use of EN enriched with probiotics in routine clinical practice. However, further research should be carried out to try to determine the potential efficacy or harms of probiotics. Lack of trials reporting on other types of EN assessed and lack of firm evidence regarding their effects suggest that additional randomised clinical trials are needed. The quality of evidence for the effects of any kind of EN on mortality was low, and further studies are likely to have an impact on the finding of improved survival with EN versus no nutritional support. Evidence remains insufficient to support the use of a specific EN formulation.
We included seven trials involving 800 women. The comparisons revealed a very high clinical heterogeneity. As a result of the heterogeneity in the randomisation unit, we did not combine trials but reported the individual trial results in the ‘Data and analysis’ section and in the text. Half of trials have unclear or high risk of bias in several domains. We did not find any trial reporting data about maternal mortality. In terms of postoperative pain, PCB does not improve the control of postoperative pain when it is compared against sedation/analgesia or versus no anaesthesia/no analgesia. In the comparison of PCB with lidocaine versus PCB with saline solution, significant differences favouring the group with lidocaine were found in one trial (moderate or severe postoperative pain) (risk ratio (RR) 0.32; 95% confidence interval (CI) 0.18 to 0.59). When opioids were used, postoperative nausea and vomiting was more frequent in two trials comparing those versus PCB. In terms of requirement of blood transfusion, two trials showed conflicting results. Particular considerations that influence the choice of anaesthesia for this procedure such as availability, effectiveness, safety, side effects, practitioner's choice, costs and woman's preferences of each technique should continue to be used until more evidence supporting the use of one technique or another.
We included 55 trials (3121 patients). Thirty-seven trials assessed physical methods, including 26 trials employing mattress encasings. Ten trials involved chemical methods and eight trials involved a combination of chemical and physical methods. Despite the fact that many trials were of poor quality and would be expected to exaggerate the reported effect, we did not find an effect of the interventions. For the most frequently reported outcome, peak flow in the morning (1665 patients), the standardised mean difference (SMD) was 0.01 (95% confidence interval (CI) -0.08 to 0.11). There were no statistically significant differences either in number of patients improved (risk ratio 1.01, 95% CI 0.80 to 1.27), asthma symptom scores (SMD -0.06, 95% CI -0.16 to 0.05), or in medication usage (SMD -0.05, 95% CI -0.17 to 0.07). Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended. It is doubtful whether further studies, similar to the ones in our review, are worthwhile. If other types of studies are considered, they should be methodologically rigorous and use other methods than those used so far, with careful monitoring of mite exposure and relevant clinical outcomes.
We included seven RCTs comprising 577 participants. There was no significant heterogeneity among trials for the outcome of PEP (P = 0.32; I2 = 15%). The PGW technique significantly increased PEP compared to other endoscopic techniques (RR 1.98, 95% CI 1.14 to 3.42; low-quality evidence). The number needed to treat for an additional harmful outcome was 13 (95% CI 5 to 89). Among the three studies that compared the PGW technique with persistent CC, the incidence of PEP was 13.5% for the PGW technique and 8.7% for persistent CC (RR 1.58, 95% CI 0.83 to 3.01; low-quality evidence). Among the two studies that compared the PGW technique with precut sphincterotomy, the incidence of PEP was 29.8% in the PGW group versus 10.3% in the precut group (RR 2.92, 95% CI 1.24 to 6.88; low-quality evidence). Among the two studies that compared the PGW technique with PD stent placement, the incidence of PEP was 11.7% for the PGW technique and 5.0% for PD stent placement (RR 1.75, 95% CI 0.08 to 37.50; very low-quality evidence). There was no significant difference in common bile duct (CBD) cannulation success with the randomised technique (RR 1.04, 95% CI 0.87 to 1.24; low-quality evidence) or overall CBD cannulation success (RR 1.04, 95% CI 0.91 to 1.18; low-quality evidence) between the PGW technique and other endoscopic techniques. There was also no statistically significant difference in the risk of other ERCP-related complications (bleeding, perforation, cholangitis, and mortality). The results were robust in sensitivity analyses. The overall quality of evidence for the outcome of PEP was low or very low because of study limitations and imprecision. In people with difficult CBD cannulation, sole use of the PGW technique appears to be associated with an increased risk of PEP. Prophylactic PD stenting after use of the PGW technique may reduce the risk of PEP. However, the PGW technique is not superior to persistent attempts with CC, precut sphincterotomy, or PD stent in achieving CBD cannulation. The influence of co-intervention in the form of rectal peri-procedural nonsteroidal anti-inflammatory drug administration is unclear.
We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine. Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.
We included one RCT (153 women) comparing the LNG-IUS administering 20 micrograms (μu) levonorgestrel per day versus 10 milligrams of continuous or cyclical oral medroxyprogesterone (MPA) for treating any type of endometrial hyperplasia. Only 19 women in this study were histologically confirmed with atypical complex hyperplasia before treatment. The evidence was of low or very low quality. The included study was at low risk of bias, but the quality of the evidence was very seriously limited by imprecision and indirectness. We did not find any RCTS comparing the LNG-IUS or oral progestogens versus placebo in women with atypical endometrial hyperplasia. Among the 19 women with atypical complex hyperplasia, after six months of treatment there was insufficient evidence to determine whether there was a difference in regression rates between the LNG-IUS group and the progesterone group (odds ratio (OR) 2.76, 95% confidence interval (CI) 0.26 to 29.73; 1 RCT subgroup, 19 women, very low-quality evidence). The rate of regression was 100% in the LNG-IUS group (n = 6/6) and 77% in the progesterone group (n = 10/13). Among the total study population (N = 153), over the six months' treatment the main adverse effects were nausea and vaginal bleeding. There was no evidence of a difference between the groups in rates of nausea (OR 0.58, 95% CI 0.28 to 1.18; 1 RCT, 153 women, very low-quality evidence). Vaginal bleeding was more common in the LNG-IUS group (OR 2.89, 95% CI 1.11 to 7.52; 1 RCT, 153 women, low-quality evidence). Except for nausea and vaginal bleeding, no other adverse effects were reported. We did not find any RCTS of women with atypical endometrial hyperplasia, and our findings derive from a subgroup of 19 women in a larger RCT. All six women who used the LNG-IUS system achieved regression of atypical hyperplasia, but there was insufficient evidence to draw any conclusions regarding the relative efficacy of LNG-IUS versus oral progesterone (MPA) in this group of women. When assessed in a population of women with any type of endometrial hyperplasia, there was no clear evidence of a difference between LNG-IUS and oral progesterone (MPA) in risk of nausea, but vaginal bleeding was more likely to occur in women using the LNG-IUS. Larger studies are necessary to assess the efficacy and safety of oral and intrauterine progestogens in treating atypical endometrial hyperplasia.
We included 25 trials with 2505 participants randomised to the different pharmacological agents and inactive controls. All the trials were at unclear risk of bias. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Participants were allowed to take additional analgesics as required in 24 of the trials. The pharmacological interventions in all the included trials were aimed at preventing pain after laparoscopic cholecystectomy. There were considerable differences in the pharmacological agents used and the methods of administration. The estimated effects of the intervention on the proportion of participants who were discharged as day-surgery, the length of hospital stay, or the time taken to return to work were imprecise in all the comparisons in which these outcomes were reported (very low quality evidence). There was no mortality in any of the groups in the two trials that reported mortality (183 participants, very low quality evidence). Differences in serious morbidity outcomes between the groups were imprecise across all the comparisons (very low quality evidence). None of the trials reported patient quality of life or time taken to return to normal activity. The pain at 4 to 8 hours was generally reduced by about 1 to 2 cm on the visual analogue scale of 1 to 10 cm in the comparisons involving the different pharmacological agents and inactive controls (low or very low quality evidence). The pain at 9 to 24 hours was generally reduced by about 0.5 cm (a modest reduction) on the visual analogue scale of 1 to 10 cm in the comparisons involving the different pharmacological agents and inactive controls (low or very low quality evidence). There is evidence of very low quality that different pharmacological agents including non-steroidal anti-inflammatory drugs, opioid analgesics, and anticonvulsant analgesics reduce pain scores in people at low anaesthetic risk undergoing elective laparoscopic cholecystectomy. However, the decision to use these drugs has to weigh the clinically small reduction in pain against uncertain evidence of serious adverse events associated with many of these agents. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.
Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported. This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.
Four trials, involving a total of 149 participants, compared the effectiveness of oral corticosteroids against placebo. All the trials were small and of low methodological quality. Although there was an overall significant effect of corticosteroids compared with placebo medication on complete caloric recovery at one month (risk ratio (RR) of 2.81; 95% confidence interval (CI) 1.32 to 6.00, P = 0.007), no significant effect was seen on complete caloric recovery at 12 months (RR 1.58; 95% CI 0.45 to 5.62, P = 0.48), or on the extent of caloric recovery at either one month (mean difference (MD) 9.60%; 95% CI -20.66 to 39.86, P = 0.53) or at 12 months (MD 6.83%; 95% CI -27.69 to 41.36, P = 0.70). In addition, there was no significant difference between corticosteroids and placebo medication in the symptomatic recovery of vestibular function following idiopathic acute vestibular dysfunction with respect to vertigo at 24 hours (RR 0.39; 95% CI 0.04 to 3.57, P = 0.40) and use of the Dizziness Handicap Inventory score at one, three, six and 12 months. Overall, there is currently insufficient evidence from these trials to support the administration of corticosteroids to patients with idiopathic acute vestibular dysfunction. We found no trials with a low risk of methodological bias that used the highest level of diagnostic criteria and outcome measures. We recommend that future studies should include health-related quality of life and symptom-based outcome measures, in addition to objective measures of vestibular improvement, such as caloric testing and electronystagmography.
A total of 10 studies recruiting 6292 apparently healthy adults met the inclusion criteria. All of the studies took place in high-income countries. The effect of interventions on self-reported PA at one year (eight studies; 6725 participants) was positive and moderate with significant heterogeneity (I² = 74%) (SMD 0.19; 95% CI 0.06 to 0.31; moderate quality evidence) but not sustained in three studies at 24 months (4235 participants) (SMD 0.18; 95% CI -0.10 to 0.46). The effect of interventions on cardiovascular fitness at one year (two studies; 349 participants) was positive and moderate with no significant heterogeneity in the observed effects (SMD 0.50; 95% CI 0.28 to 0.71; moderate quality evidence). Three studies (3277 participants) reported a positive effect on increasing PA levels when assessed as a dichotomous measure at 12 months, but this was not statistically significant (OR 1.52; 95% CI 0.88 to 2.61; high quality evidence). Although there were limited data, there was no evidence of an increased risk of adverse events (one study; 149 participants). Risk of bias was assessed as low (four studies; 4822 participants) or moderate (six studies; 1543 participants). Any conclusions drawn from this review require some caution given the significant heterogeneity in the observed effects. Despite this, there was some indication that the most effective interventions were those that offered both individual and group support for changing PA levels using a tailored approach. The long term impact, cost effectiveness and rates of adverse events for these interventions was not established because the majority of studies stopped after 12 months. Although we found evidence to support the effectiveness of face-to-face interventions for promoting PA, at least at 12 months, the effectiveness of these interventions was not supported by high quality studies. Due to the clinical and statistical heterogeneity of the studies, only limited conclusions can be drawn about the effectiveness of individual components of the interventions. Future studies should provide greater detail of the components of interventions, and assess impact on quality of life, adverse events and economic data.
The review currently includes 15 randomised controlled trials with 626 participants. No trials compared flupenthixol decanoate with placebo. One small study compared flupenthixol decanoate with an oral antipsychotic (penfluridol). Only two outcomes were reported with this single study, and it demonstrated no clear differences between the two preparations as regards leaving the study early (n = 60, 1 RCT, RR 3.00, CI 0.33 to 27.23,very low quality evidence) and requiring anticholinergic medication (1 RCT, n = 60, RR 1.19, CI 0.77 to 1.83, very low quality evidence). Ten studies in total compared flupenthixol decanoate with other depot preparations, though not all studies reported on all outcomes of interest. There were no significant differences between depots for outcomes such as relapse at medium term (n = 221, 5 RCTs, RR 1.30, CI 0.87 to 1.93, low quality evidence), and no clinical improvement at short term (n = 36, 1 RCT, RR 0.67, CI 0.36 to 1.23, low quality evidence). There was no difference in numbers of participants leaving the study early at short/medium term (n = 161, 4 RCTs, RR 1.23, CI 0.76 to 1.99, low quality evidence) nor with numbers of people requiring anticholinergic medication at short/medium term (n = 102, 3 RCTs, RR 1.38, CI 0.75 to 2.25, low quality evidence). Three studies in total compared high doses (100 to 200 mg) of flupenthixol decanoate with the standard doses (˜40mg) per injection. Two trials found relapse at medium term (n = 18, 1 RCT, RR 1.00, CI 0.27 to 3.69, low quality evidence) to be similar between the groups. However people receiving a high dose had slightly more favourable medium term mental state results on the Brief Psychiatric Rating Scale (BPRS) (n = 18, 1 RCT, MD -10.44, CI -18.70 to -2.18, low quality evidence). There was also no significant difference in the use of anticholinergic medications to deal with side effects at short term (2 RCTs n = 47, RR 1.12, CI 0.83 to 1.52 very low quality evidence). One trial comparing a very low dose of flupenthixol decanoate (˜6 mg) with a low dose (˜9 mg) per injection reported no difference in relapse rates (n = 59, 1 RCT, RR 0.34, CI 0.10 to 1.15, low quality evidence). In the current state of evidence, there is nothing to choose between flupenthixol decanoate and other depot antipsychotics. From the data reported in clinical trials, it would be understandable to offer standard dose rather than the high dose depot flupenthixol as there is no difference in relapse. However, data reported are of low or very low quality and this review highlights the need for large, well-designed and reported randomised clinical trials to address the effects of flupenthixol decanoate.
Only one study met our inclusion criteria, involving 1106 adult patients with relapsing-remitting MS (RRMS) and an entry Expanded Disability Status Scale (EDSS) score of ≤ 5.5 and an entry disease duration of ≥ 6 months. Five hundred and fifty patients treated with laquinimod at a dose of 0.6 mg orally administered once daily in a capsule were compared with 556 patients treated with a matching placebo capsule. The study had a high risk for attrition bias (21.9%). Laquinimod had potential benefits in reducing relapse rates and was safe for most patients with RRMS in the short term. The most common adverse events included headache, back pain, arthralgia, diarrhoea, cough, urinary tract infection, elevated alanine aminotransferase, insomnia, nausea, abdominal pain and sinusitis. One ongoing trial was identified. We found low-level evidence for the use of laquinimod as a disease-modifying therapy for MS because only one study with limited quality (high risk of attrition bias) was included. The published study suggests that laquinimod at a dose of 0.6 mg orally administered once daily may be safe and have potential benefits for most patients with RRMS in the short term. We are waiting for the publication of ongoing trials.
A total of 13 trials with 8,698 participants were included. Primary outcomes (HIV and STI prevalence and incidence) were reported in seven trials. Of these, HIV incidence was reported in only three trials. After a 6-month follow-up assessment, there was no evidence that social cognitive behavioral intervention was effective in reducing HIV incidence (RR 0.12, 95% CI 0.01 to 2.22). However, there was a reduction in HIV incidence at 3-month follow-up assessment of promotion of female and male condom (RR 0.07, 95% CI 0.00 to 1.38). Social cognitive interventions and promotion of female and male condom use were significantly reduced STIs incidence (RR 0.57, 95% CI 0.34 to 0.96) and (RR 0.63, 95% CI 0.45 to 0.88), respectively. Secondary outcomes were identified in 13 trials. Meta-analyses showed evidence that interventions to promote the use of female and male condoms do reduce non-condom use (RR 0.83, 95% CI 0.65 to 1.05) compared to promotion of male condoms alone, and that social cognitive interventions reduced drug use among sex workers (RR 0.65, 95% CI 0.36 to 1.16) compared to standard care. Available evidence nevertheless suggests that compared with standard care or no intervention, behavioral interventions are effective in reducing HIV and the incidence of STIs amongst female sex workers (FSWs). Given the benefits of social cognitive theory and the promotion of condom use in reducing HIV/STI and the public health need to control transmission amongst FSWs, there is a clear finding in favour of behavioral interventions. However, it should be recognized that there is a lack of information about most other outcomes and target populations, and that all of the trials were conducted in low- and middle-income countries.
We included 10 RCTs (N = 1815), which were published between 1983 and 2015. Three trials compared a single AED (phenytoin) with placebo or no treatment. One three-armed trial compared two AEDs (phenytoin, carbamazepine) with no treatment. A second three-armed trial compared phenytoin, phenobarbital with no treatment. Of these five trials comparing AEDs with placebo or no treatment, two trials reported a statistically significant advantage for AED treatment compared to controls for early seizure occurrence; all other comparisons showed no clear or statistically significant differences between AEDs and control treatment. None of the trials that were head-to-head comparisons of AEDs (phenytoin versus sodium valproate, phenytoin versus phenobarbital, levetiracetam versus phenytoin, zonisamide versus phenobarbital) reported any statistically significant differences between treatments for either early or late seizure occurrence. Incidences of death were reported in only five trials. One trial reported statistically significantly fewer deaths in the carbamazepine and no-treatment groups compared with the phenytoin group after 24 months of treatment, but not after six months of treatment. Incidences of adverse effects of treatment were poorly reported; however, three trials did show that significantly more adverse events occurred on phenytoin compared to valproate, placebo, or no treatment. No trials reported any results relating to functional outcomes such as disability. We considered the evidence to be of low quality for all reported outcomes due to methodological issues and variability of comparisons made in the trials. There is limited, low-quality evidence to suggest that AED treatment administered prophylactically is either effective or not effective in the prevention of postcraniotomy (early or late) seizures. The current evidence base is limited due to the different methodologies employed in the trials and inconsistencies in the reporting of outcomes including deaths and adverse events. Further evidence from good-quality, contemporary trials is required in order to assess the clinical effectiveness of prophylactic AED treatment compared to placebo or no treatment, or other AEDs in preventing postcraniotomy seizures in this select group of patients.
We identified three prophylactic trials which recorded 37 cases of community-acquired pneumonia in 2335 people. Only one was satisfactorily randomised, double-blind and placebo-controlled. Two trials examined military recruits and the third studied boys from "lower wage-earning classes" attending a boarding school in the UK during World War II. Each of these three trials found a statistically significant (80% or greater) reduction in pneumonia incidence in the vitamin C group. We identified two therapeutic trials involving 197 community-acquired pneumonia patients. Only one was satisfactorily randomised, double-blind and placebo-controlled. That trial studied elderly patients in the UK and found lower mortality and reduced severity in the vitamin C group; however, the benefit was restricted to the most ill patients. The other therapeutic trial studied adults with a wide age range in the former Soviet Union and found a dose-dependent reduction in the duration of pneumonia with two vitamin C doses. We identified one prophylactic trial recording 13 cases of hospital-acquired pneumonia in 37 severely burned patients; one-day administration of vitamin C had no effect on pneumonia incidence. The identified studies are clinically heterogeneous which limits their comparability. The included studies did not find adverse effects of vitamin C. The prophylactic use of vitamin C to prevent pneumonia should be further investigated in populations who have a high incidence of pneumonia, especially if dietary vitamin C intake is low. Similarly, the therapeutic effects of vitamin C should be studied, especially in patients with low plasma vitamin C levels. The current evidence is too weak to advocate prophylactic use of vitamin C to prevent pneumonia in the general population. Nevertheless, therapeutic vitamin C supplementation may be reasonable for pneumonia patients who have low vitamin C plasma levels because its cost and risks are low.
One-hundred-and-two quasi-experimental studies, with 666,615 children are included in this review. The 'Risk of bias' analysis indicates that the evidence base contains studies with unclear risk for selection bias, performance bias, detection bias, reporting bias, and attrition bias, with the highest risk associated with selection bias and the lowest associated with reporting bias. The outcome data suggest that children in kinship foster care experience fewer behavioural problems (standardised mean difference effect size -0.33, 95% confidence interval (CI) -0.49 to -0.17), fewer mental health disorders (odds ratio (OR) 0.51, 95% CI 0.42 to 0.62), better well-being (OR 0.50, 95% CI 0.38 to 0.64), and less placement disruption (OR 0.52, 95% CI 0.40 to 0.69) than do children in non-kinship foster care. For permanency, there was no difference on reunification rates, although children in non-kinship foster care were more likely to be adopted (OR 2.52, 95% CI 1.42 to 4.49), while children in kinship foster care were more likely to be in guardianship (OR 0.26, 95% CI 0.17 to 0.40). Lastly, children in non-kinship foster care were more likely to utilise mental health services (OR 1.79, 95% CI 1.35 to 2.37). This review supports the practice of treating kinship care as a viable out-of-home placement option for children removed from the home for maltreatment. However, this conclusion is tempered by the pronounced methodological and design weaknesses of the included studies.
Five RCTs involving 604 people were included. The pooled results revealed that the addition of corticosteroids reduces statistically significant the risk for acute GvHD grade I to IV (HR 0.58; 95% CI 0.45 to 0.76) and II to IV (HR 0.69; 95% CI 0.51 to 0.92). No evidence was found that it has any clinical relevance on overall survival (HR 0.99; 95% CI 0.79 to 1.25) or disease-free survival (HR 0.95; 95% CI 0.74 to 1.23). As well, no statistically significant influence was found for acute GvHD grade III to IV (HR 0.78; 95% CI 0.52 to 1.15), chronic GvHD (HR 1.21;95% CI 0.89 to 1.65]), relapse incidence (HR 0.82; 95% CI 0.57 to 1.18) or non-relapse mortality (HR 0.88;95% CI 0.61 to 1.26). No clear evidence was found that the rate of infectious complications (under the concomitant use of antiviral or antibacterial medication or both) increases with the addition of corticosteroids. With respect to the other outcomes no significant differences could be detected. The addition of corticosteroids reduces the incidences of acute GvHD grade I to IV and II to IV. This reduction, however, did not show any effect on overall survival and disease-free survival. Further randomised controlled studies are needed to evaluate if the timing of steroid administration has a significant influence on the outcome; data on quality of life should be assessed systematically.
Eleven randomised clinical trials involving 716 patients with primary biliary cirrhosis fulfilled the inclusion criteria. No significant differences were detected between colchicine and placebo/no intervention on the number of deaths (RR 1.21, 95% CI 0.71 to 2.06), the number of deaths and/or patients who underwent liver transplantation (RR 1.00, 95% CI 0.67 to 1.49), liver complications, liver biochemical variables, liver histological measurements, and adverse events. Trial methodology was generally low and some trials had high drop-out rate. A best-worst-case-scenario analysis showed no significant effect of colchicine on mortality (RR 0.59, 95%CI 0.30 to 1.15), while a worst-best-case-scenario analysis showed a significant detrimental effect of colchicine on mortality (RR 2.28, 95% CI 1.17 to 4.44). Colchicine significantly decreased the number of patients without improvement of pruritus (RR 0.75, 95% CI 0.65 to 0.87). However, this estimate was based on only 156 patients from three trials. The effect of the combined treatment with ursodeoxycholic acid was not significantly different from that of colchicine alone. We did not find evidence either to support or refute the use of colchicine for patients with primary biliary cirrhosis. As we are not able to exclude a detrimental effect of colchicine, we suggest that it is only used in randomised clinical trials.
The analysis included 24 trials reporting on 2226 participants of whom 239 developed TNS. Two studies are awaiting classification and one is ongoing. Included studies mostly had unclear to high risk of bias. The NMA included 24 studies and eight different local anaesthetics; the number of pair-wise comparisons was 32 and the number of different pair-wise comparisons was 11. This analysis showed that, compared to lidocaine, the risk ratio (RR) of TNS was lower for bupivacaine, levobupivacaine, prilocaine, procaine, and ropivacaine with RRs in the range of 0.10 to 0.23 while 2-chloroprocaine and mepivacaine did not differ in terms of RR of TNS development compared to lidocaine. Pair-wise meta-analysis showed that compared with lidocaine, most local anaesthetics were associated with a reduced risk of TNS development (except 2-chloroprocaine and mepivacaine) (bupivacaine: RR 0.16, 95% confidence interval (CI) 0.09 to 0.28; 12 studies; moderate-quality evidence; 2-chloroprocaine: RR 0.09, 95% CI 0.01 to 1.51; 2 studies; low-quality evidence; levobupivacaine: RR 0.13, 95% CI 0.02 to 0.69; 2 studies; low-quality evidence; mepivacaine: RR 1.01, 95% CI 0.18 to 5.82; 4 studies; very low-quality evidence; prilocaine: RR 0.18, 95% CI 0.07 to 0.49; 4 studies; moderate-quality evidence; procaine: RR 0.14, 95% CI 0.04 to 0.52; 2 studies; moderate-quality evidence; ropivacaine: RR 0.10, 95% CI 0.01 to 0.78; 2 studies; low-quality evidence). We were unable to perform any of our planned subgroup analyses due to the low number of TNS events. Results from both NMA and pair-wise meta-analysis indicate that the risk of developing TNS after spinal anaesthesia is lower when bupivacaine, levobupivacaine, prilocaine, procaine, and ropivacaine are used compared to lidocaine. The use of 2-chloroprocaine and mepivacaine had a similar risk to lidocaine in terms of TNS development after spinal anaesthesia. Patients should be informed of TNS as a possible adverse effect of local anaesthesia with lidocaine and the choice of anaesthetic agent should be based on the specific clinical context and parameters such as the expected duration of the procedure and the quality of anaesthesia. Due to the very low- to moderate-quality evidence (GRADE), future research efforts in this field are required to assess alternatives to lidocaine that would be able to provide high-quality anaesthesia without TNS development. The two studies awaiting classification and one ongoing study may alter the conclusions of the review once assessed.
We included 30 trials (2319 participants) of midazolam for gastrointestinal endoscopy (16 trials), bronchoscopy (3), diagnostic imaging (5), cardioversion (1), minor plastic surgery (1), lumbar puncture (1), suturing (2) and Kirschner wire removal (1). Comparisons were: intravenous diazepam (14), placebo (5) etomidate (1) fentanyl (1), flunitrazepam (1) and propofol (1); oral chloral hydrate (4), diazepam (2), diazepam and clonidine (1); ketamine (1) and placebo (3); and intranasal placebo (2). There was a high risk of bias due to inadequate reporting about randomization (75% of trials). Effect estimates were imprecise due to small sample sizes. None of the trials reported on allergic or anaphylactoid reactions. Intravenous midazolam versus diazepam (14 trials; 1069 participants) There was no difference in anxiety (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.39 to 1.62; 175 participants; 2 trials) or discomfort/pain (RR 0.60, 95% CI 0.24 to 1.49; 415 participants; 5 trials; I² = 67%). Midazolam produced greater anterograde amnesia (RR 0.45; 95% CI 0.30 to 0.66; 587 participants; 9 trials; low-quality evidence). Intravenous midazolam versus placebo (5 trials; 493 participants) One trial reported that fewer participants who received midazolam were anxious (3/47 versus 15/35; low-quality evidence). There was no difference in discomfort/pain identified in a further trial (3/85 in midazolam group; 4/82 in placebo group; P = 0.876; very low-quality evidence). Oral midazolam versus chloral hydrate (4 trials; 268 participants) Midazolam increased the risk of incomplete procedures (RR 4.01; 95% CI 1.92 to 8.40; moderate-quality evidence). Oral midazolam versus placebo (3 trials; 176 participants) Midazolam reduced pain (midazolam mean 2.56 (standard deviation (SD) 0.49); placebo mean 4.62 (SD 1.49); P < 0.005) and anxiety (midazolam mean 1.52 (SD 0.3); placebo mean 3.97 (SD 0.44); P < 0.0001) in one trial with 99 participants. Two other trials did not find a difference in numerical rating of anxiety (mean 1.7 (SD 2.4) for 20 participants randomized to midazolam; mean 2.6 (SD 2.9) for 22 participants randomized to placebo; P = 0.216; mean Spielberger's Trait Anxiety Inventory score 47.56 (SD 11.68) in the midazolam group; mean 52.78 (SD 9.61) in placebo group; P > 0.05). Intranasal midazolam versus placebo (2 trials; 149 participants) Midazolam induced sedation (midazolam mean 3.15 (SD 0.36); placebo mean 2.56 (SD 0.64); P < 0.001) and reduced the numerical rating of anxiety in one trial with 54 participants (midazolam mean 17.3 (SD 18.58); placebo mean 49.3 (SD 29.46); P < 0.001). There was no difference in meta-analysis of results from both trials for risk of incomplete procedures (RR 0.14, 95% CI 0.02 to 1.12; downgraded to low-quality evidence). We found no high-quality evidence to determine if midazolam, when administered as the sole sedative agent prior to a procedure, produces more or less effective sedation than placebo or other medications. There is low-quality evidence that intravenous midazolam reduced anxiety when compared with placebo. There is inconsistent evidence that oral midazolam decreased anxiety during procedures compared with placebo. Intranasal midazolam did not reduce the risk of incomplete procedures, although anxiolysis and sedation were observed. There is moderate-quality evidence suggesting that oral midazolam produces less effective sedation than chloral hydrate for completion of procedures for children undergoing non-invasive diagnostic procedures.
We included two studies with 1711 participants in the analyses. Both studies were conducted in UK general dental practices and involved adults without severe periodontitis who were regular attenders at dental appointments. One study measured outcomes at 24 months and the other at 36 months. Neither study measured adverse effects, changes in attachment level, tooth loss or halitosis. Comparison 1: routine scaling and polishing versus no scheduled scaling and polishing Two studies compared planned, regular interval (six- and 12-monthly) scale and polish treatments versus no scheduled treatment. We found little or no difference between groups over a two- to three-year period for gingivitis, probing depths, oral health-related quality of life (all high-certainty evidence) and plaque (low-certainty evidence). The SMD for gingivitis when comparing six-monthly scale and polish treatment versus no scheduled treatment was –0.01 (95% CI –0.13 to 0.11; two trials, 1087 participants), and for 12-monthly scale and polish versus no scheduled treatment was –0.04 (95% CI –0.16 to 0.08; two trials, 1091 participants). Regular planned scale and polish treatments produced a small reduction in calculus levels over two to three years when compared with no scheduled scale and polish treatments (high-certainty evidence). The SMD for six-monthly scale and polish versus no scheduled treatment was –0.32 (95% CI –0.44 to –0.20; two trials, 1088 participants) and for 12-monthly scale and polish versus no scheduled treatment was –0.19 (95% CI –0.31 to –0.07; two trials, 1088 participants). The clinical importance of these small reductions is unclear. Participants' self-reported levels of oral cleanliness were higher when receiving six- and 12-monthly scale and polish treatments compared to no scheduled treatment, but the certainty of the evidence is low. Comparison 2: routine scaling and polishing at different recall intervals Two studies compared routine six-monthly scale and polish treatments versus 12-monthly treatments. We found little or no difference between groups over two to three years for the outcomes of gingivitis, probing depths, oral health-related quality of life (all high-certainty evidence) and plaque (low-certainty evidence). The SMD for gingivitis was 0.03 (95% CI -0.09 to 0.15; two trials, 1090 participants; I2 = 0%). Six- monthly scale and polish treatments produced a small reduction in calculus levels over a two- to three-year period when compared with 12-monthly treatments (SMD –0.13 (95% CI –0.25 to –0.01; 2 trials, 1086 participants; high-certainty evidence). The clinical importance of this small reduction is unclear. The comparative effects of six- and 12-monthly scale and polish treatments on patients' self-reported levels of oral cleanliness were uncertain (very low-certainty evidence). Comparison 3: routine scaling and polishing provided by dentists compared with dental care professionals (dental therapists or hygienists) No studies evaluated this comparison. The review findings in relation to costs were uncertain (very low-certainty evidence). For adults without severe periodontitis who regularly access routine dental care, routine scale and polish treatment makes little or no difference to gingivitis, probing depths and oral health-related quality of life over two to three years follow-up when compared with no scheduled scale and polish treatments (high-certainty evidence). There may also be little or no difference in plaque levels over two years (low-certainty evidence). Routine scaling and polishing reduces calculus levels compared with no routine scaling and polishing, with six-monthly treatments reducing calculus more than 12-monthly treatments over two to three years follow-up (high-certainty evidence), although the clinical importance of these small reductions is uncertain. Available evidence on the costs of the treatments is uncertain. The studies did not assess adverse effects.
We identified five studies including 318 participants (180 participants with and 138 participants without common bile duct stones) that reported the diagnostic accuracy of ERCP and five studies including 654 participants (125 participants with and 529 participants without common bile duct stones) that reported the diagnostic accuracy of IOC. Most studies included people with symptoms (participants with jaundice or pancreatitis) suspected of having common bile duct stones based on blood tests, ultrasound, or both, prior to the performance of ERCP or IOC. Most studies included participants who had not previously undergone removal of the gallbladder (cholecystectomy). None of the included studies was of high methodological quality as evaluated by the QUADAS-2 tool (quality assessment tool for diagnostic accuracy studies). The sensitivities of ERCP ranged between 0.67 and 0.94 and the specificities ranged between 0.92 and 1.00. For ERCP, the summary sensitivity was 0.83 (95% confidence interval (CI) 0.72 to 0.90) and specificity was 0.99 (95% CI 0.94 to 1.00). The sensitivities of IOC ranged between 0.75 and 1.00 and the specificities ranged between 0.96 and 1.00. For IOC, the summary sensitivity was 0.99 (95% CI 0.83 to 1.00) and specificity was 0.99 (95% CI 0.95 to 1.00). For ERCP, at the median pre-test probability of common bile duct stones of 0.35 estimated from the included studies (i.e., 35% of people suspected of having common bile duct stones were confirmed to have gallstones by the reference standard), the post-test probabilities associated with positive test results was 0.97 (95% CI 0.88 to 0.99) and negative test results was 0.09 (95% CI 0.05 to 0.14). For IOC, at the median pre-test probability of common bile duct stones of 0.35, the post-test probabilities associated with positive test results was 0.98 (95% CI 0.85 to 1.00) and negative test results was 0.01 (95% CI 0.00 to 0.10). There was weak evidence of a difference in sensitivity (P value = 0.05) with IOC showing higher sensitivity than ERCP. There was no evidence of a difference in specificity (P value = 0.7) with both tests having similar specificity. Although the sensitivity of IOC appeared to be better than that of ERCP, this finding may be unreliable because none of the studies compared both tests in the same study populations and most of the studies were methodologically flawed. It appears that both tests were fairly accurate in guiding further invasive treatment as most people diagnosed with common bile duct stones by these tests had common bile duct stones. Some people may have common bile duct stones in spite of having a negative ERCP or IOC result. Such people may have to be re-tested if the clinical suspicion of common bile duct stones is very high because of their symptoms or persistently abnormal liver function tests. However, the results should be interpreted with caution given the limited quantity and quality of the evidence.
We included 20 studies with 13,102 cases of acute GABHS pharyngitis. The updated search did not identify any new eligible studies; the majority of studies were at high risk of bias. However, the majority of the results were consistent. Compared to standard duration treatment, the short duration treatment studies had shorter periods of fever (mean difference (MD) -0.30 days, 95% confidence interval (CI) -0.45 to -0.14) and throat soreness (MD -0.50 days, 95% CI -0.78 to -0.22); lower risk of early clinical treatment failure (odds ratio (OR) 0.80, 95% CI 0.67 to 0.94); no significant difference in early bacteriological treatment failure (OR 1.08, 95% CI 0.97 to 1.20) or late clinical recurrence (OR 0.95, 95% CI 0.83 to 1.08). However, the overall risk of late bacteriological recurrence was worse in the short duration treatment studies (OR 1.31, 95% CI 1.16 to 1.48), although no significant differences were found when studies of low dose azithromycin (10 mg/kg) were eliminated (OR 1.06, 95% CI 0.92 to 1.22). Three studies reported long duration complications. Out of 8135 cases of acute GABHS pharyngitis, only six cases in the short duration treatment versus eight in the standard duration treatment developed long-term complications in the form of glomerulonephritis and acute rheumatic fever, with no statistically significant difference (OR 0.53, 95% CI 0.17 to 1.64). Three to six days of oral antibiotics had comparable efficacy compared to the standard duration 10-day course of oral penicillin in treating children with acute GABHS pharyngitis. . In areas where the prevalence of rheumatic heart disease is still high, our results must be interpreted with caution.
Our search identified 604 potentially relevant studies. Of these, 14 studies (15 interventions) were RCTs and met our inclusion criteria. The numbers of participants were 352, 138 and 1745 for aspirin, steroid and NSAIDs groups, respectively. One selected study comprised two separate interventions. Interventions assessed in these studies were grouped into four categories: aspirin (three interventions), steroids (one intervention), traditional NSAIDs (six interventions), and selective cyclooxygenase-2 (COX-2) inhibitors (five interventions). All studies were evaluated for internal validity using a risk of bias assessment tool. The risk of bias was low for five studies, high for seven studies, and unclear for two studies.There was no significant improvement in cognitive decline for aspirin, steroid, traditional NSAIDs and selective COX-2 inhibitors. Compared to controls, patients receiving aspirin experienced more bleeding while patients receiving steroid experienced more hyperglycaemia, abnormal lab results and face edema. Patients receiving NSAIDs experienced nausea, vomiting, elevated creatinine, elevated LFT and hypertension. A trend towards higher death rates was observed among patients treated with NSAIDS compared with placebo and this was somewhat higher for selective COX-2 inhibitors than for traditional NSAIDs. Based on the studies carried out so far, the efficacy of aspirin, steroid and NSAIDs (traditional NSAIDs and COX-2 inhibitors) is not proven. Therefore, these drugs cannot be recommended for the treatment of AD.
One cross-over randomised controlled trial met the inclusion criteria. The trial was performed in 210 patients with moderate to severe asthma and compared the use of the LAMA tiotropium bromide with double dose beclomethasone (an ICS) using a cross-over design and 14-week treatment periods. Compared with people taking a double dose of ICS, fewer people taking a LAMA add-on had an exacerbation requiring treatment with OCS (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.22 to 1.43) or an exacerbation resulting in emergency department admission (OR 0.49, 95% CI 0.09 to 2.77), but the confidence intervals for both outcomes did not exclude the possibility that double dose ICS was more effective. Serious adverse events and exacerbations requiring hospitalisation occurred in similarly low numbers of people taking each treatment, but confidence intervals were too wide to suggest that the two treatment options were equivalent. Asthma-related quality of life was similar in both treatment groups (mean difference (MD) in change from baseline 0.10, 95% CI − 0.07 to 0.27). Those taking LAMA add-on scored slightly better on a scale measuring asthma control than those increasing their ICS dose (MD in change from baseline − 0.18, 95% CI − 0.34 to − 0.02), although the difference was clinically small. Evidence was deemed low quality for both quality of life and asthma control. There was moderate-quality evidence that participants' trough forced expiratory volume in one second (FEV1) was 100 mL better when taking LAMA add-on than with increased ICS dose (MD in change from baseline 0.10, 95% CI 0.03 to 0.17). Only one randomised trial was found, comparing tiotropium add-on to increased dose beclomethasone. Differences between the treatments were too small or imprecise to understand whether adding a LAMA to ICS is safer or more effective than increasing the dose of ICS, and there is a possibility of carry-over effects due to the study's cross-over design. LAMA add-on may lead to more improvement in lung function (FEV1) than an increased dose of ICS. The results of this review, alongside pending results from related reviews assessing the use of LAMA against other treatments, will help to define the role of these drugs in asthma management, and this review should be updated as results from future trials emerge. Studies assessing the role of LAMA add-on should be longer and include a double-ICS treatment arm so that the results can be interpreted in the context of the guideline-recommended treatment options that are available to physicians.
We included two RCTs involving 72 participants. Sixty-nine participants were included in one meta-analysis (balance). Both trials assessed QoL, along with secondary outcomes measures relating to movement and psychological outcomes; one also measured disability. In one study the Stroke Impact Scale was used to measure QoL across six domains, at baseline and post-intervention. The effect of yoga on five domains (physical, emotion, communication, social participation, stroke recovery) was not significant; however, the effect of yoga on the memory domain was significant (mean difference (MD) 15.30, 95% confidence interval (CI) 1.29 to 29.31, P = 0.03), the evidence for this finding was very low grade. In the second study, QoL was assessed using the Stroke-Specifc QoL Scale; no significant effect was found. Secondary outcomes included movement, strength and endurance, and psychological variables, pain, and disability. Balance was measured in both studies using the Berg Balance Scale; the effect of intervention was not significant (MD 2.38, 95% CI -1.41 to 6.17, P = 0.22). Sensititivy analysis did not alter the direction of effect. One study measured balance self-efficacy, using the Activities-specific Balance Confidence Scale (MD 10.60, 95% CI -7.08,= to 28.28, P = 0.24); the effect of intervention was not significant; the evidence for this finding was very low grade. One study measured gait using the Comfortable Speed Gait Test (MD 1.32, 95% CI -1.35 to 3.99, P = 0.33), and motor function using the Motor Assessment Scale (MD -4.00, 95% CI -12.42 to 4.42, P = 0.35); no significant effect was found based on very low-grade evidence. One study measured disability using the modified Rankin Scale (mRS) but reported only whether participants were independent or dependent. No significant effect was found: (odds ratio (OR) 2.08, 95% CI 0.50 to 8.60, P = 0.31); the evidence for this finding was very low grade. Anxiety and depression were measured in one study. Three measures were used: the Geriatric Depression Scale-Short Form (GCDS15), and two forms of State Trait Anxiety Inventory (STAI, Form Y) to measure state anxiety (i.e. anxiety experienced in response to stressful situations) and trait anxiety (i.e. anxiety associated with chronic psychological disorders). No significant effect was found for depression (GDS15, MD -2.10, 95% CI -4.70 to 0.50, P = 0.11) or for trait anxiety (STAI-Y2, MD -6.70, 95% CI -15.35 to 1.95, P = 0.13), based on very low-grade evidence. However, a significant effect was found for state anxiety: STAI-Y1 (MD -8.40, 95% CI -16.74 to -0.06, P = 0.05); the evidence for this finding was very low grade. No adverse events were reported. Quality of the evidence We assessed the quality of the evidence using GRADE. Overall, the quality of the evidence was very low, due to the small number of trials included in the review both of which were judged to be at high risk of bias, particularly in relation to incompleteness of data and selective reporting, and especially regarding the representative nature of the sample in one study. Yoga has the potential for being included as part of patient-centred stroke rehabilitation. However, this review has identified insufficient information to confirm or refute the effectiveness or safety of yoga as a stroke rehabilitation treatment. Further large-scale methodologically robust trials are required to establish the effectiveness of yoga as a stroke rehabilitation treatment.
Two of the seven studies analyzed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively). The other five studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls. We were not able to combine the results of the trials in analysis due to differences in the designs of the studies. Four studies evaluated our secondary endpoint of mean number of epileptic discharges, and three of the four showed a statistically significant reduction in discharges. Quality of life was not assessed in any of the studies. Adverse effects were uncommon among the studies and typically involved headache, dizziness, and tinnitus. No significant changes in medication use were found in the trials. Overall, we judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges.
We included 55 studies in the review. Thirty-three studies in 14,174 children provided information for the QCA, and 33 RCTs in 12,623 children measured the effects of interventions. Eleven studies contributed to both the QCA and the analysis of effectiveness. Most studies were conducted in North America in socially disadvantaged populations. High school students were better represented among studies contributing to the QCA than in studies contributing to effectiveness evaluations, which more commonly included younger elementary and junior high school students. The interventions all attempted to improve knowledge of asthma, its triggers, and stressed the importance of regular practitioner review, although there was variation in how they were delivered. QCA results highlighted the importance of an intervention being theory driven, along with the importance of factors such as parent involvement, child satisfaction, and running the intervention outside the child's own time as drivers of successful implementation. Compared with no intervention, school-based self-management interventions probably reduce mean hospitalisations by an average of about 0.16 admissions per child over 12 months (SMD –0.19, 95% CI -0.35 to -0.04; 1873 participants; 6 studies, moderate certainty evidence). They may reduce the number of children who visit EDs from 7.5% to 5.4% over 12 months (OR 0.70, 95% CI 0.53 to 0.92; 3883 participants; 13 studies, low certainty evidence), and probably reduce unplanned visits to hospitals or primary care from 26% to 21% at 6 to 9 months (OR 0.74, 95% CI 0.60 to 0.90; 3490 participants; 5 studies, moderate certainty evidence). Self-management interventions probably reduce the number of days of restricted activity by just under half a day over a two-week period (MD 0.38 days 95% CI -0.41 to -0.18; 1852 participants; 3 studies, moderate certainty evidence). Effects of interventions on school absence are uncertain due to the variation between the results of the studies (MD 0.4 fewer school days missed per year with self-management (-1.25 to 0.45; 4609 participants; 10 studies, low certainty evidence). Evidence is insufficient to show whether the requirement for reliever medications is affected by these interventions (OR 0.52, 95% CI 0.15 to 1.81; 437 participants; 2 studies; very low-certainty evidence). Self-management interventions probably improve children's asthma-related quality of life by a small amount (MD 0.36 units higher on the Paediatric AQLQ(95% CI 0.06 to 0.64; 2587 participants; 7 studies, moderate certainty evidence). School-based asthma self-management interventions probably reduce hospital admission and may slightly reduce ED attendance, although their impact on school attendance could not be measured reliably. They may also reduce the number of days where children experience asthma symptoms, and probably lead to small improvements in asthma-related quality of life. Many of the studies tested the intervention in younger children from socially disadvantaged populations. Interventions that had a theoretical framework, engaged parents and were run outside of children's free time were associated with successful implementation.
We included a total of 11 studies involving 1275 participants. In three trials (n = 782), EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.19 to 3.3, P = 0.009) and a non-significant increase in serious adverse events. EPO significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Two small trials of carbamylated EPO have been completed but have yet to be reported. We included eight small trials (n = 548) of G-CSF. G-CSF was associated with a non-significant reduction in early impairment (mean difference (MD) -0.4, 95% CI -1.82 to 1.01, P = 0.58) but had no effect on functional outcome at the end of the trial. G-CSF significantly elevated the white cell count and the CD34+ cell count, but had no effect on infarct volume. Further trials of G-CSF are ongoing. There are significant safety concerns regarding EPO therapy for stroke. It is too early to know whether other CSFs improve functional outcome.
We only identified one trial that met the inclusion criteria but this trial did not have any results so we could not perform the planned subgroup and sensitivity analyses in the absence of data. Two ongoing trials were identified which may provide data for analyses in a later version of this review. The completion date of these trials is currently unknown. The current review failed to find any completed randomised clinical trials with results. Therefore we are unable to conclude whether intensive glycaemic control when compared to conventional glycaemic control has a positive or detrimental effect on the treatment of foot ulcers in people with diabetes. Previous evidence has however highlighted a reduction in risk of limb amputation (from various causes) in people with type 2 diabetes with intensive glycaemic control. Whether this applies to people with foot ulcers in particular is unknown. The exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation.
We included 35 randomised clinical trials with 3556 participants. One trial compared Radix Sophorae flavescentis with placebo; the remaining 34 trials compared effects of Radix Sophorae flavescentis in addition to a co-intervention versus the same co-intervention. The included trials assessed heterogenous forms and ways of administering Radix Sophorae flavescentis (e.g. oral capsules, oral tablets, intravenous infusion, intramuscular injection, acupoint (a specifically chosen site of acupuncture) injection) with treatment duration of 1 to 24 months. Two of the trials included children up to 14 years old. Participants in two trials had cirrhosis in addition to chronic hepatitis B. All trials were assessed at high risk of bias, and certainty of the evidence for all outcomes was very low. Only one of the 35 trials assessed mortality; no deaths occurred. Ten trials assessed serious adverse events; no serious adverse events occurred. None of the trials reported health-related quality of life, hepatitis B-related mortality, or morbidity. Adverse events considered 'not to be serious' was an outcome in 19 trials; nine of these trials had zero events in both groups. Radix Sophorae flavescentis versus placebo or no intervention showed no difference in effects on adverse events considered 'not to be serious' (RR 1.10, 95% CI 0.76 to 1.59; I² = 49%; 10 trials, 1050 participants). Radix Sophorae flavescentis showed a reduction in the proportion of participants with detectable HBV-DNA (RR 0.61, 95% CI 0.55 to 0.68; I² = 56%; 29 trials, 2914 participants) and in the proportion of participants with detectable HBeAg (hepatitis B e-antigen) (RR 0.71, 95% CI 0.66 to 0.76; I² = 19%; 20 trials, 2129 participants). Seven of the 35 randomised clinical trials received academic funding from government or hospital. Four trials received no funding. The remaining 24 trials provided no information on funding. Additionally, 432 trials lacked the methodological information needed to ensure inclusion of these trials in our review. The included trials lacked data on health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The effects of Radix Sophorae flavescentis on all-cause mortality and on the proportion of participants with serious adverse events and adverse events considered 'not to be serious' remain unclear. We advise caution in interpreting results showing that Radix Sophorae flavescentis reduced the proportion of people with detectable HBV-DNA and detectable HBeAg because the trials reporting on these outcomes are at high risk of bias and both outcomes are non-validated surrogate outcomes. We were unable to obtain information on the design and conduct of a large number of trials; therefore, we were deterred from including them in our review. Undisclosed funding may influence trial results and may lead to poor trial design. Given the wide usage of Radix Sophorae flavescentis, we need large, unbiased, high-quality placebo-controlled randomised trials in which patient-centred outcomes are assessed.
We included 17 trials (2596 participants); three had low overall risk of bias. Baseline severity, glucocorticoid schemes, comparators and outcomes were heterogeneous. Glucocorticoids did not significantly reduce outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% confidence interval (CI) 0.78 to 1.08 and 0.86; 95% CI 0.7 to 1.06, respectively). There was no benefit in LOS for inpatients (mean difference -0.18 days; 95% CI -0.39 to 0.04). Unadjusted results from a large factorial low risk of bias RCT found combined high-dose systemic dexamethasone and inhaled epinephrine reduced admissions by day 7 (baseline risk of admission 26%; RR 0.65; 95% CI 0.44 to 0.95; number needed to treat 11; 95% CI 7 to 76), with no differences in short-term adverse effects. No other comparisons showed relevant differences in primary outcomes. Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalisation. Combined dexamethasone and epinephrine may reduce outpatient admissions, but results are exploratory and safety data limited. Future research should further assess the efficacy, harms and applicability of combined therapy.
We reran the searches to December 2013 and identified three new studies. These three studies did not fulfil our inclusion criteria. Therefore, no new studies were included in this updated review. In total four randomized trials involving 210 participants were included in this review. We observed no differences in mortality (OR 1.67, 95% CI 0.38 to 7.30; P = 0.50); PHTC (OR 0.80, 95% CI 0.15 to 4.18; P = 0.79); changes in MPAP (treatment effect -2.94 mm Hg, 95% CI -9.28 to 3.40; P = 0.36), MAP (treatment effect -3.55 mm Hg, 95% CI -11.86 to 4.76; P = 0.40), HR (treatment effect 0.02 bpm, 95% CI -8.13 to 8.18; P = 1.00), or PaO2:FiO2 (mean difference 17.18, 95% CI -28.21 to 62.57; P = 0.46). There was a significant increase in the methaemoglobin level (mean difference 0.30%, 95% CI 0.24 to 0.36; P < 0.00001) in patients treated with iNO, although levels did not reach toxicity levels. Data from long-term mortality, neurodevelopmental disability, and length of stay were not available. Two trials had a low risk of bias. Very low quality of the evidence was observed considering grading of the outcomes. We observed no differences with the use of iNO in the outcomes reviewed. No data were available for several clinical outcomes including long-term mortality and neurodevelopmental outcome. We found it difficult to draw valid conclusions given concerns regarding methodologic quality, sample size, and heterogeneity.
Only one study enrolling 182 patients (reported as an abstract in conference proceedings) was identified and found eligible for inclusion; the authors reported only limited results. The trial was stopped prematurely and was, therefore, under-powered to detect any significant differences and at high risk of bias. The only available outcome of clinical significance was 28-day mortality. There was no statistically significant difference between groups, with a relative risk for 28-day mortality in the partial liquid ventilation group of 1.54 (95% confidence interval 0.82 to 2.9). There is no evidence from RCTs to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome. Adequately powered, high quality RCTs are still needed to assess its efficacy. Clinically relevant outcome measures should be assessed (mortality at discharge and later, duration of both respiratory support and hospital stay, and long-term neurodevelopmental outcomes). The studies should be published in full.
We included nine studies enrolling 220 dialysis participants. Seven studies were deemed to have moderate to high risk of bias. All studies were small in size and had a short follow-up period (two to six months). Studies evaluated the effects of six different interventions against placebo or standard treatment. The interventions studied included aerobic resistance exercise, gabapentin, ropinirole, levodopa, iron dextran, and vitamins C and E (individually and in combination). Aerobic resistance exercise showed a significant reduction in severity of RLS compared to no exercise (2 studies, 48 participants: MD -7.56, 95% CI -14.20 to -0.93; I2 = 65%), and when compared to exercise with no resistance (1 study, 24 participants: MD -11.10, 95% CI -17.11 to -5.09), however there was no significant reduction when compared to ropinirole (1 study, 22 participants): MD -0.55, 95% CI -6.41 to 5.31). There were no significant differences between aerobic resistance exercise and either no exercise or ropinirole in the physical or mental component summary scores (using the SF-36 form). Improvement in sleep quality varied. There was no significant difference in subjective sleep quality between exercise and no exercise; however one study reported a significant improvement with ropinirole compared to resistance exercise (MD 3.71, 95% CI 0.89 to 6.53). Using the Epworth Sleepiness Scale there were no significant differences between resistance exercise and no exercise, ropinirole, or exercise with no resistance. Two studies reported there were no adverse events and one study did not mention if there were any adverse events. In one study, one patient in each group dropped out but the reason for dropout was not reported. Two studies reported no adverse events and one study did not report adverse events. Gabapentin was associated with reduced RLS severity when compared to placebo or levodopa, and there was a significant improvement in sleep quality, latency and disturbance reported in one study when compared to levodopa. Three patients dropped out due to lethargy (2 patients), and drowsiness, syncope and fatigue (1 patient). Because of a short duration of action, rebound and augmentation were noted with levodopa treatment even though it conferred some benefit in reducing the symptoms of RLS. Reported adverse events were severe vomiting, agitation after caffeine intake, headaches, dry mouth, and gastrointestinal symptoms. One study (25 participants) reported iron dextran reduced the severity of RLS at weeks one and two, but not at week four. Vitamins C, E and C plus E (1 study, 60 participants) helped the symptoms of RLS with minimal side effects (nausea and dyspepsia) but more evidence is needed before any conclusions can be drawn. Given the small size of the studies and short follow-up, it can only be concluded that pharmacological interventions and intra-dialytic exercise programs have uncertain effects on RLS in haemodialysis patients. There have been no studies performed in non-dialysis CKD, peritoneal dialysis patients, or kidney transplant recipients. Further studies are warranted before any conclusions can be drawn. Aerobic resistance exercise and ropinirole may be suitable interventions for further evaluation.
A total of 56 studies (3725 patients) were included in this review. These included 12 studies of bulking agents (621 patients), 29 of antispasmodics (2333 patients), and 15 of antidepressants (922 patients). The risk of bias was low for most items. However, selection bias is unclear for many of the included studies because the methods used for randomization and allocation concealment were not described. No beneficial effect for bulking agents over placebo was found for improvement of abdominal pain (4 studies; 186 patients; SMD 0.03; 95% CI -0.34 to 0.40; P = 0.87), global assessment (11 studies; 565 patients; RR 1.10; 95% CI 0.91 to 1.33; P = 0.32) or symptom score (3 studies; 126 patients SMD -0.00; 95% CI -0.43 to 0.43; P = 1.00). Subgroup analyses for insoluble and soluble fibres also showed no statistically significant benefit. Separate analysis of the studies with adequate concealment of allocation did not change these results. There was a beneficial effect for antispasmodics over placebo for improvement of abdominal pain (58% of antispasmodic patients improved compared to 46% of placebo; 13 studies; 1392 patients; RR 1.32; 95% CI 1.12 to 1.55; P < 0.001; NNT = 7), global assessment (57% of antispasmodic patients improved compared to 39% of placebo; 22 studies; 1983 patients; RR 1.49; 95% CI 1.25 to 1.77; P < 0.0001; NNT = 5) and symptom score (37% of antispasmodic patients improved compared to 22% of placebo; 4 studies; 586 patients; RR 1.86; 95% CI 1.26 to 2.76; P < 0.01; NNT = 3). Subgroup analyses for different types of antispasmodics found statistically significant benefits for cimteropium/ dicyclomine, peppermint oil, pinaverium and trimebutine. Separate analysis of the studies with adequate allocation concealment found a significant benefit for improvement of abdominal pain. There was a beneficial effect for antidepressants over placebo for improvement of abdominal pain (54% of antidepressants patients improved compared to 37% of placebo; 8 studies; 517 patients; RR 1.49; 95% CI 1.05 to 2.12; P = 0.03; NNT = 5), global assessment (59% of antidepressants patients improved compared to 39% of placebo; 11 studies; 750 patients; RR 1.57; 95% CI 1.23 to 2.00; P < 0.001; NNT = 4) and symptom score (53% of antidepressants patients improved compared to 26% of placebo; 3 studies; 159 patients; RR 1.99; 95% CI 1.32 to 2.99; P = 0.001; NNT = 4). Subgroup analyses showed a statistically significant benefit for selective serotonin releasing inhibitors (SSRIs) for improvement of  global assessment and for tricyclic antidepressants (TCAs) for improvement of abdominal pain and symptom score. Separate analysis of studies with adequate allocation concealment found a significant benefit for improvement of symptom score and global assessment. Adverse events were not assessed as an outcome in this review. There is no evidence that bulking agents are effective for treating IBS.  There is evidence that antispasmodics are effective for the treatment of IBS. The individual subgroups which are effective include: cimetropium/dicyclomine, peppermint oil, pinaverium and trimebutine. There is good evidence that antidepressants are effective for the treatment of IBS. The subgroup analyses for SSRIs and TCAs are unequivocal and their effectiveness may depend on the individual patient. Future research should use rigorous methodology and valid outcome measures.
Twenty studies (732 randomised participants, with data for 547 participants with stroke) met the inclusion criteria for this review. However, only 10 of these studies compared the effect of an intervention with a placebo, control, or no treatment group, and eight had data which could be included in meta-analyses. Only two of these eight studies presented data relating to our primary outcome of functional abilities in activities of daily living. One study reported evidence relating to adverse events. Three studies (88 participants) compared a restitutive intervention with a control, but data were only available for one study (19 participants). There was very low-quality evidence that visual restitution therapy had no effect on visual field outcomes, and a statistically significant effect on quality of life, but limitations with these data mean that there is insufficient evidence to draw any conclusions about the effectiveness of restitutive interventions as compared to control. Four studies (193 participants) compared the effect of scanning (compensatory) training with a control or placebo intervention. There was low-quality evidence that scanning training was more beneficial than control or placebo on quality of life, measured using the Visual Function Questionnaire (VFQ-25) (two studies, 96 participants, mean difference (MD) 9.36, 95% confidence interval (CI) 3.10 to 15.62). However, there was low or very-low quality evidence of no effect on measures of visual field, extended activities of daily living, reading, and scanning ability. There was low-quality evidence of no significant increase in adverse events in people doing scanning training, as compared to no treatment. Three studies (166 participants) compared a substitutive intervention (a type of prism) with a control. There was low or very-low quality evidence that prisms did not have an effect on measures of activities of daily living, extended activities of daily living, reading, falls, or quality of life, and very low-quality evidence that they may have an effect on scanning ability (one study, 39 participants, MD 9.80, 95% CI 1.91 to 17.69). There was low-quality evidence of an increased odds of an adverse event (primarily headache) in people wearing prisms, as compared to no treatment. One study (39 participants) compared the effect of assessment by an orthoptist to standard care (no assessment) and found very low-quality evidence that there was no effect on measures of activities of daily living. Due to the quality and quantity of evidence, we remain uncertain about the benefits of assessment interventions. There is a lack of evidence relating to the effect of interventions on our primary outcome of functional ability in activities of daily living. There is limited low-quality evidence that compensatory scanning training may be more beneficial than placebo or control at improving quality of life, but not other outcomes. There is insufficient evidence to reach any generalised conclusions about the effect of restitutive interventions or substitutive interventions (prisms) as compared to placebo, control, or no treatment. There is low-quality evidence that prisms may cause minor adverse events.
Combined results from the 4 eligible randomised controlled trials shows that participants allocated to FOBT screening had a statistically significant 16% reduction in the relative risk of colorectal cancer mortality (RR 0.84; CI: 0.78-0.90). In the 3 studies that used biennial screening (Funen, Minnesota, Nottingham) there was a 15% relative risk reduction (RR 0.85, CI: 0.78-0.92) in colorectal cancer mortality. When adjusted for mean screening attendance in the individual studies, there was a 25% relative risk reduction (RR 0.75, CI: 0.66 - 0.84) for those attending at least one round of screening using the faecal occult blood test. Benefits of screening include a modest reduction in colorectal cancer mortality, a possible reduction in cancer incidence through the detection and removal of colorectal adenomas, and potentially, the less invasive surgery that earlier treatment of colorectal cancers may involve.  Harmful effects of screening include the psycho-social consequences of receiving a false-positive result, the potentially significant complications of colonoscopy or a false-negative result, the possibility of overdiagnosis (leading to unnecessary investigations or treatment) and the complications associated with treatment.
Fifteen trials were included, six of which were added in this update. Three trials of a nursing intervention to manage breathlessness showed benefit in terms of symptom experience, performance status and emotional functioning. Four trials assessed structured nursing programmes and found positive effects on delay in clinical deterioration, dependency and symptom distress, and improvements in emotional functioning and satisfaction with care. Three trials assessed the effect of different psychotherapeutic, psychosocial and educational interventions in patients with lung cancer. One trial assessing counselling showed benefit for some emotional components of the illness but findings were not conclusive. One trial examined the effects of coaching sensory self monitoring and reporting on pain-related variables and found that although coaching increases the amount of pain data communicated to providers by patients with lung cancer, the magnitude of the effect is small and does not lead to improved efficacy of analgesics prescribed for each patient’s pain level. One trial compared telephone-based sessions of either caregiver-assisted coping skills training (CST) or education/support involving the caregiver and found that patients in both treatment conditions showed improvements in pain, depression, quality of life and self efficacy. Two trials assessed exercise programmes; one found a beneficial effect on self empowerment and the other study showed an increase in quadriceps strength but no significant changes for any measure of quality of life. One trial of nutritional interventions found positive effects for increasing energy intake, but no improvement in quality of life. Two small trials of reflexology showed some positive but short-lasting effects on anxiety and pain intensity. The main limitations of the studies included were the variability of the interventions assessed and the approaches to measuring the considered outcomes, and the lack of data reported in the trials regarding allocation of patients to treatment groups and blinding. Nurse follow-up programmes and interventions to manage breathlessness may produce beneficial effects. Counselling may help patients cope more effectively with emotional symptoms, but the evidence is not conclusive. Other psychotherapeutic, psychosocial and educational interventions can play some role in improving patients' quality of life. Exercise programmes and nutritional interventions have not shown relevant and lasting improvements of quality of life. Reflexology may have some beneficial effects in the short term.
We included two trials with a total of 37 children diagnosed with ASD who were randomised into groups that received either omega-3 fatty acids supplementation or a placebo. We excluded six trials because they were either non-randomised controlled trials, did not contain a control group, or the control group did not receive a placebo. Overall, there was no evidence that omega-3 supplements had an effect on social interaction (mean difference (MD) 0.82, 95% confidence interval (CI) -2.84 to 4.48, I2 = 0%), communication (MD 0.62, 95% CI -0.89 to 2.14, I2 = 0%), stereotypy (MD 0.77, 95% CI -0.69 to 2.22, I2 = 8%), or hyperactivity (MD 3.46, 95% CI -0.79 to 7.70, I2 = 0%). To date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of ASD. Given the paucity of rigorous studies in this area, there is a need for large well-conducted randomised controlled trials that examine both high and low functioning individuals with ASD, and that have longer follow-up periods.
A total of 11 trials with 419 participants met our inclusion criteria. In 10 studies the participants were adults and only one was in children. Reporting of study design was inadequate to determine risk of bias for most of the studies and poor availability of data for our key outcomes may indicate some selective outcome reporting. Four studies were parallel-group and the remainder were cross-over studies. Eight studies included people with asthma and three studies included 40 participants with exercise-induced asthma. Five studies reported results using single-dose regimes prior to bronchial challenges or exercise tests. There was marked heterogeneity in vitamin C dosage regimes used in the selected studies, compounding the difficulties in carrying out meaningful analyses. One study on 201 adults with asthma reported no significant difference in our primary outcome, health-related quality of life (HRQL), and overall the quality of this evidence was low. There were no data available to evaluate the effects of vitamin C supplementation on our other primary outcome, exacerbations in adults. One small study reported data on asthma exacerbations in children and there were no exacerbations in either the vitamin C or placebo groups (very low quality evidence). In another study conducted in 41 adults, exacerbations were not defined according to our criteria and the data were not available in a format suitable for evaluation by our methods. Lung function and symptoms data were contributed by single studies. We rated the quality of this evidence as moderate, but further research is required to assess any clinical implications that may be related to the changes in these parameters. In each of these outcomes there was no significant difference between vitamin C and placebo. No adverse events at all were reported; again this is very low quality evidence. Studies in exercise-induced bronchoconstriction suggested some improvement in lung function measures with vitamin C supplementation, but theses studies were few and very small, with limited data and we judged the quality of the evidence to be low. Currently, evidence is not available to provide a robust assessment on the use of vitamin C in the management of asthma or exercise-induced bronchoconstriction. Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the estimates. There is no indication currently that vitamin C can be recommended as a therapeutic agent in asthma. There was some indication that vitamin C was helpful in exercise-induced breathlessness in terms of lung function and symptoms; however, as these findings were provided only by small studies they are inconclusive. Most published studies to date are too small and inconsistent to provide guidance. Well-designed trials with good quality clinical endpoints, such as exacerbation rates and health-related quality of life scores, are required.
We found only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo. There were fewer treatment failures after 48 hours in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence intervals made this result non-significant [summary relative risk 0.45 (0.20 to 1.05)]. Only one infant, who was from the placebo group, was given IPPV. Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short-term failure rate in the placebo group of 8/10. It is not possible to evaluate the late responses of all those in the placebo group since they crossed over to a treatment arm. Although intravenous doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess potential adverse effects. No long-term outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.
Ten studies met the inclusion criteria for the review, and nine studies provided information on one or more outcomes for the review. A total of 1014 participants were randomly assigned to the enhanced recovery protocol (499 participants) or standard care (515 participants) in the nine RCTs. Most of the trials included low anaesthetic risk participants with high performance status undergoing different upper gastrointestinal, liver and pancreatic surgeries. Eight trials incorporated more than one element of the enhanced recovery protocol. All of the trials were at high risk of bias. The overall quality of evidence was low or very low. None of the trials reported long-term mortality, medium-term health-related quality of life(three months to one year), time to return to normal activity, or time to return to work. The difference between the enhanced recovery protocol and standard care were imprecise for short-term mortality (enhanced recovery protocol: 4/425 (adjusted proportion = 0.6%); standard care: 1/443 (0.2%); seven trials; 868 participants; RR 2.79; 95% CI 0.44 to 17.73; very low quality evidence), proportion of people with serious adverse events (enhanced recovery protocol: 4/157 (adjusted proportion = 0.6%); standard care: 0/184 (0.0%); two trials; 341 participants; RR 5.57; 95% CI 0.68 to 45.89; very low quality evidence), number of serious adverse events (enhanced recovery protocol: 34/421 (8 per 100 participants); standard care: 46/438 (11 per 100 participants); seven trials; 859 participants; rate ratio 0.72; 95% CI 0.45 to 1.13; very low quality evidence), health-related quality of life (four trials; 373 participants; SMD 0.29; 95% CI -0.04 to 0.62; very low quality evidence) and hospital readmissions (enhanced recovery protocol: 14/355 (adjusted proportion = 3.3%); standard care: 9/378 (2.4%); seven trials; 733 participants; RR 1.4; 95% CI 0.69 to 2.87; very low quality evidence). The enhanced recovery protocol group had a lower proportion of people with mild adverse events (enhanced recovery protocol: 31/254 (adjusted proportion = 10.9%); standard care: 51/271 (18.8%); four trials; 525 participants; RR 0.58; 95% CI 0.39 to 0.85; low quality evidence), fewer number of mild adverse events (enhanced recovery protocol: 69/499 (13 per 100 participants); standard care: 128/515 (25 per 100 participants); nine trials; 1014 participants; rate ratio 0.52; 95% CI 0.39 to 0.70; low quality evidence), shorter length of hospital stay (nine trials; 1014 participants; MD -2.19 days; 95% CI -2.53 to -1.85; low quality evidence) and lower costs (four trials; 282 participants; MD USD -6300; 95% CI -8400 to -4200; low quality evidence) than standard care group. Based on low quality evidence, enhanced recovery protocols may reduce length of hospital stay and costs (primarily because of reduction in hospital stay) in people undergoing major upper gastrointestinal, liver and pancreatic surgeries. However, the validity of the results is uncertain because of the risk of bias in the trials and the way the outcomes were measured. Future RCTs should be conducted with low risk of bias, and measure clinically important outcomes for including the three months to one year period.
Only one trial was found and this showed that rescue HFOV caused a reduction in any new pulmonary air leak (PAL) [RR 0.73 (95% CI 0.55,0.96), RD -0.17 (95% CI -0.32, -0.03)]. The number of infants that needed to be treated (NNT) to prevent one infant having any PAL was six (95% CI 3, 37). There was no significant difference in the rate of PIE or of gross pulmonary air leak, such as pneumomediastinum or pneumothorax. There was no significant effect on mortality or the use of IPPV at 30 days. The rate of intraventricular haemorrhage (IVH) of any grade was increased in infants treated with HFOV, [RR 1.77 (95% CI 1.06, 2.96), RD 0.16 (95% CI 0.02, 0.29)]. Thus, for every six infants (95% CI 3, 50) given rescue HFOV, one infant developed IVH of any grade. There was a stronger, but non-significant trend towards an increase in severe IVH (grades 3 or 4 IVH). There is insufficient information on the use of rescue HFOV to make recommendations for practice. The small amount of data that exists suggest that harm might outweigh any benefit. Any future use of HFOV as rescue therapy for preterm infants with severe RDS should be within randomised controlled trials and address important outcomes such as longer term pulmonary and neurological function.
Eleven randomised trials with 1205 participants with asymptomatic or mild-to-moderate cholelithiasis were included. None of the randomised clinical trials compared a single Chinese medicinal herb with a Western medicine or with surgery. No placebo-controlled trials were identified. In the trials comparing one Chinese herbal medicine (Gandanxiaoshi tablet) versus another (Aihuodantong tablet), there was no significant difference in the improvement of upper abdominal pain after the end of treatment (RR 1.21; 95% CI 0.71 to 2.05), and the heterogeneity among trials was not substantial. No other outcomes could be assessed. The remaining trials of Chinese medicinal herbs (Qingdan capsule, Danshu capsule, Paishi capsule, Rongdanpaishi capsule), did not offer specific data on symptoms, signs, or change in gallstones that would permit assessment of significant differences in curative effects between the treatment and control groups. No serious adverse events were reported. This review reveals no strong evidence that the analysed Chinese medicinal herbs have any beneficial effects on asymptomatic or mild-to-moderate cholelithiasis. Definitive conclusions will require much better designed randomised trials to reduce risk of bias and allow detailed assessment of clinical outcomes.
The search identified 40 studies with 20 of these (1936 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other solutions through the different nebuliser systems. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. Conventional nebuliser systems providing higher flows, higher respirable fractions and smaller particles decrease treatment time, increase deposition and may be preferred by people with CF, as compared to conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Nebulisers using adaptive aerosol delivery or vibrating mesh technology reduce treatment time to a far greater extent. Deposition (as a percentage of priming dose) is greater than conventional with adaptive aerosol delivery. Vibrating mesh technology systems may give greater deposition than conventional when measuring sputum levels, but lower deposition when measuring serum levels or using gamma scintigraphy. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved with systems which use these newer technologies, but also that some nebuliser systems using vibrating mesh technology may be subject to increased failures. Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use.
We identified 68 eligible trials (24 new to this update) with more than 74,000 participants. There were 63 studies involving interventions aimed directly at trial participants, while five evaluated interventions aimed at people recruiting participants. All studies were in health care. We found 72 comparisons, but just three are supported by high-certainty evidence according to GRADE. 1. Open trials rather than blinded, placebo trials. The absolute improvement was 10% (95% CI 7% to 13%). 2. Telephone reminders to people who do not respond to a postal invitation. The absolute improvement was 6% (95% CI 3% to 9%). This result applies to trials that have low underlying recruitment. We are less certain for trials that start out with moderately good recruitment (i.e. over 10%). 3. Using a particular, bespoke, user-testing approach to develop participant information leaflets. This method involved spending a lot of time working with the target population for recruitment to decide on the content, format and appearance of the participant information leaflet. This made little or no difference to recruitment: absolute improvement was 1% (95% CI −1% to 3%). We had moderate-certainty evidence for eight other comparisons; our confidence was reduced for most of these because the results came from a single study. Three of the methods were changes to trial management, three were changes to how potential participants received information, one was aimed at recruiters, and the last was a test of financial incentives. All of these comparisons would benefit from other researchers replicating the evaluation. There were no evaluations in paediatric trials. We had much less confidence in the other 61 comparisons because the studies had design flaws, were single studies, had very uncertain results or were hypothetical (mock) trials rather than real ones. The literature on interventions to improve recruitment to trials has plenty of variety but little depth. Only 3 of 72 comparisons are supported by high-certainty evidence according to GRADE: having an open trial and using telephone reminders to non-responders to postal interventions both increase recruitment; a specialised way of developing participant information leaflets had little or no effect. The methodology research community should improve the evidence base by replicating evaluations of existing strategies, rather than developing and testing new ones.
Thirteen trials met the inclusion criteria. Two hundred ninety-four individuals randomized to anabolic steroid therapy and 238 individuals randomized to placebo were included in the analysis of efficacy for change from baseline in lean body mass. Three hundred forty-three individuals randomized to anabolic steroid and 286 randomized to placebo were included in the analysis of efficacy for change from baseline in body weight. The mean methodologic quality of the included studies was 4.1, of a maximum 5 points. Although significant heterogeneity was present for both outcomes, the average change in lean body mass was 1.3 kg (95% CI: 0.6, 2.0), while the average change in total body weight was 1.1 kg (95% CI: 0.3, 2.0). A total of eight deaths occurred during the treatment period; four in the anabolic steroid treatment groups and four in the placebo-treatment groups (risk difference 0.00, 95% CI -0.03, 0.03). The risk difference for withdrawals or discontinuations of study medication due to adverse events was 0.00 (95% CI: -0.02, 0.03). Although the results of the trials were heterogeneous, on average, the administration of anabolic steroids appeared to result in a small increase in both lean body mass and body weight as compared with placebo. While these results suggest that anabolic steroids may be useful in the treatment of weight loss in HIV infected individuals, due to limitations, treatment recommendations cannot be made. Further information is required regarding the long-term benefit and adverse effects of anabolic steroid use, the specific populations for which anabolic steroid therapy may be most beneficial, and the optimal regime. In addition, the correlation of improvement in lean body mass with more clinically relevant endpoints, such as physical functioning and survival, needs to be determined.
A total of 501 liver transplant recipients undergoing liver transplantation for chronic HCV infection were randomised in 12 trials to various experimental interventions and control interventions. The proportion of genotype I varied between 49% and 100% in the seven trials that reported the genotype. Only one or two trials were included under each comparison. All the trials were of high risk of bias. Ten trials including 441 liver transplant recipients provided data for this review. There were no significant differences in the 90-day mortality (1 trial; 81 participants; 5/35 (adjusted proportion: 14.2%) in interferon group versus 5/46 (10.9%) in control group; RR 1.31; 95% CI 0.41 to 4.19); mortality at maximal follow-up (2 trials; 105 participants; 7/47 (adjusted proportion: 14.8%) in interferon group versus 10/58 (17.2%) in control group; RR 0.86; 95% CI 0.36 to 2.08); long-term mortality (1 trial; 81 participants; HR 0.45; 95% CI 0.13 to 1.56); mortality at maximal follow-up (1 trial; 54 participants; 1/26 (3.9%) in pegylated interferon group versus 2/28 (7.1%) in control group; RR 0.54; 95% CI 0.05 to 5.59); 90-day mortality (1 trial; 115 participants; 5/55 (9.1%) in pegylated interferon plus ribavirin group versus 3/60 (5.0%) in control group; RR 1.82; 95% 0.46 to 7.25); 90-day mortality (3 trials; 53 participants; 3/37 (adjusted proportion: 4.3%) in HCV antibody group versus 1/16 (6.3%) in placebo group; RR 0.69; 95% CI 0.15 to 3.11); or 90-day mortality (2 trials; 31 participants; 2/14 (adjusted proportion: 16.2%) in HCV antibody high-dose group versus 1/17 (5.9%) in HCV antibody low-dose group; RR 2.75; 95% CI; 0.30 to 25.35). There were no significant differences in the retransplantation at maximal follow-up (2 trials; 105 participants; 2/47 (adjusted proportion: 4.0%) in interferon group versus 2/58 (3.4%) in control group; RR 1.17; 95% CI 0.22 to 6.2); 90-day retransplantation (1 trial; 18 participants; 1/12 (8.3%) in HCV antibody group versus 0/6 (0%) in control group; RR 1.71; 95% CI 0.09 to 32.93); or 90-day retransplantation (1 trial; 12 participants; 1/6 (17.7%) in HCV antibody high-dose group versus 0/6 (0%) in HCV antibody low-dose group; RR 3.00; 95% CI 0.15 to 61.74). There were no significant differences in serious adverse events, graft rejection, worsening of fibrosis, or HCV recurrence between intervention and control groups in any of the comparisons that reported these outcomes. None of the trials reported quality of life, liver decompensation, intensive therapy unit stay, or hospital stay. Life-threatening adverse events were not reported in either group in any of the comparisons. There is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or retransplantation. Further randomised clinical trials with adequate trial methodology and adequate duration of follow-up are necessary.
We included 11 trials, with a total of 1,126 participants. The majority of participants were female (mean = 80.6% in 10 trials reporting gender). All trials were of psychosocial interventions; there were none of pharmacological treatments. With the exception of dialectical behaviour therapy for adolescents (DBT-A) and group-based therapy, assessments of specific interventions were based on single trials. We downgraded the quality of evidence owing to risk of bias or imprecision for many outcomes. Therapeutic assessment appeared to increase adherence with subsequent treatment compared with TAU (i.e., standard assessment; n = 70; k = 1; OR = 5.12, 95% CI 1.70 to 15.39), but this had no apparent impact on repetition of SH at either 12 (n = 69; k = 1; OR 0.75, 95% CI 0.18 to 3.06; GRADE: low quality) or 24 months (n = 69; k = 1; OR = 0.69, 05% CI 0.23 to 2.14; GRADE: low quality evidence). These results are based on a single cluster randomised trial, which may overestimate the effectiveness of the intervention. For patients with multiple episodes of SH or emerging personality problems, mentalisation therapy was associated with fewer adolescents scoring above the cut-off for repetition of SH based on the Risk-Taking and Self-Harm Inventory 12 months post-intervention (n = 71; k = 1; OR = 0.26, 95% CI 0.09 to 0.78; GRADE: moderate quality). DBT-A was not associated with a reduction in the proportion of adolescents repeating SH when compared to either TAU or enhanced usual care (n = 104; k = 2; OR 0.72, 95% CI 0.12 to 4.40; GRADE: low quality). In the latter trial, however, the authors reported a significantly greater reduction over time in frequency of repeated SH in adolescents in the DBT condition, in whom there were also significantly greater reductions in depression, hopelessness, and suicidal ideation. We found no significant treatment effects for group-based therapy on repetition of SH for individuals with multiple episodes of SH at either the six (n = 430; k = 2; OR 1.72, 95% CI 0.56 to 5.24; GRADE: low quality) or 12 month (n = 490; k = 3; OR 0.80, 95% CI 0.22 to 2.97; GRADE: low quality) assessments, although considerable heterogeneity was associated with both (I2 = 65% and 77% respectively). We also found no significant differences between the following treatments and TAU in terms of reduced repetition of SH: compliance enhancement (three month follow-up assessment: n = 63; k = 1; OR = 0.67, 95% CI 0.15 to 3.08; GRADE: very low quality), CBT-based psychotherapy (six month follow-up assessment: n = 39; k = 1; OR = 1.88, 95% CI 0.30 to 11.73; GRADE: very low quality), home-based family intervention (six month follow-up assessment: n = 149; k = 1; OR = 1.02, 95% CI 0.41 to 2.51; GRADE: low quality), and provision of an emergency card (12 month follow-up assessment: n = 105, k = 1; OR = 0.50, 95% CI 0.12 to 2.04; GRADE: very low quality). No data on adverse effects, other than the planned outcomes relating to suicidal behaviour, were reported. There are relatively few trials of interventions for children and adolescents who have engaged in SH, and only single trials contributed to all but two comparisons in this review. The quality of evidence according to GRADE criteria was mostly very low. There is little support for the effectiveness of group-based psychotherapy for adolescents with multiple episodes of SH based on the results of three trials, the evidence from which was of very low quality according to GRADE criteria. Results for therapeutic assessment, mentalisation, and dialectical behaviour therapy indicated that these approaches warrant further evaluation. Despite the scale of the problem of SH in children and adolescents there is a paucity of evidence of effective interventions. Further large-scale trials, with a range of outcome measures including adverse events, and investigation of therapeutic mechanisms underpinning these interventions, are required. It is increasingly apparent that development of new interventions should be done in collaboration with patients to ensure that these are likely to meet their needs. Use of an agreed set of outcome measures would assist evaluation and both comparison and meta-analysis of trials.
We identified three prospective RCTs for inclusion in this review (319 participants available to assess the primary outcome of anxiety). The studies included people from the outpatient setting, with the majority of participants being male. All three studies assessed psychological therapy (cognitive behavioural therapy) plus co-intervention versus co-intervention alone. We assessed the quality of evidence contributing to all outcomes as low due to small sample sizes and substantial heterogeneity in the analyses. Two of the three studies had prespecified protocols available for comparison between prespecified methodology and outcomes reported within the final publications. We observed some evidence of improvement in anxiety over 3 to 12 months, as measured by the Beck Anxiety Inventory (range from 0 to 63 points), with psychological therapies performing better than the co-intervention comparator arm (mean difference (MD) -4.41 points, 95% confidence interval (CI) -8.28 to -0.53; P = 0.03). There was however, substantial heterogeneity between the studies (I2 = 62%), which limited the ability to draw reliable conclusions. No adverse events were reported. We found only low-quality evidence for the efficacy of psychological therapies among people with COPD with anxiety. Based on the small number of included studies identified and the low quality of the evidence, it is difficult to draw any meaningful and reliable conclusions. No adverse events or harms of psychotherapy intervention were reported. A limitation of this review is that all three included studies recruited participants with both anxiety and depression, not just anxiety, which may confound the results. We downgraded the quality of evidence in the 'Summary of findings' table primarily due to the small sample size of included trials. Larger RCTs evaluating psychological interventions with a minimum 12-month follow-up period are needed to assess long-term efficacy.
We found 9 RCTs involving a total of 421 participants of which 6 were studies of egg and milk exclusion (N=288), 1 was a study of few foods (N=85) and 2 were studies of an elemental diet (N=48). There appears to be no benefit of an egg and milk free diet in unselected participants with atopic eczema. There is also no evidence of benefit in the use of an elemental or few-foods diet in unselected cases of atopic eczema. There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs - one study found 51% of the children had a significant improvement in body surface area with the exclusion diet compared to normal diet (RR 1.51, 95% CI 1.07 to 2.11) and change in surface area and severity score was significantly improved in the exclusion diet compared to the normal diet at the end of 6 weeks (MD 5.50, 95% CI 0.19 to 10.81) and end of treatment (MD 6.10, 95% CI 0.06 to12.14). Methodological difficulties have made it difficult to interpret these studies. Poor concealment of randomisation allocation, lack of blinding and high dropout rates without an intention-to-treat analysis indicates that these studies should be interpreted with great caution. There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs. Little evidence supports the use of various exclusion diets in unselected people with atopic eczema, but that may be because they were not allergic to those substances in the first place. Lack of any benefit may also be because the studies were too small and poorly reported. Future studies should be appropriately powered focusing on participants with a proven food allergy. In addition a distinction should be made between young children whose food allergies improve with time and older children/adults.
Two trials with a total of 69 participants met the inclusion criteria. The first study considered the treatment of 403 people but only included 44 participants in the surgical trial, who were randomised into surgical and non-surgical groups. However, the report did not provide information on the method of randomisation. The second study randomly allocated 25 participants into surgical or control groups using statistical charts. There was no attempt in either study to conceal allocation. Neither participants nor outcome assessors were blind to the interventions, in either study. The first study lost seven participants to follow-up and there were no losses to follow-up in the second study. Surgeons in both studies decompressed the nerves of all the surgical group participants using a retroauricular approach. The primary outcome was recovery of facial palsy at 12 months. The first study showed that the operated group and the non-operated group (who received oral prednisolone) had comparable facial nerve recovery at nine months. This study did not statistically compare the groups but the scores and size of the groups suggested that statistically significant differences are unlikely. The second study reported no statistically significant differences between the operated and control (no treatment) groups. One operated participant in the first study had 20 dB sensorineural hearing loss and persistent vertigo. We identified no new studies when we updated the searches in October 2012. There is only very low quality evidence from randomised controlled trials and this is insufficient to decide whether surgical intervention is beneficial or harmful in the management of Bell's palsy. Further research into the role of surgical intervention is unlikely to be performed because spontaneous recovery occurs in most cases.
We included 24 studies of critically ill adults. No study reported mortality as an outcome of interest. Two randomized controlled trials (RCTs) examined lateral positioning for pulmonary morbidity outcomes but provided insufficient information for meta-analysis. A total of 22 randomized trials examined effects of lateral positioning (four parallel-group and 18 cross-over designs) by measuring various continuous data outcomes commonly used to detect adverse cardiopulmonary events within critical care areas. However, parallel-group studies were not comparable, and cross-over studies provided limited data as the result of unit of analysis errors. Eight studies provided some data; most of these were single studies with small effects that were imprecise. We pooled partial pressure of arterial oxygen (PaO2) as a measure to detect hypoxaemia from two small studies of participants with unilateral lung disease (n = 19). The mean difference (MD) between lateral positions (bad lung down versus good lung down) was approximately 50 mmHg (MD -49.26 mmHg, 95% confidence interval (CI) -67.33 to -31.18; P value < 0.00001). Despite a lower mean PaO2 for bad lung down, hypoxaemia (mean PaO2 < 60 mmHg) was not consistently reported. Furthermore, pooled data had methodological shortcomings with unclear risk of bias. We had similar doubts regarding internal validity for other studies included in the review. Review authors could provide no clinical practice recommendations based on the findings of included studies. Available research could not eliminate the uncertainty surrounding benefits and/or risks associated with lateral positioning of critically ill adult patients. Research gaps include the effectiveness of lateral positioning compared with semi recumbent positioning for mechanically ventilated patients, lateral positioning compared with prone positioning for acute respiratory distress syndrome (ARDS) and less frequent changes in body position. We recommend that future research be undertaken to address whether the routine practice of repositioning patients on their side benefits all, some or few critically ill patients.
Four studies evaluating rimonabant 20 mg versus rimonabant 5 mg versus placebo in addition to a hypocaloric diet lasting at least one year were included. Compared with placebo, rimonabant 20 mg produced a 4.9 kg greater reduction in body weight in trials with one-year results. Improvements in waist circumference, high-density lipoprotein cholesterol, triglyceride levels and systolic and diastolic blood pressure were also seen. However, the results with rimonabant 5 mg demonstrated a weight reduction which was only 1.3 kg greater when compared with placebo. No clinically relevant effects on plasma lipids and blood pressure were found. Rimonabant 20 mg caused significant more adverse effects both of general and serious nature, especially of nervous system, psychiatric or gastro-intestinal origin. Attrition rates were approximately 40% at the end of one year. The use of rimonabant after one year produces modest weight loss of approximately 5%. Even modest amounts of weight loss may be potentially beneficial. The observed results should be interpreted with some caution, though, since the evaluated studies presented some deficiencies in methodological quality. Studies with longer follow-ups after the end of treatment and of more rigorous quality should be done before definitive recommendations can be made regarding the role of this new medication in the management of overweight or obese patients.
Two studies, enrolling 97 participants, met our inclusion criteria. The studies differed significantly in terms of study populations, natural history of AKI (multifactorial AKI in patients with native kidneys versus delayed graft function associated with acute tubular necrosis in transplant recipients), and study interventions; hence, data were not meta-analysed. One study reported a significant increase in the risk of all-cause mortality associated with thyroid hormone interventions compared with placebo (59 participants, RR 3.32, 95% CI 1.21 to 9.12); no deaths were reported in the other study. Both studies reported no significant difference in the need for RRT associated with thyroid hormone therapy when compared to placebo. Neither study reported incidence of progression to ESKD. There was a significantly longer duration of AKI (MD 2.00 days, 95% CI 0.18 to 3.82) and RRT (5.00 days, 95% CI 2.05 to 7.95) associated with thyroid hormone therapy compared with placebo in one study; no differences in durations of AKI (MD 2.00 days, 95% CI -3.53 to 7.53) and RRT (MD 2.00 days, 95% CI -2.36 to 6.36) were noted in the other study. One study reported similar lengths of stay in the intensive care unit and hospital in both intervention and control arms (MD -0.20 days, 95% CI -8.17 to 7.77); the other did not report this outcome. No adverse events were noted to be associated with thyroid hormone therapy in either study. Adequate data were not available to assess changes in kidney function or numbers of RRT sessions. Both included studies were small and methodological quality was suboptimal. We found a paucity of large, high quality studies to inform analysis of thyroid hormone interventions for the treatment of people with AKI. Current evidence suggested that thyroid hormone therapy may be associated with worse outcomes for patients with established AKI; therefore, its use for these patients should be avoided. The role of thyroid hormone therapy in preventing AKI has not been adequately investigated and may be considered in future clinical studies.
We included 10 RCTs that enrolled a total of 1629 participants. The characteristics of all studies matched the requirements to compare the two types of surgical reconstruction following pancreatoduodenectomy. All studies reported incidence of postoperative pancreatic fistula (the main complication) and postoperative mortality. Overall, the risk of bias in included studies was high; only one included study was assessed at low risk of bias. There was little or no difference between PJ and PG in overall risk of postoperative pancreatic fistula (PJ 24.3%; PG 21.4%; RR 1.19, 95% CI 0.88 to 1.62; 7 studies; low-quality evidence). Inclusion of studies that clearly distinguished clinically significant pancreatic fistula resulted in us being uncertain whether PJ improved the risk of pancreatic fistula when compared with PG (19.3% versus 12.8%; RR 1.51, 95% CI 0.92 to 2.47; very low-quality evidence). PJ probably has little or no difference from PG in risk of postoperative mortality (3.9% versus 4.8%; RR 0.84, 95% CI 0.53 to 1.34; moderate-quality evidence). We found low-quality evidence that PJ may differ little from PG in length of hospital stay (MD 1.04 days, 95% CI -1.18 to 3.27; 4 studies, N = 502) or risk of surgical re-intervention (11.6% versus 10.3%; RR 1.18, 95% CI 0.86 to 1.61; 7 studies, N = 1263). We found moderate-quality evidence suggesting little difference between PJ and PG in terms of risk of any surgical complication (46.5% versus 44.5%; RR 1.03, 95% CI 0.90 to 1.18; 9 studies, N = 1513). PJ may slightly improve the risk of postoperative bleeding (9.3% versus 13.8%; RR 0.69, 95% CI: 0.51 to 0.93; low-quality evidence; 8 studies, N = 1386), but may slightly worsen the risk of developing intra-abdominal abscess (14.7% versus 8.0%; RR 1.77, 95% CI 1.11 to 2.81; 7 studies, N = 1121; low quality evidence). Only one study reported quality of life (N = 320); PG may improve some quality of life parameters over PJ (low-quality evidence). No studies reported cost analysis data. There is no reliable evidence to support the use of pancreatojejunostomy over pancreatogastrostomy. Future large international studies may shed new light on this field of investigation.
Thirty-two studies were eligible for inclusion. Six were short-term biochemical tolerance studies, one was in infants at > 35 weeks' gestation, one in term surgical newborns, and three yielding no usable data. The 21 remaining studies reported clinical outcomes in very preterm or low birth weight infants for inclusion in meta-analysis for this review. Higher AA intake had no effect on mortality before hospital discharge (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14; I2 = 0%; quality of evidence: low). Evidence was insufficient to show an effect on neurodevelopment and suggest no reported benefit (quality of evidence: very low). Higher AA intake was associated with a reduction in postnatal growth failure (< 10th centile) at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3; I2 = 22%; typical RD -0.15, 95% CI -0.27 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 50; quality of evidence: very low). Subgroup analyses found reduced postnatal growth failure in infants that commenced on high amino acid intake (> 2 to ≤ 3 g/kg/day); that occurred with increased amino acid and non-protein caloric intake; that commenced on intake at < 24 hours' age; and that occurred with early lipid infusion. Higher AA intake was associated with a reduction in days needed to regain birth weight (MD -1.14, 95% CI -1.73 to -0.56; participants = 950; studies = 13; I2 = 77%). Data show varying effects on growth parameters and no consistent effects on anthropometric z-scores at any time point, as well as increased growth in head circumference at discharge (MD 0.09 cm/week, 95% CI 0.06 to 0.13; participants = 315; studies = 4; I2 = 90%; quality of evidence: very low). Higher AA intake was not associated with effects on days to full enteral feeds, late-onset sepsis, necrotising enterocolitis, chronic lung disease, any or severe intraventricular haemorrhage, or periventricular leukomalacia. Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4; I2 = 31%; quality of evidence: very low) but no difference in severe retinopathy of prematurity. Higher AA intake was associated with an increase in positive protein balance and nitrogen balance. Potential biochemical intolerances were reported, including risk of abnormal blood urea nitrogen (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7; I2 = 6%; typical RD 0.26, 95% CI 0.20 to 0.32; number needed to treat for an additional harmful outcome (NNTH) 4; 95% CI 3 to 5; quality of evidence: high). Higher amino acid intake in parenteral nutrition was associated with a reduction in hyperglycaemia (> 8.3 mmol/L) (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5; I2 = 68%), although the incidence of hyperglycaemia treated with insulin was not different. Low-quality evidence suggests that higher AA intake in parenteral nutrition does not affect mortality. Very low-quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure. Evidence was insufficient to show an effect on neurodevelopment. Very low-quality evidence suggests that higher AA intake reduces retinopathy of prematurity but not severe retinopathy of prematurity. Higher AA intake was associated with potentially adverse biochemical effects resulting from excess amino acid load, including azotaemia. Adequately powered trials in very preterm infants are required to determine the optimal intake of AA and effects of caloric balance in parenteral nutrition on the brain and on neurodevelopment.
There was no significant heterogeneity of outcome amongst individual drugs, or of drug classes either for the primary efficacy analysis (death or dependence) or for mortality at final follow up. For the primary efficacy analysis, odds of death or dependence were 1.03 (95% confidence interval (CI) 0.96 to 1.12), and for mortality 1.02 (0.92 to 1.12). Neither ion channel modulators (death or dependence 1.02 (0.90 to 1.16)) nor NMDA antagonists (death or dependence 1.05 (0.95 to 1.16)) differed from the principal analysis including all compounds. Trends for increased mortality with three NMDA antagonists were seen - selfotel (OR 1.19 (0.81 to 1.74)), aptiganel (OR 1.32 (0.91 to 1.93)) and gavestinel (OR 1.12 (0.95 to 1.32)) - but this did not achieve significance for the NMDA antagonists considered as a class (1.09 (0.96 to 1.23)). Aptiganel was also associated with a trend towards worse functional outcome (OR 1.20 (0.88 to 1.65)) although this was not the case for either of the other two compounds. No statistically significant detriment of psychotomimetic NMDA antagonists was found, although a trend towards higher mortality in this sub-group was seen (OR 1.25 (0.96 to 1.64)). There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reduction of death or dependence by 8% or more has been excluded for gavestinel and lubeluzole, which contribute most of the data for this review. However, mechanistic understanding of neuroprotection is too poor to extrapolate from these two failed development plans to all glutamate modulators. Further clinical trials of neuroprotective agents remain justified, since confidence limits around estimates of effect remain wide for most agents, and cannot reliably exclude benefit. Although numbers of patients are too small to confirm or refute a trend towards increased mortality with some NMDA antagonists, further commercial development of these agents is exceedingly unlikely.
Forty-nine trials involving 8763 women were included. The data were combined to calculate hazard ratios (HR) for survival on an intention-to-treat basis. For single non-platinum versus platinum combination chemotherapy the overall HR for survival was 0.93, 95% confidence interval (CI) 0.83 to1.05 favouring platinum-based combination chemotherapy. For non-platinum regimens compared with the same regimen plus cisplatin the survival HR was 0.88, 95% CI 0.79 to 0.98 in favour of adding platinum to drug regimens. Single platinum compared with platinum combination gave a HR of 0.91, 95% CI 0.79 to 1.05 favouring combination chemotherapy. Cisplatin versus carboplatin gave a HR of 1.02, 95% CI 0.93 to 1.12. Sub-group analyses for age, stage, grade, histology, resection, bulk of residual tumour and performance status were undertaken for cisplatin versus carboplatin only. No difference in effect was found. Available evidence, although not conclusive, suggests platinum-based chemotherapy is better than non-platinum therapy. There is some evidence that combination therapy improves survival compared with platinum alone. No difference in effect has been shown between cisplatin and carboplatin.
Eight randomized trials, including 9598 patients, tested adjusted-dose warfarin versus aspirin (in dosages ranging from 75 to 325 mg/day) in AF patients without prior stroke or TIA. The mean overall follow up was 1.9 years/participant. Oral anticoagulants were associated with lower risk of all stroke (odds ratio (OR) 0.68, 95% confidence interval (CI) 0.54 to 0.85), ischemic stroke (OR 0.53, 95% CI 0.41 to 0.68) and systemic emboli (OR 0.48, 95% CI 0.25 to 0.90). All disabling or fatal strokes (OR 0.71, 95% CI 0.59 to 1.04) and myocardial infarction (OR 0.69, 95% CI 0.47 to 1.01) were substantially but not significantly reduced by oral anticoagulants. Vascular death (OR 0.93, 95% CI 0.75 to 1.15) and all cause mortality (OR 0.99, 95% CI 0.83 to 1.18), were similar with these treatments. Intracranial hemorrhages (OR 1.98, 95% CI 1.20 to 3.28) were increased by oral anticoagulant therapy. Adjusted-dose warfarin and related oral anticoagulants reduce stroke, disabling stroke and other major vascular events for those with non-valvular AF by about one third when compared with antiplatelet therapy.
Twenty-one studies were eligible for inclusion (1745 participants; 19 in adults, 2 in adolescents). Most studies used multimodular approaches. The risk of bias was high for all studies. In adults, psychotherapy had no effect on quality of life at around 12 months (3 studies, 235 patients, SMD -0.07; 95% CI -0.33 to 0.19), emotional status (depression, 4 studies, 266 patients, SMD 0.03; 95% CI -0.22 to 0.27) or proportion of patients not in remission (5 studies, 287 patients, OR 0.85; 95% CI 0.48 to 1.48). Results were similar at 3 to 8 months. There was no evidence for statistical heterogeneity or subgroup effects based on type of disease or intensity of the therapy. In adolescents, there were positive short term effects of psychotherapy on most outcomes assessed including quality of life (2 studies, 71 patients, SMD 0.70; 95% CI 0.21 to 1.18) and depression (1 study, 41 patients, SMD -0.62; 95% CI -1.25 to 0.01). Educational interventions had no effect on quality of life at 12 months (5 studies, 947 patients, SMD 0.11; 95% CI -0.02 to 0.24), depression (3 studies, 378 patients, SMD -0.08; 95% CI -0.29 to 0.12) and proportion of patients not in remission (3 studies, 434 patients, OR 1.00; 95% CI 0.65 to 1.53). No adverse events were reported in any of the included studies. There is no evidence for efficacy of psychological therapy in adult patients with IBD in general. In adolescents, psychological interventions may be beneficial, but the evidence is limited. Further evidence is needed to assess the efficacy of these therapies in subgroups identified as being in need of psychological interventions, and to identify what type of therapy may be most useful.
Three randomised controlled trials met the inclusion criteria for our systematic review - the studies randomised a total of 524 women. We assessed the three included studies as being at a low to moderate risk of bias; the nature of the intervention made it difficult to achieve blinding of participants and personnel and none of the trial reports contained information about methods of allocation concealment (and were therefore assessed as being at an unclear risk of selection bias). In all studies, the intervention was the use of fetal biometry on ultrasound to identify fetuses displaying signs of fetal macrosomia, and the use of this information to indicate the use of medical anti-hyperglycaemic treatments. Those pregnancies were subject to more stringent blood glucose targets than those without signs of fetal macrosomia. Maternal outcomes The use of fetal biometry in addition to maternal blood glucose concentration (compared with maternal blood glucose concentration alone) may make little or no difference to the incidence of caesarean delivery (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.59 to 1.10; 2 trials, 428 women; low-certainty evidence). We are unclear about the results for hypertensive disorders of pregnancy (RR 0.80, 95% CI 0.34 to 1.89; 2 trials, 325 women) due to very low-certainty evidence. The included trials did not report on development of type 2 diabetes in the mother or maternal hypoglycaemia. Fetal and neonatal outcomes The use of fetal biometry may make little or no difference to the incidence of neonatal hypoglycaemia (RR 0.90, 95% CI 0.57 to 1.42; 3 trials, 524 women; low-certainty evidence). Very low-certainty evidence means that we are unclear about the results for large-for-gestational age (RR 0.81, 95% CI 0.38 to 1.74; 3 trials, 524 women); shoulder dystocia (RR 0.33, 95% CI 0.01 to 7.98; 1 trial, 96 women); a composite measure of perinatal morbidity or mortality (RR 1.00, 95% CI 0.21 to 4.71; 1 study, 96 women); or perinatal mortality (RR 0.33, 95% CI 0.01 to 7.98; 1 trial, 96 women). This review is based on evidence from three trials involving 524 women. The trials did not report some important outcomes of interest to this review, and the majority of our secondary outcomes were also unreported. The available evidence ranged from low- to very low-certainty, with downgrading decisions based on limitations in study design, imprecision and inconsistency. There is insufficient evidence to evaluate the use of fetal biometry (in addition to maternal blood glucose concentration values) to assist in guiding the medical management of GDM, on either maternal or perinatal health outcomes, or the associated costs. More research is required, ideally larger randomised studies which report the maternal and infant short- and long-term outcomes listed in this review, as well as those outcomes relating to financial and resource implications.
We screened 17,055 records identified through searches of databases. We obtained 746 full-text articles and assessed them for relevance. We scrutinised 49 studies to establish their eligibility for inclusion in the review and excluded 48, primarily because participants were not patients presenting solely with exertional leg pain, investigators used no reference standard or investigators used neither angiography nor duplex ultrasonography as the reference standard. We excluded most studies for more than one reason. Only one study met the eligibility criteria and provided limb-level accuracy data from just 85 participants (158 legs). This prospective study compared the manual doppler method of obtaining an ABI (performed by untrained personnel) with the automated oscillometric method. Limb-level data, as reported by the study, indicated that the accuracy of the ABI in detecting significant arterial disease on angiography is superior when stenosis is present in the femoropopliteal vessels, with sensitivity of 97% (95% confidence interval (CI) 93% to 99%) and specificity of 89% (95% CI 67% to 95%) for oscillometric ABI, and sensitivity of 95% (95% CI 89% to 97%) and specificity of 56% (95% CI 33% to 70%) for doppler ABI. The ABI threshold was not reported. Investigators attributed the lower specificity for doppler to the fact that a tibial or dorsalis pedis pulse could not be detected by doppler in 12 of 27 legs with normal vessels or non-significant lesions. The superiority of the oscillometric (automated) method for obtaining an ABI reading over the manual method with a doppler probe used by inexperienced operators may be a clinically important finding. Evidence about the accuracy of the ankle brachial index for the diagnosis of PAD in people with leg pain on exercise that is alleviated by rest is sparse. The single study included in our review provided only limb-level data from a few participants. Well-designed cross-sectional studies are required to evaluate the accuracy of ABI in patients presenting with early symptoms of peripheral arterial disease in all healthcare settings. Another systematic review of existing studies assessing the use of ABI in alternative patient groups, including asymptomatic, high-risk patients, is required.
Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisons Three of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence). In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence) In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine. Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency.
We included seven trials involving 447 infants younger than two years with respiratory distress secondary to viral bronchiolitis. All children were recruited from a paediatric intensive care unit (PICU; 378 infants), except in one trial (emergency department; 69 infants). All children were younger than two (under nine months in two trials and under three months in one trial). Positive tests for respiratory syncytial virus (RSV) were required for inclusion in five trials. The two other trials were carried out in the bronchiolitis seasons. Seven different protocols were used for inhalation therapy with heliox. When heliox was used in the PICU, we observed no significant reduction in the rate of intubation: risk ratio (RR) 2.73 (95% confidence interval (CI) 0.96 to 7.75, four trials, 408 infants, low quality evidence). When heliox inhalation was used in the emergency department, we observed no increase in the rate of discharge: RR 0.51 (95% CI 0.17 to 1.55, one trial, 69 infants, moderate quality evidence). There was no decrease in the length of treatment for respiratory distress: mean difference (MD) -0.19 days (95% CI -0.56 to 0.19, two trials, 320 infants, moderate quality evidence). However, in the subgroup of infants who were started on nasal continuous positive airway pressure (nCPAP) right from the start, because of severe respiratory distress, heliox therapy reduced the length of treatment: MD -0.76 days (95% CI -1.45 to -0.08, one trial, 21 infants, low quality evidence). No adverse events related to heliox inhalation were reported. We found that infants treated with heliox inhalation had a significantly lower mean clinical respiratory score in the first hour after starting treatment when compared to those treated with air or oxygen inhalation: MD -1.04 (95% CI -1.60 to -0.48, four trials, 138 infants, moderate quality evidence). This outcome had statistical heterogeneity, which remained even after removing the study using a standard high-concentration reservoir mask. Several factors may explain this heterogeneity, including first the limited number of patients in each trial, and the wide differences in the baseline severity of disease between studies, with the modified Wood Clinical Asthma Score (m-WCAS) in infants treated with heliox ranging from less than two to more than seven. Current evidence suggests that the addition of heliox therapy may significantly reduce a clinical score evaluating respiratory distress in the first hour after starting treatment in infants with acute RSV bronchiolitis. We noticed this beneficial effect regardless of which heliox inhalation protocol was used. Nevertheless, there was no reduction in the rate of intubation, in the rate of emergency department discharge, or in the length of treatment for respiratory distress. Heliox could reduce the length of treatment in infants requiring CPAP for severe respiratory distress. Further studies with homogeneous logistics in their heliox application are needed. Inclusion criteria must include a clinical severity score that reflects severe respiratory distress to avoid inclusion of children with mild bronchiolitis who may not benefit from heliox inhalation. Such studies would provide the necessary information as to the appropriate place for heliox in the therapeutic schedule for severe bronchiolitis.
We included eight RCTs of 1562 children receiving oral homeopathic medicinal products or a control treatment (placebo or conventional treatment) for upper respiratory tract infections (URTIs). Four treatment studies examined the effect on URTI recovery, and four studies investigated the effect on preventing URTIs after one to three months of treatment, followed up for the remainder of the year. Two treatment and two prevention studies involved homeopaths individualising treatment. The other studies used predetermined, non-individualised treatments. All studies involved highly diluted homeopathic medicinal products. We found several limitations to the included studies, in particular methodological inconsistencies and high attrition rates, failure to conduct intention-to-treat analysis, selective reporting, and apparent protocol deviations. We assessed three studies as at high risk of bias in at least one domain, and many had additional domains with unclear risk of bias. Three studies received funding from homeopathy manufacturers; one support from a non-government organisation; two government support; one was cosponsored by a university; and one did not report funding support. Methodological inconsistencies and significant clinical and statistical heterogeneity precluded robust quantitative meta-analysis. Only four outcomes were common to more than one study and could be combined for analysis. Odds ratios (OR) were generally small with wide confidence intervals (CI), and the contributing studies found conflicting effects, so there was little certainty that the efficacy of the intervention could be ascertained. All studies assessed as at low risk of bias showed no benefit from oral homeopathic medicinal products; trials at uncertain and high risk of bias reported beneficial effects. We found low-quality evidence that non-individualised homeopathic medicinal products confer little preventive effect on ARTIs (OR 1.14, 95% CI 0.83 to 1.57). We found low-quality evidence from two individualised prevention studies that homeopathy has little impact on the need for antibiotic usage (N = 369) (OR 0.79, 95% CI 0.35 to 1.76). We also assessed adverse events, hospitalisation rates and length of stay, days off school (or work for parents), and quality of life, but were not able to pool data from any of these secondary outcomes. There is insufficient evidence from two pooled individualised treatment studies (N = 155) to determine the effect of homeopathy on short-term cure (OR 1.31 favouring placebo, 95% CI 0.09 to 19.54; very low-quality evidence) and long-term cure rates (OR 0.99, 95% CI 0.10 to 9.67; very low-quality evidence). Adverse events were reported inconsistently; however, serious events were not reported. One study found an increase in the occurrence of non-severe adverse events in the treatment group. Pooling of two prevention and two treatment studies did not show any benefit of homeopathic medicinal products compared to placebo on ARTI recurrence or cure rates in children. We found no evidence to support the efficacy of homeopathic medicinal products for ARTIs in children. Adverse events were poorly reported, so conclusions about safety could not be drawn.
The search identified 60 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used. Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval (CI) 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months. One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% CI 0.02 to 0.79). One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence . A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups. A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). Using GRADE, the quality of evidence for outcomes was downgraded to moderate to very low. Downgrading decisions for Pseudomonas aeruginosa eradication and lung function were based on applicability (participants mostly children) and limitations in study design, with imprecision an additional limitation for lung function, growth parameters and adverse effects. We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.
We included two trials with 493 randomised participants with various Child-Pugh scores. The trials had a low risk of bias. The rHuFVIIa administration did not reduce the risk of mortality within five days (21/288 (7.3%) versus 15/205 (7.3%); risk ratio (RR) 0.88, 95% confidence interval (CI) 0.48 to 1.64, I2 = 49%) and within 42 days (5/286 (1.7%) versus 36/205 (17.6%); RR 1.01, 95% CI 0.55 to 1.87, I2 = 55%) when compared with placebo. Trial sequential analysis demonstrated that there is sufficient evidence to exclude that rHuFVIIa decreases mortality by 80%, but there is insufficient evidence to exclude smaller effects. The rHuFVIIa did not increase the risk of adverse events by number of patients (218/297 (74%) and 164/210 (78%); RR 0.94, 95% CI 0.84 to 1.04, I2 = 1%), serious adverse events by adverse events reported (164/590 (28%) versus 123/443 (28%); RR 0.91, 95% CI 0.75 to 1.11, I2 = 0%), and thromboembolic adverse events (16/297 (5.4%) versus 14/210 (6.7%); RR 0.80, 95% CI 0.40 to 1.60, I2 = 0%) when compared with placebo. We found no evidence to support or reject the administration of rHuFVIIa for patients with liver disease and upper gastrointestinal bleeding. Further adequately powered randomised clinical trials are needed in order to evaluate the proper role of rHuFVIIa for treating upper gastrointestinal bleeding in patients with liver disease. Although the results are based on trials with low risk of bias, the heterogeneity and the small sample size result in rather large confidence intervals that cannot exclude the possibility that the intervention has some beneficial or harmful effect. Further trials with alow risk of bias are required to make more confident conclusions about the effects of the intervention.
Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow-up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate-stage hepatocellular carcinoma arising from viral and non-viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow-up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow-up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I2 = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health-related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials. Currently, there is no evidence from randomised clinical trials that people with intermediate-stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high-quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all-cause mortality or health-related quality of life).
A total of 43 trials were identified with 1673 participants. All trials used small patient numbers (average trial size of 39 participants); the methods of randomisation and concealment of allocation were poor or not stated in most trials. Blinded assessors were used in just over half of the trials and only 10 stated that they used intention-to-treat analysis. A wide variety of validated and customised outcome measures were used to assess the effectiveness of physiotherapy interventions. The most frequently reported physiotherapy outcomes were gait speed and timed up and go, in 19 and 15 trials respectively. Only five of the 43 trials reported data on falls (12%). The motor subscales of the Unified Parkinson’s Disease Rating Scale and Parkinson’s Disease Questionnaire-39 were the most commonly reported clinician-rated disability and patient-rated quality of life outcome measures, used in 22 and 13 trials respectively. The content and delivery of the physiotherapy interventions varied widely in the trials included within this review, so no quantitative meta-analysis could be performed. Considering the small number of participants examined, the methodological flaws in many of the studies, the possibility of publication bias, and the variety of interventions, formal comparison of the different physiotherapy techniques could not be performed. There is insufficient evidence to support or refute the effectiveness of one physiotherapy intervention over another in PD. This review shows that a wide range of physiotherapy interventions to treat PD have been tested . There is a need for more specific trials with improved treatment strategies to underpin the most appropriate choice of physiotherapy intervention and the outcomes measured.
We identified one RCT and no CCTs; in this update no additional eligible studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.
We identified 24 RCTs involving 3739 participants which were included in the review. IHCAs had a significant positive effect on knowledge (SMD 0.46; 95% confidence interval (CI) 0.22 to 0.69), social support (SMD 0.35; 95% CI 0.18 to 0.52) and clinical outcomes (SMD 0.18; 95% CI 0.01 to 0.35). Results suggest it is more likely than not that IHCAs have a positive effect on self-efficacy (a person's belief in their capacity to carry out a specific action) (SMD 0.24; 95% CI 0.00 to 0.48). IHCAs had a significant positive effect on continuous behavioural outcomes (SMD 0.20; 95% CI 0.01 to 0.40). Binary behavioural outcomes also showed a positive effect for IHCAs, although this result was not statistically significant (OR 1.66; 95% CI 0.71 to 3.87). It was not possible to determine the effects of IHCAs on emotional or economic outcomes. IHCAs appear to have largely positive effects on users, in that users tend to become more knowledgeable, feel better socially supported, and may have improved behavioural and clinical outcomes compared to non-users. There is a need for more high quality studies with large sample sizes to confirm these preliminary findings, to determine the best type and best way to deliver IHCAs, and to establish how IHCAs have their effects for different groups of people with chronic illness.
We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas. There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women). There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women). Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year. The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.
For this fourth update six new trials were included, bringing the total of included trials to 59. Foam alternatives to standard hospital foam mattresses reduce the incidence of pressure ulcers in people at risk (RR 0.40 95% CI 0.21 to 0.74). The relative merits of alternating- and constant low-pressure devices are unclear. One high-quality trial suggested that alternating-pressure mattresses may be more cost effective than alternating-pressure overlays in a UK context. Pressure-relieving overlays on the operating table reduce postoperative pressure ulcer incidence, although two trials indicated that foam overlays caused adverse skin changes. Meta-analysis of three trials suggest that Australian standard medical sheepskins prevent pressure ulcers (RR 0.56 95% CI 0.32 to 0.97). People at high risk of developing pressure ulcers should use higher-specification foam mattresses rather than standard hospital foam mattresses. The relative merits of higher-specification constant low-pressure and alternating-pressure support surfaces for preventing pressure ulcers are unclear, but alternating-pressure mattresses may be more cost effective than alternating-pressure overlays in a UK context. Medical grade sheepskins are associated with a decrease in pressure ulcer development. Organisations might consider the use of some forms of pressure relief for high risk patients in the operating theatre.
For this update of the review, we identified one new trial, bringing the total to 17 trials (1034 participants) - all of which were generally at moderate or high risk of bias. In 12 trials participants also received compression bandaging. Eleven trials compared a graft with standard care in which no graft was used. Two of these trials (102 participants) compared a dressing with an autograft; three trials (80 participants) compared frozen allografts with dressings, and two trials (45 participants) compared fresh allografts with dressings. Two trials (345 participants) compared tissue-engineered skin (bilayer artificial skin) with a dressing. In two trials (97 participants) a single-layer dermal replacement was compared with standard care. Six trials compared alternative skin grafting techniques. The first trial (92 participants) compared autografts with frozen allograft, a second (51 participants) compared a pinch graft (autograft) with porcine dermis (xenograft), the third (110 participants) compared growth-arrested human keratinocytes and fibroblasts with placebo, the fourth (10 participants) compared an autograft delivered on porcine pads with an autograft delivered on porcine gelatin microbeads, the fifth trial (92 participants) compared a meshed graft with a cultured keratinocyte autograft, and the sixth trial (50 participants) compared a frozen keratinocyte allograft with a lyophilised (freeze-dried) keratinocyte allografts. Significantly more ulcers healed when treated with bilayer artificial skin than with dressings. There was insufficient evidence from the other trials to determine whether other types of skin grafting increased the healing of venous ulcers. Bilayer artificial skin, used in conjunction with compression bandaging, increases venous ulcer healing compared with a simple dressing plus compression. Further research is needed to assess whether other forms of skin grafts increase ulcer healing.
We found six trials recruiting a total of 549 infants. One trial showed that use of a percutaneous central venous catheter was associated with a smaller deficit between prescribed and actual nutrient intake during the trial period (mean difference (MD) -7.1%, 95% confidence interval (CI) -11.02 to -3.2). Infants in the percutaneous central venous catheter group needed significantly fewer catheters/cannulae (MD -4.3, 95% CI -5.24, -3.43). Meta-analysis of data from all trials revealed no evidence of an effect on the incidence of invasive infection (typical risk ratio (RR) 0.95, 95% CI 0.72 to 1.25; typical risk difference (RD) -0.01, 95% CI -0.08 to 0.06). Data from one small trial suggest that use of percutaneous central venous catheters to deliver parenteral nutrition increases nutrient input. The significance of this in relation to long-term growth and developmental outcomes is unclear. Three trials suggest that use of percutaneous central venous catheters decreases the number of catheters/cannulae needed to deliver nutrition. No evidence suggests that percutaneous central venous catheter use increases risks of adverse events, particularly invasive infection, although none of the included trials was large enough to rule out an effect on uncommon severe adverse events such as pericardial effusion.
We included 39 studies involving 2441 participants with unilateral peripheral vestibular disorders in the review. Trials addressed the effectiveness of vestibular rehabilitation against control/sham interventions, medical interventions or other forms of vestibular rehabilitation. Non-blinding of outcome assessors and selective reporting were threats that may have biased the results in 25% of studies, but otherwise there was a low risk of selection or attrition bias. Individual and pooled analyses of the primary outcome, frequency of dizziness, showed a statistically significant effect in favour of vestibular rehabilitation over control or no intervention (odds ratio (OR) 2.67, 95% confidence interval (CI) 1.85 to 3.86; four studies, 565 participants). Secondary outcomes measures related to levels of activity or participation measured, for example, with the Dizziness Handicap Inventory, which also showed a strong trend towards significant differences between the groups (standardised mean difference (SMD) -0.83, 95% CI -1.02 to -0.64). The exception to this was when movement-based vestibular rehabilitation was compared to physical manoeuvres for benign paroxysmal positional vertigo (BPPV), where the latter was shown to be superior in cure rate in the short term (OR 0.19, 95% CI 0.07 to 0.49). There were no reported adverse effects. There is moderate to strong evidence that vestibular rehabilitation is a safe, effective management for unilateral peripheral vestibular dysfunction, based on a number of high-quality randomised controlled trials. There is moderate evidence that vestibular rehabilitation resolves symptoms and improves functioning in the medium term. However, there is evidence that for the specific diagnostic group of BPPV, physical (repositioning) manoeuvres are more effective in the short term than exercise-based vestibular rehabilitation; although a combination of the two is effective for longer-term functional recovery. There is insufficient evidence to discriminate between differing forms of vestibular rehabilitation.
There were 24 included studies with 11959 participants in total. Many studies were of cross-over design and first-phase data were unavailable, or could not be extracted. Global impression of change (GIC) was the only outcome for which pooling of data was possible, involving only four studies. There was evidence of heterogeneity in the results, Chi2 test = 19.17 (df = 3, P < 0.001). The odds ratio (OR) for improvement in the piracetam group compared with placebo was 3.43 (95% confidence interval (CI) 2.32 to 5.07). Using a fixed-effect model, the OR for improvement with piracetam compared with placebo was 3.55 (95% CI 2.45 to 5.16). This estimate was derived from completers rather than from an intention-to-treat analysis as relevant data could not be extracted from the reports. In the limited data available, no significant differences were found between treatment and placebo groups for cognition (immediate memory, visuospatial, Mini Mental Status Examination (MMSE), delayed memory or speech) for dependency, or for depression. The large volume of unpublished and untraceable data not available to the review authors raises the possibility of publication bias. Published evidence does not support the use of piracetam in the treatment of people with dementia or cognitive impairment. Although effects were found on global impression of change, no benefit was shown by any of the more specific measures of cognitive function. The evidence indicates a need for further evaluation of piracetam.
We were unable to find any randomized controlled trials on antibiotic treatment approaches for community-acquired pneumonia in people with sickle cell disease. The updated review was unable to identify randomized controlled trials on efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from community-acquired pneumonia. Randomized controlled trials are needed to establish the optimum antibiotic treatment for this condition. The trials regarding this issue should be structured and reported according to the CONSORT statement for improving the quality of reporting of efficacy and improved reports of harms in clinical research. Triallists should consider including the following outcomes in new trials: number of days to become afebrile; mortality; onset of pain crisis or complications of sickle cell disease following community-acquired pneumonia; diagnosis; hospitalization (admission rate and length of hospital stay); respiratory failure rate; and number of participants receiving a blood transfusion. There are no trials included in the review and we have not identified any relevant trials up to September 2016. We therefore do not plan to update this review until new trials are published.
We included 33 studies of STPP involving 2173 randomised participants with common mental disorders. Studies were of diverse conditions in which problems with emotional regulation were purported to play a causative role albeit through a range of symptom presentations. These studies evaluated STPP for this review's primary outcomes (general, somatic, anxiety and depressive symptom reduction), as well as interpersonal problems and social adjustment. Except for somatic measures in the short-term, all outcome categories suggested significantly greater improvement in the treatment versus the control groups in the short-term and medium-term. Effect sizes increased in long-term follow-up, but some of these effects did not reach statistical significance. A relatively small number of studies (N < 20) contributed data for the outcome categories. There was also significant heterogeneity between studies in most categories, possibly due to observed differences between manualised versus non-manualised treatments, short versus longer treatments, studies with observer-rated versus self report outcomes, and studies employing different treatment models. There has been further study of STPP and it continues to show promise, with modest to large gains for a wide variety of people. However, given the limited data, loss of significance in some measures at long-term follow-up and heterogeneity between studies, these findings should be interpreted with caution. Furthermore, variability in treatment delivery and treatment quality may limit the reliability of estimates of effect for STPP. Larger studies of higher quality and with specific diagnoses are warranted.
This updated review includes two new randomized trials. In total, 10 randomized trials with 432 participants and four comparisons are included in this review. One trial had a low risk of bias. No differences were demonstrated in mortality, with risk ratio (RR) of 0.97 (95% confidence interval (CI) 0.20 to 4.59; P value 0.97; 268 participants, six trials, very low quality of evidence (grading of recommendations assessment, development and evaluation (GRADE)), and in pneumonia, with RR of 0.40 (95% CI 0.11 to 1.39; P value 0.15; 120 participants, three trials, very low quality of evidence (GRADE)). Statistically significant results included the following: The PEEP group had higher arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) on day one postoperatively, with a mean difference of 22.98 (95% CI 4.40 to 41.55; P value 0.02; 80 participants, two trials, very low quality of evidence (GRADE)), and postoperative atelectasis (defined as an area of collapsed lung, quantified by computerized tomography scan) was less in the PEEP group (standard mean difference -1.2, 95% CI -1.78 to -0.79; P value 0.00001; 88 participants, two trials, very low quality of evidence (GRADE)). No adverse events were reported in the three trials that adequately measured these outcomes (barotrauma and cardiac complications). Using information size calculations, we estimated that a further 21,200 participants would have to be randomly assigned to allow a reliable conclusion about PEEP and mortality. Evidence is currently insufficient to permit conclusions about whether intraoperative PEEP alters risks of postoperative mortality and respiratory complications among undifferentiated surgical patients.
Three studies were eligible for inclusion in the review. Two small studies (randomising a total of 104 infants) evaluated the effect of prophylactic caffeine on short term outcomes. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnoea, bradycardia, hypoxaemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups. One large trial of caffeine therapy (CAP 2006) in a heterogeneous group of infants at risk for and having apnoea of prematurity demonstrated an improved rate of survival without developmental disability at 18 to 21 months corrected age. The reports of the subgroup of infants treated with prophylactic caffeine did not demonstrate any significant differences in clinical outcomes except for a decrease in the risk of PDA ligation. The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnoea. Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnoea. This should include examination of important clinical outcomes such as need for IPPV, neonatal morbidity, length of hospital stay and long term development.
We included eight cohort studies of which six were performed in primary care (total number of patients; n = 6622), one study was from an accident and emergency setting (n = 482), and one study was from a secondary care setting (n = 257). In the six primary care studies, the prevalence of spinal malignancy ranged from 0% to 0.66%. Overall, data from 20 index tests were extracted and presented, however only seven of these were evaluated by more than one study. Because of the limited number of studies and clinical heterogeneity, statistical pooling of diagnostic accuracy data was not performed. There was some evidence from individual studies that having a previous history of cancer meaningfully increases the probability of malignancy. Most "red flags" such as insidious onset, age > 50, and failure to improve after one month have high false positive rates. All of the tests were evaluated in isolation and no study presented data on a combination of positive tests to identify spinal malignancy. For most "red flags," there is insufficient evidence to provide recommendations regarding their diagnostic accuracy or usefulness for detecting spinal malignancy. The available evidence indicates that in patients with LBP, an indication of spinal malignancy should not be based on the results of one single "red flag" question. Further research to evaluate the performance of different combinations of tests is recommended.
We included two studies (one RCT and one CBA study) in this review (n = 311). Both of these studies indicated that a training workshop increased the knowledge about HIV/AIDS of traditional healers. With regards to behaviour change, Peltzer 2006 detected a significant difference in traditional healers' reports of managing their patients; however, there was no evidence of a reduction of HIV/STI risk behaviours and referral practices, as assessed by self-report. The study by Poudyal 2003 did not assess this outcome. Two studies met the inclusion criteria for this review. Although these studies reported some positive outcomes, the few studies and methodological heterogeneity limits the conclusions that can be drawn about the effectiveness of HIV training programs aimed at traditional healers. More rigorous studies (i.e. those employing rigorous randomisation procedures, reliable outcome measures and larger sample sizes) are needed to provide better evidence of the impact of HIV training programs aimed at traditional healers.
Nineteen studies involving a total of 2,159 participants met criteria for inclusion. It was not possible to conduct a meta-analysis due to study heterogeneity with respect to populations, interventions, comparison groups, outcomes, and length of follow-up. Sample sizes ranged from 22 to 367. The populations studied ranged from general HIV-positive populations to studies focusing exclusively on children, women, Latinos, or adults with a history of alcohol dependence, to studies focusing almost exclusively on men. Study interventions included cognitive behavioral therapy, motivational interviewing, medication management strategies, and interventions indirectly targeting adherence, such as programs directed to reduce risky sexual behaviours. Ten studies demonstrated a beneficial effect of the intervention on adherence. We found that interventions targeting practical medication management skills, those administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. We also found that interventions targeting marginalized populations such as women, Latinos, or patients with a past history of alcoholism were not successful at improving adherence. We were unable to determine whether effective adherence interventions were associated with improved virological or immunological outcomes. Most studies had several methodological shortcomings leaving them vulnerable to potential biases. We found evidence to support the effectiveness of patient support and education interventions intended to improve adherence to antiretroviral therapy. Interventions targeting practical medication management skills, those interventions administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. There is a need for standardization and increased methodological rigour in the conduct of adherence trials.
Forty-one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single-blind and three studies were open-label. However, two open-label studies and four of the single-blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5-ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty-one per cent of 5-ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5-ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5-ASA for maintenance of remission. Forty-eight per cent of 5-ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP-controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Twenty-nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-four per cent of patients in the 5-ASA group relapsed compared to 41% of patients in the 5-ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty-three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty-seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty-five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, 5-ASA and SASP, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulations and 5-ASA dose ranging studies. The trials that compared 5-ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP-related adverse events. 5-ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5-ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5-ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.
Seven trials involving a total of 199 participants were included. A trial of adrenocorticotrophic hormone (43 participants) did not show any advantage compared with placebo for the treatment of ocular myasthenia gravis. Two double-blind trials compared prednisone with placebo for generalised myasthenia gravis. In the first (13 participants), the improvement was slightly greater in the prednisone group at six months. In the second (20 participants) which was a short-term trial, the improvement was significantly greater at two weeks. Two trials compared glucocorticosteroids with azathioprine (41 and 10 participants respectively). In one of these the rate of treatment failure was greater in the prednisone group. In a trial of glucocorticosteroids versus intravenous immunoglobulin (33 participants) no differences in treatment responses were encountered during a treatment period of 14 days. An open trial (39 participants) evaluating different corticosteroid doses revealed a shorter time to improvement in the high-dose group. None fulfilled the presently accepted standards of a high-quality trial. All these studies have risks of bias and have a weak statistical power. Limited evidence from randomised controlled trials suggests that corticosteroid treatment offers short-term benefit in myasthenia gravis compared with placebo. This supports the conclusions of observational studies and expert opinion. Limited evidence from randomised controlled trials does not show any difference in efficacy between corticosteroids and either azathioprine or intravenous immunoglobulin.
This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 mcg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 mcg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung function at the end of the study compared with those on placebo (trough forced expiratory volume in one second (FEV1) MD 118.92 mL; 95% CI 113.07 to 124.77). This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The trials included in this review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg Handihaler.
We included seven RCTs with a total of 571 participants in the review. Two of the seven trials involved 36 participants undergoing non-cardiac vascular surgery (infrarenal aortic surgery), and five involved 535 participants undergoing cardiac surgery, including valvular surgery, coronary artery bypass surgery, and cardiopulmonary bypass surgery. The intervention was started from 11 days to 25 minutes before surgery in six trials and during surgery in one trial. We considered all seven RCTs to carry a high risk of bias. The effects of ACEIs or ARBs on perioperative mortality and acute myocardial infarction were uncertain because the quality of the evidence was very low. The risk of death was 2.7% in the ACEIs or ARBs group and 1.6% in the placebo group (risk ratio (RR) 1.61; 95% confidence interval (CI) 0.44 to 5.85). The risk of acute myocardial infarction was 1.7% in the ACEIs or ARBs group and 3.0% in the placebo group (RR 0.55; 95% CI 0.14 to 2.26). ACEIs or ARBs may improve congestive heart failure (cardiac index) perioperatively (mean difference (MD) -0.60; 95% CI -0.70 to -0.50, very low-quality evidence). In terms of rate of complications, there was no difference in perioperative cerebrovascular complications (RR 0.48; 95% CI 0.18 to 1.28, very low-quality evidence) and hypotension (RR 1.95; 95% CI 0.86 to 4.41, very low-quality evidence). Cardiac surgery-related renal failure was not reported. ACEIs or ARBs were associated with shortened length of hospital stay (MD -0.54; 95% CI -0.93 to -0.16, P value = 0.005, very low-quality evidence). These findings should be interpreted cautiously due to likely confounding by the clinical backgrounds of the participants. ACEIs or ARBs may shorten the length of hospital stay, (MD -0.54; 95% CI -0.93 to -0.16, very low-quality evidence) Two studies reported adverse events, and there was no evidence of a difference between the ACEIs or ARBs and control groups. Overall, this review did not find evidence to support that perioperative ACEIs or ARBs can prevent mortality, morbidity, and complications (hypotension, perioperative cerebrovascular complications, and cardiac surgery-related renal failure). We found no evidence showing that the use of these drugs may reduce the rate of acute myocardial infarction. However, ACEIs or ARBs may increase cardiac output perioperatively. Due to the low and very low methodology quality, high risk of bias, and lack of power of the included studies, the true effect may be substantially different from the observed estimates. Perioperative (mainly elective cardiac surgery, according to included studies) initiation of ACEIs or ARBs therapy should be individualized.
Thirteen studies met the eligibility criteria of the review, randomising 2157 adults. Education significantly reduced future hospital admissions (RR 0.50; 95% CI 0.27 to 0.91, high quality evidence); however, the estimated reduction in risk of re-presentation at ED following intervention was imprecise and did not reach statistical significance (RR 0.72; 95% CI 0.47 to 1.11, low quality evidence). Symptom control improved following education. The lack of statistically significant differences between asthma education and control groups in terms of peak flow, quality of life, study withdrawal and days lost were hard to interpret given the low number of studies contributing to these outcomes and statistical variation between the study results. Two studies from the USA measured costs: one study from the early 1990s measured cost and found no difference for total costs and costs related to physician visits and admissions to hospital. If data were restricted to emergency department treatment, education led to lower costs than control. A study from 2009 showed that associated costs of ED presentation and hospitalisation were lower following educational intervention. Our findings support educational interventions applied in the emergency department as a means of reducing subsequent asthma admissions to hospital. Whilst the direction of the effect on ED presentations was consistent with the reduction in risk of admission, the results were not definitive.. Outcomes were measured on average at 6 months after index ED presentation. The impact of educational intervention in this context on longer term outcomes relating to asthma morbidity is unclear. Priorities for additional research in this area include assessment of health-related quality of life, lung function assessment, exploration of the relationship between socio-economic status and asthma morbidity, and better description of the intervention assessed.
Six trials with 151 Japanese patients were included. All trials had high risk of bias. Four trials compared bezafibrate plus UDCA with no intervention plus UDCA (referenced as bezafibrate versus no intervention in the remaining text), and two trials compared bezafibrate with UDCA. No patient died and no patient developed liver-related complications in any of the included trials. Bezafibrate was without significant effects on the occurrence of adverse events compared with no intervention (5/32 (16%) versus 0/28 (0%)) (RR 5.40, 95% CI 0.69 to 42.32; 3 trials with 60 patients; I² = 0%) or with UDCA (2/32 (6%) versus 0/37 (0%)) (RR 6.19, 95% CI 0.31 to 122.05; 2 trials with 69 patients; I² = 0%). Bezafibrate significantly decreased the activity of serum alkaline phosphatases compared with no intervention (MD -186.04 U/L, 95% CI -249.03 to -123.04; 4 trials with 79 patients; I² = 34%) and when compared with UDCA (MD -162.90 U/L, 95% CI -199.68 to -126.12; 2 trials with 48 patients; I² = 0%). These results were supported by trial sequential analyses. Bezafibrate compared with no intervention significantly decreased plasma immunoglobulin M (MD -164.00 mg/dl, 95% CI -259.47 to -68.53; 3 trials with 50 patients; I² = 46%) and serum bilirubin concentration (MD -0.19 mg/dl, 95% CI -0.38 to -0.00; 2 trials with 34 patients; I² = 0%). However, the latter two results were not supported by trial sequential analyses. Bezafibrate compared with no intervention had no significant effect on the activity of serum gamma-glutamyltransferase (MD -1.22 U/L, 95% CI -11.97 to 9.52; 4 trials with 79 patients; I² = 42%) and serum alanine aminotransferase (MD -5.61 U/L, 95% CI -24.50 to 13.27; 2 trials with 35 patients; I² = 34%). Bezafibrate compared with UDCA had no significant effect on the activity of serum gamma-glutamyltransferase (MD 38.44 U/L, 95% CI -180.67 to 257.55; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -2.34 U/L, 95% CI -34.73 to 30.06; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -20.23 mg/dl, 95% CI -218.71 to 178.25; 2 trials with 41 patients; I² = 90%) in random-effects model meta-analyses, but bezafibrate significantly decreased the activity of serum gamma-glutamyltransferase (MD -58.18, 95% CI -76.49 to -39.88; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -13.94, 95% CI -18.78 to -9.09; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -99.90, 95% CI -130.72 to -69.07; 2 trials with 41 patients; I² = 90%) in fixed-effect model meta-analyses. One patient had bezafibrate withdrawn due to an adverse event compared to no intervention (RD 0.03, 95% CI -0.09 to 0.16; 2 trials with 60 patients; I² = 0%). This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver-related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors.
We included 24 studies (9,997 participants). Eighteen studies evaluated amiodarone for primary prevention and six for secondary prevention. Only three studies used an ICD concomitantly with amiodarone for the comparison (all of them for secondary prevention). For primary prevention, amiodarone compared to placebo or no intervention (17 studies, 8383 participants) reduced SCD (RR 0.76; 95% CI 0.66 to 0.88), cardiac mortality (RR 0.86; 95% CI 0.77 to 0.96) and all-cause mortality (RR 0.88; 95% CI 0.78 to 1.00). The quality of the evidence was low. Compared to other antiarrhythmics (three studies, 540 participants), amiodarone reduced SCD (RR 0.44; 95% CI 0.19 to 1.00), cardiac mortality (RR 0.41; 95% CI 0.20 to 0.86) and all-cause mortality (RR 0.37; 95% CI 0.18 to 0.76). The quality of the evidence was moderate. For secondary prevention, amiodarone compared to placebo or no intervention (two studies, 440 participants) appeared to increase the risk of SCD (RR 4.32; 95% CI 0.87 to 21.49) and all-cause mortality (RR 3.05; 1.33 to 7.01). However, the quality of the evidence was very low. Compared to other antiarrhythmics (four studies, 839 participants) amiodarone appeared to increase the risk of SCD (RR 1.40; 95% CI 0.56 to 3.52; very low quality of evidence), but there was no effect in all-cause mortality (RR 1.03; 95% CI 0.75 to 1.42; low quality evidence). Amiodarone was associated with an increase in pulmonary and thyroid adverse events. There is low to moderate quality evidence that amiodarone reduces SCD, cardiac and all-cause mortality when compared to placebo or no intervention for primary prevention, and its effects are superior to other antiarrhythmics. It is uncertain if amiodarone reduces or increases SCD and mortality for secondary prevention because the quality of the evidence was very low.
Nine randomised controlled trials involving 395 patients were included. Six out of nine studies had a follow-up of less than one year, the longest study duration was 24 months. Only a third of the analysed studies revealed a low risk of bias. No information was available on quality of life, all-cause mortality and morbidity. Compared with conventional management, IGB did not show convincing evidence of a greater weight loss. On the other hand, complications of intragastric balloon placement occurred, however few of a serious nature. The relative risks for minor complications like gastric ulcers and erosions were significantly raised. Evidence from this review is limited for decision making, since there was large heterogeneity in IGB trials, regarding both methodological and clinical aspects. However, a co-adjuvant factor described by some authors in the loss and maintenance of weight has been the motivation and the encouragement to changing eating habits following a well-organized diet and a program of behavioural modification. The IGB alone and the technique of positioning appear to be safe. Despite the evidence for little additional benefit of the intragastric balloon in the loss of weight, its cost should be considered against a program of eating and behavioural modification.
Seventeen trials with 1067 participants met the inclusion criteria. However, the required data from three included trials and some of the data from a fourth trial were not published and not made available. The included trials were highly heterogeneous in terms of subtype and severity of participants' dementia, and type, duration, and frequency of exercise. Only two trials included participants living at home. Our meta-analysis revealed that there was no clear evidence of benefit from exercise on cognitive functioning. The estimated standardized mean difference between exercise and control groups was 0.43 (95% CI -0.05 to 0.92, P value 0.08; 9 studies, 409 participants). There was very substantial heterogeneity in this analysis (I² value 80%), most of which we were unable to explain, and we rated the quality of this evidence as very low. We found a benefit of exercise programs on the ability of people with dementia to perform ADLs in six trials with 289 participants. The estimated standardized mean difference between exercise and control groups was 0.68 (95% CI 0.08 to 1.27, P value 0.02). However, again we observed considerable unexplained heterogeneity (I² value 77%) in this meta-analysis, and we rated the quality of this evidence as very low. This means that there is a need for caution in interpreting these findings. In further analyses, in one trial we found that the burden experienced by informal caregivers providing care in the home may be reduced when they supervise the participation of the family member with dementia in an exercise program. The mean difference between exercise and control groups was -15.30 (95% CI -24.73 to -5.87; 1 trial, 40 participants; P value 0.001). There was no apparent risk of bias in this study. In addition, there was no clear evidence of benefit from exercise on neuropsychiatric symptoms (MD -0.60, 95% CI -4.22 to 3.02; 1 trial, 110 participants; P value .0.75), or depression (SMD 0.14, 95% CI -0.07 to 0.36; 5 trials, 341 participants; P value 0.16). We could not examine the remaining outcomes, quality of life, mortality, and healthcare costs, as either the appropriate data were not reported, or we did not retrieve trials that examined these outcomes. There is promising evidence that exercise programs may improve the ability to perform ADLs in people with dementia, although some caution is advised in interpreting these findings. The review revealed no evidence of benefit from exercise on cognition, neuropsychiatric symptoms, or depression. There was little or no evidence regarding the remaining outcomes of interest (i.e., mortality, caregiver burden, caregiver quality of life, caregiver mortality, and use of healthcare services).
No new trials were included from the 2012 search. The review still includes two trials of short duration comparing sulpiride with placebo (total n = 113). No study reported our primary outcome of interest of 'global state: clinically significant response', nor our secondary outcomes of interest of 'quality of life', 'severe adverse effects', and 'safety assessments'. As regards mental state, there were no clear differences between groups for either positive or negative symptoms; measured positive symptoms using the Manchester scale were skewed and therefore not included in meta-analysis (n = 18, 1 RCT, very low quality evidence). Measured negative symptoms using the Manchester scale also demonstrated no clear difference (n = 18, 1 RCT, MD -3.0 CI -1.66 to 1.06, very low quality evidence). Few people left these studies by three months (n = 113, 2 RCTs, RR 1.00 CI 0.25 to 4.00). One subscore finding demonstrated a significant improvement in social behaviour using the Current Behaviour Schedule (CBS) when receiving placebo (n = 18, 1 RCT, MD -2.90 CI -5.60 to -0.20). There were no data for many important outcomes such as global outcomes, service use or adverse effects. Sulpiride may be an effective antipsychotic drug but evidence of its superiority over placebo from randomised trials is very limited. Practice will have to use evidence from sources other than trials until better evidence is generated.
We included five RCTs involving a total of 1231 participants with NMIBC in this review. Due to poor reporting, the risk of bias in the included studies was often unclear. We assessed the studies under two main comparisons: intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs), and intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT). Intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs): We observed no clear difference between BCG plus IFN-α and BCG alone for recurrence (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.44 to 1.32; 4 RCTs; 925 participants; very low-quality evidence) or progression (average RR 0.26, 95% CI 0.04 to 1.87; 2 RCTs; 219 participants; low-quality evidence). The included RCTs did not report on the other primary outcome of this review, discontinuation of therapy due to adverse events. Regarding secondary outcomes, we observed no clear difference for disease-specific mortality (RR 0.38, 95% CI 0.05 to 3.05; 1 RCT; 99 participants; very low-quality evidence). Two RCTs reporting contradictory findings for adverse events could not be pooled due to variation in definitions. There were no data from the included RCTs on time-to-death or disease-specific quality of life. Intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT): We observed shorter time-to-recurrence for participants in the BCG alternating with IFN-α group compared with the BCG alone group (hazard ratio (HR) 2.86, 95% CI 1.98 to 4.13; 1 RCT; 205 participants; low-quality evidence), but no clear differences in time-to-progression (HR 2.39, 95% CI 0.92 to 6.21; 1 RCT; 205 participants; low-quality evidence) and discontinuation of therapy due to adverse events (RR 2.97, 95% CI 0.31 to 28.09; 1 RCT; 205 participants; low-quality evidence). Regarding secondary outcomes, there were no clear differences between the BCG alternating with IFN-α and BCG alone groups for disease-specific mortality (HR 2.74, 95% CI 0.73 to 10.28; 1 RCT; 205 participants; low-quality evidence), time-to-death (overall survival) (HR 1.00, 95% CI 0.68 to 1.47; 1 RCT; 205 participants; low-quality evidence), or systemic or local adverse events (RR 1.65, 95% CI 0.41 to 6.73; 1 RCT; 205 participants; low-quality evidence). There were no data on disease-specific quality of life. We found low- to very low-quality evidence suggesting no clear differences in recurrence or progression with BCG plus IFN-α compared with BCG alone for people with NMIBC; there was no information to determine the effect on discontinuation of therapy due to adverse events. Low-quality evidence suggests BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggests no clear differences for time-to-progression or discontinuation of therapy due to adverse events. Additional high-quality, adequately powered trials using standardised instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumour characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to adverse events, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.
We identified 3745 citations after de-duplication of search results and excluded 3619 records during title and abstract reviews. We assessed 126 full-text papers for inclusion in the review, of which four publications (on three RCTs) providing data from 1100 people met eligibility criteria for this review. All three RCTs had methodological limitations due to high attrition rates. Overall, moderate-quality evidence indicates that bupropion XL is an efficacious intervention for prevention of recurrence of depressive episodes in people with a history of SAD (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.44 to 0.72; 3 RCTs, 1100 participants). However, bupropion XL leads to greater risk of headaches (moderate-quality evidence), insomnia and nausea (both low-quality evidence) when compared with placebo. Numbers needed to treat for additional beneficial outcomes (NNTBs) vary by baseline risks. For a population with a yearly recurrence rate of 30%, the NNTB is 8 (95% CI 6 to 12). For populations with yearly recurrence rates of 50% and 60%, NNTBs are 5 (95% CI 4 to 7) and 4 (95% CI 3 to 6), respectively. We could find no studies on other SGAs and no studies comparing SGAs with other interventions of interest, such as light therapy, psychological therapies, melatonin or agomelatine. Available evidence indicates that bupropion XL is an effective intervention for prevention of recurrence of SAD. Nevertheless, even in a high-risk population, three out of four people will not benefit from preventive treatment with bupropion XL and will be at risk for harm. Clinicians need to discuss with patients advantages and disadvantages of preventive SGA treatment, and might want to consider offering other potentially efficacious interventions, which might confer a lower risk of adverse events. Given the lack of comparative evidence, the decision for or against initiating preventive treatment of SAD and the treatment selected should be strongly based on patient preferences. Future researchers need to assess the effectiveness and risk of harms of SGAs other than bupropion for prevention of SAD. Investigators also need to compare benefits and harms of pharmacological and non-pharmacological interventions.
Four controlled trials of 3,4-diaminopyridine compared with placebo in a total of 54 participants with Lambert-Eaton myasthenic syndrome were eligible: three cross-over trials and one parallel group. Two were added at this update. One of these trials also assessed pyridostigmine in conjunction with 3,4-diaminopyridine. A further cross-over trial compared intravenous immunoglobulin (IVIg) to placebo in nine participants. Four trials of 3,4-diaminopyridine reported significant improvement in the primary outcome, muscle strength score, or myometric limb measurement for between hours and a week following treatment, and significant improvement in resting compound muscle action potential (CMAP) amplitude following 3,4-diaminopyridine, compared with placebo. A meta-analysis of the primary endpoint showed Quantitative Myasthenia Gravis (QMG) muscle score assessed between three and eight days was likely to improve by a mean of 2.44 points (95% confidence interval 3.6 to 1.22). Meta-analysis of the secondary endpoint CMAP amplitude also showed a mean improvement of 1.36 mV (95% confidence interval 0.99 to 1.72) over the same period. The risk of bias was determined to be low, and quality of evidence moderate to high. A single cross-over trial reported significant improvement in myometric limb strength and non-significant improvement in mean resting CMAP amplitude with IVIg compared to placebo. Clinical improvement lasted for up to eight weeks. Limited but moderate to high quality evidence from randomised controlled trials showed that over days 3,4-diaminopyridine, or for up to 8 weeks IVIg, improved muscle strength scores and CMAP amplitudes in participants with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this effect. Other possible treatments have not been tested in randomised controlled trials.
We identified 104 trials including 111,653 participants that met the inclusion criteria. Participants were mostly adult smokers from the general population, but some studies included teenagers, pregnant women, and people with long-term or mental health conditions. Most trials (58.7%) were at high risk of bias, while 30.8% were at unclear risk, and only 11.5% were at low risk of bias for all domains assessed. Most studies (100/104) assessed proactive telephone counselling, as opposed to reactive forms. Among trials including smokers who contacted helplines (32,484 participants), quit rates were higher for smokers receiving multiple sessions of proactive counselling (risk ratio (RR) 1.38, 95% confidence interval (CI) 1.19 to 1.61; 14 trials, 32,484 participants; I2 = 72%) compared with a control condition providing self-help materials or brief counselling in a single call. Due to the substantial unexplained heterogeneity between studies, we downgraded the certainty of the evidence to moderate. In studies that recruited smokers who did not call a helpline, the provision of telephone counselling increased quit rates (RR 1.25, 95% CI 1.15 to 1.35; 65 trials, 41,233 participants; I2 = 52%). Due to the substantial unexplained heterogeneity between studies, we downgraded the certainty of the evidence to moderate. In subgroup analysis, we found no evidence that the effect of telephone counselling depended upon whether or not other interventions were provided (P = 0.21), no evidence that more intensive support was more effective than less intensive (P = 0.43), or that the effect of telephone support depended upon whether or not people were actively trying to quit smoking (P = 0.32). However, in meta-regression, telephone counselling was associated with greater effectiveness when provided as an adjunct to self-help written support (P < 0.01), or to a brief intervention from a health professional (P = 0.02); telephone counselling was less effective when provided as an adjunct to more intensive counselling. Further, telephone support was more effective for people who were motivated to try to quit smoking (P = 0.02). The findings from three additional trials of smokers who had not proactively called a helpline but were offered telephone counselling, found quit rates were higher in those offered three to five telephone calls compared to those offered just one call (RR 1.27, 95% CI 1.12 to 1.44; 2602 participants; I2 = 0%). There is moderate-certainty evidence that proactive telephone counselling aids smokers who seek help from quitlines, and moderate-certainty evidence that proactive telephone counselling increases quit rates in smokers in other settings. There is currently insufficient evidence to assess potential variations in effect from differences in the number of contacts, type or timing of telephone counselling, or when telephone counselling is provided as an adjunct to other smoking cessation therapies. Evidence was inconclusive on the effect of reactive telephone counselling, due to a limited number studies, which reflects the difficulty of studying this intervention.
We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit). We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.
We included 61 studies with a total population of 6264 subfertile men, aged between 18 and 65 years, part of a couple who had been referred to a fertility clinic and some of whom were undergoing assisted reproductive techniques (ART). Investigators compared and combined 18 different oral antioxidants. The evidence was of 'low' to 'very low' quality: the main limitation was that out of the 44 included studies in the meta-analysis only 12 studies reported on live birth or clinical pregnancy. The evidence is current up to February 2018. Live birth: antioxidants may lead to increased live birth rates (OR 1.79, 95% CI 1.20 to 2.67, P = 0.005, 7 RCTs, 750 men, I2 = 40%, low-quality evidence). Results suggest that if in the studies contributing to the analysis of live birth rate, the baseline chance of live birth following placebo or no treatment is assumed to be 12%, the chance following the use of antioxidants is estimated to be between 14% and 26%. However, this result was based on only 124 live births from 750 couples in seven relatively small studies. When studies at high risk of bias were removed from the analysis, there was no evidence of increased live birth (Peto OR 1.38, 95% CI 0.89 to 2.16; participants = 540 men, 5 RCTs, P = 0.15, I2 = 0%). Clinical pregnancy rate: antioxidants may lead to increased clinical pregnancy rates (OR 2.97, 95% CI 1.91 to 4.63, P < 0.0001, 11 RCTs, 786 men, I2 = 0%, low-quality evidence) compared to placebo or no treatment. This suggests that if in the studies contributing to the analysis of clinical pregnancy, the baseline chance of clinical pregnancy following placebo or no treatment is assumed to be 7%, the chance following the use of antioxidants is estimated to be between 12% and 26%. This result was based on 105 clinical pregnancies from 786 couples in 11 small studies. Adverse events Miscarriage: only three studies reported on this outcome and the event rate was very low. There was no difference in miscarriage rate between the antioxidant and placebo or no treatment group (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low-quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, the chance following the use of an antioxidant would result in the risk of a miscarriage between 1% and 13%. Gastrointestinal: antioxidants may lead to an increase in mild gastrointestinal upsets when compared to placebo or no treatment (OR 2.51, 95% CI 1.25 to 5.03, P = 0.010, 11 RCTs, 948 men, I2 = 50%, very low-quality evidence). This suggests that if the chance of gastrointestinal upsets following placebo or no treatment is assumed to be 2%, the chance following the use of antioxidants is estimated to be between 2% and 9%. However, this result was based on a low event rate of 35 out of 948 men in 10 small or medium-sized studies, and the quality of the evidence was rated very low and was high in heterogeneity. We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as insufficient studies compared the same interventions. In this review, there is low-quality evidence from seven small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low-quality evidence suggests that clinical pregnancy rates may also increase. Overall, there is no evidence of increased risk of miscarriage, however antioxidants may give more mild gastrointestinal upsets but the evidence is of very low quality. Subfertilte couples should be advised that overall, the current evidence is inconclusive based on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes. Further large well-designed randomised placebo-controlled trials reporting on pregnancy and live births are still required to clarify the exact role of antioxidants.
We included five trials with a total of 1920 women. Two placebo-controlled trials of women with PMDD showed less severe premenstrual symptoms after three months with drospirenone 3 mg plus ethinyl estradiol 20 μg than with placebo (MD -7.92; 95% CI -11.16 to -4.67). The drospirenone group had greater mean decreases in impairment of productivity (MD -0.31; 95% CI -0.55 to -0.08), social activities (MD -0.29; 95% CI -0.54 to -0.04), and relationships (MD -0.30; 95% CI -0.54 to -0.06). Side effects more common with the use of the drospirenone COC contraceptive were nausea, intermenstrual bleeding, and breast pain. The respective odds ratios were 3.15 (95% CI 1.90 to 5.22), 4.92 (95% CI 3.03 to 7.96), and 2.67 (95% CI 1.50 to 4.78). Total adverse events related to the study drug were more likely for the drospirenone COC group (OR 2.36; 95% CI 1.62 to 3.44). Three trials studied the effect of drospirenone 3 mg plus ethinyl estradiol 30 μg on less severe symptoms. A placebo-controlled six-month trial had insufficient data for primary outcome analysis. Another six-month study used levonorgestrel 150 µg plus ethinyl estradiol 30 µg for the comparison group but did not provide enough data on premenstrual symptoms. In a two-year trial, the drospirenone COC group had similar premenstrual symptoms to the comparison group given desogestrel 150 µg plus ethinyl estradiol 30 µg (OR 0.87; 95% CI 0.63 to 1.22). The groups were also similar for adverse events related to treatment (OR 1.02; 95% CI 0.78 to 1.33). Drospirenone 3 mg plus ethinyl estradiol 20 μg may help treat premenstrual symptoms in women with severe symptoms, that is, premenstrual dysphoric disorder. The placebo also had a large effect. We do not know whether the combined oral contraceptive works after three cycles, helps women with less severe symptoms, or is better than other oral contraceptives. Larger and longer trials of higher quality are needed to address these issues. Trials should follow CONSORT guidelines.
Ten trials met the inclusion criteria. Telehealthcare was assessed as part of a complex intervention, including nurse case management and other interventions. Telehealthcare was associated with a clinically significant increase in quality of life in two trials with 253 participants (mean difference -6.57 (95% confidence interval (CI) -13.62 to 0.48); minimum clinically significant difference is a change of -4.0), but the confidence interval was wide. Telehealthcare showed a significant reduction in the number of patients with one or more emergency department attendances over 12 months; odds ratio (OR) 0.27 (95% CI 0.11 to 0.66) in three trials with 449 participants, and the OR of having one or more admissions to hospital over 12 months was 0.46 (95% CI 0.33 to 0.65) in six trials with 604 participants. There was no significant difference in the OR for deaths over 12 months for the telehealthcare group as compared to the usual care group in three trials with 503 participants; OR 1.05 (95% CI 0.63 to 1.75). Telehealthcare in COPD appears to have a possible impact on the quality of life of patients and the number of times patients attend the emergency department and the hospital. However, further research is needed to clarify precisely its role since the trials included telehealthcare as part of more complex packages.
Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome. About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms. A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.
Four studies were eligible for inclusion (281 participants): Two studies compared relaxation with electroacupuncture or superficial needling, one study compared relaxation with paced respiration or placebo control (α-wave electroencephalographic biofeedback) and one study compared relaxation with no treatment. No evidence was found of a difference between relaxation and acupuncture or superficial needle insertion in the number of hot flushes per 24 hours (mean difference (MD) 0.05, 95% confidence interval (CI) -1.33 to 1.43, two studies, 72 participants, I2 = 0%; very low-quality evidence). Nor did any evidence suggest a difference between the two interventions in hot flush severity, measured using the Kupperman Index (MD -1.32, 95% CI -5.06 to 2.43, two studies, 72 participants, I2 = 0%; very low-quality evidence). The other two studies found no clear evidence of a difference in hot flush frequency between relaxation and paced respiration, placebo or no treatment. The data for these comparisons were unsuitable for analysis. None of these studies reported night sweats, sleep disturbances associated with night sweats or adverse effects as an outcome. The main limitations of identified evidence were lack of data, imprecision and failure to report study methods in adequate detail. Evidence is insufficient to show the effectiveness of relaxation techniques as treatment for menopausal vasomotor symptoms, or to determine whether this treatment is more effective than no treatment, placebo, acupuncture, superficial needle insertion or paced respiration.
Our searches identified 1840 records, from which we included 40 completed reviews (19 Cochrane; 21 non-Cochrane), covering 18 individual interventions and dose and setting of interventions. The 40 reviews contain 503 studies (18,078 participants). We extracted pooled data from 31 reviews related to 127 comparisons. We judged the quality of evidence to be high for 1/127 comparisons (transcranial direct current stimulation (tDCS) demonstrating no benefit for outcomes of activities of daily living (ADLs)); moderate for 49/127 comparisons (covering seven individual interventions) and low or very low for 77/127 comparisons. Moderate-quality evidence showed a beneficial effect of constraint-induced movement therapy (CIMT), mental practice, mirror therapy, interventions for sensory impairment, virtual reality and a relatively high dose of repetitive task practice, suggesting that these may be effective interventions; moderate-quality evidence also indicated that unilateral arm training may be more effective than bilateral arm training. Information was insufficient to reveal the relative effectiveness of different interventions. Moderate-quality evidence from subgroup analyses comparing greater and lesser doses of mental practice, repetitive task training and virtual reality demonstrates a beneficial effect for the group given the greater dose, although not for the group given the smaller dose; however tests for subgroup differences do not suggest a statistically significant difference between these groups. Future research related to dose is essential. Specific recommendations for future research are derived from current evidence. These recommendations include but are not limited to adequately powered, high-quality RCTs to confirm the benefit of CIMT, mental practice, mirror therapy, virtual reality and a relatively high dose of repetitive task practice; high-quality RCTs to explore the effects of repetitive transcranial magnetic stimulation (rTMS), tDCS, hands-on therapy, music therapy, pharmacological interventions and interventions for sensory impairment; and up-to-date reviews related to biofeedback, Bobath therapy, electrical stimulation, reach-to-grasp exercise, repetitive task training, strength training and stretching and positioning. Large numbers of overlapping reviews related to interventions to improve upper limb function following stroke have been identified, and this overview serves to signpost clinicians and policy makers toward relevant systematic reviews to support clinical decisions, providing one accessible, comprehensive document, which should support clinicians and policy makers in clinical decision making for stroke rehabilitation. Currently, no high-quality evidence can be found for any interventions that are currently used as part of routine practice, and evidence is insufficient to enable comparison of the relative effectiveness of interventions. Effective collaboration is urgently needed to support large, robust RCTs of interventions currently used routinely within clinical practice. Evidence related to dose of interventions is particularly needed, as this information has widespread clinical and research implications.
We did not identify any trial comparing one TPO mimetic versus another. We analysed six eligible trials involving 746 adult patients. All trials were reported as randomised and double-blind trials including male and female patients. Two trials compared TPO mimetics (romiplostim or eltrombopag) with placebo, one trial evaluated eltrombopag in addition to the hypomethylating agent azacitidine, two trials analysed romiplostim additionally to a hypomethylating agent (azacitidine or decitabine) and one trial evaluated romiplostim in addition to the immunomodulatory drug lenalidomide. There are more data on romiplostim (four included, completed, full-text trials) than on eltrombopag (two trials included: one full-text publication, one abstract publication). Due to small sample sizes and imbalances in baseline characteristics in three trials and premature termination of two studies, we judged the potential risk of bias of all included trials as high. Due to heterogenous reporting, we were not able to pool data for OS. Instead of that, we analysed mortality during study. There is little or no evidence for a difference in mortality during study for thrombopoietin mimetics compared to placebo (RR 0.97, 95% confidence interval (CI) 0.73 to 1.27, N = 6 trials, 746 patients, low-quality evidence). It is unclear whether the use of TPO mimetics induces an acceleration of transformation to AML (RR 1.02, 95% CI 0.59 to 1.77, N = 5 trials, 372 patients, very low-quality evidence).Thrombopoietin mimetics probably improve the incidence of all bleeding events (RR 0.92, 95% CI 0.86 to 0.99, N = 5 trials, 390 patients, moderate-quality evidence). This means that in the study population, 713 out of 1000 in the placebo arm will have a bleeding event, compared to 656 of 1000 (95% CI 613 to 699) in the TPO mimetics arm. There is little or no evidence for a difference that TPO mimetics significantly diminish the rate of transfusion requirement (RR 0.83, 95% CI 0.66 to 1.05, N = 4 trials, 358 patients, low-quality evidence). No studies were found that looked at quality of life or duration of thrombocytopenia. There is no evidence that patients given TPO mimetics suffer more all adverse events (RR 1.01, 95% CI 0.96 to 1.07, N = 5 trials, 390 patients, moderate-quality evidence). There is uncertainty whether the number of serious adverse events decrease under therapy with TPO mimetics (RR 0.89, 95% CI 0.54 to 1.46, N = 4 trials, 356 patients, very low-quality evidence). We identified one ongoing study and one study marked as completed (March 2015), but without publication of results for MDS patients (only results reported for AML and MDS patients together). Both studies evaluate MDS patients receiving eltrombopag in comparison to placebo. No trial evaluated one TPO mimetic versus another. Six trials including adult patients analysed one TPO mimetic versus placebo, sometimes combined with standard therapy in both arms. Given the uncertainty of the quality of evidence, meta-analyses show that there is little or no evidence for a difference in mortality during study and premature progress to AML. However, these assumptions have to be further explored. Treatment with TPO mimetics resulted in a lower number of MDS patients suffering from bleeding events.There is no evidence for a difference between study groups regarding transfusion requirement. Enlarged sample sizes and a longer follow-up of future trials should improve the estimate of safety and efficacy of TPO mimetics, moreover health-related quality of life should be evaluated. As two ongoing studies currently investigate eltrombopag (one already completed, but without published results), we are awaiting results for this drug.
We identified six trials for inclusion. Five studies on 206 participants contributed data, while one study was available in abstract form only and was not fully incorporated into this review. For the primary outcome of endotracheal intubation there were two studies that contributed data: two intubations were needed in 45 participants on NPPV and no intubations in 41 control patients (risk ratio 4.48; 95% CI 0.23 to 89.13). There were no deaths in either of these studies. Length of hospital stay was reported in two studies, though meta-analysis was not possible. Hospitalisation was reported in one small study, in which there were three admissions out of 17 on NPPV and 10 admissions out of 16 in control patients (RR 0.28, 95% CI 0.09, 0.84). This review of studies has highlighted the paucity of data that exist to support the use of NPPV in patients in status asthmaticus. As such this course of treatment remains controversial despite its continued use in current clinical practice. Larger, prospective randomised controlled trials of rigorous methodological design are needed to determine the role of NPPV in patients with asthma.
We have included 18 studies (involving 1498 women) in this review. However, only nine of the included studies (with 750 women) reported 24 comparisons of analgesia with other analgesia or placebo and had data that could be included in our meta-analyses. The majority of studies investigated pharmacological analgesics and these were grouped into classes for this review. Non-steroidal anti-inflammatory drugs (NSAIDs) were significantly better than placebo at relieving pain from uterine involution as assessed by their summed pain intensity differences (SPID) (mean difference (MD) 4.34; 95% confidence interval (CI) 2.87 to 5.82; three studies, 204 women) and summed pain relief scores (MD 5.94; 95% CI 3.83 to 8.01; three studies, 204 women). NSAIDS were compared with opioids in one small study of 23 women reporting SPID and summed pain relief and found no difference. A larger study of 127 women found NSAIDs to be significantly better than opioids at reducing pain intensity six hours following study intervention (MD -0.70; 95% CI -1.04 to -0.35). Opioids were compared with placebo in three studies that could be included in meta-analyses; one small study of 23 women reporting SPID and summed pain relief and found no difference. One study of 95 women found no difference in pain intensity six hours following the study intervention. A third study of 108 women found significantly more women in the placebo group reported no pain relief than women in the opioid group (risk ratio 0.10; 95% CI 0.04 to 0.23). Aspirin was significantly better than paracetamol when pain intensity score was assessed six hours after study intervention (MD 0.85; 95% CI 0.29 to 1.41; one study 48 women) at relieving pain from uterine involution. Paracetamol was not better than placebo when pain intensity was assessed six hours after the study intervention in one study of 48 women. Non-steroidal anti-inflammatory drugs (NSAID) including aspirin were better than placebo at relieving pain from uterine cramping/involution following vaginal birth. NSAIDs were better than paracetamol and paracetamol was not better than placebo, though numbers of participants for these comparisons were small. Data for opioids compared with NSAIDs and opioids compared with placebo were conflicting, with some measures showing similar effect and others indicating NSAIDs were better than opioids and opioids were not better than placebo. There were insufficient data to make conclusions regarding the effectiveness of opioids at relieving pain from uterine cramping/involution. The median year of publication of included studies was 1981; therefore more research is needed to assess the effectiveness of current pharmacological and non-pharmacological analgesia at relieving pain from uterine cramping/involution following vaginal birth.
The updated search resulted in no new trials meeting the inclusion criteria of this review, thus leaving it to the seven already included randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention, and one evaluating tauro-ursodeoxycholic acid versus no intervention) enrolling a total of 335 participants. The administration of bile acids began one day or more after liver transplantation. All patients received the standard triple-drug immunosuppressive regimen (steroids, azathioprine, and cyclosporine or tacrolimus) to suppress the allograft rejection response after liver transplantation. Bile acids compared with placebo or no intervention did not significantly change all-cause mortality (RR 0.85, 95% CI 0.53 to 1.36), mortality related to allograft rejection (RR 0.30, 95% CI 0.01 to 7.12), retransplantation (RR 0.76, 95% CI 0.20 to 2.86), acute cellular rejection, or number of patients with steroid-resistant rejection. Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in a random-effects model meta-analysis. Bile acids were safe and well tolerated by liver-transplanted patients. However, this observation is based on data analysis from three trials with only 187 patients. We did not find evidence to support or refute bile acids for liver-transplanted patients. Further randomised trials are necessary before bile acids can be recommended to liver-transplanted patients.
This review update includes a total of 12 trials (944) women (type 1 diabetes: 660 women; type 2 diabetes: 113 women; type 1 or type 2 (unspecified): 171 women. The trials took place in Europe, the USA and Canada. Three of the 12 included studies are at low risk of bias, eight studies are at moderate risk of bias, and one study is at high risk of bias. Four trials reported that they were provided with the continuous glucose monitors free of charge or at a reduced cost by the manufacturer. Continuous glucose monitoring (CGM) versus intermittent glucose monitoring, (four studies, 609 women) CGM may reduce hypertensive disorders of pregnancy (pre-eclampsia and pregnancy-induced hypertension) (risk ratio (RR) 0.58, 95% confidence interval (CI) 0.39 to 0.85; 2 studies, 384 women; low-quality evidence), although it should be noted that only two of the four relevant studies reported data for this composite outcome. Conversely, this did not translate into a clear reduction for pre-eclampsia (RR 0.65, 95% CI 0.39 to 1.08; 4 studies, 609 women, moderate-quality evidence). There was also no clear reduction in caesarean section (average RR 0.94, 95% CI 0.75 to 1.18; 3 studies, 427 women; I2 = 41%; moderate-quality evidence) or large-for-gestational age (average RR 0.84, 95% CI 0.57 to 1.26; 3 studies, 421 women; I2 = 70%; low-quality evidence) with CGM. There was not enough evidence to assess perinatal mortality (RR 0.82, 95% CI 0.05 to 12.61, 71 infants, 1 study; low-quality evidence), or mortality or morbidity composite (RR 0.80, 95% CI 0.61 to 1.06; 1 study, 200 women) as the evidence was based on single studies of low quality. CGM appears to reduce neonatal hypoglycaemia (RR 0.66, 95% CI 0.48 to 0.93; 3 studies, 428 infants). Neurosensory disability was not reported. Other methods of glucose monitoring For the following five comparisons, self-monitoring versus a different type of self-monitoring (two studies, 43 women); self-monitoring at home versus hospitalisation (one study, 100 women), pre-prandial versus post-prandial glucose monitoring (one study, 61 women), automated telemedicine monitoring versus conventional system (three studies, 84 women), and constant CGM versus intermittent CGM (one study, 25 women), it is uncertain whether any of the interventions has any impact on any of our GRADE outcomes (hypertensive disorders of pregnancy, caesarean section, large-for-gestational age) because the quality of the evidence was found to be very low. This was due to evidence largely being derived from single trials, with design limitations and limitations with imprecision (wide CIs, small sample sizes, and few events). There was not enough evidence to assess perinatal mortality and neonatal mortality and morbidity composite. Other important outcomes, such as neurosensory disability, were not reported in any of these comparisons. Two new studies (406 women) have been incorporated to one of the comparisons for this update. Although the evidence suggests that CGM in comparison to intermittent glucose monitoring may reduce hypertensive disorders of pregnancy, this did not translate into a clear reduction for pre-eclampsia, and so this result should be viewed with caution. There was no evidence of a difference for other primary outcomes for this comparison. The evidence base for the effectiveness of other monitoring techniques analysed in the other five comparisons is weak and based on mainly single studies with very low-quality evidence. Additional evidence from large well-designed randomised trials is required to inform choices of other glucose monitoring techniques and to confirm the effectiveness of CGM.
Four trials involving 1873 participants, heterogeneous with respect to aetiology of ED, were included. Study design was two cross-over and two parallel group trials. Only the latter provided adequate data for meta-analyses. PGE1 was effective during follow-up in the "at least one successful intercourse" outcome (Peto Odds Ratio, OR 7.22, 95% CI. 5.68-9.18) . One cross-over study reported "at least one successful intercourse" in 63.6% of participants with at least one dose of PGE1 (P < 0.01 for each active dose versus placebo). In the other cross-over study, only one of three treatment groups conducted a self-evaluation (55.5%: "good" or "excellent" response). Adverse effects were most frequent in the treated groups and occurred more often and intensely as doses increased. Penile pain (Peto OR 7.39, 95% CI. 5.40-10.12) and minor urethral trauma (Peto OR 3.79, 95% CI. 1.88-7.65) were predominant. PGE1 was beneficial for many participants with ED of different aetiology. Adverse effects were proportional to dosage, albeit never serious. The use of PGE1 in ED could have been better interpreted if its effectiveness were compared by aetiology and with different forms of administrations, a longer follow-up were considered and more emphasis given to patient/partner relationships and quality of life.
Eleven studies met our inclusion criteria. Two studies did not report any outcome data relevant to the review, so the results of the review are based on nine trials that contributed data. Primary outcomes were perinatal mortality, serious maternal or infant outcomes, adverse drug reactions, birth before 48 hours of trial entry, birth before 34 weeks' gestation and preterm neonates delivered without a full course of antenatal steroids completed 24 hours before birth. The quality of evidence in included trials was mixed; only three of the trials were placebo controlled. The included trials examined seven different comparisons: intravenous (IV) ritodrine plus oral or IV magnesium (sulphate or gluconate) versus IV ritodrine alone (three trials, 231 women); IV ritodrine plus indomethacin suppositories versus IV ritodrine alone (one trial, 208 women); IV ritodrine plus vaginal progesterone versus IV ritodrine alone (one trial, 83 women); IV hexoprenaline sulphate plus IV magnesium hydrochloride versus IV hexoprenaline sulphate alone (one trial, 24 women); IV fenoterol plus oral naproxen versus IV fenoterol alone (one trial, 72 women); oral pentoxifylline plus IV magnesium sulphate plus IV fenoterol versus IV magnesium sulphate plus IV fenoterol (one trial, 125 women); and, IV terbutaline plus oral metoprolol versus IV terbutaline alone (one trial, 17 women). Few studies with small numbers of women were available for each comparison, hence very little data were pooled in meta-analysis. In all trials, not many of the primary outcomes were reported. Three trials examined intravenous (IV) ritodrine plus IV or oral magnesium (sulphate or gluconate) compared with IV ritodrine alone. One study, with 41 women, reported more adverse drug reactions in the group receiving the combined tocolytics (risk ratio (RR) 7.79, 95% confidence interval (CI) 1.11 to 54.80). Two trials reported discontinuation of therapy due to severe side effects (results were not combined due to high statistical heterogeneity, I² = 83%); one trial reported increased severe side effects in the group receiving IV ritodrine alone (RR 7.79, 95% CI 1.11 to 54.80, 41 women); in the other trial there was no clear difference between groups (RR 0.23, 95% CI 0.03 to 1.97, 107 women). Other primary outcomes were not reported. One trial assessed IV ritodrine plus indomethacin suppositories versus IV ritodrine alone. There were no significant differences between groups for perinatal mortality or serious neonatal morbidity. Results for other primary outcomes were not reported. There were no significant differences between groups receiving IV ritodrine plus vaginal progesterone compared with IV ritodrine alone for most outcomes reported, although the latency period (time from recruitment to delivery) was increased in the group receiving the combination of tocolytics. For other combinations of tocolytic agents, primary outcomes were rarely reported and for secondary outcomes results did not demonstrate differences between groups. It is unclear whether a combination of tocolytic drugs for preterm labour is more advantageous for women and/or newborns due to a lack of large, well-designed trials including the outcomes of interest. There are no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine) and/or oxytocin receptor antagonists (atosiban). Further trials are needed before specific conclusions on use of combination tocolytic therapy for preterm labour can be made.
We found four relevant studies providing data for 1809 employees, 60% of whom were allocated to the intervention group. All studies assessed outcomes immediately after the intervention had finished and the intervention duration varied between three to six months. All studies had usual treatment control conditions; however one study's usual treatment was an alternative physical activity programme while the other three had minimally active controls. In general, there was high risk of bias mainly due to lack of blinding, self reported outcome measurement, incomplete outcome data due to attrition, and most of the studies had not published protocols, which increases the likelihood of selective reporting. Three studies compared the pedometer programme to a minimally active control group, but the results for physical activity could not be combined because each study used a different measure of activity. One study observed an increase in physical activity under a pedometer programme, but the other two did not find a significant difference. For secondary outcomes we found improvements in body mass index, waist circumference, fasting plasma glucose, the quality of life mental component and worksite injury associated with the pedometer programmes, but these results were based on limited data from one or two small studies. There were no differences between the pedometer programme and the control group for blood pressure, a number of biochemical outcomes and the quality of life physical component. Sedentary behaviour and disease risk scores were not measured by any of the included studies. One study compared a pedometer programme and an alternative physical activity programme, but baseline imbalances made it difficult to distinguish the true improvements associated with either programme. Overall, there was insufficient evidence to assess the effectiveness of pedometer interventions in the workplace. There is a need for more high quality randomised controlled trials to assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes. To improve the quality of the evidence available, future studies should be registered in an online trials register, publish a protocol, allocate time and financial support to reducing attrition, and try to blind personnel (especially those who undertake measurement). To better identify the effects of pedometer interventions, future studies should report a core set of outcomes (total physical activity in METs, total time sitting in hours and minutes, objectively measured cardiovascular disease and type II diabetes risk factors, quality of life and injury), assess outcomes in the long term and undertake subgroup analyses based upon demographic subgroups (e.g. age, gender, educational status). Future studies should also compare different types of active intervention to test specific intervention components (eligibility, duration, step goal, step diary, settings), and settings (occupation, intervention provider). There was limited and low quality data providing insufficient evidence to assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes.
We identified 3745 citations through electronic searches and reviews of reference lists after deduplication of search results. We excluded 3619 records during title and abstract review and assessed 126 full-text papers for inclusion in the review. Only one study, providing data of 225 participants, met our eligibility criteria and compared agomelatine (25 mg/day) with placebo. We rated it as having high risk of attrition bias because nearly half of the participants left the study before completion. We rated the certainty of the evidence as very low for all outcomes, because of high risk of bias, indirectness, and imprecision. The main analysis based on data of 199 participants rendered an indeterminate result with wide confidence intervals (CIs) that may encompass both a relevant reduction as well as a relevant increase of SAD incidence by agomelatine (risk ratio (RR) 0.83, 95% CI 0.51 to 1.34; 199 participants; very low-certainty evidence). Also the severity of SAD may be similar in both groups at the end of the study with a mean SIGH-SAD (Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders) score of 8.3 (standard deviation (SD) 9.4) in the agomelatine group and 10.1 (SD 10.6) in the placebo group (mean difference (MD) -1.80, 95% CI -4.58 to 0.98; 199 participants; very low-certainty evidence). The incidence of adverse events and serious adverse events may be similar in both groups. In the agomelatine group, 64 out of 112 participants experienced at least one adverse event, while 61 out of 113 did in the placebo group (RR 1.06, 95% CI 0.84 to 1.34; 225 participants; very low-certainty evidence). Three out of 112 patients experienced serious adverse events in the agomelatine group, compared to 4 out of 113 in the placebo group (RR 0.76, 95% CI 0.17 to 3.30; 225 participants; very low-certainty evidence). No data on quality of life or interpersonal functioning were reported. We did not identify any studies on melatonin. Given the uncertain evidence on agomelatine and the absence of studies on melatonin, no conclusion about efficacy and safety of agomelatine and melatonin for prevention of SAD can currently be drawn. The decision for or against initiating preventive treatment of SAD and the treatment selected should consider patient preferences and reflect on the evidence base of all available treatment options.
We identified RCTs for the eight cardioprotective agents N-acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta-analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified. No definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient.
Findings were based on the results of a single study with some design limitations. Data were available from one study involving 162 women with a multiple pregnancy. For the only reported primary outcome, perinatal mortality, we are uncertain whether specialised antenatal clinics makes any difference compared to standard care (risk ratio (RR) 1.02; 95% confidence interval (CI) 0.26 to 4.03; 324 infants, very low quality evidence). Women receiving specialised antenatal care were significantly more likely to birth by caesarean section (RR 1.38; 95% CI 1.06 to 1.81; 162 women, moderate quality evidence). Data were not reported in the study on the following primary outcomes: small-for-gestational age, very preterm birth or maternal death. There were no differences identified between specialised antenatal care and standard care for other secondary outcomes examined: postnatal depression (RR 0.48; 95% CI 0.19 to 1.20; 133 women, very low quality evidence), breastfeeding (RR 0.63; 95% CI 0.24 to 1.68; 123 women, very low quality evidence), stillbirth (RR 0.68; 0.12 to 4.04) or neonatal death (RR 2.05; 95% CI 0.19 to 22.39) (324 infants). There is currently limited information available from randomised controlled trials to assess the role of 'specialised' antenatal clinics for women with a multiple pregnancy compared with 'standard' antenatal care in improving maternal and infant health outcomes. The value of 'specialised' multiple pregnancy clinics in improving health outcomes for women and their infants requires evaluation in appropriately powered and designed randomised controlled trials.
The searches identified two multicentre, randomized, double-blind controlled clinical trials eligible for inclusion in the review with a total of 78 participants (adults and children); one trial was done in people who were clinically stable, the other in people experiencing pulmonary exacerbations. These trials prospectively assessed whether the use of biofilm antimicrobial susceptibility testing improved microbiological and clinical outcomes in participants with cystic fibrosis who were infected with Pseudomonas aeruginosa. The primary outcome was the change in sputum Pseudomonas aeruginosa density from the beginning to the end of antibiotic therapy. Although the intervention was shown to be safe, the data from these two trials did not provide evidence that biofilm susceptibility testing was superior to conventional susceptibility testing either in terms of microbiological or lung function outcomes. One of the trials also measured risk and time to subsequent exacerbation as well as quality of life measures and did not demonstrate any difference between groups in these outcomes. Both trials had an overall low risk of bias and the quality of the evidence using GRADE criteria was deemed to be moderate to high for the outcomes selected. The current evidence is insufficient to recommend choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infections in people with cystic fibrosis. Biofilm antimicrobial susceptibility testing may be more appropriate in the development of newer, more effective formulations of drugs which can then be tested in clinical trials.
We included 10 randomised clinical trials with 474 participants. The trials compared terlipressin versus noradrenaline (seven trials), octreotide (one trial), midodrine and octreotide (one trial), or dopamine (one trial). All participants in both groups received albumin as cointervention. We classified two trials at low risk of bias and eight trials at high risk of bias in the assessment of mortality and all trials at high risk of bias for remaining outcomes. In five trials, investigators specifically stated that they did not receive funding from for-profit organisations. We had no information about the funding source from the remaining five trials. Terlipressin was not superior or inferior compared with other vasoactive drugs in regard to mortality when including the two trials with a low risk of bias (RR 0.92, 95% CI 0.63 to 1.36; 94 participants, very low quality evidence) or when including all 10 trials (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). One meta-analysis including nine trials suggested a beneficial effect of terlipressin on hepatorenal syndrome (RR 0.79, 95% CI 0.63 to 0.99; 394 participants; I² = 26%; very low quality evidence). Due to the high mortality of hepatorenal syndrome, the registration of other serious adverse events is uncertain, but comparing terlipressin and other vasoactive drugs we found no significant difference (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). Several trials did not report systematically of adverse events, but terlipressin seemed to increase the risks of diarrhoea or abdominal pain, or both (RR 3.50, 95% CI 1.19 to 10.27; 221 participants; 5 trials, I² = 0%). However, Trial Sequential Analyses found insufficient evidence to support or refute any differences between interventions for all outcomes. Considering reversal of hepatorenal syndrome, subgroup analyses on the type of other vasoactive drugs found that terlipressin was superior compared with midodrine and octreotide (RR 0.47, 95% CI 0.30 to 0.72) or octreotide alone (RR 0.56, 95% CI 0.33 to 0.96), but each subgroup only included one small trial. None of the remaining subgroup or sensitivity analyses found differences between terlipressin and other vasoactive drugs. We downgraded the evidence to very low quality because of the high risk of bias, imprecision, and the results of the Trial Sequential Analyses. This review found insufficient evidence to support or refute beneficial or harmful effects of terlipressin and albumin versus other vasoactive drugs and albumin. Additional research is needed to evaluate if clinically meaningful differences exist between interventions.
Three small RCTs met our inclusion criteria and included a total of 148 participants. These compared three treatments with topical phenytoin: hydrocolloid dressings, triple antibiotic ointment and simple dressings. In the three RCTs, 79% of participants had grade II ulcers, and 21% of participants had grade I ulcers; no participants had grade III or IV ulcers. Two RCTs had a high risk of bias overall and the other RCT was at unclear risk of bias due to poor reporting. Two RCTs had three intervention arms and the other had two intervention arms. Two studies compared topical phenytoin with hydrocolloid dressing (84 participants analysed). The available data suggest that hydrocolloid dressings may improve ulcer healing compared to topical phenytoin (39.3% ulcers healed for phenytoin versus 71.4% ulcers healed for hydrocolloid dressings (RR 0.55, 95% CI 0.33 to 0.92; 56 participants, 1 study; low quality evidence). We downgraded the evidence twice: once due to serious limitations (high risk of bias) and once due to the small sample size and small number of events. Two studies compared topical phenytoin with simple dressings (81 participants analysed). From the available data, we are uncertain whether topical phenytoin improves ulcer healing compared to simple dressings (39.3% ulcers healed for phenytoin versus 29.6% ulcers healed for the simple dressing (RR 1.33, 95% CI 0.63 to 2.78; 55 participants, 1 study; very low quality evidence). This evidence was downgraded once due to serious limitations (high risk of bias) and twice due to the low number of outcome events and resulting wide CI which included the possibility of both increased healing and reduced healing. We therefore considered it to be insufficient to determine the effect of topical phenytoin on ulcer healing. One study compared topical phenytoin with triple antibiotic ointment, however, none of the outcomes of interest to this review were reported. No adverse drug reactions or interactions were detected in any of the three RCTs. Minimal pain was reported in all groups in one trial that compared topical phenytoin with hydrocolloid dressings and triple antibiotic ointment. This review has considered the available evidence and the result shows that it is uncertain whether topical phenytoin improves ulcer healing for patients with grade I and II pressure ulcers. No adverse events were reported from three small trials and minimal pain was reported in one trial. Therefore, further rigorous, adequately powered RCTs examining the effects of topical phenytoin for treating pressure ulcers, and to report on adverse events, quality of life and costs are necessary.
We included 12 trials with 798 participants undergoing elective laparoscopic cholecystectomy randomised to different methods of intraperitoneal local anaesthetic instillation. All the trials were at high risk of bias. Most trials included only people with low anaesthetic risk. The comparisons included in the trials that met the eligibility criteria were the following; comparison of one local anaesthetic agent with another local anaesthetic agent (three trials); comparison of timing of delivery (six trials); comparison of different methods of delivery of the anaesthetic agent (two trials); comparison of location of the instillation of the anaesthetic agent (one trial); three trials reported mortality and morbidity. There were no mortalities or serious adverse events in either group in the following comparisons: bupivacaine (0/100 (0%)) versus lignocaine (0/106 (0%)) (one trial; 206 participants); just after creation of pneumoperitoneum (0/55 (0%)) versus end of surgery (0/55 (0%)) (two trials; 110 participants); just after creation of pneumoperitoneum (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (one trial; 30 participants); end of surgery (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (one trial; 30 participants). None of the trials reported quality of life, the time taken to return to normal activity, or the time taken to return to work. The differences in the proportion of people who were discharged as day-surgery and the length of hospital stay were imprecise in all the comparisons included that reported these outcomes (very low quality evidence). There were some differences in the pain scores on the visual analogue scale (1 to 10 cm) but these were neither consistent nor robust to fixed-effect versus random-effects meta-analysis or sensitivity analysis. The currently available evidence is inadequate to determine the effects of one method of local anaesthetic intraperitoneal instillation compared with any other method of local anaesthetic intraperitoneal instillation in low anaesthetic risk individuals undergoing elective laparoscopic cholecystectomy. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.
We identified eight eligible trials (236 participants), which tested intravenous immunoglobulin (IVIg), interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Two trials of IVIg (22 and 11 participants, including 20 with antibodies against MAG), had comparable interventions and outcomes, but both were short-term trials. We also included two trials of rituximab with comparable interventions and outcomes. There were very few clinical or statistically significant benefits of the treatments used on the outcomes predefined for this review, but not all the predefined outcomes were used in every included trial and more responsive outcomes are being developed. A well-performed trial of IVIg, which was at low risk of bias, showed a statistical benefit in terms of improvement in mRS at two weeks and 10-metre walk time at four weeks, but these short-term outcomes are of questionable clinical significance. Cyclophosphamide failed to show any benefit in the single trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. Two trials of rituximab (80 participants) have been published, one of which (26 participants) was at high risk of bias. In the meta-analysis, although the data are of low quality, rituximab is beneficial in improving disability scales (Inflammatory Neuropathy Cause and Treatment (INCAT) improved at eight to 12 months (risk ratio (RR) 3.51, 95% confidence interval (CI) 1.30 to 9.45; 73 participants)) and significantly more participants improve in the global impression of change score (RR 1.86, 95% CI 1.27 to 2.71; 70 participants). Other measures did not improve significantly, but wide CIs do not preclude some effect. Reported adverse effects of rituximab were few, and mostly minor. There were few serious adverse events in the other trials. There is inadequate reliable evidence from trials of immunotherapies in anti-MAG paraproteinaemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. IVIg has a statistically but probably not clinically significant benefit in the short term. The meta-analysis of two trials of rituximab provides, however, low-quality evidence of a benefit from this agent. The conclusions of this meta-analysis await confirmation, as one of the two included studies is of very low quality. We require large well-designed randomised trials of at least 12 months' duration to assess existing or novel therapies, preferably employing unified, consistent, well-designed, responsive, and valid outcome measures.
We included 12 studies randomising 310 patients, with data available for 266 patients after dropout. All but one study evaluated a fixed concentration of low dialysate [Na+], and one profiled dialysate [Na+]. Three studies were parallel group, and the remaining nine cross-over. Of the latter, only two used a washout between intervention and control periods. Most studies were short-term with a median (interquartile range) follow-up of 3 (3, 8.5) weeks. Two were of a single HD session, and two of a single week's HD. Half of the studies were conducted prior to 2000, and five reported use of obsolete HD practices. Risks of bias in the included studies were often high or unclear, lowering confidence in the results. Compared to neutral or high dialysate [Na+], low dialysate [Na+] had the following effects on "efficacy" endpoints: reduced interdialytic weight gain (10 studies: MD -0.35 kg, 95% CI -0.18 to -0.51; high certainty evidence); probably reduced predialysis mean arterial blood pressure (BP) (4 studies: MD -3.58 mmHg, 95% CI -5.46 to -1.69; moderate certainty evidence); probably reduced postdialysis mean arterial BP (MAP) (4 studies: MD -3.26 mmHg, 95% CI -1.70 to -4.82; moderate certainty evidence); probably reduced predialysis serum [Na+] (7 studies: MD -1.69 mM, 95% CI -2.36 to -1.02; moderate certainty evidence); may have reduced antihypertensive medication (2 studies: SMD -0.67 SD, 95% CI -1.07 to -0.28; low certainty evidence). Compared to neutral or high dialysate [Na+], low dialysate [Na+] had the following effects on "safety" endpoints: probably increased intradialytic hypotension events (9 studies: RR 1.56, 95% 1.17 to 2.07; moderate certainty evidence); probably increased intradialytic cramps (6 studies: RR 1.77, 95% 1.15 to 2.73; moderate certainty evidence). Compared to neutral or high dialysate [Na+], low dialysate [Na+] may make little or no difference to: intradialytic BP (2 studies: MD for systolic BP -3.99 mmHg, 95% CI -17.96 to 9.99; diastolic BP 1.33 mmHg, 95% CI -6.29 to 8.95; low certainty evidence); interdialytic BP (2 studies:, MD for systolic BP 0.17 mmHg, 95% CI -5.42 to 5.08; diastolic BP -2.00 mmHg, 95% CI -4.84 to 0.84; low certainty evidence); dietary salt intake (2 studies: MD -0.21g/d, 95% CI -0.48 to 0.06; low certainty evidence). Due to very low quality of evidence, it is uncertain whether low dialysate [Na+] changed extracellular fluid status, venous tone, arterial vascular resistance, left ventricular mass or volumes, thirst or fatigue. Studies did not examine cardiovascular or all-cause mortality, cardiovascular events, or hospitalisation. It is likely that low dialysate [Na+] reduces intradialytic weight gain and BP, which are effects directionally associated with improved outcomes. However, the intervention probably also increases intradialytic hypotension and reduces serum [Na+], effects that are associated with increased mortality risk. The effect of the intervention on overall patient health and well-being is unknown. Further evidence is needed in the form of longer-term studies in contemporary settings, evaluating end-organ effects in small-scale mechanistic studies using optimal methods, and clinical outcomes in large-scale multicentre RCTs.
We found few controlled trials. They were of short duration and enrolled small numbers of patients. Because of their poor internal validity, the characteristics of the populations studied, and the types of interventions and outcomes, none of the trials fitted our criteria for inclusion. However, all these trials found BtA to be superior to placebo as did large case-control and cohort studies, which reported that around 90% of patients benefited. There are no high quality, randomised, controlled efficacy data to support the use of Bt for blepharospasm. Despite this, other studies suggest that BtA is highly effective and safe for treating blepharospasm and support its use.  The effect size (90% of patients benefit) seen in open studies makes it very difficult and probably unethical to perform new placebo-controlled trials of efficacy of BtA for blepharospasm.  Future trials should explore technical factors such as the optimum treatment intervals, different injection techniques, doses, Bt types and formulations. Other issues include service delivery, quality of life, long-term efficacy, safety, and immunogenicity.
We included 10 trials involving 1904 participants. The risk of bias was low in six studies. Four studies were open label and were rated as high risk of performance bias. One of these studies was also rated as high risk for attrition bias. Four trials reported on poor outcome (death, vegetative state, or severe disability) with a pooled risk ratio (RR) of 1.02 (95% confidence interval (CI) 0.91 to 1.15). All trials reported on death from all causes with a pooled RR of 1.00 (95% CI 0.85 to 1.18). In a trial that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for cerebral ischaemia the RR for poor outcome was 0.85 (95% CI 0.64 to 1.14). Antifibrinolytic treatment reduced the risk of re-bleeding reported at the end of follow-up (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 participants), but there was heterogeneity (I² = 62%) between the trials. The pooled RR for reported cerebral ischaemia was 1.41 (95% CI 1.04 to 1.91, 83 per 1000 participants), again with heterogeneity between the trials (I² = 52%). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus in five trials (RR 1.11, 95% CI 0.90 to 1.36). The current evidence does not support the use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage, even in those who have concomitant treatment strategies to prevent cerebral ischaemia. Results on short-term treatment are promising, but not conclusive. Further randomised trials evaluating short-term antifibrinolytic treatment are needed to evaluate its effectiveness.
This update included 94 studies (62 new) with 9,821 participants. Most participants were women living in their own home. Most trials were judged at unclear risk of selection bias, generally reflecting inadequate reporting of the randomisation methods, but at high risk of performance bias relating to lack of participant blinding, which is largely unavoidable for these trials. Most studies only reported outcome up to the end of the exercise programme. There were eight categories of exercise programmes. These are listed below together with primary measures of balance for which there was some evidence of a statistically significant effect at the end of the exercise programme. Some trials tested more than one type of exercise. Crucially, the evidence for each outcome was generally from only a few of the trials for each exercise category.   1. Gait, balance, co-ordination and functional tasks (19 studies of which 10 provided primary outcome data): Timed Up & Go test (mean difference (MD) -0.82 s; 95% CI -1.56 to -0.08 s, 114 participants, 4 studies); walking speed (standardised mean difference (SMD) 0.43; 95% CI 0.11 to 0.75, 156 participants, 4 studies), and the Berg Balance Scale (MD 3.48 points; 95% CI 2.01 to 4.95 points, 145 participants, 4 studies). 2. Strengthening exercise (including resistance or power training) (21 studies of which 11 provided primary outcome data): Timed Up & Go Test (MD -4.30 s; 95% CI -7.60 to -1.00 s, 71 participants, 3 studies); standing on one leg for as long as possible with eyes closed (MD 1.64 s; 95% CI 0.97 to 2.31 s, 120 participants, 3 studies); and walking speed (SMD 0.25; 95% CI 0.05 to 0.46, 375 participants, 8 studies). 3. 3D (3 dimensional) exercise (including Tai Chi, qi gong, dance, yoga) (15 studies of which seven provided primary outcome data): Timed Up & Go Test (MD -1.30 s; 95% CI -2.40 to -0.20 s, 44 participants, 1 study); standing on one leg for as long as possible with eyes open (MD 9.60 s; 95% CI 6.64 to 12.56 s, 47 participants, 1 study), and with eyes closed (MD 2.21 s; 95% CI 0.69 to 3.73 s, 48 participants, 1 study); and the Berg Balance Scale (MD 1.06 points; 95% CI 0.37 to 1.76 points, 150 participants, 2 studies). 4. General physical activity (walking) (seven studies of which five provided primary outcome data).   5. General physical activity (cycling) (one study which provided data for walking speed).   6. Computerised balance training using visual feedback (two studies, neither of which provided primary outcome data).   7. Vibration platform used as intervention (three studies of which one provided primary outcome data). 8. Multiple exercise types (combinations of the above) (43 studies of which 29 provided data for one or more primary outcomes): Timed Up & Go Test (MD -1.63 s; 95% CI -2.28 to -0.98 s, 635 participants, 12 studies); standing on one leg for as long as possible with eyes open (MD 5.03 s; 95% CI 1.19 to 8.87 s, 545 participants, 9 studies), and with eyes closed ((MD 1.60 s; 95% CI -0.01 to 3.20 s, 176 participants, 2 studies); and the Berg Balance Scale ((MD 1.84 points; 95% CI 0.71 to 2.97 points, 80 participants, 2 studies). Few adverse events were reported but most studies did not monitor or report adverse events. In general, the more effective programmes ran three times a week for three months and involved dynamic exercise in standing. There is weak evidence that some types of exercise (gait, balance, co-ordination and functional tasks; strengthening exercise; 3D exercise and multiple exercise types) are moderately effective, immediately post intervention, in improving clinical balance outcomes in older people. Such interventions are probably safe. There is either no or insufficient evidence to draw any conclusions for general physical activity (walking or cycling) and exercise involving computerised balance programmes or vibration plates. Further high methodological quality research using core outcome measures and adequate surveillance is required.
We included seven randomised controlled trials (recruiting a total of 799 participants) evaluating four distinct models of care: multi-systemic therapy (MST) at home, specialist outpatient service, intensive home treatment and intensive home-based crisis intervention ('Homebuilders' model for crisis intervention). Young people receiving home-based MST experienced some improved functioning in terms of externalising symptoms and they spent fewer days out of school and out-of-home placement. At short term follow up the control group had a greater improvement in terms of adaptability and cohesion; this was not sustained at four months follow up. There were small, significant patient improvements reported in both groups in the trial evaluating the intensive home-based crisis intervention using the 'Homebuilders' model. No differences at follow up were reported in the two trials evaluating intensive home treatment, or in the trials evaluating specialist outpatient services. The quality of the evidence base currently provides very little guidance for the development of services. If randomised controlled trials are not feasible then consideration should be given to alternative study designs, such as prospective systems of audit conducted across several centres, as this has the potential to improve the current level of evidence. These studies should include baseline measurement at admission along with demographic data, and outcomes measured using a few standardised robust instruments.
We included 33 trials with 10,325 participants, of which 17 trials were new trials. Ten trials compared a daily multiple micronutrient supplement to placebo in doses up to 20 times the dietary reference intake, and one trial compared a daily standard dose with a high daily dose of multivitamins. Nineteen trials compared supplementation with single or dual micronutrients (such as vitamins A and D, zinc, and selenium) to placebo, and three trials compared different dosages or combinations of micronutrients. Multiple micronutrients We conducted analyses across antiretroviral therapy (ART)-naive adults (3 trials, 1448 participants), adults on antiretroviral therapy (ART) (1 trial, 400 participants), and ART-naive adults with concurrent active tuberculosis (3 trials, 1429 participants). Routine multiple micronutrient supplementation may have little or no effect on mortality in adults living with HIV (RR 0.91, 95% CI 0.72 to 1.15; 7 trials, 2897 participants, low certainty evidence). Routine supplementation for up to two years may have little or no effect on the average of mean CD4+ cell count (MD 26.40 cells/mm³, 95% CI −22.91 to 75.70; 6 trials, 1581 participants, low certainty evidence), or the average of mean viral load (MD −0.1 log10viral copies, 95% CI −0.26 to 0.06; 4 trials, 840 participants, moderate certainty evidence). One additional trial in ART-naïve adults did report an increase in the time to reach a CD4+ cell count < 250 cells/mm³ after two years of high dose supplementation in Botswana (HR 0.48, 95% CI 0.26 to 0.88; 1 trial, 439 participants). However, the trial authors reported this effect only in the trial arm that received multiple micronutrients plus selenium (not either supplementation alone), which is inconsistent with the findings of other trials that used similar combinations of micronutrients and selenium. In one additional trial that compared high-dose multiple micronutrient supplementation with standard doses in people on ART, peripheral neuropathy was lower with high dose supplements compared to standard dose (incidence rate ratio (IRR) 0.81, 95% CI 0.7 to 0.94; 1 trial, 3418 participants), but the trial was stopped early due to increased adverse events (elevated alanine transaminase (ALT) levels) in the high dose group. Single or dual micronutrients None of the trials of single or dual micronutrient supplements were adequately powered to assess for effects on mortality or morbidity outcomes. No clinically significant changes in CD4 cell count (data not pooled, 14 trials, 2370 participants, very low or low certainty evidence) or viral load (data not pooled, seven studies, 1334 participants, very low or low certainty evidence), were reported. Supplementation probably does increase blood concentrations of vitamin D and zinc (data not pooled, vitamin D: 4 trials, 299 participants, zinc: 4 trials, 484 participants, moderate certainty evidence) and may also increase blood concentrations of vitamin A (data not pooled, 3 trials, 495 participants, low certainty evidence), especially in those who are deficient. The analyses of the available trials have not revealed consistent clinically important benefits with routine multiple micronutrient supplementation in people living with HIV. Larger trials might reveal small but important effects. These findings should not be interpreted as a reason to deny micronutrient supplements for people living with HIV where specific deficiencies are found or where the person's diet is insufficient to meet the recommended daily allowance of vitamins and minerals.
We identified one additional study enrolling 38 participants for inclusion in this update, for a total of nine studies reporting on 544 infants. In general, the quality of the studies was low, mainly owing to lack of blinding and small sample sizes. Six studies enrolling 424 infants compared CL versus ND. No study reported on weight at three or six months. One study (n = 40) found no statistically significant difference in weight at four months between CL and ND groups. In another study (n = 62), the ratio of day-night activity before discharge favoured the CL group (mean difference (MD) 0.18, 95% confidence interval (CI) 0.17 to 0.19), indicating 18% more activity during the day than during the night in the CL group compared with the ND group. Two studies (n = 189) reported on retinopathy of prematurity (stage ≥ 3) and reported no statistically significant differences between CL and ND groups (typical risk ratio (RR) 0.53, 95% CI 0.25 to 1.11, I2 = 0%; typical risk difference (RD) -0.09, 95% CI -0.19 to 0.01, I2 = 0%). Two studies (n = 77) reported length of hospital stay (days) and noted a significant reduction in length of stay between CL and ND groups favouring the CL group (weighted mean difference (WMD) -13 days, 95% CI -23 to -2, I2 = 0%; no heterogeneity). The quality of the evidence according to GRADE was low for this outcome. One study (n = 37) reported less crying at 11 weeks' corrected age (CA) in the CL group compared with the ND group (MD -0.57 hours/24 h, 95% CI -1.09 to -0.05). Tests for heterogeneity were not applicable. Three studies enrolling 120 infants compared CL versus CBL. Two studies (n = 79) reported significantly shorter length of stay in the CL group compared with the CBL group (WMD -16.5 days, 95% CI -26.2 to -6.8, I2 = 0%; no heterogeneity). The quality of the evidence according to GRADE was low for this outcome. One study (n = 41) reported higher mean weight at three months' CA among infants cared for in the CL nursery (P value < 0.02) and a lower mean number of hours spent awake in 24 hours at three months of age (P value < 0.005). Data could not be entered into RevMan or GRADE. One study (n = 41) reported shorter time on the ventilator in the CL compared with the CBL group (MD -18.2 days, 95% CI -31.40 to -5.0). One study (n = 41) reported a shorter time to first oral feeding in the CL group (MD -6.8 days, 95% CI -13.29 to -0.31). We identified no safety issues. Trials assessing the effects of CL have enrolled 544 infants. No study reported on our primary outcome of weight at three or six months. Results from one additional study strengthen our findings that CL versus CBL shortens length of stay, as does CL versus ND. The quality of the evidence on both comparisons for this outcome according to GRADE was low. Future research should focus on comparing CL versus ND.
We included 12 RCTs (1249 participants), three more than the previous Cochrane review, comparing physiotherapy with no intervention. Five trials (246 participants) evaluated conventional techniques (vibration and percussion plus postural drainage), and seven trials (1003 participants) evaluated passive flow-oriented expiratory techniques: slow passive expiratory techniques in four trials, and forced passive expiratory techniques in three trials. Conventional techniques failed to show a benefit in the primary outcome of change in severity status of bronchiolitis measured by means of clinical scores (five trials, 241 participants analysed). Safety of conventional techniques has been studied only anecdotally, with one case of atelectasis, the collapse or closure of the lung resulting in reduced or absent gas exchange, reported in the control arm of one trial. Slow passive expiratory techniques failed to show a benefit in the primary outcomes of severity status of bronchiolitis and in time to recovery (low quality of evidence). Three trials analysing 286 participants measured severity of bronchiolitis through clinical scores, with no significant differences between groups in any of these trials, conducted in patients with moderate and severe disease. Only one trial observed a transient significant small improvement in the Wang clinical score immediately after the intervention in patients with moderate severity of disease. There is very low quality evidence that slow passive expiratory techniques seem to be safe, as two studies (256 participants) reported that no adverse effects were observed. Forced passive expiratory techniques failed to show an effect on severity of bronchiolitis in terms of time to recovery (two trials, 509 participants) and time to clinical stability (one trial, 99 participants analysed). This evidence is of high quality and corresponds to patients with severe bronchiolitis. Furthermore, there is also high quality evidence that these techniques are related to an increased risk of transient respiratory destabilisation (risk ratio (RR) 5.4, 95% confidence interval (CI) 1.6 to 18.4, one trial) and vomiting during the procedure (RR 10.2, 95% CI 1.3 to 78.8, one trial). Results are inconclusive for bradycardia with desaturation (RR 1.0, 95% CI 0.2 to 5.0, one trial) and bradycardia without desaturation (RR 3.6, 95% CI 0.7 to 16.9, one trial), due to the limited precision of estimators. However, in mild to moderate bronchiolitis patients, forced expiration combined with conventional techniques produced an immediate relief of disease severity (one trial, 13 participants). None of the chest physiotherapy techniques analysed in this review (conventional, slow passive expiratory techniques or forced expiratory techniques) have demonstrated a reduction in the severity of disease. For these reasons, these techniques cannot be used as standard clinical practice for hospitalised patients with severe bronchiolitis. There is high quality evidence that forced expiratory techniques in severe patients do not improve their health status and can lead to severe adverse events. Slow passive expiratory techniques provide an immediate and transient relief in moderate patients without impact on duration. Future studies should test the potential effect of slow passive expiratory techniques in mild to moderate non-hospitalised patients and patients who are respiratory syncytial virus (RSV) positive. Also, they could explore the combination of chest physiotherapy with salbutamol or hypertonic saline.
We included four trials in which 3267 children aged two to 35 months participated. Analysis showed that zinc supplementation in addition to standard antibiotic therapy in children with severe and non-severe pneumonia failed to show a statistically significant effect on time-to-clinical recovery (hazard ratio 1.02; 95% confidence interval (CI) 0.93 to 1.11). Similary, zinc supplementation in children with severe pneumonia, as an adjunct to standard antibiotic therapy, did not show a statistically significant effect on time-to-recovery from tachypnoea (respiratory rate > 50 breaths per minute) (hazard ratio 1.13; 95% CI 0.82 to 1.57) and time-to-recovery from chest in-drawing (hazard ratio 1.08; 95% CI 0.88 to 1.31) as compared to the control group. Zinc supplementation in children with severe pneumonia also showed a non-significant effect on time-to-hospital discharge as compared to the control (hazard ratio 1.04; 95% CI 0.89 to 1.22). Evidence provided in this review is insufficient to recommend the use of zinc as an adjunct to standard antibiotic therapy for pneumonia in children aged two to 35 months.
Twenty-one studies (772 participants) were included in this review with two additional 2012 studies identified as 'awaiting classification'. Physical training was well tolerated with no adverse effects reported. None of the studies mentioned worsening of asthma symptoms following physical training. Physical training showed marked improvement in cardiopulmonary fitness as measured by a statistically and clinically significant increase in maximum oxygen uptake (mean difference (MD) 4.92 mL/kg/min; 95% confidence interval (CI) 3.98 to 5.87; P < 0.00001; 8 studies on 267 participants); however, no statistically significant effects were observed for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), minute ventilation at maximal exercise (VEmax) or peak expiratory flow rate (PEFR). Meta-analysis of four studies detected a statistically significant increase in maximum heart rate, and following a sensitivity analysis and removal of two studies significance was maintained (MD 3.67 bpm; 95% CI 0.90 to 3.44; P = 0.01). Although there were insufficient data to pool results due to diverse reporting tools, there was some evidence to suggest that physical training may have positive effects on health-related quality of life, with four of five studies producing a statistically and clinically significant benefit. This review demonstrated that physical training showed significant improvement in maximum oxygen uptake, though no effects were observed in other measures of pulmonary function. Physical training was well tolerated among people with asthma in the included studies and, as such, people with stable asthma should be encouraged to participate in regular exercise training, without fear of symptom exacerbation. More research is needed to understand the mechanisms by which physical activity impacts asthma management.
Five studies including a total of 1146 participants met the inclusion criteria for this review. As ever with systematic reviews of complex interventions, studies varied by design (cluster and individually randomised), duration (2.5 to 9 months), setting (school, day camp, primary care) and intervention content. Most risk of bias concerns were related to blinding and incomplete reporting, which limited the meta-analyses that could be performed. Studies generally controlled well for selection and attrition biases. All participants were between 11 and 17 years of age. Asthma diagnosis and severity varied, as did smoking prevalence. Three studies used the Triple A programme; one of these studies tested the addition of a smoke-free pledge; another delivered peer support group sessions and mp3 messaging to encourage adherence; and the third compared a peer-led asthma day camp with an equivalent camp led by healthcare practitioners. We had low confidence in all findings owing to risk of bias, inconsistency and imprecision. Results from an analysis of asthma-related quality of life based on the prespecified random-effects model were imprecise and showed no differences (MD 0.40, 95% confidence interval (CI) -0.02 to 0.81); a sensitivity analysis based on a fixed-effect model and a responder analysis suggested small benefit may be derived for this outcome. Most other results were summarised narratively and did not show an important benefit of the intervention; studies provided no analysable data on asthma exacerbations or unscheduled visits (data were skewed), and one study measuring adherence reported a drop in both groups. Effects on asthma control favoured the intervention but findings were not statistically significant. Results from two studies with high levels of baseline smoking showed some promise for self-efficacy to stop smoking, but overall nicotine dependence and smoking-related knowledge were not significantly better in the intervention group. Investigators did not report adverse events. Although weak evidence suggests that lay-led and peer support interventions could lead to a small improvement in asthma-related quality of life for adolescents, benefits for asthma control, exacerbations and medication adherence remain unproven. Current evidence is insufficient to reveal whether routine use of lay-led or peer support programmes is beneficial for adolescents receiving asthma care. Ongoing and future research may help to identify target populations for lay-led and peer support interventions, along with attributes that constitute a successful programme.
Two studies involving 1002 participants compared personal assistance versus usual care. Whilst personal assistance was generally preferred over other services, some people prefer other services. Personal assistance may have some benefits for some recipients and may benefit caregivers. Paid assistance probably substitutes for informal care and may cost government more than alternatives; however, some evidence suggests it may reduce costs. The total costs to recipients and society are unknown. Research in this field is limited. Personal assistance is expensive and difficult to organise, especially in places that do not already have services in place, but its total cost relative to other services is unknown. When implementing new programmes, recipients could be randomly assigned to different forms of assistance (e.g. organised by individual users versus organised through a cooperative). While advocates may support personal assistance for myriad reasons, this review demonstrates that further studies are required to determine which models of assistance are most effective and efficient for particular people.
New searches in 2013 did not identify any relevant new studies. All six included studies used a single dose of triptan to treat an attack of moderate to severe pain intensity. Subcutaneous sumatriptan was given to 131 participants at a 6 mg dose, and 88 at a 12 mg dose. Oral or intranasal zolmitriptan was given to 231 participants at a 5 mg dose, and 223 at a 10 mg dose. Placebo was given to 326 participants. Triptans were more effective than placebo for headache relief and pain-free responses. By 15 minutes after treatment with subcutaneous sumatriptan 6 mg, 48% of participants were pain-free and 75% had no pain or mild pain (17% and 32% respectively with placebo). NNTs for subcutaneous sumatriptan 6 mg were 3.3 (95% CI 2.4 to 5.0) and 2.4 (1.9 to 3.2) respectively. Intranasal zolmitriptan 10 mg was of less benefit, with 12% of participants pain-free and 28% with no or mild pain (3% and 7% respectively with placebo). NNTs for intranasal zolmitriptan 10 mg were 11 (6.4 to 49) and 4.9 (3.3 to 9.2) respectively. Based on limited data, subcutaneous sumatriptan 6 mg was superior to intranasal zolmitriptan 5 mg or 10 mg for rapid (15 minute) responses, which are important in this condition. Oral routes of administration are not appropriate.
We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%. Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period. Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial. One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.
We included 48 studies (224 reports) that involved 7803 randomised participants. Of these, three studies were conducted in children (346 participants). The 2009 review included 30 studies (94 reports, 5949 participants). Risk of bias was assessed as low for sequence generation in 19 studies and allocation concealment in 14 studies. Incomplete outcome data were adequately addressed in 22 studies and 37 were free of selective reporting. The 48 included studies evaluated three different comparisons: steroid avoidance or withdrawal compared with steroid maintenance, and steroid avoidance compared with steroid withdrawal. For the adult studies there was no significant difference in patient mortality either in studies comparing steroid withdrawal versus steroid maintenance (10 studies, 1913 participants, death at one year post transplantation: RR 0.68, 95% CI 0.36 to 1.30) or in studies comparing steroid avoidance versus steroid maintenance (10 studies, 1462 participants, death at one year after transplantation: RR 0.96, 95% CI 0.52 to 1.80). Similarly no significant difference in graft loss was found comparing steroid withdrawal versus steroid maintenance (8 studies, 1817 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.17, 95% CI 0.72 to 1.92) and comparing steroid avoidance versus steroid maintenance (7 studies, 1211 participants, graft loss excluding death with functioning graft at one year after transplantation: RR 1.09, 95% CI 0.64 to 1.86). The risk of acute rejection significantly increased in patients treated with steroids for less than 14 days after transplantation (7 studies, 835 participants: RR 1.58, 95% CI 1.08 to 2.30) and in patients who were withdrawn from steroids at a later time point after transplantation (10 studies, 1913 participants, RR 1.77, 95% CI 1.20 to 2.61). There was no evidence to suggest a difference in harmful events, such as infection and malignancy, in adult kidney transplant recipients. The effect of steroid withdrawal in children is unclear. This updated review increases the evidence that steroid avoidance and withdrawal after kidney transplantation significantly increase the risk of acute rejection. There was no evidence to suggest a difference in patient mortality or graft loss up to five year after transplantation, but long-term consequences of steroid avoidance and withdrawal remain unclear until today, because prospective long-term studies have not been conducted.
We included 25 trials randomising a total of 12,503 participants. All trials were at high risk of bias, and the quality of evidence according to GRADE was low to very low. We included 22 trials where the participants presented with ST-elevation myocardial infarction, 1 trial where participants presented with non-ST-elevation myocardial infarction, and 2 trials where participants presented with a mix of acute coronary syndromes. Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of all-cause mortality or major cardiovascular events. The absolute risk of death was 6.97% in the drug-eluting stents group compared with 7.74% in the bare-metal stents group based on the risk ratio (RR) of 0.90 (95% confidence interval (CI) 0.78 to 1.03, 11,250 participants, 21 trials/22 comparisons, low-quality evidence). The absolute risk of a major cardiovascular event was 6.36% in the drug-eluting stents group compared with 6.63% in the bare-metal stents group based on the RR of 0.96 (95% CI 0.83 to 1.11, 10,939 participants, 19 trials/20 comparisons, very low-quality evidence). The results of Trial Sequential Analysis showed that we did not have sufficient information to confirm or reject our anticipated risk ratio reduction of 10% on either all-cause mortality or major cardiovascular events at maximum follow-up. Meta-analyses at maximum follow-up showed evidence of a benefit when comparing drug-eluting stents with bare-metal stents on the risk of a serious adverse event. The absolute risk of a serious adverse event was 18.04% in the drug-eluting stents group compared with 23.01% in the bare-metal stents group based on the RR of 0.80 (95% CI 0.74 to 0.86, 11,724 participants, 22 trials/23 comparisons, low-quality evidence), and Trial Sequential Analysis confirmed this result. When assessing each specific type of adverse event included in the serious adverse event outcome separately, the majority of the events were target vessel revascularisation. When target vessel revascularisation was analysed separately, meta-analysis showed evidence of a benefit of drug-eluting stents, and Trial Sequential Analysis confirmed this result. Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of cardiovascular mortality (RR 0.91, 95% CI 0.76 to 1.09, 9248 participants, 14 trials/15 comparisons, very low-quality evidence) or myocardial infarction (RR 0.98, 95% CI 0.82 to 1.18, 10,217 participants, 18 trials/19 comparisons, very low-quality evidence). The results of the Trial Sequential Analysis showed that we had insufficient information to confirm or reject our anticipated risk ratio reduction of 10% on cardiovascular mortality and myocardial infarction. No trials reported results on quality of life or angina. The current evidence suggests that drug-eluting stents may lead to fewer serious adverse events compared with bare-metal stents without increasing the risk of all-cause mortality or major cardiovascular events. However, our Trial Sequential Analysis showed that there currently was not enough information to assess a risk ratio reduction of 10% for all-cause mortality, major cardiovascular events, cardiovascular mortality, or myocardial infarction, and there were no data on quality of life or angina. The evidence in this review was of low to very low quality, and the true result may depart substantially from the results presented in this review. More randomised clinical trials with low risk of bias and low risks of random errors are needed if the benefits and harms of drug-eluting stents for acute coronary syndrome are to be assessed properly. More data are needed on the outcomes all-cause mortality, major cardiovascular events, quality of life, and angina to reduce the risk of random error.
We included three new studies (201 participants) in this updated review, for a total of nine studies (455 participants). All but one study employed placebo as the control group intervention. For the primary outcome, antifibrinolytic drugs decreased the amount of perioperative blood loss by 427 mL (95% confidence interval (CI) 251 to 603 mL), for a reduction of over 20% versus placebo. We rated the quality of evidence for our primary outcome as low on the basis of unclear risk of bias for several domains in most studies and the small total number of participants. For secondary outcomes, fewer participants receiving antifibrinolytic drugs received transfusion (allogeneic or autologous) versus those receiving placebo (risk ratio (RR) 0.65, 95% CI 0.50 to 0.85, number needed to treat to prevent one additional harmful outcome (NNTp) 5; very low-quality evidence). Only two studies specifically evaluated the number of participants transfused with only allogeneic blood (risk difference (RD) -0.15, 95% CI -0.26 to -0.03, NNTp 7; very low-quality evidence). Antifibrinolytic drugs decreased the volume of blood transfused by 327 mL (95% CI -186 to -469 mL; low-quality evidence). No study reported deaths in active or control groups. Data were insufficient to allow performance of meta-analysis for any safety outcome. No studies adequately described their methods in assessing safety. The only adverse event of note occurred in one study, when three participants in the placebo group developed postoperative deep vein thrombosis. Since the last published version of this review (2008), we have found three new studies. Additional evidence shows that antifibrinolytics reduce the requirement for both autologous and allogeneic blood transfusion. Limited evidence of low to very low quality supports the use of antifibrinolytic drugs for reducing blood loss and decreasing the risk, and volume, of transfusion in children undergoing scoliosis surgery. Evidence is insufficient to support the use of a particular agent, although tranexamic acid may be preferred, given its widespread availability. The optimal dose regimen for any of these three agents has not been established. Although adverse events appear to occur infrequently, evidence is insufficient to confirm the safety of these agents, particularly for rare but potentially catastrophic events. No long-term safety data are available.
Twelve trials randomised 694 diabetic participants to intensive control and 709 diabetic participants to conventional glycaemic control. The duration of the intervention ranged from just the duration of the surgical procedure up to 90 days. The number of participants ranged from 13 to 421, and the mean age was 64 years. Comparison of intensive with conventional glycaemic control demonstrated the following results for our predefined primary outcomes: analysis restricted to studies with low or unclear detection or attrition bias for infectious complications showed a risk ratio (RR) of 0.46 (95% confidence interval (CI) 0.18 to 1.18), P = 0.11, 627 participants, eight trials, moderate quality of the evidence (grading of recommendations assessment, development and evaluation - (GRADE)). Evaluation of death from any cause revealed a RR of 1.19 (95% CI 0.89 to 1.59), P = 0.24, 1365 participants, 11 trials, high quality of the evidence (GRADE). On the basis of a posthoc analysis, there is the hypothesis that intensive glycaemic control may increase the risk of hypoglycaemic episodes if longer-term outcome measures are analysed (RR 6.92, 95% CI 2.04 to 23.41), P = 0.002, 724 patients, three trials, low quality of the evidence (GRADE). Analysis of our predefined secondary outcomes revealed the following findings: cardiovascular events had a RR of 1.03 (95% CI 0.21 to 5.13), P = 0.97, 682 participants, six trials, moderate quality of the evidence (GRADE) when comparing the two treatment modalities; and renal failure also did not show significant differences between intensive and regular glucose control (RR 0.61, 95% CI 0.34 to 1.08), P = 0.09, 434 participants, two trials, moderate quality of the evidence (GRADE). We did not meta-analyse length of hospital stay and intensive care unit (ICU) stay due to substantial unexplained heterogeneity. Mean differences between intensive and regular glucose control groups ranged from -1.7 days to 2.1 days for ICU stay and between -8 days to 3.7 days for hospital stay (moderate quality of the evidence (GRADE)). One trial assessed health-related quality of life in 12/37 (32.4%) of participants in the intervention group and 13/44 (29.5%) of participants in the control group, and did not show an important difference (low quality of the evidence (GRADE)) in the measured physical health composite score of the short-form 12-item health survey (SF-12). None of the trials examined the effects of the interventions in terms of costs. The included trials did not demonstrate significant differences for most of the outcomes when targeting intensive perioperative glycaemic control compared with conventional glycaemic control in patients with diabetes mellitus. However, posthoc analysis indicated that intensive glycaemic control was associated with an increased number of patients experiencing hypoglycaemic episodes. Intensive glycaemic control protocols with near-normal blood glucose targets for patients with diabetes mellitus undergoing surgical procedures are currently not supported by an adequate scientific basis. We suggest that insulin treatment regimens, patient- and health-system relevant outcomes, and time points for outcome measures should be defined in a thorough and uniform way in future studies.
We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies. The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33). The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20). Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG. Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35). Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment. Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression. Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life. From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.
We deemed six studies (309 participants), based on adult populations with intellectual disabilities, suitable for inclusion in the current version of this review. These studies examined a range of cognitive-behavioural therapy (CBT) approaches: anger management (three studies (n = 235); one individual therapy and two group-based); relaxation (one study; n = 12), mindfulness based on meditation (one study; n = 34), problem solving and assertiveness training (one study; n = 28). We were unable to include any studies using behavioural interventions. There were no studies of children. Only one study reported moderate quality of evidence for outcomes of interest as assessed by the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We judged the evidence for the remaining studies to be of very low to low quality. Most studies were at risk of bias in two or more domains: one study did not randomly allocate participants and in two studies the process of randomisation was unclear; in one study there was no allocation concealment and in three studies this was unclear; blinding of assessors did not occur in three studies; incomplete outcome data were presented in one study and unclear in two studies; there was selective reporting in one study; and other biases were present in one study and unclear in four studies. Three of the six studies showed some benefit of the intervention on improving anger ratings. We did not conduct a meta-analysis, as we considered the studies too heterogeneous to combine (e.g. due to differences in the types of participants, sample size interventions, and outcome measures). Follow-up data for anger ratings for both the treatment and control groups were available for two studies. Only one of these studies (n = 161) had adequate long-term data (10 months), which found some benefit of treatment at follow-up (continued improvement in anger coping skills as rated by key workers; moderate-quality evidence). Two studies (n = 192) reported some evidence that the intervention reduces the number of incidents of aggression and one study (n = 28) reported evidence that the intervention improved mental health symptoms. One study investigated the effects of the intervention on quality of life and cost of health and social care utilisation. This study provided moderate-quality evidence, which suggests that compared to no treatment, behavioural or cognitive-behavioural interventions do not improve quality of life at 16 weeks (n = 129) or at 10 months follow-up (n = 140), or reduce the cost of health service utilisation (n = 133). Only one study (n = 28) assessed adaptive functioning. It reported evidence that assertiveness and problem-solving training improved adaptive behaviour. No studies reported data on adverse events. The existing evidence on the effectiveness of behavioural and cognitive-behavioural interventions on outwardly-directed aggression in children and adults with intellectual disabilities is limited. There is a paucity of methodologically sound clinical trials and a lack of long-term follow-up data. Given the impact of such behaviours on the individual and his or her support workers, effective interventions are essential. We recommend that randomised controlled trials of sufficient power are carried out using primary outcomes that include reduction in outward-directed aggressive behaviour, improvement in quality of life, and cost effectiveness.
Our search retrieved 1311 unique citations, of which 1289 were excluded after title and abstract screening. Of the remaining 22, we excluded 19 because they were empirical studies that were not randomized, quasi-randomized or cluster-randomized controlled trials (n = 12), because they were review articles (n = 3), because they described protocols only (n = 2), they were conducted among cigarette smokers only (n = 1), or they had only a three-month follow-up (n = 1). We identified three controlled trials which tested cessation interventions for waterpipe smokers. Studies were carried out in Egypt (Mohlman 2013), Pakistan (Dogar 2014), and the US (Lipkus 2011). One was a randomized controlled trial and two were cluster-randomized trials. Two studies tested individual-level interventions, and one tested a community-level intervention. Two studies included only behavioural interventions, and one study (Dogar 2014) included two intervention groups: one behavioural, and the other behavioural with bupropion. The Lipkus and Mohlman studies delivered waterpipe-specific interventions, and the Dogar study delivered a non-specific tobacco intervention. Due to study variation we did not pool results, and intervention effects are reported descriptively. Compared to control groups, waterpipe smoking cessation rates were higher in the intervention groups in all three studies, with a significant difference in two studies. For the Dogar study, the RRs for waterpipe smoking abstinence at 25 weeks among waterpipe-only smokers were 2.2 (95% confidence interval (CI) 1.3 to 3.8; 180 participants) in the behavioural group, and 2.5 (95% CI 1.3 to 4.7; 84 participants) in the behavioural plus bupropion group. In our analysis we have combined both groups, to give a RR of 2.28 (95% CI 1.36 to 3.83; 200 participants). The Mohlman study delivered a RR in male waterpipe-smokers at one year in favour of the intervention of 3.25 (95% CI 1.19 to 8.89). Although the literature on waterpipe cessation interventions remains sparse, the reviewed studies provide a basis for developing interventions in this area. The lack of statistically significant effects in one of the three studies is not unexpected, given the small and pilot nature of the studies. The studies highlight important design and content issues that need to be considered for future cessation trials in waterpipe smokers. These include building on the vast experience developed in the study of smoking cessation interventions in cigarette smokers, whilst including components and assessment tools that address the specific aspects of waterpipe smoking, such as its social dimension, unique experiences, and cues.
Twelve trials involving 1586 women met inclusion criteria for this review. One trial did not report on the outcomes of interest in this review. Risk of bias of included studies: The included studies generally were of low quality based on inadequate reporting of methodology. Only three trials had low risk of bias for random sequence generation and one had low risk of bias for allocation concealment and participant blinding. Most studies were either high risk of bias or uncertain in these key areas. Comparison 1: Ethanol versus placebo/control (two trials, 77 women) Compared to controls receiving pain medications and dextrose solution, ethanol did not improve any of the primary outcomes: birth < 48 hours after trial entry (one trial, 35 women; risk ratio (RR) 0.93, 95% confidence interval (CI) 0.43 to 2.00), or neonatal mortality (one trial, 35 women; RR 1.06, 95% CI 0.31 to 3.58). Serious maternal adverse events and perinatal mortality were not reported by either of the two trials in this comparison. Maternal adverse events (overall) were not reported but one trial (42 women) reported that there were no maternal adverse events that required stopping or changing drug) in either group. One trial did report delay until delivery but this outcome was reported as a median with no mention of the standard deviation (median 19 days in ethanol group versus "less than 1" day in the glucose/water group). There were no differences in any secondary outcomes reported: preterm birth < 34 weeks or < 37 weeks; serious infant outcome; fetal alcohol syndrome/fetal alcohol spectrum disorder; or small-for-gestational age. Comparison 2: Ethanol versus other tocolytic (betamimetics) (nine trials, 1438 women) Compared to betamimetics (the only tocolytic used as a comparator in these studies), ethanol was associated with no clear difference in the rate of birth < 48 hours after trial entry (two trials, 130 women; average RR 1.12, 95% CI 0.53 to 2.37, Tau² = 0.19, I² = 59%), similar rates of perinatal mortality (six trials, 698 women; RR1.20, 95% CI 0.78 to 1.84), higher rates of neonatal mortality (eight trials, 1238 women; RR 1.43, 95% CI 1.02 to 2.02), higher rates of preterm birth < 34 weeks (two trials, 599 women; RR 1.56, 95% CI 1.11 to 2.19), higher rates of neonatal respiratory distress syndrome (three trials, 823 women; RR 1.76, 95% CI 1.33 to 2.33), and higher rates of low birthweight babies < 2500 g (five trials, 834 women; RR 1.30, 95% CI 1.09 to 1.54). These outcomes are likely all related to the lower incidence of preterm birth seen with other tocolytics, which for all these comparisons were betamimetics. Serious maternal adverse events were not reported in any of the nine trial reports. However, ethanol had a trend towards a lower rate of maternal adverse events requiring stopping or changing the drug (three trials, 214 women; RR 0.25, 95% CI 0.06 to 0.97). There were no differences in other secondary outcomes of preterm birth < 37 weeks, number of days delivery was delayed, or overall maternal adverse events. Planned sensitivity analysis, excluding quasi-randomized trials did not substantially change the results of the primary outcome analyses with the exception of neonatal mortality which no longer showed a clear difference between the ethanol and other tocolytic groups (3 trials, 330 women; RR 1.49, 95% CI 0.82 to 2.72). This review is based on evidence from twelve studies which were mostly low quality. There is no evidence that to suggest that ethanol is an effective tocolytic compared to placebo. There is some evidence that ethanol may be better tolerated than other tocolytics (in this case betamimetics), but this result is based on few studies and small sample size and therefore should be interpreted with caution. Ethanol appears to be inferior to betamimetics for preventing preterm birth in threatened preterm labor. Ethanol is generally no longer used in current practice due to safety concerns for the mother and her baby. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth in threatened preterm labour. However, it would be useful for long-term follow-up studies on the babies born to mothers from the existing studies in order to assess the risk of long-term neurodevelopmental status.
Ninteen studies were included, reporting on 57 MEDLINE filters and 13 EMBASE filters. Thirty MEDLINE and four EMBASE filters were tested in an evaluation study where the performance of one or more filters was tested against one or more gold standards. The reported outcome measures varied. Some studies reported specificity as well as sensitivity if a reference set containing non-gold standard records in addition to gold standard records was used. In some cases, the original development study did not report any performance data on the filters. Original performance from the development study was not available for 17 filters that were subsequently tested in evaluation studies. All 19 studies reported the sensitivity of the filters that they developed or evaluated, nine studies reported the specificities and 14 studies reported the precision. No filter which had original performance data from its development study, and was subsequently tested in an evaluation study, had what we defined a priori as acceptable sensitivity (> 90%) and precision (> 10%). In studies that developed MEDLINE filters that were evaluated in another study (n = 13), the sensitivity ranged from 55% to 100% (median 86%) and specificity from 73% to 98% (median 95%). Estimates of performance were lower in eight studies that evaluated the same 13 MEDLINE filters, with sensitivities ranging from 14% to 100% (median 73%) and specificities ranging from 15% to 96% (median 81%). Precision ranged from 1.1% to 40% (median 9.5%) in studies that developed MEDLINE filters and from 0.2% to 16.7% (median 4%) in studies that evaluated these filters. A similar range of specificities and precision were reported amongst the evaluation studies for MEDLINE filters without an original performance measure. Sensitivities ranged from 31% to 100% (median 71%), specificity ranged from 13% to 90% (median 55.5%) and precision from 1.0% to 11.0% (median 3.35%). For the EMBASE filters, the original sensitivities reported in two development studies ranged from 74% to 100% (median 90%) for three filters, and precision ranged from 1.2% to 17.6% (median 3.7%). Evaluation studies of these filters had sensitivities from 72% to 97% (median 86%) and precision from 1.2% to 9% (median 3.7%). The performance of EMBASE search filters in development and evaluation studies were more alike than the performance of MEDLINE filters in development and evaluation studies. None of the EMBASE filters in either type of study had a sensitivity above 90% and precision above 10%. None of the current methodological filters designed to identify reports of primary DTA studies in MEDLINE or EMBASE combine sufficiently high sensitivity, required for systematic reviews, with a reasonable degree of precision. This finding supports the current recommendation in the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy that the combination of methodological filter search terms with terms for the index test and target condition should not be used as the only approach when conducting formal searches to inform systematic reviews of DTA.
Three trials met eligibility criteria. A 16-week behaviour therapy intervention was used in two trials, and a 12-week cognitive-behaviour therapy intervention in the third. Duration of follow-up varied, ranging from 0 to 12 months.  Two trials (total 166 participants) provided data comparing combination with psychotherapy alone (both using behaviour therapy). No statistically significant differences were observed in response during the intervention (relative risk (RR) for combination 1.25, 95% CI 0.78 to 2.03, P = 0.35), at the end of the intervention (RR 0.78, 0.45 to 1.35, P = 0.37), or at the last follow-up time point, although the follow-up data suggested that the combination might be inferior to behaviour therapy alone (RR 0.62, 0.36 to 1.07, P = 0.08).  One trial (77 participants) compared combination with a benzodiazepine alone. No differences were found in response during the intervention (RR 1.57, 0.83 to 2.98, P = 0.17). Although the combination appeared to be superior to the benzodiazepine alone at the end of treatment (RR 3.39, 1.03 to 11.21, P = 0.05) the finding was only borderline statistically significant, and no significant differences were observed at the 7-month follow-up (RR 2.31, 0.79 to 6.74, P = 0.12). The review established the paucity of high quality evidence investigating the efficacy of psychotherapy combined with benzodiazepines for panic disorder. Currently, there is inadequate evidence to assess the clinical effects of psychotherapy combined with benzodiazepines for patients who are diagnosed with panic disorder.
Seven trials were included with a total of 426 children studied (274 with oral prednisone vs. placebo, 106 with intravenous steroids vs placebo and 46 with nebulised budesonide vs prednisolone). A significant number of steroid treated children were discharged early after admission (>4 hours) with an OR of 7.00 (95% CI: 2.98 to 16.45) and NNT of 3 (95%CI: 2 to 8). The length of stay was shorter in the steroid groups with a WMD of -8.75 hours (95% CI: -19.23 to 1.74). There were no significant differences between groups in pulmonary function or oxygen saturation measurements. Children treated with steroids in hospital were less likely to relapse within one to three months with OR 0.19 (95%CI: 0.07 to 0.55) and NNT of 3 (95%CI: 2 to 7). The single small study that compared nebulised budesonide to oral prednisone failed to demonstrate equivalence or a difference between each therapy. Systemic corticosteroids produce some improvements for children admitted to hospital with acute asthma. The benefits may include earlier discharge and fewer relapses. Inhaled or nebulised corticosteroids cannot be recommended as equivalent to systemic steroids at this time. Further studies examining differing doses and routes of administration for corticosteroids will clarify the optimal therapy.
Two RCTs met our inclusion criteria, involving a total of 827 participants. Both studies only recruited children with acute URTIs (adults were not involved in either study): 558 children from 61 general practices in England and Wales; and 269 primary care doctors who provided data on 33,792 patient-doctor consultations in Kentucky, USA. The UK study had a high risk of bias due to lack of blinding and the US cluster-randomised study had a high risk of bias because the methods to allocate participants to treatment groups was not clear, and there was evidence of baseline imbalance. In both studies, clinicians provided written information to parents of child patients during primary care consultations: one trained general practitioners (GPs) to discuss an eight-page booklet with parents; the other conducted a factorial trial with two comparison groups (written information compared to usual care and written information plus prescribing feedback to clinicians compared to prescribing feedback alone). Doctors in the written information arms received 25 copies of two-page government-sponsored pamphlets to distribute to parents. Compared to usual care, we found moderate quality evidence (one study) that written information significantly reduced the number of antibiotics used by patients (RR 0.53, 95% CI 0.35 to 0.80; absolute risk reduction (ARR) 20% (22% versus 42%)) and had no significant effect on reconsultation rates (RR 0.79, 95% CI 0.47 to 1.32), or parent satisfaction with consultation (RR 0.95, 95% CI 0.87 to 1.03). Low quality evidence (two studies) demonstrated that written information also reduced antibiotics prescribed by clinicians (RR 0.47, 95% CI 0.28 to 0.78; ARR 21% (20% versus 41%); and RR 0.84, 95% CI 0.81 to 0.86; 9% ARR (45% versus 54%)). Neither study measured resolution of symptoms, patient knowledge about antibiotics for acute URTIs, or complications for this comparison. Compared to prescribing feedback, we found low quality evidence that written information plus prescribing feedback significantly increased the number of antibiotics prescribed by clinicians (RR 1.13, 95% CI 1.09 to 1.17; absolute risk increase 6% (50% versus 44%)). Neither study measured reconsultation rate, resolution of symptoms, patient knowledge about antibiotics for acute URTIs, patient satisfaction with consultation or complications for this comparison. Compared to usual care, moderate quality evidence from one study showed that trained GPs providing written information to parents of children with acute URTIs in primary care can reduce the number of antibiotics used by patients without any negative impact on reconsultation rates or parental satisfaction with consultation. Low quality evidence from two studies shows that, compared to usual care, GPs prescribe fewer antibiotics for acute URTIs but prescribe more antibiotics when written information is provided alongside prescribing feedback (compared to prescribing feedback alone). There was no evidence addressing resolution of patients' symptoms, patient knowledge about antibiotics for acute URTIs, or frequency of complications. To fill evidence gaps, future studies should consider testing written information on antibiotic use for adults with acute URTIs in high- and low-income settings provided without clinician training and presented in different formats (such as electronic). Future study designs should endeavour to ensure blinded outcome assessors. Study aims should include measurement of the effect of written information on the number of antibiotics used by patients and prescribed by clinicians, patient satisfaction, reconsultation, patients' knowledge about antibiotics, resolution of symptoms, and complications.
We included 31 trials with a total of 2257 participants in the subacute or chronic stages of stroke. The methodological quality of most of the included trials was not high. The quality of evidence for the main outcomes was low or very low based on the assessment by the system of Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Two trials compared real acupuncture plus baseline treatment with sham acupuncture plus baseline treatment. There was no evidence of differences in the changes of motor function and quality of life between real acupuncture and sham acupuncture for people with stroke in the convalescent stage. Twenty-nine trials compared acupuncture plus baseline treatment versus baseline treatment alone. Compared with no acupuncture, for people with stroke in the convalescent phase, acupuncture had beneficial effects on the improvement of dependency (activity of daily living) measured by Barthel Index (nine trials, 616 participants; mean difference (MD) 9.19, 95% confidence interval (CI) 4.34 to 14.05; GRADE very low), global neurological deficiency (seven trials, 543 participants; odds ratio (OR) 3.89, 95% CI 1.78 to 8.49; GRADE low), and specific neurological impairments including motor function measured by Fugl-Meyer Assessment (four trials, 245 participants; MD 6.16, 95% CI 4.20 to 8.11; GRADE low), cognitive function measured by the Mini-Mental State Examination (five trials, 278 participants; MD 2.54, 95% CI 0.03 to 5.05; GRADE very low), depression measured by the Hamilton Depression Scale (six trials, 552 participants; MD -2.58, 95% CI -3.28 to -1.87; GRADE very low), swallowing function measured by drinking test (two trials, 200 participants; MD -1.11, 95% CI -2.08 to -0.14; GRADE very low), and pain measured by the Visual Analogue Scale (two trials, 118 participants; MD -2.88, 95% CI -3.68 to -2.09; GRADE low). Sickness caused by acupuncture and intolerance of pain at acupoints were reported in a few participants with stroke in the acupuncture groups. No data on death, the proportion of people requiring institutional care or requiring extensive family support, and all-cause mortality were available in all included trials. From the available evidence, acupuncture may have beneficial effects on improving dependency, global neurological deficiency, and some specific neurological impairments for people with stroke in the convalescent stage, with no obvious serious adverse events. However, most included trials were of inadequate quality and size. There is, therefore, inadequate evidence to draw any conclusions about its routine use. Rigorously designed, randomised, multi-centre, large sample trials of acupuncture for stroke are needed to further assess its effects.
We included one randomised clinical trial with 61 participants (43 male and 18 female) with colorectal cancer with liver metastases: 22 received transarterial embolisation (TAE; hepatic artery embolisation), 19 received transarterial chemoembolisation (TACE; 5-fluorouracil hepatic artery infusion chemotherapy with degradable microspheres), and 20 received 'no active therapeutic intervention' as a control. Most tumours were synchronous, unresectable metastases involving up to 75% of the liver. Participants were followed for a minimum of seven months. The trial was at high risk of bias. Very-low-certainty evidence found inconclusive results for mortality at 44 months between the TAE and TACE versus no intervention groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06; 61 participants). Local recurrence was reported in 10 participants without any details about the group allocation. Very-low-certainty evidence found little or no difference in mortality between the TAE and no intervention groups (RR 0.91, 95% CI 0.75 to 1.10; 42 participants). Median survival was 7 months from trial entry (range 2 to 44 months) in the TAE group and 7.9 months (range 1 to 26 months) in the control group, and 8.7 months after diagnosis (range 2 to 49 months) in the TAE group and 9.6 months (range 1 to 27 months) in the control group. The trial authors reported the differences were not statistically significant. There were no reported side effects in the control group. In the TAE group, 18 participants experienced short-term symptoms of 'post-embolisation syndrome', which were relieved with symptomatic treatment; one participant also had a local puncture site haematoma. Very-low-certainty evidence found little or no difference in mortality between the TACE and no intervention groups (RR 0.83, 95% CI 0.65 to 1.07; 39 participants). Median survival in the TACE group was 10.7 months (range 3 to 38 months) from trial entry, and 13.0 months (range 3 to 38 months) after diagnosis. The trial authors reported that differences between groups were not statistically significant. All participants experienced short-term nausea, with or without vomiting, immediately after treatment; one participant developed a wound infection, and one developed deep vein thrombosis. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Cancer Research Campaign, a non-profit organisation, provided a grant for the trial; Pharmacia Ltd. delivered the Port-a-Cath arterial delivery systems and degradable starch microspheres. We identified one ongoing trial comparing TACE plus chemotherapy versus chemotherapy alone in people with unresectable colorectal liver metastases who failed with first-line chemotherapy (NCT03783559). Based on one, small randomised trial at high risk of bias, the evidence is very uncertain about the effect of TAE or TACE versus no active therapeutic intervention on mortality for people with liver metastases as the true effect may be substantially different. The trial did not measure failure to clear liver metastases, time to progression of liver metastases, tumour response measures, or health-related quality of life. Short-term, minor adverse events were recorded in the intervention groups only. Large trials, following current standards of conduct and reporting, are required to explore the benefits and harms of TAE or TACE compared with no intervention or placebo in people with resectable and unresectable liver metastasis.
This updated review includes 12 studies (6177 women), 11 in women in labour for whom a vaginal birth was intended, and one in women where an assisted birth was anticipated. Two were trials each with more than 1000 women (Argentina and the UK), and the rest were smaller (from Canada, Germany, Spain, Ireland, Malaysia, Pakistan, Columbia and Saudi Arabia). Eight trials included primiparous women only, and four trials were in both primiparous and multiparous women. For risk of bias, allocation was adequately concealed and reported in nine trials; sequence generation random and adequately reported in three trials; blinding of outcomes adequate and reported in one trial, blinding of participants and personnel reported in one trial. For women where an unassisted vaginal birth was anticipated, a policy of selective episiotomy may result in 30% fewer women experiencing severe perineal/vaginal trauma (RR 0.70, 95% CI 0.52 to 0.94; 5375 women; eight RCTs; low-certainty evidence). We do not know if there is a difference for blood loss at delivery (an average of 27 mL less with selective episiotomy, 95% CI from 75 mL less to 20 mL more; two trials, 336 women, very low-certainty evidence). Both selective and routine episiotomy have little or no effect on infants with Apgar score less than seven at five minutes (four trials, no events; 3908 women, moderate-certainty evidence); and there may be little or no difference in perineal infection (RR 0.90, 95% CI 0.45 to 1.82, three trials, 1467 participants, low-certainty evidence). For pain, we do not know if selective episiotomy compared with routine results in fewer women with moderate or severe perineal pain (measured on a visual analogue scale) at three days postpartum (RR 0.71, 95% CI 0.48 to 1.05, one trial, 165 participants, very low-certainty evidence). There is probably little or no difference for long-term (six months or more) dyspareunia (RR1.14, 95% CI 0.84 to 1.53, three trials, 1107 participants, moderate-certainty evidence); and there may be little or no difference for long-term (six months or more) urinary incontinence (average RR 0.98, 95% CI 0.67 to 1.44, three trials, 1107 participants, low-certainty evidence). One trial reported genital prolapse at three years postpartum. There was no clear difference between the two groups (RR 0.30, 95% CI 0.06 to 1.41; 365 women; one trial, low certainty evidence). Other outcomes relating to long-term effects were not reported (urinary fistula, rectal fistula, and faecal incontinence). Subgroup analyses by parity (primiparae versus multiparae) and by surgical method (midline versus mediolateral episiotomy) did not identify any modifying effects. Pain was not well assessed, and women's preferences were not reported. One trial examined selective episiotomy compared with routine episiotomy in women where an operative vaginal delivery was intended in 175 women, and did not show clear difference on severe perineal trauma between the restrictive and routine use of episiotomy, but the analysis was underpowered. In women where no instrumental delivery is intended, selective episiotomy policies result in fewer women with severe perineal/vaginal trauma. Other findings, both in the short or long term, provide no clear evidence that selective episiotomy policies results in harm to mother or baby. The review thus demonstrates that believing that routine episiotomy reduces perineal/vaginal trauma is not justified by current evidence. Further research in women where instrumental delivery is intended may help clarify if routine episiotomy is useful in this particular group. These trials should use better, standardised outcome assessment methods.
We included two RCTs conducted in Taiwan with a total of 131 participants. We did not perform a meta-analysis as the trials were assessing different outcomes. Neither trial met our pre-defined primary outcome criteria of myopia progression defined as one diopter mean change. Only one trial reported the changes of axial length without non-significant difference among groups and both trials reported that several children experienced mild pain during acupuncture stimulation. Two trials are included in this review but no conclusions can be drawn for the benefit of co-acupressure for slowing progress of myopia in children. Further evidence in the form of RCTs are needed before any recommendations can be made for the use of acupuncture treatment in clinical use. These trials should compare acupuncture to placebo and have large sample sizes. Other types of acupuncture (such as auricular acupuncture) should be explored further as well as compliance with treatment for at least six months or longer. Axial length elongation of the eye should be investigated for at least one year. The potential to reduce/eliminate pain from acupuncture experienced by children should also be reviewed.
We included six trials randomising 359 participants, 178 to T-tube drainage and 181 to primary closure. All trials were at high risk of bias. There was no significant difference in mortality between the two groups (4/178 (weighted percentage 1.2%) in the T-tube group versus 1/181 (0.6%) in the primary closure group; RR 2.25; 95% CI 0.55 to 9.25; six trials). There was no significant difference in the serious morbidity rate between the two groups (24/136 (weighted serious morbidity rate, 145 events per 1000 patients) in the T-tube group versus 9/136 (weighted serious morbidity rate, 66 events per 1000 patients) in the primary closure group; RaR 2.19; 95% CI 0.98 to 4.91; four trials). Quality of life and return to work were not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 28.90 minutes; 95% CI 17.18 to 40.62 minutes; one trial). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 4.72 days; 95% CI 0.83 days to 8.60 days; five trials). T-tube drainage appeared to result in significantly longer operating time and hospital stay compared with primary closure without any apparent evidence of benefit on clinically important outcomes after open common bile duct exploration. Based on the currently available evidence, there is no justification for the routine use of T-tube drainage after open common bile duct exploration in patients with common bile duct stones. T-tube drainage should not be used outside well designed randomised clinical trials. More randomised trials comparing the effects of T-tube drainage versus primary closure after open common bile duct exploration may be needed. Such trials should be conducted with low risk of bias and assessing the long-term beneficial and harmful effects of T-tube drainage, including long-term complications such as bile stricture and recurrence of common bile duct stones.
We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials. Source of funding: seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials. Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life. Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).
We included 14 studies (of which six have been published since the first version of this review in 2013), with a total of 1358 participants. We found studies that investigated exercises, predischarge home visits for hospitalised patients, the provision of single lens distance vision glasses instead of multifocal glasses, a servo-assistive rollator and non-invasive brain stimulation for preventing falls. Exercise compared to control for preventing falls in people after stroke The pooled result of eight studies showed that exercise may reduce the rate of falls but we are uncertain about this result (rate ratio 0.72, 95% CI 0.54 to 0.94, 765 participants, low-quality evidence). Sensitivity analysis for single exercise interventions, omitting studies using multiple/multifactorial interventions, also found that exercise may reduce the rate of falls (rate ratio 0.66, 95% CI 0.50 to 0.87, 626 participants). Sensitivity analysis for the effect in the chronic phase post stroke resulted in little or no difference in rate of falls (rate ratio 0.58, 95% CI 0.31 to 1.12, 205 participants). A sensitivity analysis including only studies with low risk of bias found little or no difference in rate of falls (rate ratio 0.88, 95% CI 0.65 to 1.20, 462 participants). Methodological limitations mean that we have very low confidence in the results of these sensitivity analyses. For the outcome of number of fallers, we are very uncertain of the effect of exercises compared to the control condition, based on the pooled result of 10 studies (risk ratio 1.03, 95% CI 0.90 to 1.19, 969 participants, very low quality evidence). The same sensitivity analyses as described above gives us very low certainty that there are little or no differences in number of fallers (single interventions: risk ratio 1.09, 95% CI 0.93 to 1.28, 796 participants; chronic phase post stroke: risk ratio 0.94, 95% CI 0.73 to 1.22, 375 participants; low risk of bias studies: risk ratio 0.96, 95% CI 0.77 to 1.21, 462 participants). Other interventions for preventing falls in people after stroke We are very uncertain whether interventions other than exercise reduce the rate of falls or number of fallers. We identified very low certainty evidence when investigating the effect of predischarge home visits (rate ratio 0.85, 95% CI 0.43 to 1.69; risk ratio 1.48, 95% CI 0.71 to 3.09; 85 participants), provision of single lens distance glasses to regular wearers of multifocal glasses (rate ratio 1.08, 95% CI 0.52 to 2.25; risk ratio 0.74, 95% CI 0.47 to 1.18; 46 participants) and a servo-assistive rollator (rate ratio 0.44, 95% CI 0.16 to 1.21; risk ratio 0.44, 95% CI 0.16 to 1.22; 42 participants). Finally, transcranial direct current stimulation (tDCS) was used in one study to examine the effect on falls post stroke. We have low certainty that active tDCS may reduce the number of fallers compared to sham tDCS (risk ratio 0.30, 95% CI 0.14 to 0.63; 60 participants). At present there exists very little evidence about interventions other than exercises to reduce falling post stroke. Low to very low quality evidence exists that this population benefits from exercises to prevent falls, but not to reduce number of fallers. Fall research does not in general or consistently follow methodological gold standards, especially with regard to fall definition and time post stroke. More well-reported, adequately-powered research should further establish the value of exercises in reducing falling, in particular per phase, post stroke.
Fourteen unique trials with 1497 randomised participants were included. Antifungal prophylaxis did not reduce mortality (RR 0.90, 95% CI 0.57 to 1.44). In liver transplant recipients, a significant reduction in IFIs was demonstrated for fluconazole (RR 0.28, 95% CI 0.13 to 0.57). Although less data were available for itraconazole and liposomal amphotericin B, indirect comparisons and one direct comparative trial suggested similar efficacy. Fluconazole prophylaxis did not significantly increase invasive infections or colonisation with fluconazole-resistant fungi. In renal and cardiac transplant recipients, neither ketoconazole nor clotrimazole significantly reduced invasive infections. Overall, the strength and precision of comparisons however were limited by a paucity of data. For liver transplant recipients, antifungal prophylaxis with fluconazole significantly reduces the incidence of IFIs with no definite mortality benefit. Given a 10% incidence of IFI, 14 liver transplant recipients would require fluconazole prophylaxis to prevent one infection. In transplant centres where the incidence of IFIs is high, or in situations where the individual risk is great, antifungal prophylaxis should be considered.
We identified two new studies (89 participants) in this updated review. A total of 11 studies (1760 participants) met the entry criteria of the review, one of which accounted for 68% of recruited participants. The quality of evidence ranged from low to moderate owing to an unclear risk of bias across many studies, lack of blinding and low participant numbers for some outcomes. Eight of the studies compared LVRS versus standard medical care, one compared two closure techniques (stapling vs laser ablation), one looked at the effect of buttressing the staple line on the effectiveness of LVRS and one compared traditional 'resectional' LVRS with a non-resectional surgical approach. Participants completed a mandatory course of pulmonary rehabilitation/physical training before the procedure commenced. Short-term mortality was higher for LVRS (odds ratio (OR) 6.16, 95% confidence interval (CI) 3.22 to 11.79; 1489 participants; five studies; moderate-quality evidence) than for control, but long-term mortality favoured LVRS (OR 0.76, 95% CI 0.61 to 0.95; 1280 participants; two studies; moderate-quality evidence). Participants identified post hoc as being at high risk of death from surgery were those with particularly impaired lung function, poor diffusing capacity and/or homogenous emphysema. Participants with upper lobe-predominant emphysema and low baseline exercise capacity showed the most favourable outcomes related to mortality, as investigators reported no significant differences in early mortality between participants treated with LVRS and those in the control group (OR 0.87, 95% CI 0.23 to 3.29; 290 participants; one study), as well as significantly lower mortality at the end of follow-up for LVRS compared with control (OR 0.45, 95% CI 0.26 to 0.78; 290 participants; one study). Trials in this review furthermore provided evidence of low to moderate quality showing that improvements in lung function parameters other than forced expiratory volume in one second (FEV1), quality of life and exercise capacity were more likely with LVRS than with usual follow-up. Adverse events were more common with LVRS than with control, specifically the occurrence of (persistent) air leaks, pulmonary morbidity (e.g. pneumonia) and cardiovascular morbidity. Although LVRS leads to an increase in quality-adjusted life-years (QALYs), the procedure is relatively costly overall. Lung volume reduction surgery, an effective treatment for selected patients with severe emphysema, may lead to better health status and lung function outcomes, specifically for patients who have upper lobe-predominant emphysema with low exercise capacity, but the procedure is associated with risks of early mortality and adverse events.
We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). Most of the data included in the review came from the three large, well-designed cluster-randomised trials that took place in Argentina, Cuba, Saudi Arabia, Thailand and Zimbabwe. All results have been adjusted for the cluster design effect. All of the trials were at some risk of bias as blinding of women and staff was not feasible with this type of intervention. For primary outcomes, evidence was graded as being of moderate or low quality, with downgrading decisions due to risks of bias and imprecision of effects. The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal-oriented'. Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31; five trials, 56,431 babies; moderate-quality evidence). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (RR 0.90; 95% CI 0.45 to 1.80, two trials); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (RR 1.15; 95% CI 1.01 to 1.32, three trials). There was no clear difference between groups for our other primary outcomes: maternal death (RR 1.13, 95%CI 0.50 to 2.57, three cluster-randomised trials, 51,504 women, low-quality evidence); hypertensive disorders of pregnancy (various definitions including pre-eclampsia) (RR 0.95, 95% CI 0.80 to 1.12, six studies, 54,108 women, low-quality evidence); preterm birth (RR 1.02, 95% CI 0.94 to 1.11; seven studies, 53,661 women, moderate-quality evidence); and small-for-gestational age (RR 0.99, 95% CI 0.91 to 1.09, four studies 43,045 babies, moderate-quality evidence). Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02, five studies, 43,048 babies, moderate quality evidence). There were no clear differences between the groups for the other secondary clinical outcomes. Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome.
We included 49 trials (56 comparisons) with 3342 participants. Data were available for: (1) pharmacological interventions with placebo (with 20 pharmacological comparisons); (2) one of various forms of non-invasive brain stimulation with sham stimulation or usual care (with eight non-invasive brain stimulation comparisons); (3) one of various forms of psychological therapy with usual care and/or attention control (with 16 psychological therapy comparisons); (4) pharmacological intervention and various forms of psychological therapy with pharmacological intervention and usual care and/or attention control (with two comparisons); and (5) non-invasive brain stimulation and pharmacological intervention with pharmacological intervention and sham stimulation or usual care (with 10 comparisons). We found no trials for the following comparisons: (6) pharmacological intervention and various forms of psychological therapy interventions versus placebo and psychological therapy; (7) pharmacological intervention and non-invasive brain stimulation versus placebo plus non-invasive brain stimulation; (8) non-invasive brain stimulation and one of various forms of psychological therapy versus non-invasive brain stimulation plus usual care and/or attention control; and (9) non-invasive brain stimulation and one of various forms of psychological therapy versus sham brain stimulation or usual care plus psychological therapy. Treatment effects observed: very low-certainty evidence from eight trials suggests that pharmacological interventions decreased the number of people meeting study criteria for depression (RR 0.70, 95% CI 0.55 to 0.88; 1025 participants) at end of treatment, and very low-certainty evidence from six trials suggests that pharmacological interventions decreased the number of people with less than 50% reduction in depression scale scores at end of treatment (RR 0.47, 95% CI 0.32 to 0.69; 511 participants) compared to placebo. No trials of non-invasive brain stimulation reported on meeting study criteria for depression at end of treatment. Only one trial of non-invasive brain stimulation reported on the outcome <50% reduction in depression scale scores; thus, we were unable to perform a meta-analysis for this outcome. Very low-certainty evidence from six trials suggests that psychological therapy decreased the number of people meeting the study criteria for depression at end of treatment (RR 0.77, 95% CI 0.62 to 0.95; 521 participants) compared to usual care/attention control. No trials of combination therapies reported on the number of people meeting the study criteria for depression at end of treatment. Only one trial of combination (non-invasive brain stimulation and pharmacological intervention) therapy reported <50% reduction in depression scale scores at end of treatment. Thus, we were unable to perform a meta-analysis for this outcome. Five trials reported adverse events related to the central nervous system (CNS) and noted significant harm in the pharmacological interventions group (RR 1.55, 95% CI 1.12 to 2.15; 488 participants; very low-certainty evidence). Four trials found significant gastrointestinal adverse events in the pharmacological interventions group (RR 1.62, 95% CI 1.19 to 2.19; 473 participants; very low-certainty evidence) compared to the placebo group. No significant deaths or adverse events were found in the psychological therapy group compared to the usual care/attention control group. Non-invasive brain stimulation interventions and combination therapies resulted in no deaths. Very low-certainty evidence suggests that pharmacological or psychological therapies can reduce the prevalence of depression. This very low-certainty evidence suggests that pharmacological therapy, psychological therapy, non-invasive brain stimulation, and combined interventions can reduce depressive symptoms. Pharmacological intervention was associated with adverse events related to the CNS and the gastrointestinal tract. More research is required before recommendations can be made about the routine use of such treatments.
We included five trials with a total of 1115 women and their babies (922 women and their babies contributed outcome data). Four of the five included trials had small sample sizes with one large trial that recruited 855 women and babies. All five included trials had a moderate risk of bias. When comparing women receiving additional exercise interventions with those having routine antenatal care, there was no significant difference in GDM incidence (three trials, 826 women, risk ratio (RR) 1.10, 95% confidence interval (CI) 0.66 to 1.84), caesarean section (two trials, 934 women, RR 1.33, 95% CI 0.97 to 1.84) or operative vaginal birth (two trials, 934 women, RR 0.83, 95% CI 0.58 to 1.17). No trial reported the infant primary outcomes prespecified in the review. None of the five included trials found significant differences in insulin sensitivity. Evidence from one single large trial suggested no significant difference in the incidence of developing pregnancy hyperglycaemia not meeting GDM diagnostic criteria, pre-eclampsia or admission to neonatal ward between the two study groups. Babies born to women receiving exercise interventions had a non-significant trend to a lower ponderal index (mean difference (MD) -0.08 gram x 100 m3, 95% CI -0.18 to 0.02, one trial, 84 infants). No significant differences were seen between the two study groups for the outcomes of birthweight (two trials, 167 infants, MD -102.87 grams, 95% CI -235.34 to 29.60), macrosomia (two trials, 934 infants, RR 0.91, 95% CI 0.68 to 1.22), or small-for-gestational age (one trial, 84 infants, RR 1.05, 95% CI 0.25 to 4.40) or gestational age at birth (two trials, 167 infants, MD -0.04 weeks, 95% CI -0.37 to 0.29) or Apgar score less than seven at five minutes (two trials, 919 infants, RR 1.00, 95% CI 0.27 to 3.65). None of the trials reported long-term outcomes for women and their babies. No information was available on health services costs. There is limited randomised controlled trial evidence available on the effect of exercise during pregnancy for preventing pregnancy glucose intolerance or GDM. Results from three randomised trials with moderate risk of bias suggested no significant difference in GDM incidence between women receiving an additional exercise intervention and routine care. Based on the limited data currently available, conclusive evidence is not available to guide practice. Larger, well-designed randomised trials, with standardised behavioural interventions are needed to assess the effects of exercise on preventing GDM and other adverse pregnancy outcomes including large-for-gestational age and perinatal mortality. Longer-term health outcomes for both women and their babies and health service costs should be included. Several such trials are in progress. We identified another seven trials which are ongoing and we will consider these for inclusion in the next update of this review.
Thirteen studies on 6000 participants met the inclusion criteria. Four used mepolizumab, four used reslizumab, and five used benralizumab. One study in benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. Eight included children over 12 years but these results were not reported separately. We deemed the risk of bias to be low, with all studies contributing data being of robust methodology. We considered the quality of the evidence for all comparisons to be high overall using the GRADE scheme, with the exception of intravenous mepolizumab because this is not currently a licensed delivery route. All of the anti-IL-5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard of care (at least medium-dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) 1.5 or more). Non-eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, but no data were available for non-eosinophilic participants, and mepolizumab or reslizumab. We saw modest improvements in validated HRQoL scores with all anti-IL-5 agents in severe eosinophilic asthma. However these did not exceed the minimum clinically important difference for ACQ and Asthma Quality of Life Questionnaire (AQLQ), with St. George's Respiratory Questionnaire (SGRQ) only assessed in two studies. The improvement in HRQoL scores in non-eosinophilic participants treated with benralizumab, the only intervention for which data were available in this subset, was not statistically significant, but the test for subgroup difference was negative. All anti-IL-5 treatments produced a small but statistically significant improvement in mean pre-bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.11 L. There were no excess serious adverse events with any anti-IL-5 treatment, and indeed a reduction in favour of mepolizumab that could be due to a beneficial effect on asthma-related serious adverse events. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (36/1599 benralizumab versus 9/998 placebo). Mepolizumab, reslizumab and benralizumab all markedly reduced blood eosinophils, but benralizumab resulted in almost complete depletion, whereas a small number remained with mepolizumab and reslizumab. The implications for efficacy and/or adverse events are unclear. Overall our study supports the use of anti-IL-5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. There were no safety concerns regarding mepolizumab or reslizumab, and no excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation. Further research is needed on biomarkers for assessing treatment response, optimal duration and long-term effects of treatment, risk of relapse on withdrawal, non-eosinophilic patients, children (particularly under 12 years), and comparing anti-IL-5 treatments to each other and, in people eligible for both, to anti-immunoglobulin E. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.
We identified 71 RCTs randomly assigning 73,062 people with COPD to 184 treatment arms of interest. Trials were similar with regards to methodology, inclusion and exclusion criteria and key baseline characteristics. Participants were more often male, aged in their mid sixties, with FEV1 predicted normal between 40% and 50% and with substantial smoking histories (40+ pack-years). The risk of bias was generally low, although missing information made it hard to judge risk of selection bias and selective outcome reporting. Fixed effects were used for SGRQ analyses, and random effects for Trough FEV1 analyses, based on model fit statistics and deviance information criteria (DIC). SGRQ  SGRQ data were available in 42 studies (n = 54,613). At six months, 39 pairwise comparisons were made between 18 treatments in 25 studies (n = 27,024). Combination LABA/ICS was the highest ranked intervention, with a mean improvement over placebo of -3.89 units at six months (95% credible interval (CrI) -4.70 to -2.97) and -3.60 at 12 months (95% CrI -4.63 to -2.34). LAMAs and LABAs were ranked second and third at six months, with mean differences of -2.63 (95% CrI -3.53 to -1.97) and -2.29 (95% CrI -3.18 to -1.53), respectively. Inhaled corticosteroids were ranked fourth (MD -2.00, 95% CrI -3.06 to -0.87). Class differences between LABA, LAMA and ICS were less prominent at 12 months. Indacaterol and aclidinium were ranked somewhat higher than other members of their classes, and formoterol 12 mcg, budesonide 400 mcg and formoterol/mometasone combination were ranked lower within their classes. There was considerable overlap in credible intervals and rankings for both classes and individual treatments. Trough FEV1   Trough FEV1 data were available in 46 studies (n = 47,409). At six months, 41 pairwise comparisons were made between 20 treatments in 31 studies (n = 29,271). As for SGRQ, combination LABA/ICS was the highest ranked class, with a mean improvement over placebo of 133.3 mL at six months (95% CrI 100.6 to 164.0) and slightly less at 12 months (mean difference (MD) 100, 95% CrI 55.5 to 140.1). LAMAs (MD 103.5, 95% CrI 81.8 to 124.9) and LABAs (MD 99.4, 95% CrI 72.0 to 127.8) showed roughly equivalent results at six months, and ICSs were the fourth ranked class (MD 65.4, 95% CrI 33.1 to 96.9). As with SGRQ, initial differences between classes were not so prominent at 12 months. Indacaterol and salmeterol/fluticasone were ranked slightly better than others in their class, and formoterol 12, aclidinium, budesonide and formoterol/budesonide combination were ranked lower within their classes. All credible intervals for individual rankings were wide. This network meta-analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators. Quality of life and lung function were improved most on combination inhalers (LABA and ICS) and least on ICS alone at 6 and at 12 months. Overall LAMA and LABA inhalers had similar effects, particularly at 12 months. The network has demonstrated the benefit of ICS when added to LABA for these outcomes in participants who largely had an FEV1 that was less than 50% predicted, but the additional expense of combination inhalers and any potential for increased adverse events (which has been established by other reviews) require consideration. Our findings are in keeping with current National Institute for Health and Care Excellence (NICE) guidelines.
Only two trials of limited quality met our inclusion criteria. One study compared two biphasic pills and one triphasic pill, each containing levonorgestrel and ethinyl estradiol. No important differences emerged, and the frequency of discontinuation due to medical problems was similar with all three pills. The other trial compared a biphasic pill containing norethindrone (Ortho 10/11) with a triphasic pill containing levonorgestrel (Triphasil) and with another triphasic containing norethindrone (Ortho 7/7/7). The biphasic pill had inferior cycle control compared with the levonorgestrel triphasic. The odds ratio of cycles with intermenstrual bleeding was 1.70 (95% confidence interval (CI) 1.29 to 2.24) for the biphasic compared with the triphasic levonorgestrel pill. The odds ratio of cycles without withdrawal bleeding was 6.48 (95% CI 3.13 to 13.39). In contrast, cycle control with the biphasic pill was comparable to that of the triphasic containing the same progestin (norethindrone). The available evidence is limited and the internal validity of these trials is questionable. Given the high losses to follow up, these reports may even be considered observational. Given that caveat, the biphasic pill containing norethindrone was associated with inferior cycle control compared with the triphasic pill containing levonorgestrel. The choice of progestin may be more important than the phasic regimen in determining bleeding patterns.
No RCTs were identified. Five observational studies (N = 7199) met the inclusion criteria. The studies scored well on the Newcastle-Ottawa scale, but due to the nature of observational studies, a high risk of bias was assigned to all the studies. Three studies were pooled to assess the rate of cancer detected in the surveillance group compared to the non-surveillance group. The studies found a significantly higher rate of cancer detection in the non surveillance group compared to the surveillance group. CRC was detected in 1.83% (53/2895) of patients in the surveillance group compared to 3.17% (135/4256) of patients in the non-surveillance group (OR 0.58, 95% CI 0.42 to 0.80; P = 0.0009). Four studies were pooled to assess the death rate associated with CRC in patients who underwent surveillance compared to patients who did not undergo surveillance. There was a significantly lower death rate associated with CRC in the surveillance group compared to the non-surveillance group. Eight per cent (15/176) of patients in the surveillance group died from CRC compared to 22% (79/354) of patients in the non-surveillance group (OR 0.36, 95% CI 0.19 to 0.69, P=0.002). Data were pooled from two studies to examine the rate of early stage versus late stage colorectal cancer (Duke stages A & B compared to Duke stages C & D) in patients who underwent surveillance compared to patients who do not undergo surveillance. A significantly higher rate of early stage CRC (Duke A & B) was detected in the surveillance group compared to the non-surveillance group. Sixteen per cent (17/110) of patients in the surveillance group had early stage CRC compared to 8% (9/117) of patients in the non-surveillance group (OR 5.40, 95% CI 1.51 to 19.30; P = 0.009). A higher rate of late stage CRC (Duke C & D) was observed in the non-surveillance group compared to the surveillance group. Nine per cent (10/110) of patients in the surveillance group had late stage CRC compared to 16% (19/117) of patients in the non-surveillance group (OR 0.46, 95% CI 0.08 to 2.51; P = 0.37). A GRADE analysis indicated that the quality of the data was very low for all of these outcomes. The included studies did not report on the other pre-specified outcomes including time to cancer detection, time to death and adverse events. The current data suggest that colonoscopic surveillance in IBD may reduce the development of both CRC and the rate of CRC-associated death through early detection, although the quality of the evidence is very low. The detection of earlier stage CRC in the surveillance group may explain some of the survival benefit observed. RCTs assessing the efficacy of endoscopic surveillance in people with IBD are unlikely to be undertaken due to ethical considerations.
The review included 31 trials (10 of which were new for this update) involving 1817 women from 14 countries. Overall, trials were of small-to-moderate size, with follow-ups generally less than 12 months and many were at moderate risk of bias. There was considerable variation in the intervention's content and duration, study populations and outcome measures. There was only one study of women with MUI and only one study with UUI alone, with no data on cure, cure or improvement, or number of episodes of UI for these subgroups. Symptomatic cure of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were eight times more likely to report cure (56% versus 6%; risk ratio (RR) 8.38, 95% confidence interval (CI) 3.68 to 19.07; 4 trials, 165 women; high-quality evidence). For women with any type of UI, PFMT groups were five times more likely to report cure (35% versus 6%; RR 5.34, 95% CI 2.78 to 10.26; 3 trials, 290 women; moderate-quality evidence). Symptomatic cure or improvement of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were six times more likely to report cure or improvement (74% versus 11%; RR 6.33, 95% CI 3.88 to 10.33; 3 trials, 242 women; moderate-quality evidence). For women with any type of UI, PFMT groups were two times more likely to report cure or improvement than women in the control groups (67% versus 29%; RR 2.39, 95% CI 1.64 to 3.47; 2 trials, 166 women; moderate-quality evidence). UI-specific symptoms and quality of life (QoL) at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT group were more likely to report significant improvement in UI symptoms (7 trials, 376 women; moderate-quality evidence), and to report significant improvement in UI QoL (6 trials, 348 women; low-quality evidence). For any type of UI, women in the PFMT group were more likely to report significant improvement in UI symptoms (1 trial, 121 women; moderate-quality evidence) and to report significant improvement in UI QoL (4 trials, 258 women; moderate-quality evidence). Finally, for women with mixed UI treated with PFMT, there was one small trial (12 women) reporting better QoL. Leakage episodes in 24 hours at the end of treatment: PFMT reduced leakage episodes by one in women with SUI (mean difference (MD) 1.23 lower, 95% CI 1.78 lower to 0.68 lower; 7 trials, 432 women; moderate-quality evidence) and in women with all types of UI (MD 1.00 lower, 95% CI 1.37 lower to 0.64 lower; 4 trials, 349 women; moderate-quality evidence). Leakage on short clinic-based pad tests at the end of treatment: women with SUI in the PFMT groups lost significantly less urine in short (up to one hour) pad tests. The comparison showed considerable heterogeneity but the findings still favoured PFMT when using a random-effects model (MD 9.71 g lower, 95% CI 18.92 lower to 0.50 lower; 4 trials, 185 women; moderate-quality evidence). For women with all types of UI, PFMT groups also reported less urine loss on short pad tests than controls (MD 3.72 g lower, 95% CI 5.46 lower to 1.98 lower; 2 trials, 146 women; moderate-quality evidence). Women in the PFMT group were also more satisfied with treatment and their sexual outcomes were better. Adverse events were rare and, in the two trials that did report any, they were minor. The findings of the review were largely supported by the 'Summary of findings' tables, but most of the evidence was downgraded to moderate on methodological grounds. The exception was 'participant-perceived cure' in women with SUI, which was rated as high quality. Based on the data available, we can be confident that PFMT can cure or improve symptoms of SUI and all other types of UI. It may reduce the number of leakage episodes, the quantity of leakage on the short pad tests in the clinic and symptoms on UI-specific symptom questionnaires. The authors of the one economic evaluation identified for the Brief Economic Commentary reported that the cost-effectiveness of PFMT looks promising. The findings of the review suggest that PFMT could be included in first-line conservative management programmes for women with UI. The long-term effectiveness and cost-effectiveness of PFMT needs to be further researched.
We included 15 RCTs involving 1007 participants in this third review update. One trial compared abdominal with perineal approaches to surgery, three trials compared fixation methods, three trials looked at the effects of lateral ligament division, one trial compared techniques of rectosigmoidectomy, two trials compared laparoscopic with open surgery, and two trials compared resection with no resection rectopexy. One new trial compared rectopexy versus rectal mobilisation only (no rectopexy), performed with either open or laparoscopic surgery. One new trial compared different techniques used in perineal surgery, and another included three comparisons: abdominal versus perineal surgery, resection versus no resection rectopexy in abdominal surgery and different techniques used in perineal surgery. The heterogeneity of the trial objectives, interventions and outcomes made analysis difficult. Many review objectives were covered by only one or two studies with small numbers of participants. Given these caveats, there is insufficient data to say which of the abdominal and perineal approaches are most effective. There were no detectable differences between the methods used for fixation during rectopexy. Division, rather than preservation, of the lateral ligaments was associated with less recurrent prolapse but more postoperative constipation. Laparoscopic rectopexy was associated with fewer postoperative complications and shorter hospital stay than open rectopexy. Bowel resection during rectopexy was associated with lower rates of constipation. Recurrence of full-thickness prolapse was greater for mobilisation of the rectum only compared with rectopexy. There were no differences in quality of life for patients who underwent the different kinds of prolapse surgery. The lack of high quality evidence on different techniques, together with the small sample size of included trials and their methodological weaknesses, severely limit the usefulness of this review for guiding practice. It is impossible to identify or refute clinically important differences between the alternative surgical operations. Longer follow-up with current studies and larger rigorous trials are needed to improve the evidence base and to define the optimum surgical treatment for full-thickness rectal prolapse.
The search yielded 39 studies. We included five studies in the review with a total of 884 participants. We excluded 31 studies and designated three as awaiting assessment. The data from the included studies provide some evidence that hydroxyzine is more effective than placebo for GAD (odds ratio (OR) 0.30, 95% CI 0.15 to 0.58) and that it is also acceptable/tolerable (OR 1.00, 95% CI 0.63 to 1.58) (OR 1.49, 95% CI 0.92 to 2.40). Compared to other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in terms of efficacy, acceptability and tolerability (hydroxyzine vs chloridiazepoxide: OR 0.75, 95% CI 0.35 to 1.62; hydroxyzine vs buspirone efficacy OR 0.76, 95% CI 0.40 to 1.42). In terms of side effects, hydroxyzine was associated with a higher rate of sleepiness/drowsiness than the active comparators (OR 1.74, 95% CI 0.86 to 3.53). There was, however, a high risk of bias in the included studies. The included studies did not report on all the outcomes that were pre-specified in the protocol for this review. Even though more effective than placebo, due to the high risk of bias of the included studies, the small number of studies and the overall small sample size, it is not possible to recommend hydroxyzine as a reliable first-line treatment in GAD.
Fifty-two studies met our inclusion criteria, randomly assigning 5077 participants to comparisons of interest. Most studies were double-blind and placebo-controlled, but studies varied in duration from one day to three years. Most participants had mild or intermittent asthma, often with co-morbid allergic rhinitis. Eighteen studies recruited only adults, 25 recruited only children and several recruited both or did not specify (n = 9). With the exception of adverse events, reporting of outcomes of interest to this review was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence. Allocation procedures generally were not well described, about a quarter of the studies were at high risk of bias for performance or detection bias or both and participant attrition was high or unknown in around half of the studies. One short study reported exacerbations requiring a hospital visit and observed no adverse events. Five studies reported quality of life, but the data were not suitable for meta-analysis. Serious adverse events were infrequent, and analysis using risk differences suggests that no more than 1 in 100 are likely to suffer a serious adverse event as a result of treatment with SLIT (RD 0.0012, 95% confidence interval (CI) -0.0077 to 0.0102; participants = 2560; studies = 22; moderate-quality evidence). Within secondary outcomes, wide but varied reporting of largely unvalidated asthma symptom and medication scores precluded meaningful meta-analysis; a general trend suggested SLIT benefit over placebo, but variation in scales meant that results were difficult to interpret. Changes in inhaled corticosteroid use in micrograms per day (MD 35.10 mcg/d, 95% CI -50.21 to 120.42; low-quality evidence), exacerbations requiring oral steroids (studies = 2; no events) and bronchial provocation (SMD 0.69, 95% CI -0.04 to 1.43; very low-quality evidence) were not often reported. This led to many imprecise estimates with wide confidence intervals that included the possibility of both benefit and harm from SLIT. More people taking SLIT had adverse events of any kind compared with control (OR 1.70, 95% CI 1.21 to 2.38; low-quality evidence; participants = 1755; studies = 19), but events were usually reported to be transient and mild. Lack of data prevented most of the planned subgroup and sensitivity analyses. Lack of data for important outcomes such as exacerbations and quality of life and use of different unvalidated symptom and medication scores have limited our ability to draw a clinically useful conclusion. Further research using validated scales and important outcomes for patients and decision makers is needed so that SLIT can be properly assessed as clinical treatment for asthma. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma, so we cannot comment on the safety of SLIT for those with moderate or severe asthma. SLIT is associated with increased risk of all adverse events.
We included nine reviews investigating TENS use in people with defined chronic pain or in people with chronic conditions associated with ongoing pain. One review investigating TENS for phantom or stump-associated pain in people following amputation did not have any included studies. We therefore extracted data from eight reviews which represented 51 TENS-related RCTs representing 2895 TENS-comparison participants entered into the studies. The included reviews followed consistent methods and achieved overall high scores on the AMSTAR checklist. The evidence reported within each review was consistently rated as very low quality. Using review authors' assessment of risk of bias, there were significant methodological limitations in included studies; and for all reviews, sample sizes were consistently small (the majority of studies included fewer than 50 participants per group). Six of the eight reviews presented a narrative synthesis of included studies. Two reviews reported a pooled analysis. Primary and secondary outcomes One review reported a beneficial effect of TENS versus sham therapy at reducing pain intensity on a 0 to 10 scale (MD −1.58, 95% CI −2.08 to −1.09, P < 0.001, I² = 29%, P = 0.22, 5 studies, 207 participants). However the quality of the evidence was very low due to significant methodological limitations and imprecision. A second review investigating pain intensity performed a pooled analysis by combining studies that compared TENS to sham with studies that compared TENS to no intervention (SMD −0.85, 95% CI −1.36 to −0.34, P = 0.001, I² = 83%, P < 0.001). This pooled analysis was judged as offering very low quality evidence due to significant methodological limitations, large between-trial heterogeneity and imprecision. We considered the approach of combining sham and no intervention data to be problematic since we would predict these different comparisons may be estimating different true effects. All remaining reviews also reported pain intensity as an outcome measure; however the data were presented in narrative review form only. Due to methodological limitation and lack of useable data, we were unable to offer any meaningful report on the remaining primary outcome regarding nature/incidence of adverse effects, nor for the remaining secondary outcomes: disability, health-related quality of life, analgesic medication use and participant global impression of change for any comparisons. We found the included reviews had a number of inconsistencies when evaluating the evidence from TENS studies. Approaches to assessing risk of bias around the participant, personnel and outcome-assessor blinding were perhaps the most obvious area of difference across included reviews. We also found wide variability in terms of primary and secondary outcome measures, and inclusion/exclusion criteria for studies varied with respect to including studies which assessed immediate effects of single interventions. We found the methodological quality of the reviews was good, but quality of the evidence within them was very low. We were therefore unable to conclude with any confidence that, in people with chronic pain, TENS is harmful, or beneficial for pain control, disability, health-related quality of life, use of pain relieving medicines, or global impression of change. We make recommendations with respect to future TENS study designs which may meaningfully reduce the uncertainty relating to the effectiveness of this treatment in people with chronic pain.
We included 13 RCTs involving a total of 7292 participants, both children (n = 6402) and adults (n = 890). Nine studies were conducted in middle-income countries, three studies in high-income countries, and only one study in a low-income country. Five studies did not report methods of randomisation, and one study failed to conceal the allocations. Eleven studies did not blind participants, and six studies did not blind outcome assessments. Two studies had high attrition rates, and one study selectively reported the results. Three studies were funded by pharmaceutical companies. Paralytic poliomyelitis. No study reported data on this outcome. Seroconversion rates. These were significantly higher for all three types of wild poliovirus for children given intramuscular full-dose IPV after a single primary dose and two primary doses, but only significantly higher for type two wild poliovirus given intramuscularly after three primary doses: • dose one (six studies): poliovirus type 1 (odds ratio (OR) 0.30, 95% confidence interval (CI) 0.22 to 0.41; 2570 children); poliovirus type 2 (OR 0.43, 95% CI 0.31 to 0.60; 2567 children); poliovirus type 3 (OR 0.19, 95% CI 0.12 to 0.30; 2571 children); • dose two (three studies): poliovirus type 1 (OR 0.23, 95% CI 0.16 to 0.33; 981 children); poliovirus type 2 (OR 0.41, 95% CI 0.28 to 0.60; 853 children); and poliovirus type 3 (OR 0.12, 95% CI 0.07 to 0.22; 855 children); and • dose three (three studies): poliovirus type 1 (OR 0.45, 95% CI 0.07 to 3.15; 973 children); poliovirus type 2 (OR 0.34, 95% CI 0.19 to 0.63; 973 children); and poliovirus type 3 (OR 0.18, 95% CI 0.01 to 2.58; 973 children). Using the GRADE approach, we rated the certainty of the evidence as low or very low for seroconversion rate (after a single, two, or three primary doses) for all three poliovirus types due to significant risk of bias, heterogeneity, and indirectness in applicability/generalisability. Geometric mean titres. No study reported mean antibody titres. Median antibody titres were higher for intramuscular full-dose IPV (7 studies with 4887 children); although these studies also reported a rise in antibody titres in the intradermal group, none reported the duration for which the titres remained high. Any vaccine-related adverse event. Five studies (2217 children) reported more adverse events, such as fever and redness, in the intradermal group, whilst two studies (1904 children) reported more adverse events in the intramuscular group. There is low- and very low-certainty evidence that intramuscular full-dose IPV may result in a slight increase in seroconversion rates for all three types of wild poliovirus, compared with intradermal fractional-dose IPV. We are uncertain whether intradermal fractional-dose (one-fifth) IPV has better protective effects and causes fewer adverse events in children than intramuscular full-dose IPV.
21 randomized controlled trials (RCTs) in 1,993 patients with primary hypertension met the inclusion criteria for this review - ACEIs (5 trials), CCBs (7 trials), ARBs (6 trials), diuretics (2 trials), alpha-blockers (1 trial), and beta-blockers (1 trial). Meta-analysis showed significant heterogeneity across trials. No RCT reported on all cause mortality, cardiovascular mortality, cardiovascular morbidity and serious adverse events. There was no statistically significant difference for overall adverse events (RR=0.78, 95%CI: 0.37 to 1.65) and withdrawals due to adverse events (RR=0.53, 95%CI: 0.26 to 1.07). No significant differences were noted for morning SBP (-1.62 mm Hg, 95% CI: -4.19 to 0.95) and morning DBP (-1.21 mm Hg, 95% CI: -3.28 to 0.86); but 24-hour BP (SBP: -1.71 mm Hg, 95% CI: -2.78 to -0.65; DBP: -1.38 mm Hg, 95% CI: -2.13 to -0.62) showed a statistically significant difference. No RCT reported on clinically relevant outcome measures - all cause mortality, cardiovascular morbidity and morbidity. There were no significant differences in overall adverse events and withdrawals due to adverse events among the evening versus morning dosing regimens. In terms of BP lowering efficacy, for 24-hour SBP and DBP, the data suggests that better blood pressure control was achieved with bedtime dosing than morning administration of antihypertensive medication, the clinical significance of which is not known.
We included 17 randomised clinical trials which compared peginterferon alpha-2a plus ribavirin versus peginterferon alpha-2b plus ribavirin in 5847 patients. All trials had a high risk of bias. Very few trials reported data on very few patients for the patient-relevant outcomes all-cause mortality, liver-related morbidity, serious adverse events, and quality of life. Accordingly, we were unable to conduct meta-analyses on all-cause mortality, liver-related morbidity, and quality of life. Twelve trials reported on adverse events leading to discontinuation of treatment without clear evidence of a difference between the two peginterferons (197/2171 (9.1%) versus 311/3169 (9.9%); RR 0.84, 95% CI 0.57 to 1.22; I2 = 44%; low quality evidence). A trial sequential analysis showed that we could exclude a relative risk reduction of 20% or more on this outcome. Peginterferon alpha-2a significantly increased the number of patients who achieved a sustained virological response in the blood serum compared with peginterferon alpha-2b (1069/2099 (51%) versus 1327/3075 (43%); RR 1.12, 95% CI 1.06 to 1.18; I2= 0%, 12 trials; moderate quality evidence). Trial sequential analyses supported this result. Subgroup analyses based on risk of bias, viral genotype, and treatment history yielded similar results. Trial sequential analyses supported the results in patients with genotypes 1 and 4, but not in patients with genotypes 2 and 3. There is lack of evidence on patient-important outcomes and paucity of evidence on adverse events. Moderate quality evidence suggests that peginterferon alpha-2a is associated with a higher sustained virological response in serum than with peginterferon alpha-2b. This finding may be affected by the high risk of bias of the included studies . The clinical consequences of peginterferon alpha-2a versus peginterferon alpha-2b are unknown, and we cannot translate an effect on sustained virological response into comparable clinical effects because sustained virological response is still an unvalidated surrogate outcome for patient-important outcomes. The lack of evidence on patient-important outcomes and the paucity of evidence on adverse events means that we are unable to draw any conclusions about the effects of one peginterferon over the other.
We included 16 trials involving 2648 participants. We were able to analyse 15 of the trials with 2496 participants. The pooled analysis of all the trials showed that there was no significant difference in the incidence of clinical failure on about days 10 to 14 between the two groups (risk ratio (RR), random-effects 1.09; 95% confidence interval (CI) 0.64 to 1.85). A subgroup analysis in trials with acute bronchitis participants showed significantly lower clinical failure in the azithromycin group compared to amoxycillin or amoxyclav (RR random-effects 0.63; 95% CI 0.45 to 0.88). A sensitivity analysis showed a non-significant reduction in clinical failure in azithromycin-treated participants (RR 0.55; 95% CI 0.25 to 1.21) in three adequately concealed studies, compared to RR 1.32; 95% CI 0.70 to 2.49 in 12 studies with inadequate concealment. Twelve trials reported the incidence of microbial eradication and there was no significant difference between the two groups (RR 0.95; 95% CI 0.87 to 1.03). The reduction of adverse events in the azithromycin group was RR 0.76 (95% CI 0.57 to 1.00). There is unclear evidence that azithromycin is superior to amoxycillin or amoxyclav in treating acute LRTI. In patients with acute bronchitis of a suspected bacterial cause, azithromycin tends to be more effective in terms of lower incidence of treatment failure and adverse events than amoxycillin or amoxyclav. However, most studies were of unclear methodological quality and had small sample sizes; future trials of high methodological quality and adequate sizes are needed.
Nineteen studies met the inclusion criteria of which 16 contributed data on 267 participants with COPD (mean age 56 to 76 years and 67% were men). Of these 16 studies, seven explored the effect of NMES versus usual care and nine explored the effect of NMES plus conventional exercise training versus conventional exercise training alone. Six studies utilised sham stimulation in the control group. When applied in isolation, NMES produced an increase in peripheral muscle force (SMD 0.34, 95% CI 0.02 to 0.65; low-quality evidence) and quadriceps endurance (SMD 1.36, 95% CI 0.59 to 2.12; low-quality evidence) but the effect on thigh muscle size was unclear (MD 0.25, 95% CI -0.11 to 0.61; low-quality evidence). There were increases in six-minute walk distance (6MWD) (MD 39.26 m, 95% CI 16.31 to 62.22; low-quality evidence) and time to symptom limitation exercising at a submaximal intensity (MD 3.62 minutes, 95% CI 2.33 to 4.91). There was a reduction in the severity of leg fatigue on completion of an exercise test (MD -1.12 units, 95% CI -1.81 to -0.43). The increase in peak rate of oxygen uptake (VO2peak) was of borderline significance (MD 0.10 L/minute, 95% CI 0.00 to 0.19). For NMES with conventional exercise training, there was an uncertain effect on peripheral muscle force (SMD 0.47, 95% CI -0.10 to 1.04; very low-quality evidence) and there were insufficient studies to undertake a meta-analysis on the effect on quadriceps endurance or thigh muscle size. However, there was an increase in 6MWD in favour of NMES combined with conventional exercise training (MD 25.87 m, 95% CI 1.06 to 50.69; very low-quality evidence). In people admitted to either in an intensive care unit or a respiratory high dependency centre, NMES combined with conventional exercise reduced the time taken for participants to first sit out of bed by 4.98 days (95% CI -8.55 to -1.41; very low-quality evidence), although the statistical heterogeneity for this analysis was high (I2 = 60%). For both types of studies (i.e. NMES versus usual care and NMES with conventional exercise training versus conventional exercise training alone), there was no risk difference for mortality or minor adverse events in participants who received NMES. NMES, when applied in isolation, increased quadriceps force and endurance, 6MWD and time to symptom limitation exercising at a submaximal intensity, and reduced the severity of leg fatigue on completion of exercise testing. It may increase VO2peak, but the true effect on this outcome measure could be trivial. However, the quality of evidence was low or very low due to risk of bias within the studies, imprecision of the estimates, small number of studies and inconsistency between the studies. Although there were no additional gains in quadriceps force with NMES plus conventional exercise training, there was evidence of an increase in 6MWD. Further, in people who were the most debilitated, the addition of NMES may have accelerated the achievement of a functional milestone, that is, the first time someone sits out of bed.
We included 29 trials involving 2612 participants. Twenty-eight trials involved patients undergoing surgery and one trial involved patients with epistaxis (nosebleed). Tranexamic acid (TXA) reduced blood loss by 29% (pooled ratio 0.71, 95% confidence interval (CI) 0.69 to 0.72; P < 0.0001). There was uncertainty regarding the effect on death (risk ratio (RR) 0.28, 95% CI 0.06 to 1.34; P = 0.11), myocardial infarction (RR 0.33, 95% CI 0.04 to 3.08; P = 0.33), stroke (RR 0.33, 95% CI 0.01 to 7.96; P = 0.49), deep vein thrombosis (RR 0.69, 95% CI 0.31 to 1.57; P = 0.38) and pulmonary embolism (RR 0.52, 95% CI 0.09 to 3.15; P = 0.48). TXA reduced the risk of receiving a blood transfusion by a relative 45% (RR 0.55, 95% CI 0.55 to 0.46; P < 0.0001). There was substantial statistical heterogeneity between trials for the blood loss and blood transfusion outcomes. There is reliable evidence that topical application of tranexamic acid reduces bleeding and blood transfusion in surgical patients, however the effect on the risk of thromboembolic events is uncertain. The effects of topical tranexamic acid in patients with bleeding from non-surgical causes has yet to be reliably assessed. Further high-quality trials are warranted to resolve these uncertainties before topical tranexamic acid can be recommended for routine use.
Nineteen trials, of which two were newly included in this update, involving 3044 participants, were included. There was considerable variation in the types of implants and techniques used for both internal fixation and arthroplasty in the included trials. The risk of selection bias was low in just three trials, unclear in 13 trials and high in the three quasi-randomised trials. Just three trials reported assessor blinding of functional outcomes. Length of surgery, operative blood loss, need for blood transfusion and risk of deep wound infection were significantly less for internal fixation compared with arthroplasty. Fixation had a significantly higher re-operation rate in comparison with arthroplasty (40% versus 11%; risk ratio 3.22, 95% CI 2.31 to 4.47, 19 trials). No definite differences for hospital stay, mortality, or regain of pre-injury residential state were found. Limited information from some studies suggested pain was less and function was better for a cemented arthroplasty in comparison with fixation. Internal fixation is associated with less initial operative trauma but has an increased risk of re-operation on the hip. Definite conclusions cannot be made for differences in pain and residual disability between the two groups. Future studies should concentrate on better reporting of final outcome measures and function. There is still a need for studies to define which patient groups are better served by the different treatment methods.
We included 13 studies evaluating 19 interventions from high-income countries (HICs). At update stage (from our 2015 search), one previously included study was removed and three new studies added (since our 2012 search). We found no sufficiently robust evaluations conducted in low- and middle-income countries (LMICs). Study quality overall was low and measurements used by studies variable. Participants were classified as drop-in and shelter-based. No studies measured the primary outcome of reintegration and none reported on adverse effects.We found no consistent results on a range of relevant outcomes within domains of psychosocial health, substance misuse and sexually risky behaviours . Interventions evaluated consisted of time-limited therapeutically based programmes that proved no more effective than standard shelter or drop-in services and other control interventions used for most outcomes in most studies. Favourable changes from baseline were reported for outcomes for most participants following therapy interventions and standard services. We noted considerable heterogeneity between studies and inconsistent reporting of equity data. No studies measured the primary outcome of reintegration or reported on adverse effects. Analysis revealed no consistently significant benefit for focused therapeutic interventions compared with standard services such as drop-in centres, case management and other comparable interventions for street-connected children and young people. Commonly available services, however, were not rigorously evaluated. Robust evaluation of interventions, including comparison with no intervention, would establish a more reliable evidence base to inform service implementation. More robust research is needed in LMICs to examine interventions for street-connected children and young people with different backgrounds and service needs.
Six trials involving 1740 children were included. There was no significant reduction in mortality associated with pneumonia in children treated with vitamin A compared to those who were not (pooled odds ratio (OR) 1.29; 95% confidence interval (CI) 0.63 to 2.66). Also, there was no statistically significant difference in duration of hospital stay (mean difference (MD) 0.08; 95% CI -0.43 to 0.59). Disease severity after supplementary high-dose vitamin A was significantly worse compared with placebo. However, low-dose vitamin A significantly reduced the recurrence rate of bronchopneumonia (OR 0.12; 95% CI 0.03 to 0.46). Moderate vitamin A significantly reduced the time to remission of signs in children with normal serum retinol (> 200 ug/L). The evidence does not suggest a significant reduction in mortality, measures of morbidity, nor an effect on the clinical course of pneumonia with vitamin A adjunctive treatment in children with non-measles pneumonia. However, not all studies measured all outcomes, which limited the number of studies that could be incorporated into the meta-analyses, so that there may have been a lack of statistical power to detect statistically significant differences.
The review includes three trials, which were all at low risk of bias, involving 530 people with peripheral neuropathy. The effects of amantadine from one randomised, double-blind, placebo-controlled, cross-over trial comparing amantadine with placebo for the treatment of fatigue in 80 people with Guillain-Barré syndrome (GBS) were uncertain for the proportion of people achieving a favourable outcome six weeks post-intervention (odds ratio (OR) 0.56 (95% confidence interval (CI) 0.22 to 1.35, N = 74, P = 0.16). We assessed the quality of this evidence as low. Two parallel-group randomised double-blind, placebo-controlled trials comparing the effects of two doses of ascorbic acid with placebo for reducing fatigue in adults with Charcot-Marie-Tooth disease type 1A (CMT1A) showed that the effects of ascorbic acid at either dose are probably small (standardised mean difference (SMD) -0.12 (95% CI -0.32 to 0.08, n = 404, P = 0.25)) for change in fatigue after 12 to 24 months (moderate quality evidence). Neither ascorbic acid study measured fatigue at four to 12 weeks, which was our primary outcome measure. No serious adverse events were reported with amantadine. Serious adverse events were reported in the trials of ascorbic acid. However,risk of serious adverse events was similar with ascorbic acid and placebo. One small imprecise study in people with GBS showed uncertain effects of amantadine on fatigue. In two studies in people with CMT1A there is moderate-quality evidence that ascorbic acid has little meaningful benefit on fatigue. Information about adverse effects was limited, although both treatments appear to be well tolerated and safe in these conditions. There was no evidence available from RCTs to evaluate the effect of other drugs or other interventions for fatigue in either GBS, CMT1A or other causes of peripheral neuropathy. The cost effectiveness of different interventions should also be considered in future randomised clinical trials.
We included nine RCTs with 1069 participants, describing 37 comparisons: six were NSAIDs versus placebo and three were NSAIDs versus NSAIDs. The overall risk of bias in the included studies was mixed. In a pooled analysis, NSAIDs did not significantly reduce the total symptom score (SMD -0.40, 95% CI -1.03 to 0.24, three studies, random-effects model), or duration of colds (MD -0.23, 95% CI -1.75 to 1.29, two studies, random-effects model). For respiratory symptoms, cough did not improve (SMD -0.05, 95% CI -0.66 to 0.56, two studies, random-effects model) but the sneezing score significantly improved (SMD -0.44, 95% CI -0.75 to -0.12, two studies, random-effects model). For outcomes related to the analgesic effects of NSAIDs (headache, ear pain, and muscle and joint pain) the treatment produced significant benefits. The risk of adverse effects was not high with NSAIDs (RR 2.94, 95% CI 0.51 to 17.03, two studies, random-effects model) but it is difficult to conclude that such drugs are no different from placebo. The quality of the evidence may be estimated as 'moderate' because of imprecision. The major limitations of this review are that the results of the studies are quite diverse and the number of studies for one result is quite small. NSAIDs are somewhat effective in relieving the discomfort caused by a cold but there is no clear evidence of their effect in easing respiratory symptoms. The balance of benefit and harms needs to be considered when using NSAIDs for colds.
A comprehensive search of the literature yielded the following results: CENTRAL (1022 references), MEDLINE (2874 references), and Embase (2820 references). After de-duplication, we screened titles and abstracts of 4880 references and excluded 4864 that did not meet the review inclusion criteria. Of the 16 references that potentially met the review inclusion, we excluded all 16 reports after reviewing the full texts. We did not identify any ongoing trials. There is currently an absence of evidence to indicate the effectiveness of health education interventions involving healthcare providers or individuals or both to promote early presentation and referral for women with endometrial cancer symptoms. High-quality RCTs are needed to assess whether health education interventions enhance early presentation and referral. If health education interventions can be shown to reduce treatment delays in endometrial cancer, further studies would be required to determine which interventions are most effective.
Forty-five studies (3186 participants) met the inclusion criteria; (dietary advice compared with: no advice (1053 participants); with oral nutritional supplements (332 participants); with dietary advice and oral nutritional supplements (731 participants); and dietary advice plus oral nutritional supplements compared with no additional intervention (1070 participants). Follow-up ranged from 18 days to 24 months. No comparison showed a significant difference between groups for mortality or morbidity. There was a significant change in weight found between groups when comparing dietary advice to no advice for interventions lasting greater than 12 months, mean difference 3.75 kg (95% confidence interval 0.97 to 6.53), and when all studies were combined, mean difference 1.47 kg (95% confidence interval 0.32 to 2.61) although there was significant heterogeneity in the combined analysis (I2 = 90%). Similar improvements in weight were found for the comparison of dietary advice with nutritional supplements if required versus no advice, mean difference 2.20 kg (95% confidence interval 1.16 to 3.25). Dietary advice compared with no advice was also associated with significantly improved mid-arm muscle circumference when all studies were combined, but with moderate heterogeneity, mean difference 0.81 mm (95% confidence interval 0.31 to 1.31). Dietary advice given with nutritional supplements compared with dietary advice alone resulted in improvements in: mid-arm muscle circumference, mean difference -0.89 mm (95% confidence interval -1.35 to -0.43); triceps skinfold thickness, mean difference -1.22 mm (95% confidence interval -2.34 to -0.09); and grip strength, mean difference -1.67 kg (95% confidence interval -2.96 to -0.37), although the effects on triceps skinfold thickness and grip strength were heterogeneous. Dietary advice with supplements if required resulted in a significant increase in triceps skinfold thickness compared with no advice, mean difference 0.40 mm (95% confidence interval 0.10 to 0.70), although these results are from a single trial with only 29 participants. Evidence of variable quality suggests that dietary advice with or without oral nutritional supplements may improve weight, body composition and grip strength. We found no evidence of benefit of dietary advice or oral nutritional supplements given alone or in combination on survival. Studies addressing the impact of nutritional interventions on nutritional, functional and patient-centred outcomes are needed.
978 unique references were identified via the search strategy. All but 50 were excluded by title and abstract screening. Three RCTs met the inclusion criteria; for one small RCT, data were insufficient for inclusion in the meta-analysis. The two RCTs included in the analysis randomly assigned 1945 women, reported HRs for survival adjusted for prognostic factors and based on 1851 women and had an overall low risk of bias, as they satisfied four of the assessment criteria. The third study had an overall unclear risk of bias, as information provided was not adequate concerning random sequence generation, allocation concealment, blinding, or completeness of outcome reporting. Results of the meta-analysis remained unchanged from the previous versions of this review and indicated no differences in overall and recurrence-free survival between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy (pooled hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.81 to 1.43; HR 1.23, 95% CI 0.96 to 1.58 for overall and recurrence-free survival, respectively) (1851 participants, two studies; moderate-quality evidence). We found no difference in risk of direct surgical morbidity between women who underwent lymphadenectomy and those who did not undergo lymphadenectomy. However, women who underwent lymphadenectomy had a significantly higher risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation than those who did not undergo lymphadenectomy (RR 3.72, 95% CI 1.04 to 13.27; RR 8.39, 95% CI 4.06 to 17.33 for risk of surgery-related systemic morbidity and lymphoedema/lymphocyst formation, respectively) (1922 participants, two studies; high-quality evidence). This review found no evidence that lymphadenectomy decreases risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. Evidence on serious adverse events suggests that women who undergo lymphadenectomy are more likely to experience surgery-related systemic morbidity or lymphoedema/lymphocyst formation. Currently, no RCT evidence shows the impact of lymphadenectomy in women with higher-stage disease and in those at high risk of disease recurrence.
We included one trial, which was judged to be at high risk of performance, detection and attrition bias. The 117 participants with a root-filled, premolar tooth restored with a carbon fibre post, were randomised to either a full coverage metal-ceramic crown or direct adhesive composite restoration. None experienced a catastrophic failure (i.e. when the restoration cannot be repaired), although only 104 teeth were included in the final, three-year assessment. There was no clear difference between the crown and composite group and the composite only group for non-catastrophic failures of the restoration (1/54 versus 3/53; RR 0.33; 95% CI 0.04 to 3.05) or failures of the post (2/54 versus 1/53; RR 1.96; 95% CI 0.18 to 21.01) at three years. The quality of the evidence for these outcomes is very low. There was no evidence available for any of our secondary outcomes: patient satisfaction and quality of life, incidence or recurrence of caries, periodontal health status, and costs. There is insufficient evidence to assess the effects of crowns compared to conventional fillings for the restoration of root-filled teeth. Until more evidence becomes available, clinicians should continue to base decisions about how to restore root-filled teeth on their own clinical experience, whilst taking into consideration the individual circumstances and preferences of their patients.
In total 437 eligible women were randomised to receive high dose chemotherapy with autograft and 413 were randomised to receive conventional treatment. There were fifteen treatment-related deaths among the high dose group and two in the control (conventional dose) group (RR 4.08, 95% CI 1.40 to 11.93). There was no statistically significant difference in overall survival between the high dose and control groups at three years or five years. At five years of follow up, there was a statistically significant difference in event-free survival, favouring the high dose group (RR 2.84, 95% CI 1.07 to 7.50). Toxicity was more severe in the high dose group. Only one of the trials has followed up all women for five years. Although there is evidence that high dose chemotherapy and autograft significantly improves event-free survival compared to conventional chemotherapy in women with metastatic breast cancer there is no significant evidence of benefit in overall survival. High dose chemotherapy with bone marrow or stem cell transplantation should not be given to women with metastatic breast cancer outside of clinical trials.
We identified 11 completed trials (1369 participants) and one ongoing trial. Trials were heterogeneous in participants recruited, qigong duration and length of follow-up periods. We were unable to ascertain the risk of bias in nine trials published in Chinese, as insufficient methodological details were reported and we were unable to contact the study authors to clarify this. We performed no meta-analyses, as trials were small and were at significant risk of bias. Clinical events were detailed in subsequent reports of two trials when statistically significant effects of qigong were seen for all-cause mortality, stroke mortality and stroke incidence at 20 to 30 years after completion of the trials. However, these trials were designed to examine outcomes in the short term, and it is not clear whether qigong was practised during extended periods of follow-up; therefore effects cannot be attributed to the intervention. None of the included studies reported other non-fatal CVD events. Six trials provided data that could be used to examine the effects of qigong on blood pressure. Reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were seen in three and two trials, respectively. Three trials examined the effects of qigong on blood lipids when favourable effects were seen in one trial for total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, and two trials showed favourable effects on high-density lipoprotein (HDL) cholesterol. The only trial considered at low risk of selection and detection bias did not demonstrate statistically significant effects on CVD risk factors with qigong, but this study was small and was underpowered. None of the included studies reported incidence of type 2 diabetes (T2D), adverse events, quality of life or costs. Currently, very limited evidence is available on the effectiveness of qigong for the primary prevention of CVD. Most of the trials included in this review are likely to be at high risk of bias, so we have very low confidence in the validity of the results. Publication of the ongoing trial will add to the limited evidence base, but further trials of high methodological quality with sufficient sample size and follow-up are needed to be incorporated in an update of this review before the effectiveness of qigong for CVD prevention can be established.
We included one cluster-randomised trial conducted in four rural districts in Ghana that randomised 28 community health officers (CHOs) (serving 2404 potentially eligible pregnant women) to the intervention group and 26 CHOs (serving 3515 potentially eligible pregnant women) to the control group. Overall, the trial had a high risk of bias. CHOs delivered the intervention in the experimental group (injection of 10 IU (international units) of oxytocin in the thigh one minute following birth using a prefilled, auto-disposable syringe). In the control group, CHOs did not provide this prophylactic injection to the women they observed. CHOs had no midwifery skills and did not in any way manage the birth. All other CHO activities (outcome measurement, data collection, and early treatment and referral when necessary) were identical across the control and oxytocin CHOs. Although only one of the nine cases of severe PPH (blood loss greater or equal to 1000 mL) occurred in the oxytocin group, the effect estimate for this outcome was very imprecise and it is uncertain whether the intervention prevents severe PPH (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.02 to 1.30; 1570 women (very low-quality evidence)). Similarly, because of the lack of cases of severe maternal morbidity (e.g. uterine rupture) and maternal deaths, it was not possible to obtain effect estimates for those outcomes (both very low-quality evidence). Oxytocin compared with the control group decreased the incidence of PPH (> 500 mL) in both our unadjusted (RR 0.48, 95% CI 0.28 to 0.81; 1569 women) and adjusted (RR 0.49, 95% CI 0.27 to 0.90; 1174 women (both low-quality evidence)) analyses. There was little or no difference between the oxytocin and control groups on the rates of transfer or referral of the mother to a healthcare facility (RR 0.72, 95% CI 0.34 to 1.56; 1586 women (low-quality evidence)), stillbirths (RR 1.27, 95% CI 0.67 to 2.40; 2006 infants (low-quality evidence)); andearly infant deaths (0 to three days) (RR 1.03, 95% CI 0.35 to 3.07; 1969 infants (low-quality evidence)). There were no cases of needle-stick injury or any other maternal major or minor adverse event or unanticipated harmful event. There were no cases of oxytocin use during labour. There were no data reported for some of this review's secondary outcomes: manual removal of placenta, maternal anaemia, neonatal death within 28 days, neonatal transfer to health facility for advanced care, breastfeeding rates. Similarly, the women's or the provider's satisfaction with the intervention was not reported. It is uncertain if oxytocin administered by CHO in non-facility settings compared with a control group reduces the incidence of severe PPH (>1000 mL), severe maternal morbidity or maternal deaths. However, the intervention probably decreases the incidence of PPH (> 500 mL). The quality of the one trial included in this review was limited because of the risk of attrition and recruitment biases related to limitations in the follow-up of pregnant women in both arms of the trials and some baseline imbalance on the size of babies at birth. Additionally, there was serious imprecision of the effect estimates for most of the primary outcomes mainly because of the size of the trial, very few or no events and CIs around both relative and absolute estimates of effect that include both appreciable benefit and appreciable harm. Although the trial presented data both for primary and secondary outcomes, it seemed to be underpowered to detect differences in the primary outcomes that are the ones more relevant for making judgments about the potential applicability of the intervention in other settings (especially severe PPH). Therefore, taking into account the extreme setting where the intervention was implemented, the limited role of the CHO in the trial and the lack of power for detecting effects on primary (relevant) outcomes, the applicability of the evidence found seems to be rather limited. Further well-executed and adequately-powered randomised controlled trials assessing the effects of using oxytocin in pre-filled injection devices or other new delivery systems (spray-dried ultrafine formulation of oxytocin) on severe PPH are urgently needed. Likewise, other important outcomes like possible adverse events and acceptability of the intervention by mothers and other community stakeholders should also be assessed.
We found one RCT with 174 participants and five CBAs with 48,058 participants assessing the effectiveness of vocational training (n = 1) and antiretroviral therapy (ART) (n = 5). We found no studies assessing psychological interventions. The one RCT was conducted in the United States; the five CBA studies were conducted in South Africa, India, Kenya, and Uganda. We graded all six studies as having a high risk of bias. The effectiveness of vocational intervention was assessed in only one study but we could not infer the intervention effect due to a lack of data. For pharmacological interventions, we found very low-quality evidence for a beneficial effect of ART on employment outcomes in five studies. Due to differences in outcome measurement we could only combine the results of two studies in a meta-analysis. Two studies compared employment outcomes of HIV+ persons on ART therapy to healthy controls. One study found a MD of -1.22 days worked per month (95% confidence interval (CI) -1.74 to -1.07) at 24-months follow-up. The other study found that the likelihood of being employed steadily increased for HIV+ persons compared to healthy individuals from ART initiation (OR 0.35, 95% CI 0.26 to 0.47) to three- to five-years follow-up (OR 0.73, 95% CI 0.42 to 1.28). Three other studies compared HIV+ persons on ART to HIV+ persons not yet on ART. Two studies indicated an increase in the likelihood of employment over time due to the impact of ART for HIV+ persons compared to HIV+ persons pre-ART (OR 1.75, 95% CI 1.44 to 2.12). One study found that the group on ART worked 12.1 hours more (95% CI 6.99 to 17.21) per week at 24-months follow-up than the average of the cohort of ART and pre-ART HIV+ persons which was 20.1 hours. We rated the evidence as very low quality for all comparisons due to a high risk of bias. We found very low-quality evidence showing that ART interventions may improve employment outcomes for HIV+ persons. For vocational interventions, the one included study produced no evidence of an intervention effect. We found no studies that assessed psychological interventions. We need more high-quality, preferably randomized studies to assess the effectiveness of RTW interventions for HIV+ persons.
Nine small trials involving 510 adults with potentially or evidently unstable fractures, were grouped into five comparisons. The interventional, clinical and methodological heterogeneity of trials precluded data pooling. Only one trial had secure allocation concealment. Two trials comparing a bridging (of the wrist) external fixator versus pins and plaster external fixation found no significant differences in function or deformity. One trial found tendencies for more serious complications but less subsequent discomfort and deformity in the fixator group. Three trials compared non-bridging versus bridging fixation. Of the two trials testing uni-planar non-bridging fixation, one found no significant differences in functional or clinical outcomes; the other found non-bridging fixation significantly improved grip strength, wrist flexion and anatomical outcome. The third trial found no significant findings in favour of multi-planar non-bridging fixation of complex intra-articular fractures. One trial using a bridging external fixator found that deploying an extra external fixator pin to fix the 'floating' distal fragment gave superior functional and anatomical results. One trial found no evidence of differences in clinical outcomes for hydroxyapatite coated pins compared with standard uncoated pins. Two trials compared dynamic versus static external fixation. One trial found no significant effects from early dynamism of an external fixator. The poor quality of the other trial undermines its findings of poorer functional and anatomical outcomes for dynamic fixation. There is insufficient robust evidence to determine the relative effects of different methods of external fixation. Adequately powered studies could provide better evidence.
We included eight RCTs with 311 participants in this review. After exclusion of five participants, we included 306 participants in one or more outcomes. Five trials (240 participants) investigated the three main treatments: open necrosectomy (121 participants), minimally invasive step-up approach (80 participants), and peritoneal lavage (39 participants) and were included in the network meta-analysis. Three trials (66 participants) investigated the variations in the main treatments: early open necrosectomy (25 participants), delayed open necrosectomy (11 participants), video-assisted minimally invasive step-up approach (12 participants), endoscopic minimally invasive step-up approach (10 participants), minimally invasive step-up approach (planned surgery) (four participants), and minimally invasive step-up approach (continued percutaneous drainage) (four participants). The trials included infected or sterile necrotising pancreatitis of varied aetiology. All the trials were at unclear or high risk of bias and the overall quality of evidence was low or very low for all the outcomes. Overall, short-term mortality was 30% and serious adverse events rate was 139 serious adverse events per 100 participants. The differences in short-term mortality and proportion of people with serious adverse events were imprecise in all the comparisons. The number of serious adverse events and adverse events were fewer in the minimally invasive step-up approach compared to open necrosectomy (serious adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study; adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study). The proportion of people with organ failure and the mean costs were lower in the minimally invasive step-up approach compared to open necrosectomy (organ failure: OR 0.20, 95% CI 0.07 to 0.60; 88 participants; 1 study; mean difference in costs: USD -11,922; P value < 0.05; 88 participants; 1 studies). There were more adverse events with video-assisted minimally invasive step-up approach group compared to endoscopic-assisted minimally invasive step-up approach group (rate ratio 11.70, 95% CI 1.52 to 89.87; 22 participants; 1 study), but the number of interventions per participant was less with video-assisted minimally invasive step-up approach group compared to endoscopic minimally invasive step-up approach group (difference in medians: 2 procedures; P value < 0.05; 20 participants; 1 study). The differences in any of the other comparisons for number of serious adverse events, proportion of people with organ failure, number of adverse events, length of hospital stay, and intensive therapy unit stay were either imprecise or were not consistent. None of the trials reported long-term mortality, infected pancreatic necrosis (trials that included participants with sterile necrosis), health-related quality of life at any time frame, proportion of people with adverse events, requirement for additional invasive intervention, time to return to normal activity, and time to return to work. Low to very low quality evidence suggested that the minimally invasive step-up approach resulted in fewer adverse events, serious adverse events, less organ failure, and lower costs compared to open necrosectomy. Very low quality evidence suggested that the endoscopic minimally invasive step-up approach resulted in fewer adverse events than the video-assisted minimally invasive step-up approach but increased the number of procedures required for treatment. There is currently no evidence to suggest that early open necrosectomy is superior or inferior to peritoneal lavage or delayed open necrosectomy. However, the CIs were wide and significant benefits or harms of different treatments cannot be ruled out. The TENSION trial currently underway in Netherlands is assessing the optimal way to perform the minimally invasive step-up approach (endoscopic drainage followed by endoscopic necrosectomy if necessary versus percutaneous drainage followed by video-assisted necrosectomy if necessary) and is assessing important clinical outcomes of interest for this review. Implications for further research on this topic will be determined after the results of this RCT are available.
We included 18 studies that randomised a total of 2438 participants - both adults and children - and performed comparisons of interest. Included studies assessed higher versus lower doses of prednisolone (n = 4); longer versus shorter courses of prednisolone (n = 3) or dexamethasone (n = 1); tapered versus non-tapered courses of prednisolone (n = 4); and prednisolone versus dexamethasone (n = 6). Follow-up duration ranged from seven days to six months. The smallest study randomised just 15 participants, and the largest 638 (median 93). The varied interventions and outcomes reported limited the number of meaningful meta-analyses that we could perform. For two of our primary outcomes - hospital admission and serious adverse events - events were too infrequent to permit conclusions about the superiority of one treatment over the other, or their equivalence. Researchers in the included studies reported asthma symptoms in different ways and rarely used validated scales, again limiting our conclusions. Secondary outcome meta-analysis was similarly hampered by heterogeneity among interventions and outcome measures used. Overall, we found no convincing evidence of differences in outcomes between a higher dose or longer course and a lower dose or shorter course of prednisolone or dexamethasone, or between prednisolone and dexamethasone. Included studies were generally of reasonable methodological quality. Review authors assessed most outcomes in the review as having low or very low quality, meaning we are not confident in the effect estimates. The predominant reason for downgrading was imprecision, but indirectness and risk of bias also reduced our confidence in some estimates. Evidence is not strong enough to reveal whether shorter or lower-dose regimens are generally less effective than longer or higher-dose regimens, or indeed that the latter are associated with more adverse events. Any changes recommended for current practice should be supported by data from larger, well-designed trials. Varied study design and outcome measures limited the number of meta-analyses that we could perform. Greater emphasis on palatability and on whether some regimens might be easier to adhere to than others could better inform clinical decisions for individual patients.
In two eligible trials, a total of 381 participants underwent distal pancreatic resection and were randomised to closure of the pancreatic remnant either with stapler (n = 191) or scalpel resection followed by hand-sewn closure (n = 190). One was a single centre pilot RCT and the other was a multicentre blinded RCT. The single centre pilot RCT evaluated 69 participants in five intervention arms (stapler, hand-sewn, fibrin glue, mesh and pancreaticojejunostomy), although we only assessed the stapler and hand-sewn closure groups (14 and 15 participants, respectively). The multicentre RCT had two interventional arms: stapler (n = 177) and hand-sewn closure (n = 175). The rate of postoperative pancreatic fistula was the main outcome, and it occurred in 79 of 190 participants in the hand-sewn group compared to 65 of 191 participants in the stapler group. Neither the individual trials nor the meta-analysis showed a significant difference between resection techniques (RR 0.90; 95% CI 0.55 to 1.45; P = 0.66). In the same way, postoperative mortality and operation time did not differ significantly. The single centre RCT had an unclear risk of bias in the randomisation, allocation and both blinding domains. However, the much larger multicentre RCT had a low risk of bias in all domains. Due to the small number of events and the wide confidence intervals that cannot exclude clinically important benefit or harm with stapler versus hand-sewn closure, there is a serious possibility of imprecision, making the overall quality of evidence moderate. The quality of evidence is moderate and mainly based on the high weight of the results of one multicentre RCT. Unfortunately, there are no other completed RCTs on this topic except for one relevant ongoing trial. Neither stapler nor scalpel resection followed by hand-sewn closure of the pancreatic remnant for distal pancreatectomy showed any benefit compared to the other method in terms of postoperative pancreatic fistula, overall postoperative mortality or operation time. Currently, the choice of closure is left up to the preference of the individual surgeon and the anatomical characteristics of the patient. Another (non-European) multicentre trial (e.g. with an equality or non-inferiority design) would help to corroborate the findings of this meta-analysis. Future trials assessing novel methods of stump closure should compare them either with stapler or hand-sewn closure as a control group to ensure comparability of results.
We included five small trials involving 169 participants with patella fractures. Participant age ranged from 16 to 76 years. There were 68 females and 100 males; the gender of one participant was not reported. Two trials were conducted in China and one each in Finland, Mexico and Turkey. All five trials compared different surgical interventions. Two trials compared biodegradable versus metallic implants for treating displaced patella fractures; one trial compared patellectomy with advancement of vastus medialis obliquus versus simple patellectomy for treating comminuted patella fractures; and two trials compared percutaneous osteosynthesis (both procedures were 'novel' and one used a new device) versus open surgery for treating displaced patella fractures. All the trials had design flaws, such as lack of assessor blinding, which put them at high risk of bias, potentially limiting the reliability of their findings. No trial reported on health-related quality of life, return to previous activity or cosmetic appearance. Very low quality evidence from two trials (48 participants) comparing biodegradable versus metallic implants indicated little difference between the two interventions at two-year follow-up in the numbers of participants with occasional knee pain (1/23 versus 2/24), incurring adverse events (3/24 versus 1/24) or with reduced knee motion (2/23 versus 2/24). Neither trial reported patient-rated knee function scores. In one trial, as per routine practice, metallic implants were removed one year after surgery (four participants). The other trial did not report on this aspect. Very low quality evidence from one trial (28 participants) indicated that compared with simple patellectomy, patellectomy with advancement of vastus medialis obliquus surgery for treating comminuted patella fractures resulted in more participants with a 'good' result based on a subjectively rated score (12/12 versus 11/16; risk ratio (RR) 1.42, 95% confidence interval (CI) 1.01 to 2.01), fewer participants experiencing knee pain (5/12 versus 13/16; RR 3.11, 95% CI 1.01 to 9.60) and more participants with unlimited activity and no loss in quadriceps strength at four-year follow-up. The only adverse event reported was a patellar tendon subluxation in the simple patellectomy group. Neither trial comparing percutaneous osteosynthesis (using novel devices or methods) versus open surgery reported on patient-rated knee function scores. Very low quality evidence from two trials (93 participants) showed that percutaneous osteosynthesis improved knee pain measured using visual analogue scale (0 to 10 where 10 is worst pain) at one month (mean difference (MD) -2.24, 95% CI -2.80 to -1.68) and at up to three months (MD -1.87, 95% CI -2.45 to -1.29). This effect did not persist at six months (very low quality evidence from one trial). Very low quality evidence from the two trials showed significantly fewer participants with adverse events (loss of reduction, infection, hardware complications, delayed wound healing) after percutaneous surgery (8/47 versus 28/46; RR 0.28, 95% CI 0.14 to 0.55). Very low quality evidence from the two trials indicated better clinician-rated knee function scores after percutaneous fixation at two to three months and 12 months follow-up; however, the between-group difference was not clinically important at 24 months. Very low quality evidence showed a lower incidence of hardware removal in the percutaneous group at two years; however, the results in the two trials were heterogeneous and the reasons for removal were not given in detail. There is very limited evidence from RCTs about the relative effects of different surgical interventions for treating fractures of the patella in adults. There is no evidence from RCTs evaluating the relative effects of surgical versus conservative treatment or different types of conservative interventions. Based on very low quality evidence, biodegradable implants seem to be no better than metallic implants for displaced patellar fractures; patellectomy with vastus medialis obliquus advancement may give better results than simple patellectomy for comminuted patellar fractures; and two novel methods of percutaneous osteosynthesis may give better results than conventional open surgery. However, until conclusive evidence becomes available, treatment options must be chosen on an individual patient basis, carefully considering the relative benefits and harms of each intervention and patient preferences. Further randomised trials are needed, but in order to optimise research effort, these should be preceded by research that aims to identify priority questions.
We included 15 studies with 724 participants. We found a range of treatment protocols in terms of duration of care, TENS application times and intensity of application. Briefly, duration of care ranged from four days through to three months. Similarly, we found variation of TENS application times; from 15 minutes up to hourly sessions applied four times daily. We typically found intensity of TENS set to comfortable perceptible tingling with very few studies titrating the dose to maintain this perception. Of the comparisons, we had planned to explore, we were only able to undertake a quantitative synthesis for TENS versus sham TENS. Insufficient data and large diversity in the control conditions prevented us from undertaking a quantitative synthesis for the remaining comparisons. For TENS compared to sham TENS, five studies were suitable for pooled analysis. We described the remainder of the studies in narrative form. Overall, we judged 11 studies at high risk of bias, and four at unclear risk. Due to the small number of eligible studies, the high levels of risk of bias across the studies and small sample sizes, we rated the quality of the evidence as very low for the pooled analysis and very low individual GRADE rating of outcomes from single studies. For the individual studies discussed in narrative form, the methodological limitations, quality of reporting and heterogeneous nature of interventions compared did not allow for reliable overall estimates of the effect of TENS. Five studies (across various neuropathic conditions) were suitable for pooled analysis of TENS versus sham TENS investigating pain intensity using a visual analogue scale. We found a mean postintervention difference in effect size favouring TENS of -1.58 (95% confidence interval (CI) -2.08 to -1.09, P < 0.00001, n = 207, six comparisons from five studies) (very low quality evidence). There was no significant heterogeneity in this analysis. While this exceeded our prespecified minimally important difference for pain outcomes, we assessed the quality of evidence as very low meaning we have very little confidence in this effect estimate and the true effect is likely to be substantially different from that reported in this review. Only one study of these five investigated health related quality of life as an outcome meaning we were unable to report on this outcome in this comparison. Similarly, we were unable to report on global impression of change or changes in analgesic use in this pooled analysis. Ten small studies compared TENS to some form of usual care. However, there was great diversity in what constituted usual care, precluding pooling of data. Most of these studies found either no difference in pain outcomes between TENS versus other active treatments or favoured the comparator intervention (very low quality evidence). We were unable to report on other primary and secondary outcomes in these single trials (health-related quality of life, global impression of change and changes in analgesic use). Of the 15 included studies, three reported adverse events which were minor and limited to 'skin irritation' at or around the site of electrode placement (very low quality evidence). Three studies reported no adverse events while the remainder did not report any detail with regard adverse events. In this review, we reported on the comparison between TENS and sham TENS. The quality of the evidence was very low meaning we were unable to confidently state whether TENS is effective for pain control in people with neuropathic pain. The very low quality of evidence means we have very limited confidence in the effect estimate reported; the true effect is likely to be substantially different. We make recommendations with respect to future TENS study designs which may meaningfully reduce the uncertainty relating to the effectiveness of this treatment modality.
We included five randomized trials (208 participants, 104 in the intervention group and 104 in the control group). Interventions ranged from three to six months. Four trials reported results in non-Asian populations published in English. One trial reported results in Chinese people published in Chinese. Overall, the risk of bias of included trials was high or unclear. There were no outcome data on death from any cause, morbidity, complications, health-related quality of life and costs. Two trials reported adverse effects, including gastrointestinal discomfort (bloating and constipation) and an increased number of hot flushes. None of the trials found serious adverse events. There was a slight significant effect on triglycerides in favour of isoflavones when compared with placebo (mean difference (MD) -0.46 mmol/L (95% confidence interval (CI) -0.84 to -0.09; P = 0.02; 52 participants; 2 trials). No statistically significant effects on total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were shown in favour of isoflavones. We found no evidence for effects of isoflavones on patient-important outcomes or lowering of cholesterol levels in people with hypercholesterolaemia. Our findings have to be interpreted with caution due to high or unclear risk of bias in several risk of bias domains, and low number of participants in trials.
Eighteen trials met our inclusion criteria. Eleven studies are complete (1392 participants), and seven are ongoing. Of the completed studies, seven interventions are broad, targeting the lifestyle management of CHD, and four focused on physical activity promotion. The comparison group in trials was usual care (n = 6), minimal intervention (n = 3), or traditional cardiac rehabilitation (n = 2). We found no effects of Internet-based interventions for all-cause mortality (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.04 to 1.63; participants = 895; studies = 6; low-quality evidence). There was only one case of cardiovascular mortality in a control group (participants = 895; studies = 6). No incidences of non-fatal re-infarction were reported across any of the studies. We found no effects for revascularisation (OR 0.69, 95% CI 0.37 to 1.27; participants = 895; studies = 6; low-quality evidence). We found no effects for total cholesterol (mean difference (MD) 0.00, 95% CI -0.27 to 0.28; participants = 439; studies = 4; low-quality evidence), high-density lipoprotein (HDL) cholesterol (MD 0.01, 95% CI -0.06 to 0.07; participants = 437; studies = 4; low-quality evidence), or triglycerides (MD 0.01, 95% CI -0.17 to 0.19; participants = 439; studies = 4; low-quality evidence). We did not pool the data for low-density lipoprotein (LDL) cholesterol due to considerable heterogeneity. Two out of six trials measuring LDL cholesterol detected favourable intervention effects, and four trials reported no effects. Seven studies measured systolic and diastolic blood pressure; we did not pool the data due to substantial heterogeneity. For systolic blood pressure, two studies showed a reduction with the intervention, but the remaining studies showed no effect. For diastolic blood pressure, two studies showed a reduction with the intervention, one study showed an increase with the intervention, and the remaining four studies showed no effect. Five trials measured health-related quality of life (HRQOL). We could draw no conclusions from one study due to incomplete reporting; one trial reported no effect; two studies reported a short- and medium-term effect respectively; and one study reported both short- and medium-term effects. Five trials assessed dietary outcomes: two reported favourable effects, and three reported no effects. Eight studies assessed physical activity: five of these trials reported no physical activity effects, and three reported effectiveness. Trials are yet to measure the impact of these interventions on compliance with medication. Two studies measured healthcare utilisation: one reported no effects, and the other reported increased usage of healthcare services compared to a control group in the intervention group at nine months' follow-up. Two trials collected cost data: both reported that Internet-delivered interventions are likely to be cost-effective. In terms of the risk of bias, the majority of studies reported appropriate randomisation and appropriate concealment of randomisation processes. A lack of blinding resulted in a risk of performance bias in seven studies, and a risk of detection bias in five trials. Two trials were at risk of attrition bias, and five were at risk for reporting bias. In general, evidence was of low quality due to lack of blinding, loss to follow-up, and uncertainty around the effect size. Few studies measured clinical events, and of those that did, a very small number of events were reported, and therefore no firm conclusions can be made. Similarly, there was no clear evidence of effect for cardiovascular risk factors, although again the number of studies reporting these was small. There was some evidence for beneficial effects on HRQOL, dietary outcomes, and physical activity, although firm conclusions cannot yet be made. The effects on healthcare utilisation and cost-effectiveness are also inconclusive, and trials are yet to measure the impact of Internet interventions on compliance with medication. The comparison groups differed across trials, and there were insufficient studies with usable data for subgroup analyses. We intend to study the intensity of comparison groups in future updates of this review when more evidence is available. The completion of the ongoing trials will add to the evidence base.
We included 24 trials involving 23,748 participants. The quality of the trials varied considerably. The anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. Over 90% of the evidence relates to the effects of anticoagulant therapy initiated within the first 48 hours of onset. Based on 11 trials (22,776 participants) there was no evidence that anticoagulant therapy started within the first 14 days of stroke onset reduced the odds of death from all causes (odds ratio (OR) 1.05; 95% confidence interval (CI) 0.98 to 1.12) at the end of follow-up. Similarly, based on eight trials (22,125 participants), there was no evidence that early anticoagulation reduced the odds of being dead or dependent at the end of follow-up (OR 0.99; 95% CI 0.93 to 1.04). Although early anticoagulant therapy was associated with fewer recurrent ischaemic strokes (OR 0.76; 95% CI 0.65 to 0.88), it was also associated with an increase in symptomatic intracranial haemorrhages (OR 2.55; 95% CI 1.95 to 3.33). Similarly, early anticoagulation reduced the frequency of symptomatic pulmonary emboli (OR 0.60; 95% CI 0.44 to 0.81), but this benefit was offset by an increase in extracranial haemorrhages (OR 2.99; 95% CI 2.24 to 3.99). Since the last version of the review, no new relevant studies have been published and so there is no additional information to change the conclusions. Early anticoagulant therapy is not associated with net short- or long-term benefit in people with acute ischaemic stroke. Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis and pulmonary embolism, but increased bleeding risk. The data do not support the routine use of any of the currently available anticoagulants in acute ischaemic stroke.
We included 26 randomised controlled trials involving 1728 participants. Six studies compared an alpha2-adrenergic agonist with placebo, 12 with reducing doses of methadone, four with symptomatic medications, and five compared different alpha2-adrenergic agonists. We assessed 10 studies as having a high risk of bias in at least one of the methodological domains that were considered. We found moderate-quality evidence that alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57; 3 studies; 148 participants). We found moderate-quality evidence that completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 1.95, 95% CI 1.34 to 2.84; 3 studies; 148 participants). Peak withdrawal severity may be greater with alpha2-adrenergic agonists than with reducing doses of methadone, as measured by the likelihood of severe withdrawal (RR 1.18, 95% CI 0.81 to 1.73; 5 studies; 340 participants; low quality), and peak withdrawal score (standardised mean difference (SMD) 0.22, 95% CI -0.02 to 0.46; 2 studies; 263 participants; moderate quality), but these differences were not significant and there is no significant difference in severity when considered over the entire duration of the withdrawal episode (SMD 0.13, 95% CI -0.24 to 0.49; 3 studies; 119 participants; moderate quality). The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists. The duration of treatment was significantly longer with reducing doses of methadone (SMD -1.07, 95% CI -1.31 to -0.83; 3 studies; 310 participants; low quality). Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10; 6 studies; 464 participants; low quality), but there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05; 9 studies; 659 participants; low quality). There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists. Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine. Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. We detected no significant difference in efficacy between treatment regimens based on clonidine or lofexidine and those based on reducing doses of methadone over a period of around 10 days, but methadone was associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.
Twelve RCTs and three CCTs were identified, all focusing on BN, BED, EDNOS or combinations of these, in adults, using manual-based PSH/GSH across various settings. Primary comparisons:  At end of treatment, PSH/GSH did not significantly differ from waiting list in abstinence from bingeing (RR 0.72, 95% CI 0.47 to 1.09), or purging (RR 0.86, 95% CI 0.68 to 1.08), although these treatments produced greater improvement on other eating disorder symptoms, psychiatric symptomatology and interpersonal functioning but not depression. Compared to other formal psychological therapies, PSH/GSH did not differ significantly at end of treatment or follow-up in improvement on bingeing and purging (RR 0.99, 95% CI 0.75 to 1.31), other eating disorder symptoms, level of interpersonal functioning or depression. There were no significant differences in treatment dropout. Secondary comparisons:  One small study in BED found that cognitive-behavioural GSH compared to a non-specific control treatment produced significantly greater improvements in abstinence from bingeing and other eating disorder symptoms. Studies comparing PSH with GSH found no significant differences between treatment groups at end of treatment or follow-up. Comparison between different types of PSH/GSH found significant differences on eating disorder symptoms but not on bingeing/purging abstinence rates. PSH/GSH may have some utility as a first step in treatment and may have potential as an alternative to formal therapist-delivered psychological therapy. Future research should focus on producing large well-conducted studies of self-help treatments in eating disorders including health economic evaluations, different types and modes of delivering self-help (e.g. computerised versus manual-based) and different populations and settings.
We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review. None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I2 = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I2 = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I2 = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'. Funding: two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding. The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking.
A total of 12 studies involving 2342 children were included. Eleven out of 12 trials were conducted in North America, within urban or suburban settings involving vulnerable populations. The studies were overall of good methodological quality. They differed markedly in terms of age, severity of asthma, context and content of the educational intervention leading to substantial clinical heterogeneity. Due to this clinical heterogeneity, we did not pool results for our primary outcome, the number of patients with exacerbations requiring emergency department (ED) visit. The mean number of exacerbations requiring ED visits per person at six months was not significantly different between the home-based intervention and control groups (N = 2 studies; MD 0.04; 95% confidence interval (CI) -0.20 to 0.27). Only one trial contributed to our other primary outcome, exacerbations requiring a course of oral corticosteroids. Hospital admissions also demonstrated wide variation between trials with significant changes in some trials in both directions. Quality of life improved in both education and control groups over time. A table summarising some of the key components of the education programmes is included in the review. We found inconsistent evidence for home-based asthma educational interventions compared to standard care, education delivered outside of the home or a less intensive educational intervention delivered at home. Although education remains a key component of managing asthma in children, advocated in numerous guidelines, this review does not contribute further information on the fundamental content and optimum setting for such educational interventions.
We included 12 studies, involving 622 participants with 648 fractures. Eight studies were randomised placebo-controlled trials, two were randomised controlled trials without placebo controls, one was a quasi-randomised placebo-controlled trial and one was a quasi-randomised controlled trial without placebo control. Eleven trials tested LIPUS and one trial tested ECSW. Four trials included participants with conservatively treated upper limb complete fractures and six trials included participants with lower limb complete fractures; these were surgically fixed in four trials. The remaining two trials reported results for conservatively treated tibial stress fractures. 'Risk of bias' assessment of the included studies was hampered by the poor reporting of methods, frequently resulting in the risk of bias of individual domains being judged as ‘unclear’. Both quasi-randomised studies were at high risk of bias, including selection and attrition bias. Three studies were at low risk of selection bias relating to allocation concealment the majority of studies were at low risk of performance bias as they employed a form of intervention blinding. Only limited data were available from three of only four studies reporting on functional outcome. One study of complete fractures found little evidence of a difference between the two groups in the time to return to work (mean difference (MD) 1.95 days favouring control, 95% confidence interval (CI) -2.18 to 6.08; 101 participants). Pooled data from two studies found LIPUS did not significantly affect the time to return to training or duty in soldiers or midshipmen with stress fractures (MD -8.55 days, 95% CI -22.71 to 5.61; 93 participants). We adopted a conservative strategy for data analysis that was more likely to underestimate than to overestimate a benefit of the intervention. After pooling results from eight studies (446 fractures), the data showed no statistically significant reduction in time to union of complete fractures treated with LIPUS (standardised mean difference (SMD) -0.47, 95% CI -1.14 to 0.20). This result could include a clinically important benefit or harm, and should be seen in the context of the highly significant statistical heterogeneity (I² = 90%). This heterogeneity was not explained by the a priori subgroup analyses (upper limb versus lower limb fracture, smoking status). An additional subgroup analysis comparing conservatively and operatively treated fractures raised the possibility that LIPUS may be effective in reducing healing time in conservatively managed fractures, but the test for subgroup differences did not confirm a significant difference between the subgroups. Pooled results from five of the eight trials (333 fractures) reporting proportion of delayed union or non-union showed no significant difference between LIPUS and control (10/168 versus 13/165; RR 0.75; 95% CI 0.24 to 2.28). Adverse effects directly associated with LIPUS and associated devices were found to be few and minor, and compliance with treatment was generally good. One study reporting on pain scores found no difference between groups at eight weeks (101 participants). One quasi-randomised study found no significant difference in non-union at 12 months between internal fixation supplemented with ECSW and internal fixation alone (3/27 versus 6/30; RR 0.56, 95% CI 0.15 to 2.01). There was a clinically small but statistically significant difference in the visual analogue scores for pain in favour of ECSW at three month follow-up (MD -0.80, 95% CI -1.23 to -0.37). The only reported complication was infection, with no significant difference between the two groups. While a potential benefit of ultrasound for the treatment of acute fractures in adults cannot be ruled out, the currently available evidence from a set of clinically heterogeneous trials is insufficient to support the routine use of this intervention in clinical practice. Future trials should record functional outcomes and follow-up all trial participants.
We included 40 new trials bringing the total to 87 included trials (7140 randomised teeth) for this update. All were small, single-centre trials (median number of randomised teeth = 68). All trials were assessed at unclear or high risk of bias. The 87 trials examined 125 different comparisons: 75 comparisons of different medicaments or techniques for pulpotomy; 25 comparisons of different medicaments for pulpectomy; four comparisons of pulpotomy and pulpectomy; and 21 comparisons of different medicaments for direct pulp capping. The proportion of clinical failures and radiological failures was low in all trials. In many trials, there were either no clinical failures or no radiographic failures in either study arm. For pulpotomy, we assessed three comparisons as providing moderate-quality evidence. Compared with formocresol, MTA reduced both clinical and radiological failures, with a statistically significant difference at 12 months for clinical failure and at six, 12 and 24 months for radiological failure (12 trials, 740 participants). Compared with calcium hydroxide, MTA reduced both clinical and radiological failures, with statistically significant differences for clinical failure at 12 and 24 months. MTA also appeared to reduce radiological failure at six, 12 and 24 months (four trials, 150 participants) (low-quality evidence). When comparing calcium hydroxide with formocresol, there was a statistically significant difference in favour of formocresol for clinical failure at six and 12 months and radiological failure at six, 12 and 24 months (six trials (one with no failures), 332 participants). Regarding pulpectomy, we found moderate-quality evidence for two comparisons. The comparison between Metapex and zinc oxide and eugenol (ZOE) paste was inconclusive, with no clear evidence of a difference between the interventions for failure at 6 or 12 months (two trials, 62 participants). Similarly inconclusive, there was no clear evidence of a difference in failure between Endoflas and ZOE (outcomes measured at 6 months; two trials, 80 participants). There was low-quality evidence of a difference in failure at 12 months that suggested ZOE paste may be better than Vitapex (calcium hydroxide/iodoform) paste (two trials, 161 participants). Regarding direct pulp capping, the small number of studies undertaking the same comparison limits any interpretation. We assessed the quality of the evidence as low or very low for all comparisons. One trial appeared to favour formocresol over calcium hydroxide; however, there are safety concerns about formocresol. Pulp treatment for extensive decay in primary teeth is generally successful. Many included trials had no clinical or radiological failures in either trial arm, and the overall proportion of failures was low. Any future trials in this area would require a very large sample size and follow up of a minimum of one year. The evidence suggests MTA may be the most efficacious medicament to heal the root pulp after pulpotomy of a deciduous tooth. As MTA is relatively expensive, future research could be undertaken to confirm if Biodentine, enamel matrix derivative, laser treatment or Ankaferd Blood Stopper are acceptable second choices, and whether, where none of these treatments can be used, application of sodium hypochlorite is the safest option. Formocresol, though effective, has known concerns about toxicity. Regarding pulpectomy, there is no conclusive evidence that one medicament or technique is superior to another, and so the choice of medicament remains at the clinician's discretion. Research could be undertaken to confirm if ZOE paste is more effective than Vitapex and to evaluate other alternatives. Regarding direct pulp capping, the small number of studies and low quality of the evidence limited interpretation. Formocresol may be more successful than calcium hydroxide; however, given its toxicity, any future research should focus on alternatives.
We included 26 trials (2756 participants), all conducted in China. All participants were inpatients within the first few days after stroke onset (mean age 58 to 75 years and male proportion 45% to 80%). Most trials delivered buflomedil intravenously, with a daily dose of 200 mg for 14 days. The study quality was generally poor and many trials were poorly reported. Only one trial reported long-term death and disability, where stroke survivors in the buflomedil group had a lower risk of suffering 'death or disability' than those in the control group (200 participants, RR 0.71, 95% confidence interval (CI) 0.53 to 0.94). All 26 trials assessed outcomes by the end of treatment (eight trials with 1056 participants reported death, one trial with 85 participants reported disability, and 26 trials with 2756 participants reported neurological deficits), but there was no robust evidence for any of these short-term outcomes. Seventeen trials (1899 participants) investigated the presence of adverse events during the treatment, of which six trials (853 participants) reported "no significant adverse event in any participants" and the other 11 trials (1046 participants) reported a total of 38 adverse events in the buflomedil group and two events in the control group. In general, for each of these outcomes the quality of evidence was low according to the GRADE principles. There is insufficient evidence on the efficacy or safety of buflomedil to support its use for the treatment of acute ischaemic stroke. Given these uncertainties, the data support the rationale for an adequately powered RCT of buflomedil in people with acute ischaemic stroke.
We included 12 eligible trials with a total of 1450 mothers and 1204 known infants. Eleven trials administered probiotics to mothers during pregnancy and one trial administered probiotics to mothers after birth of their preterm infants. No studies compared maternal probiotic administration directly with neonatal administration. Included prenatal trials were highly variable in the indication for the trial, the gestational age and duration of administration of probiotics, as well as the dose and formulation of the probiotics. The pregnant women included in these trials were overall at low risk for preterm birth. In a meta-analysis of trial data, oral probiotic administration to pregnant women did not reduce the incidence of preterm birth < 37 weeks (typical risk ratio (RR) 0.92, 95% confidence interval (CI) 0.32 to 2.67; 4 studies, 518 mothers and 506 infants), < 34 weeks (typical risk difference (RD) 0.00, 95% CI -0.02 to 0.02; 2 studies, 287 mothers and infants), the incidence of infant mortality (typical RD 0.00, 95% CI -0.02 to 0.02; 2 studies, 309 mothers and 298 infants), or the gestational age at birth (mean difference (MD) 0.15, 95% CI -0.33 to 0.63; 2 studies, 209 mothers with 207 infants). One trial studied administration of probiotics to mothers after preterm birth and included 49 mothers and 58 infants. There were no significant differences in the risk of any NEC (RR 0.44, 95% CI 0.13 to 1.46; 1 study, 58 infants), surgery for NEC (RR 0.15, 95% CI 0.01 to 2.58; 1 study, 58 infants), death (RR 0.66, 95% CI 0.06 to 6.88; 1 study, 58 infants), and death or NEC (RR 0.53, 95% CI 0.19 to 1.49; 1 study, 58 infants). There was an improvement in time to reach 50% enteral feeds in infants whose mothers received probiotics, but the estimate is imprecise (MD -9.60 days, 95% CI -19.04 to -0.16 days; 58 infants). No other improvement in any neonatal outcomes were reported. The estimates were imprecise and do not exclude the possibility of meaningful harms or benefits from maternal probiotic administration. There were no cases of culture-proven sepsis with the probiotic organism. The GRADE quality of evidence was judged to be low to very low due to inconsistency and imprecision. There is insufficient evidence to conclude whether there is appreciable benefit or harm to neonates of either oral supplementation of probiotics administered to pregnant women at low risk for preterm birth or oral supplementation of probiotics to mothers of preterm infants after birth. Oral supplementation of probiotics to mothers of preterm infants after birth may decrease time to 50% enteral feeds, however, this estimate is extremely imprecise. More research is needed for post-natal administration of probiotics to mothers of preterm infants, as well as to pregnant mothers at high risk for preterm birth.
We identified and included 22 RCTs randomly assigning 8641 people with COPD to either once-daily LABA/LAMA FDC (6252 participants) or placebo (3819 participants); nine studies had a cross-over design. Studies had a duration of between three and 52 weeks (median 12 weeks). The mean age of participants across the included studies ranged from 59 to 65 years and in 21 of 22 studies, participants had GOLD stage II or III COPD. Concomitant inhaled corticosteroid (ICS) use was permitted in all of the included studies (where stated); across the included studies, between 28% to 58% of participants were using ICS at baseline. Six studies evaluated the once-daily combination of IND/GLY (110/50 μg), seven studies evaluated TIO/OLO (2.5/5 or 5/5 μg), eight studies evaluated UMEC/VI (62.5/5, 125/25 or 500/25 μg) and one study evaluated ACD/FOR (200/6, 200/12 or 200/18 μg); all LABA/LAMA combinations were compared with placebo. The risk of bias was generally considered to be low or unknown (insufficient detail provided), with only one study per domain considered to have a high risk of bias except for the domain 'other bias' which was determined to be at high risk of bias in four studies (in three studies, disease severity was greater at baseline in participants receiving LABA/LAMA compared with participants receiving placebo, which would be expected to shift the treatment effect in favour of placebo). Compared to the placebo, the pooled results for the primary outcomes for the once-daily LABA/LAMA arm were as follows: all-cause mortality, OR 1.88 (95% CI 0.81 to 4.36, low-certainty evidence); all-cause serious adverse events (SAEs), OR 1.06 (95% CI 0.88 to 1.28, high-certainty evidence); acute exacerbations of COPD (AECOPD), OR 0.53 (95% CI 0.36 to 0.78, moderate-certainty evidence); adjusted St George's Respiratory Questionnaire (SGRQ) score, MD -4.08 (95% CI -4.80 to -3.36, high-certainty evidence); proportion of SGRQ responders, OR 1.75 (95% CI 1.54 to 1.99). Compared with placebo, the pooled results for the secondary outcomes for the once-daily LABA/LAMA arm were as follows: adjusted trough forced expiratory volume in one second (FEV1), MD 0.20 L (95% CI 0.19 to 0.21, moderate-certainty evidence); adjusted peak FEV1, MD 0.31 L (95% CI 0.29 to 0.32, moderate-certainty evidence); and all-cause AEs, OR 0.95 (95% CI 0.86 to 1.04; high-certainty evidence). No studies reported data for the 6-minute walk test. The results were generally consistent across subgroups for different LABA/LAMA combinations and doses. Compared with placebo, once-daily LABA/LAMA (either IND/GLY, UMEC/VI or TIO/OLO) via a combination inhaler is associated with a clinically significant improvement in lung function and health-related quality of life in patients with mild-to-moderate COPD; UMEC/VI appears to reduce the rate of exacerbations in this population. These conclusions are supported by moderate or high certainty evidence based on studies with an observation period of up to one year.
Eighteen studies were identified by the searches. Only one study could be included which reported results from 17 participants aged 10 to 41 years with an infective exacerbation of Pseudomonas aeruginosa. All their 31 admissions (18 hospital and 13 at home after two to four days of hospital treatment) were analysed as independent events. Outcomes were measured at 0, 10 and 21 days after initiation of treatment. Home participants underwent fewer investigations than hospital participants (P < 0.002) and general activity was higher in the home group. No significant differences were found for clinical outcomes, adverse events, complications or change of intravenous lines,or time to next admission. Home participants received less low-dose home maintenance antibiotic. Quality of life measures showed no significant differences for dyspnoea and emotional state, but fatigue and mastery were worse for home participants, possibly due to a higher general activity and need of support. Personal, family, sleeping and eating disruptions were less important for home than hospital admissions. Home therapy was cheaper for families and the hospital. Indirect costs were not determined. Current evidence is restricted to a single randomized clinical trial. It suggests that, in the short term, home therapy does not harm individuals, entails fewer investigations, reduces social disruptions and can be cost-effective. There were both advantages and disadvantages in terms of quality of life. The decision to attempt home treatment should be based on the individual situation and appropriate local resources. More research is urgently required.
From 85 papers describing IQCODE, we included three papers, representing data from 626 individuals. Of this total, 22% (N = 135/626) were excluded because of prevalent dementia. There was substantial attrition; 47% (N = 295) of the study population received reference standard assessment at first follow-up (three to six months) and 28% (N = 174) received reference standard assessment at final follow-up (one to three years). Prevalence of dementia ranged from 12% to 26% at first follow-up and 16% to 35% at final follow-up. The three studies were considered to be too heterogenous to combine, so we did not perform meta-analyses to describe summary estimates of interest. Included patients were poststroke (two papers) and hip fracture (one paper). The IQCODE was used at three thresholds of positivity (higher than 3.0, higher than 3.12 and higher than 3.3) to predict those at risk of a future diagnosis of dementia. Using a cut-off of 3.0, IQCODE had a sensitivity of 0.75 (95%CI 0.51 to 0.91) and a specificity of 0.46 (95%CI 0.34 to 0.59) at one year following stroke. Using a cut-off of 3.12, the IQCODE had a sensitivity of 0.80 (95%CI 0.44 to 0.97) and specificity of 0.53 (95C%CI 0.41 to 0.65) for the clinical diagnosis of dementia at six months after hip fracture. Using a cut-off of 3.3, the IQCODE had a sensitivity of 0.84 (95%CI 0.68 to 0.94) and a specificity of 0.87 (95%CI 0.76 to 0.94) for the clinical diagnosis of dementia at one year after stroke. In generaI, the IQCODE was sensitive for identification of those who would develop dementia, but lacked specificity. Methods for both excluding prevalent dementia at baseline and assessing for the development of dementia were varied, and had the potential to introduce bias. Included studies were heterogenous, recruited from specialist settings, and had potential biases. The studies identified did not allow us to make specific recommendations on the use of the IQCODE for the future diagnosis of dementia in clinical practice. The included studies highlighted the challenges of delayed verification dementia research, with issues around prevalent dementia assessment, loss to follow-up over time, and test non-completion potentially limiting the studies. Future research should recognise these issues and have explicit protocols for dealing with them.
Three studies met the inclusion criteria for the review. Two studies were based on oral sensorimotor interventions for participants with cerebral palsy compared to standard care and a third study trialled lip strengthening exercises for children with myotonic dystrophy type 1 compared to no treatment (Sjogreen 2010). A meta-analysis combining results across the three studies was not possible because one of the studies had participants with a different condition, and the remaining two, although using oral sensorimotor treatments, used vastly different approaches with different intensities and durations. The decision not to combine these was in line with our protocol. In this review, we present the results from individual studies for four outcomes: physiological functions of the oropharyngeal mechanism for swallowing, the presence of chest infection and pneumonia, diet consistency, and changes in growth. However, it is not possible to reach definitive conclusions on the effectiveness of particular interventions for oropharyngeal dysphagia based on these studies. One study had a high risk of attrition bias owing to missing data, had statistically significant differences (in weight) across experimental and control groups at baseline, and did not describe other aspects of the trial sufficiently to enable assessment of other potential risks of bias. Another study was at high risk of detection bias as some outcomes were assessed by parents who knew whether their child was in the intervention or control group. The third study overall seemed to be at low risk of bias, but like the other two studies, suffered from a small sample size. The review demonstrates that there is currently insufficient high-quality evidence from randomised controlled trials or quasi-randomised controlled trials to provide conclusive results about the effectiveness of any particular type of oral-motor therapy for children with neurological impairment. There is an urgent need for larger-scale (appropriately statistically powered), randomised trials to evaluate the efficacy of interventions for oropharyngeal dysphagia.
Three studies involving 1257 women met our inclusion criteria. Cord drainage reduced the length of the third stage of labour (mean difference (MD) -2.85 minutes, 95% confidence interval (CI) -4.04 to -1.66; three trials, 1257 women (heterogeneity: T² = 0.87; Chi²P=17.19, I² = 88%)) and reduced the average amount of blood loss (MD -77.00 ml, 95% CI -113.73 to -40.27; one trial, 200 women). No incidence of retained placenta at 30 minutes after birth was observed in the included studies, therefore, it was not possible to compare this outcome. The differences between the cord drainage and the control group were not statistically significant for postpartum haemorrhage or manual removal of the placenta. None of the included studies reported fetomaternal transfusion outcomes and there were no data relating to maternal pain or discomfort during the third stage of labour. There was a small reduction in the length of the third stage of labour and also in the amount of blood loss when cord drainage was applied compared with no cord drainage. The clinical importance of such observed statistically significant reductions, is open to debate. There is no clear difference in the need for manual removal of placenta, blood transfusion or the risk of postpartum haemorrhage. Due to small trials with medium risk of bias, the results should be interpreted with caution.
Foe effectiveness, one report met inclusion criteria. Two dosages of naltrexone depot injections (192 and 384 mg) were compared to placebo. High-dose significantly increased days in treatment compared to placebo (WMD 21.00, 95% CI 10.68 to 31.32, p<0.0001). High-dose compared to low-dose significantly increased days in treatment (WMD 12.00, 95% CI 1.69 to 22.31, p=0.02). Number of patients retained in treatment did not show significant differences between groups. For adverse effects, seventeen reports met inclusion criteria analyses, six were RCTs. Side effects were significantly more frequent in naltrexone depot groups compared to placebo. In alcohol dependent samples only, adverse effects appeared to be significantly more frequent in the low-dose naltrexone depot groups compared to placebo (RR 1.18, 95% CI 1.02 to 1.36, p=0.02). In the opioid dependent sample, group differences were not statistically significant. Reports on systematic assessment of side effects and adverse events were scarce. There is insufficient evidence to evaluate the effectiveness of sustained-release naltrexone for treatment of opioid dependence.  For naltrexone injections, administration site-related adverse effects appear to be frequent, but of moderate intensity and time limited. For a harm-benefit evaluation of naltrexone implants, more data on side effects and adverse events are needed.
We included one trial with a total of 60 children with a diagnosis of ASD who randomly received hyperbaric oxygen therapy or a sham treatment. Using GRADE criteria, we rated the quality of the evidence as low because of the small sample size and wide confidence intervals (CIs). Other problems included selection bias and short duration or follow-up. Overall, study authors reported no improvement in social interaction and communication, behavioral problems, communication and linguistic abilities, or cognitive function. With regard to the safety of hyperbaric oxygen therapy (adverse events), they reported minor-grade ear barotrauma events. Investigators found significant differences between groups in total number of side effect events (Peto odds ratio (OR) 3.87, 95% CI 1.53 to 9.82) and in the number of children who experienced side effects (Peto OR 4.40, 95% CI 1.33 to 14.48). To date, there is no evidence that hyperbaric oxygen therapy improves core symptoms and associated symptoms of ASD. It is important to note that adverse effects (minor-grade ear barotrauma events) can occur. Given the absence of evidence of effectiveness and the limited biological plausibility and possible adverse effects, the need for future RCTs of hyperbaric oxygen therapy must be carefully considered.
We included four trials. One trial evaluated mass treatment of all individuals in a particular community. The other three trials evaluated various combinations of improved syndromic STI management in clinics, STI counselling, and STI treatment. In the mass treatment trial in rural southwestern Uganda, after three rounds of treatment of all community members for STIs, the adjusted rate ratio (aRR) of incident HIV infection was 0.97 (95% CI 0.81 - 1.2), indicating no effect of the intervention. The three STI management intervention studies were all conducted in rural parts of Africa. One study, in northern Tanzania, showed that the incidence of HIV infection in the intervention groups (strengthened syndromic management of STIs in primary care clinics) was 1.2% compared with 1.9% in the control groups (aRR = 0.58, 95% CI 0.42 - 0.79), corresponding to a 42% reduction (95% CI 21.0% - 58.0%) in HIV incidence in the intervention group. Another study, conducted in rural southwestern Uganda, showed that the aRR of behavioural intervention and STI management compared to control on HIV incidence was 1.00 (95% CI 0.63 - 1.58). In the third STI management trial, in eastern Zimbabwe, there was no effect of the intervention on HIV incidence (aRR = 1.3, 95% CI 0.92 - 1.8). These are consistent with data from the mass treatment trial showing no intervention effect. Overall, pooling the data of the four studies showed no significant effect of any intervention (rate ratio [RR] = 0.97, 95% CI 0.78 - 1.2). Combining the mass treatment trial and one of the STI management trials, we find that there is a significant 12.0% reduction in the prevalence of syphilis for those receiving a biomedical STI intervention (RR 0.88, 95% CI 0.80 - 0.96). For gonorrhoea, we find a statistically significant 51.0% reduction in its prevalence in those receiving any of these interventions (RR 0.49, 95% CI 0.31 - 0.77). Finally, for chlamydia, we found no significant difference between any biomedical intervention and control (RR 1.03, 95% CI 0.77 - 1.4). We failed to confirm the hypothesis that STI control is an effective HIV prevention strategy. Improved STI treatment services were shown in one study to reduce HIV incidence in an environment characterised by an emerging HIV epidemic (low and slowly rising prevalence), where STI treatment services were poor and where STIs were highly prevalent; Incidence was not reduced in two other settings. There is no evidence for substantial benefit from a presumptive treatment intervention for all community members. There are, however, other compelling reasons why STI treatment services should be strengthened, and the available evidence suggests that when an intervention is accepted it can substantially improve quality of services provided.
We found six Cochrane systematic reviews and judged them to be of high methodological quality. They included 148 randomised controlled trials (RCTs) in 98,093 participants. Compared with usual care alone, the addition of exercise-based cardiac rehabilitation in low-risk people after myocardial infarction or percutaneous coronary intervention or with heart failure appeared to have no impact on mortality, but did reduce hospital admissions and improved health-related quality of life. Psychological- and education-based interventions alone appeared to have little or no impact on mortality or morbidity but may have improved health-related quality of life. Home- and centre-based programmes were equally effective in improving quality of life outcomes at similar healthcare costs. Selected interventions can increase the uptake of cardiac rehabilitation programmes whilst there is currently only weak evidence to support interventions that improve adherence to cardiac rehabilitation programmes. The quality of the primary RCTs in the included systematic reviews was variable, and limitations in the methodological quality of the RCTs led to downgrading of the quality of the evidence, which varied widely by review and by outcome. Exercise-based cardiac rehabilitation is an effective and safe therapy to be used in the management of clinically stable people following myocardial infarction or percutaneous coronary intervention or who have heart failure. Future RCTs of cardiac rehabilitation need to improve their reporting methods and reflect the real world practice better including the recruitment of higher risk people and consideration of contemporary models of cardiac rehabilitation delivery, and identify effective interventions for enhancing adherence to rehabilitation.
Two trials enrolling 54 infants in total, fulfilled the inclusion criteria. Both reported only the short term results (4 to 6 hours) of the interventions. Only one infant (randomised to NCPAP) required intubation during this period. In a cross-over study of 20 infants, Ryan 1989 showed no significant difference in rates of apnea (events/hr) between the two interventions [WMD -0.10 (-0.53,0.33)]. Lin (1998) randomised 34 infants and demonstrated a greater reduction in frequency of apneas (events/hr) with NIPPV compared to NCPAP [WMD -1.19 (-2.31,-0.07)]. Meta-analysis of both trials showed no difference in pC02 (mmHg) at the end of the 4-6 hour study period [WMD 0.95 (-3.05,4.94)]. No data were reported on gastrointestinal complications. Implications for practice: NIPPV may be a useful method of augmenting the beneficial effects of NCPAP in preterm infants with apnea that is frequent or severe. Its use appears to reduce the frequency of apneas more effectively than NCPAP. Additional safety and efficacy data are required before recommending NIPPV as standard therapy for apnea. Implications for research: Future trials with sufficient power should assess the efficacy (reduction in failure of therapy) and safety (GI complications) of NIPPV. Outcomes should be assessed throughout the entire period during which the infant requires assisted ventilation. The recent ability to synchronise NIPPV with an infant's spontaneous respirations is a promising development requiring further assessment.
We included nine trials of 4433 participants. Odds ratios for mortality after stenting compared to balloon angioplasty at 30 days, 6 and 12 months were 1.16 (95% CI 0.78 to 1.73), 1.27 (95% CI 0.89 to 1.83), and 1.06 (95% CI 0.77 to 1.45). At 30 days, 6 and 12 months odds ratios for reinfarction after stenting compared to balloon angioplasty were 0.52 (95% CI 0.31 to 0.87), 0.67 (95% CI 0.45 to 1.00), and 0.67 (95% CI 0.45-0.98) and odds ratio for target vessel revascularization after stenting compared to balloon angioplasty were 0.45 (95%CI 0.34 to 0.60), 0.42 (95% CI 0.35 to 0.51), and 0.47 (95% CI 0.38 to 0.57). The odds ratio for post-interventional bleeding complications after stenting compared to balloon angioplasty was 1.34 (95% CI 0.95 to 1.88; test of heterogeneity p > 0.1). There is no evidence to suggest that primary stenting reduces mortality when compared to balloon angioplasty. Stenting seems to be associated with a reduced risk of reinfarction and target vessel revascularization, but potential confounding due to unbalanced post-interventional antithrombotic/anticoagulant therapies can not be ruled out on basis of this review.
We included seventeen trials with overall 2134 participants. We performed two separate meta-analyses: one that evaluated the use of systemic prophylactic antibiotics and another that evaluated the use of antibiotic-impregnated systems. All studies included shunt infection in their primary outcome. We could not analyse all-cause mortality regarding systemic antibiotics due to lack of data. No significant differences were found (odds ratio (OR): 1.47, 95% confidence intervals (CI) 0.83 to 2.62) for this outcome regarding the use of antibiotic-impregnated catheters compared with standard ones. The use of systemic antibiotic prophylaxis and the use of antibiotic-impregnated catheters were associated with a decrease in shunt infection (OR: 0.52, 95% CI 0.36 to 0.74 and OR: 0.21, 95% CI 0.08 to 0.55 respectively). We found no significant benefit for shunt revision in both meta-analyses that evaluated systemic antibiotics and impregnated-shunt systems. We found no significant differences between the subgroups evaluated: type of shunt (internal/external, ventriculoperitoneal/ventriculoatrial), age and duration of the administration of antibiotics. We could demonstrate a benefit of systemic prophylactic antibiotics for the first 24 hours postoperatively to prevent shunt infection, regardless of the patient's age and the type of internal shunt used. The benefit of its use after this period remains uncertain. However this data derives from the rate of shunt infection, which is an intermediary outcome. Future trials should evaluate the effectiveness of different regimens of systemic antibiotics rather than placebo, and should include all-cause mortality, shunt revision and adverse events as additional outcomes. Evidence suggests that antibiotic-impregnated catheters reduce the incidence of shunt infection although more well-designed clinical trials testing the effect of antibiotic-impregnated shunts are required to confirm their net benefit.
From the 468 references identified after removing duplicates, we found two trials comprising 86 participants that met our inclusion criteria. Both trials included participants with Brugada syndrome who were randomized to ICD versus β-blocker therapy for secondary prevention for sudden cardiac death. Both studies were small, were performed by the same investigators, and exhibited a high risk of bias across multiple domains. In the group randomized to ICD therapy, there was a nine-fold lower risk of mortality compared with people randomized to medical therapy (0% with ICD versus 18% with medical therapy; RR 0.11, 95% CI 0.01 to 0.83; 2 trials, 86 participants). There was low quality evidence of a difference in the rates of combined fatal and non-fatal cardiovascular events, and the results were imprecise (26% with ICD versus 18% with medical therapy; RR 1.49, 95% CI 0.66 to 3.34; 2 trials, 86 participants). The rates of adverse events were higher in the ICD group, but these results were imprecise (28% with ICD versus 10% with medical therapy; RR 2.44, 95% CI 0.92 to 6.44; 2 trials, 86 participants). For secondary outcomes, the risk of non-fatal cardiovascular events was higher in the ICD group, but these results were imprecise and were driven entirely by appropriate ICD-termination of cardiac arrhythmias (26% with ICD versus 0% with medical therapy; RR 11.4, 95% CI 1.57 to 83.3; 2 trials, 86 participants). Approximately 25% of the ICD group experienced inappropriate ICD firing, all of which was corrected by device reprogramming. No data were available for quality of life or cost. We considered the quality of evidence low using the GRADE methodology, due to study limitations and imprecision of effects. Among people with Brugada syndrome who have survived a prior episode of sudden cardiac death, ICD therapy appeared to reduce mortality when compared to β-blocker therapy, but the true magnitude may be substantially different from the estimate of the effect because of study limitations and imprecision. Due to the large magnitude of effect, it is unlikely that there will be additional studies evaluating the role of ICDs for secondary prevention in this population. Further studies are necessary to determine the optimal treatment, if any, to prevent an initial episode of sudden cardiac death in people with cardiac ion channelopathies.
Sixteen trials, with a combined total of 3299 participants fulfilled our inclusion criteria. According to GRADE, the quality of evidence was moderate for recurrent VTE, low for major bleeding, and moderate for mortality. We downgraded the quality of the evidence for imprecision (recurrent VTE, mortality) and for risk of bias and inconsistency (major bleeding). We found no clear differences in recurrent VTE between LMWH and VKA (Peto OR 0.83, 95% confidence interval (CI) 0.60 to 1.15; P = 0.27; 3299 participants; 16 studies; moderate-quality evidence). We found less bleeding with LMWH than with VKA (Peto OR 0.51, 95% CI 0.32 to 0.80; P = 0.004; 3299 participants; 16 studies; low-quality evidence). However, when comparing only high-quality studies for bleeding, we observed no clear differences between LMWH and VKA (Peto OR 0.62, 95% CI 0.36 to 1.07; P = 0.08; 1872 participants; seven studies). We found no clear differences between LMWH and VKA in terms of mortality (Peto OR 1.08, 95% CI 0.75 to 1.56; P = 0.68; 3299 participants; 16 studies; moderate-quality evidence). Moderate-quality evidence shows no clear differences between LMWH and VKA in preventing symptomatic VTE and death after an episode of symptomatic DVT. Low-quality evidence suggests fewer cases of major bleeding with LMWH than with VKA. However, comparison of only high-quality studies for bleeding shows no clear differences between LMWH and VKA. LMWH may represent an alternative for some patients, for example, those residing in geographically inaccessible areas, those who are unable or reluctant to visit the thrombosis service regularly, and those with contraindications to VKA.
Seventeen RCTs with 1103 participants were included. These studies differed in the both thrombolytic agent used and in the technique used to deliver it. Systemic, loco-regional and catheter-directed thrombolysis (CDT) were all included. Fourteen studies were rated as low risk of bias and three studies were rated as high risk of bias. We combined the results as any (all) thrombolysis compared to standard anticoagulation. Complete clot lysis occurred significantly more often in the treatment group at early follow-up (RR 4.91; 95% CI 1.66 to 14.53, P = 0.004) and at intermediate follow-up (RR 2.44; 95% CI 1.40 to 4.27, P = 0.002; moderate quality evidence). A similar effect was seen for any degree of improvement in venous patency. Up to five years after treatment significantly less PTS occurred in those receiving thrombolysis (RR 0.66, 95% CI 0.53 to 0.81; P < 0.0001; moderate quality evidence). This reduction in PTS was still observed at late follow-up (beyond five years), in two studies (RR 0.58, 95% CI 0.45 to 0.77; P < 0.0001; moderate quality evidence). Leg ulceration was reduced although the data were limited by small numbers (RR 0.87; 95% CI 0.16 to 4.73, P = 0.87). Those receiving thrombolysis had increased bleeding complications (RR 2.23; 95% CI 1.41 to 3.52, P = 0.0006; moderate quality evidence). Three strokes occurred in the treatment group, all in trials conducted pre-1990, and none in the control group. There was no significant effect on mortality detected at either early or intermediate follow-up. Data on the occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. Systemic thrombolysis and CDT had similar levels of effectiveness. Studies of CDT included two trials in femoral and iliofemoral DVT, and results from these are consistent with those from trials of systemic thrombolysis in DVT at other levels of occlusion. Thrombolysis increases the patency of veins and reduces the incidence of PTS following proximal DVT by a third. Evidence suggests that systemic administration and CDT have similar effectiveness. Strict eligibility criteria appears to improve safety in recent studies and may be necessary to reduce the risk of bleeding complications. This may limit the applicability of this treatment. In those who are treated there is a small increased risk of bleeding. Using GRADE assessment, the evidence was judged to be of moderate quality due to many trials having low numbers of participants. However, the results across studies were consistent and we have reasonable confidence in these results.
We included two randomised controlled trials with a total of 80 participants in this review. 1. Early versus delayed open appendicectomy for appendiceal phlegmon Forty participants (paediatric and adults) with appendiceal phlegmon were randomised either to early appendicectomy (appendicectomy as soon as appendiceal mass resolved within the same admission) (n = 20), or to delayed appendicectomy (initial conservative treatment followed by interval appendicectomy six weeks later) (n = 20). The trial was at high risk of bias. There was no mortality in either group. There is insufficient evidence to determine the effect of using either early or delayed open appendicectomy onoverall morbidity (RR 13.00; 95% CI 0.78 to 216.39; very low-quality evidence), the proportion of participants who developed wound infection (RR 9.00; 95% CI 0.52 to 156.91; very low quality evidence) or faecal fistula (RR 3.00; 95% CI 0.13 to 69.52; very low quality evidence). The quality of evidence for increased length of hospital stay and time away from normal activities in the early appendicectomy group (MD 6.70 days; 95% CI 2.76 to 10.64, and MD 5.00 days; 95% CI 1.52 to 8.48, respectively) is very low quality evidence. The trial reported neither quality of life nor pain outcomes. 2. Early versus delayed laparoscopic appendicectomy for appendiceal abscess Forty paediatric participants with appendiceal abscess were randomised either to early appendicectomy (emergent laparoscopic appendicectomy) (n = 20) or to delayed appendicectomy (initial conservative treatment followed by interval laparoscopic appendicectomy 10 weeks later) (n = 20). The trial was at high risk of bias. The trial did not report on overall morbidity or complications. There was no mortality in either group. We do not have sufficient evidence to determine the effects of using either early or delayed laparoscopic appendicectomy for outcomes relating to hospital stay between the groups (MD −0.20 days; 95% CI −3.54 to 3.14; very low quality of evidence). Health-related quality of life was measured with the Pediatric Quality of Life Scale-Version 4.0 questionnaire (a scale of 0 to 100 with higher values indicating a better quality of life). Health-related quality of life score measured at 12 weeks after appendicectomy was higher in the early appendicectomy group than in the delayed appendicectomy group (MD 12.40 points; 95% CI 9.78 to 15.02) but the quality of evidence was very low. This trial reported neither the pain nor the time away from normal activities. It is unclear whether early appendicectomy prevents complications compared to delayed appendicectomy for people with appendiceal phlegmon or abscess. The evidence indicating increased length of hospital stay and time away from normal activities in people with early open appendicectomy is of very low quality. The evidence for better health-related quality of life following early laparoscopic appendicectomy compared with delayed appendicectomy is based on very low quality evidence. For both comparisons addressed in this review, data are sparse, and we cannot rule out significant benefits or harms of early versus delayed appendicectomy. Further trials on this topic are urgently needed and should specify a set of criteria for use of antibiotics, percutaneous drainage of the appendiceal abscess prior to surgery and resolution of the appendiceal phlegmon or abscess. Future trials should include outcomes such as time away from normal activities, quality of life and the length of hospital stay.
Fifteen trials met the inclusion criteria. The overall methodology of all the trials assessed was either low or very low GRADE level. None of the trials were of strong to moderate GRADE level. The results showed very low level evidence that certain massage techniques (traditional Chinese massage, classical and modified strain/counterstrain technique) may have been more effective than control or placebo treatment in improving function and tenderness. There was very low level evidence that massage may have been more beneficial than education in the short term for pain bothersomeness. Along with that, there was low level evidence that ischaemic compression and passive stretch may have been more effective in combination rather than individually for pain reduction. The clinical applicability assessment showed that only 4/15 trials adequately described the massage technique. The majority of the trials assessed outcomes at immediate post-treatment, which is not an adequate time to assess clinical change. Due to the limitations in the quality of existing studies, we were unable to make any firm statement to guide clinical practice. We noted that only five of the 15 studies reported side effects. All five studies reported post-treatment pain, discomfort and soreness as a side effect and one study (Irnich 2001) showed that 22% of the participants experienced low blood pressure following treatment. No recommendations for practice can be made at this time because the effectiveness of massage for neck pain remains uncertain. As a stand-alone treatment, massage for MND was found to provide an immediate or short-term effectiveness or both in pain and tenderness. Additionally, future research is needed in order to assess the long-term effects of treatment and treatments provided on more than one occasion.
We included two RCTs in this review, in which 2343 participants with AMD were randomised to receive either omega 3 fatty acid supplements or a placebo. The trials, which had a low risk of bias, were conducted in the USA and France. Overall, there was no evidence that people who took omega 3 fatty acid supplements were at decreased (or increased risk) of progression to advanced AMD (pooled hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.84 to 1.10, high quality evidence). Similarly, people taking these supplements were no more (or less) likely to lose 15 or more letters of visual acuity (USA study HR 0.96, 95% CI 0.84 to 1.10; French study at 36 months risk ratio (RR) 1.25, 95% CI 0.69 to 2.26, participants = 230). The number of adverse events was similar in the intervention and placebo groups (USA study participants with one or more serious adverse event RR 1.00, 95% CI 0.91 to 1.09, participants = 2080; French study total adverse events RR 1.05, 95% CI 0.97 to 1.13, participants = 263). This review found that omega 3 LCPUFA supplementation in people with AMD for periods up to five years does not reduce the risk of progression to advanced AMD or the development of moderate to severe visual loss. No published randomised trials were identified on dietary omega 3 fatty acids for primary prevention of AMD. Currently available evidence does not support increasing dietary intake of omega 3 LCPUFA for the explicit purpose of preventing or slowing the progression of AMD.
Two studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to -223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day). Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain.
We identified five RCTs that randomised 544 children (three studies) and 205 adults (exclusively from two studies). They all compared saline irrigation to routine care or other nose sprays, rather than placebo. We included two new trials in this update, which did not contribute data of sufficient size or quality to materially change the original findings. Most trials were small and we judged them to be of low quality, contributing to an unclear risk of bias. Most outcome measures differed greatly between included studies and therefore could not be pooled. Most results showed no difference between nasal saline treatment and control. However, one larger trial, conducted with children, did show a significant reduction in nasal secretion score (mean difference (MD) -0.31, 95% confidence interval (CI) -0.48 to -0.14) and nasal breathing (obstruction) score (MD -0.33, 95% CI -0.47 to -0.19) in the saline group. However, a MD of -0.33 on a four-point symptom scale may have minimal clinical significance. The trial also showed a significant reduction in the use of decongestant medication by the saline group. Minor nasal discomfort and/or irritation was the only side effect reported by a minority of participants. Nasal saline irrigation possibly has benefits for relieving the symptoms of acute URTIs. However, the included trials were generally too small and had a high risk of bias, reducing confidence in the evidence supporting this. Future trials should involve larger numbers of participants and report standardised and clinically meaningful outcome measures.
We included two RCTs and one non-randomized study, involving a total of 181 participants. Both RCTs were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes, the other involving 76 participants with postherpetic neuralgia. Study phases were 20 days and approximately eight weeks, respectively. The non-randomized study retrospectively evaluated 86 outpatients over an average of 8.8 ± 6.3 months. One RCT reported average pain intensity and pain relief, and found statistically significant improvements versus placebo for both outcomes, with 10 mg and 20 mg daily doses of methadone. The second RCT reported differences in pain reduction between methadone and morphine and found morphine to be statistically superior. The non-randomized study found that in patients initially prescribed methadone it was effective in fewer participants than in those initially prescribed other long-acting opioids (28% versus 42%, 33% and 50% for morphine, oxycodone and transdermal fentanyl, respectively). One RCT compared incidences for several individual adverse events, but found a difference between methadone and placebo for only one event, dizziness (P = 0.041). The three studies provide very limited evidence of the efficacy of methadone for CNCP, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. No conclusions can be made regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.
Six RCTs with a total of 1211 participants were eligible; five trials evaluated oral aciclovir, and one, with 419 participants, evaluated oral famciclovir. We were able to conduct meta-analyses as there were sufficient similarities in the included studies, such as the reporting of the presence of PHN, duration of rash before treatment initiation and treatment regimen. For our primary outcome, based on three trials (609 participants) we found no significant difference between the aciclovir and control groups in the incidence of PHN four months after the onset of the acute herpetic rash (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.51 to 1.11), nor was there a significant difference at six months (RR 1.05, 95% CI 0.87 to 1.27, two trials, 476 participants). In four of the trials (692 participants), there was some evidence for a reduction in the incidence of pain four weeks after the onset of rash. In the trial of famciclovir versus placebo, neither 500 mg nor 750 mg doses of famciclovir reduced the incidence of herpetic neuralgia significantly. The most commonly reported adverse events were nausea, vomiting, diarrhoea and headache for aciclovir, and headache and nausea for famciclovir. For neither treatment was the incidence of adverse events significantly different from placebo. None of the studies were at high risk of bias, although the risk of bias was unclear in at least one domain for all but one study. We found no new RCTs when we updated the searches in April 2013. There is high quality evidence that oral aciclovir does not reduce the incidence of PHN significantly. In addition, there is insufficient evidence to determine the effect of other antiviral treatments; therefore, further well-designed RCTs are needed to investigate famciclovir or other new antiviral agents in preventing PHN. Future trials should pay more attention to the severity of pain and quality of life of participants, and should be conducted among different subgroups of people, such as people who are immunocompromised.
We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear. Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.
We included 56 trials with 3105 participants in this updated review. The average age of the participants was 60 years, and the studies were carried out in both inpatient and outpatient settings. All participants had at least some walking difficulties and many could not walk without assistance. Overall, the use of treadmill training did not increase the chances of walking independently compared with other physiotherapy interventions (risk difference (RD) -0.00, 95% confidence interval (CI) -0.02 to 0.02; 18 trials, 1210 participants; P = 0.94; I² = 0%; low-quality evidence). Overall, the use of treadmill training in walking rehabilitation for people after stroke increased the walking velocity and walking endurance significantly. The pooled mean difference (MD) (random-effects model) for walking velocity was 0.06 m/s (95% CI 0.03 to 0.09; 47 trials, 2323 participants; P < 0.0001; I² = 44%; moderate-quality evidence) and the pooled MD for walking endurance was 14.19 metres (95% CI 2.92 to 25.46; 28 trials, 1680 participants; P = 0.01; I² = 27%; moderate-quality evidence). Overall, the use of treadmill training with body weight support in walking rehabilitation for people after stroke did not increase the walking velocity and walking endurance at the end of scheduled follow-up. The pooled MD (random-effects model) for walking velocity was 0.03 m/s (95% CI -0.05 to 0.10; 12 trials, 954 participants; P = 0.50; I² = 55%; low-quality evidence) and the pooled MD for walking endurance was 21.64 metres (95% CI -4.70 to 47.98; 10 trials, 882 participants; P = 0.11; I² = 47%; low-quality evidence). In 38 studies with a total of 1571 participants who were independent in walking at study onset, the use of treadmill training increased the walking velocity significantly. The pooled MD (random-effects model) for walking velocity was 0.08 m/s (95% CI 0.05 to 0.12; P < 0.00001; I2 = 49%). There were insufficient data to comment on any effects on quality of life or activities of daily living. Adverse events and dropouts did not occur more frequently in people receiving treadmill training and these were not judged to be clinically serious events. Overall, people after stroke who receive treadmill training, with or without body weight support, are not more likely to improve their ability to walk independently compared with people after stroke not receiving treadmill training, but walking speed and walking endurance may improve slightly in the short term. Specifically, people with stroke who are able to walk (but not people who are dependent in walking at start of treatment) appear to benefit most from this type of intervention with regard to walking speed and walking endurance. This review did not find, however, that improvements in walking speed and endurance may have persisting beneficial effects. Further research should specifically investigate the effects of different frequencies, durations, or intensities (in terms of speed increments and inclination) of treadmill training, as well as the use of handrails, in ambulatory participants, but not in dependent walkers.
This review includes a total of three studies (one cross-over and two parallel RCTs) which involved 110 participants. All three studies looked at intravesical instillation of a low virulent Escherichia coli (E. coli) strain in reducing the risk of symptomatic UTI in participants with neuropathic bladder, predominantly from SCI. Two studies used the E. coli 83972 strain and one study used the E. coli HU2117 strain. We did not find any RCTs involving other probiotics or other routes of administration for preventing UTI in people with neuropathic bladder. There was consistency in definition of symptomatic UTI in all three studies. Symptoms that all studies considered were relevant to diagnose UTI were adequately defined. All three studies defined microbiological diagnosis of symptomatic UTI. Asymptomatic bacteriuria was not considered an outcome measure in any of the included studies; however it was defined in two studies to establish successful inoculation. It is uncertain if the risk of symptomatic UTI is reduced with bladder inoculation using E. coli because the certainty of the evidence is very low (3 studies, 110 participants: RR 0.32, 95% CI 0.08 to 1.19; I2 = 82%). Two studies reported adverse events. One study reported one episode of autonomic dysreflexia. One study reported three symptomatic UTI occurring in two patients, and two studies mentioned the absence of septicaemia and pyelonephritis. Intravesical instillation was reported as "generally safe". One study reported high attrition rates in participants due to the need to adhere to strict instillation protocols. The overall quality of the studies was poor. All three studies had high risk of attrition bias due to failure of an intention-to-treat analysis which undermines the randomisation process and weakened the results of the studies. All three studies also had high risk of reporting bias. In this review, there were no studies identified addressing oral probiotics in preventing UTI in people with neuropathic bladder. It is uncertain if the risk of symptomatic UTI is reduced in people with neuropathic bladders via intravesical instillation of non-pathogenic E. coli as data were derived from small studies with high risk of bias. Although very minimal levels of harm was reported with this procedure, due to variable success rates, the need for strict adherence to instillation protocols together with high attrition rates in these studies, it is doubtful bladder instillation will be a widely accepted intervention in its current form. It is recommended that further appropriately powered RCTs with more robust methodological reporting be carried out.
In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review. Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea-supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low-certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low-certainty evidence). No evidence of effect of non-melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low-certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies. In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case-control studies, which were on average of intermediate to high methodological quality based on Newcastle-Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low-certainty evidence). Conversely, we found no association between green tea consumption and cancer-related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low-certainty evidence). For most of the site-specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case-control studies. Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites. Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case-control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk.
We identified 22 new trials for inclusion in this update. In total, the evidence of this review rests on 52 trials with a total of 3731 participants. We included music therapy interventions offered by trained music therapists, as well as music medicine interventions, which are defined as listening to pre-recorded music, offered by medical staff. We categorized 23 trials as music therapy trials and 29 as music medicine trials. The results suggest that music interventions may have a beneficial effect on anxiety in people with cancer, with a reported average anxiety reduction of 8.54 units (95% confidence interval (CI) −12.04 to −5.05, P < 0.0001) on the Spielberger State Anxiety Inventory - State Anxiety (STAI-S) scale (range 20 to 80) and −0.71 standardized units (13 studies, 1028 participants; 95% CI −0.98 to −0.43, P < 0.00001; low quality evidence) on other anxiety scales, a moderate to strong effect. Results also suggested a moderately strong, positive impact on depression (7 studies, 723 participants; standardized mean difference (SMD): −0.40, 95% CI −0.74 to −0.06, P = 0.02; very low quality evidence), but because of the very low quality of the evidence for this outcome, this result needs to be interpreted with caution. We found no support for an effect of music interventions on mood or distress. Music interventions may lead to small reductions in heart rate, respiratory rate and blood pressure but do not appear to impact oxygen saturation level. We found a large pain-reducing effect (7 studies, 528 participants; SMD: −0.91, 95% CI −1.46 to −0.36, P = 0.001, low quality evidence). In addition, music interventions had a small to moderate treatment effect on fatigue (6 studies, 253 participants; SMD: −0.38, 95% CI −0.72 to −0.04, P = 0.03; low quality evidence), but we did not find strong evidence for improvement in physical functioning. The results suggest a large effect of music interventions on patients' quality of life (QoL), but the results were highly inconsistent across studies, and the pooled effect size for the music medicine and music therapy studies was accompanied by a large confidence interval (SMD: 0.98, 95% CI −0.36 to 2.33, P = 0.15, low quality evidence). A comparison between music therapy and music medicine interventions suggests a moderate effect of music therapy interventions for patients' quality of life (QoL) (3 studies, 132 participants; SMD: 0.42, 95% CI 0.06 to 0.78, P = 0.02; very low quality evidence), but we found no evidence of an effect for music medicine interventions. A comparison between music therapy and music medicine studies was also possible for anxiety, depression and mood, but we found no difference between the two types of interventions for these outcomes. The results of single studies suggest that music listening may reduce the need for anesthetics and analgesics as well as decrease recovery time and duration of hospitalization, but more research is needed for these outcomes. We could not draw any conclusions regarding the effect of music interventions on immunologic functioning, coping, resilience or communication outcomes because either we could not pool the results of the studies that included these outcomes or we could only identify one trial. For spiritual well-being, we found no evidence of an effect in adolescents or young adults, and we could not draw any conclusions in adults. The majority of studies included in this review update presented a high risk of bias, and therefore the quality of evidence is low. This systematic review indicates that music interventions may have beneficial effects on anxiety, pain, fatigue and QoL in people with cancer. Furthermore, music may have a small effect on heart rate, respiratory rate and blood pressure. Most trials were at high risk of bias and, therefore, these results need to be interpreted with caution.
We identified seven RCTs that compared therapeutic platelet transfusions to prophylactic platelet transfusions in haematology patients undergoing myelosuppressive chemotherapy or HSCT. One trial is still ongoing, leaving six trials eligible with a total of 1195 participants. These trials were conducted between 1978 and 2013 and enrolled participants from fairly comparable patient populations. We were able to critically appraise five of these studies, which contained separate data for each arm, and were unable to perform quantitative analysis on one study that did not report the numbers of participants in each treatment arm. Overall the quality of evidence per outcome was low to moderate according to the GRADE approach. None of the included studies were at low risk of bias in every domain, and all the studies identified had some threats to validity. We deemed only one study to be at low risk of bias in all domains other than blinding. Two RCTs (801 participants) reported at least one bleeding episode within 30 days of the start of the study. We were unable to perform a meta-analysis due to considerable statistical heterogeneity between studies. The statistical heterogeneity seen may relate to the different methods used in studies for the assessment and grading of bleeding. The underlying patient diagnostic and treatment categories also appeared to have some effect on bleeding risk. Individually these studies showed a similar effect, that a therapeutic-only platelet transfusion strategy was associated with an increased risk of clinically significant bleeding compared with a prophylactic platelet transfusion policy. Number of days with a clinically significant bleeding event per participant was higher in the therapeutic-only group than in the prophylactic group (one RCT; 600 participants; mean difference 0.50, 95% confidence interval (CI) 0.10 to 0.90; moderate-quality evidence). There was insufficient evidence to determine whether there was any difference in the number of participants with severe or life-threatening bleeding between a therapeutic-only transfusion policy and a prophylactic platelet transfusion policy (two RCTs; 801 participants; risk ratio (RR) 4.91, 95% CI 0.86 to 28.12; low-quality evidence). Two RCTs (801 participants) reported time to first bleeding episode. As there was considerable heterogeneity between the studies, we were unable to perform a meta-analysis. Both studies individually found that time to first bleeding episode was shorter in the therapeutic-only group compared with the prophylactic platelet transfusion group. There was insufficient evidence to determine any difference in all-cause mortality within 30 days of the start of the study using a therapeutic-only platelet transfusion policy compared with a prophylactic platelet transfusion policy (two RCTs; 629 participants). Mortality was a rare event, and therefore larger studies would be needed to establish the effect of these alternative strategies. There was a clear reduction in the number of platelet transfusions per participant in the therapeutic-only arm (two RCTs, 991 participants; standardised mean reduction of 0.50 platelet transfusions per participant, 95% CI -0.63 to -0.37; moderate-quality evidence). None of the studies reported quality of life. There was no evidence of any difference in the frequency of adverse events, such as transfusion reactions, between a therapeutic-only and prophylactic platelet transfusion policy (two RCTs; 991 participants; RR 1.02, 95% CI 0.62 to 1.68), although the confidence intervals were wide. We found low- to moderate-grade evidence that a therapeutic-only platelet transfusion policy is associated with increased risk of bleeding when compared with a prophylactic platelet transfusion policy in haematology patients who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT. There is insufficient evidence to determine any difference in mortality rates and no evidence of any difference in adverse events between a therapeutic-only platelet transfusion policy and a prophylactic platelet transfusion policy. A therapeutic-only platelet transfusion policy is associated with a clear reduction in the number of platelet components administered.
Five RCTs met the pre-specified inclusion criteria for this review. No trials evaluated strict glycaemic control in the immediate pre-operative period or outside the intensive care unit. Due to heterogeneity in patient populations, peri-operative period, glycaemic target, route of insulin administration, and definitions of outcome measures, combination of the results of the five included trials into a meta-analysis was not appropriate. The methodological quality of the trials was variable. In terms of outcomes, only one trial demonstrated a significant reduction in SSIs with strict glycaemic control, but the quality of this trial was difficult to assess as a result of poor reporting; furthermore the baseline rate of SSIs was high (30%). The other trials were either underpowered to detect a difference in SSIs, due to a low baseline rate (less than or equal to 5%), or did not report SSIs as a single outcome but as part of a composite. Of the three trials reporting hypoglycaemia (which was not consistently defined) all had a higher rate in the strict glycaemic control group but none attributed significant morbidity to the hypoglycaemia. Adequacy of glucose control between groups was measured differently among studies. Studies could not be compared due to differences in target ranges, and were susceptible to measurement bias due to differences in frequency of measurement and lack of blinding by the providers following the glycaemic protocols. Infection-related mortality was not reported in any of the trials, and no trials demonstrated a significant difference in all-cause mortality. Length of hospital stay was significantly reduced in the strict glycaemic control groups in only one trial. There is insufficient evidence to support strict glycaemic control versus conventional management (maintenance of glucose < 200 mg/dL) for the prevention of SSIs. No trials were found that evaluated strict glycaemic control in the immediate pre-operative period or outside the setting of an intensive care unit. The trials were limited by small sample size, inconsistencies in the definitions of the outcome measures and methodological quality. Further large randomised trials are required to address this question and may be most appropriately performed in patients at high risk for SSIs.
We included seven RCTS in the review; we included six of these, totalling 485 couples, in the meta-analysis. No trials reported the primary outcome of live birth. The evidence was of very low-quality. The main limitations were (unclear) risk of bias, signs of imprecision and inconsistency in results among studies and the small number of studies/participants included. Swim-up versus gradient technique Considering the quality of evidence, we are uncertain whether there was a difference between clinical pregnancy rates (CPR) for swim-up versus a gradient technique (odds ratio (OR) 0.83, 95% CI 0.51 to 1.35; I² = 71%; 4 RCTs, 370 participants; very low-quality evidence). The results suggest that if the chance of pregnancy after the use of a gradient technique is assumed to be 24%, the chance of pregnancy after using the swim-up technique is between 14% and 30%. We are uncertain whether there was a real difference between ongoing pregnancy rates per couple (OR 0.39, 95% CI 0.19 to 0.82; heterogeneity not applicable; 1 RCT, 223 participants; very low-quality evidence). Considering the quality of evidence, we are uncertain whether there was a difference between multiple pregnancy rates (MPR) per couple comparing a swim-up versus gradient technique (MPR per couple 0% versus 0%; 1 RCT, 25 participants; very low-quality of evidence). Considering the quality of evidence, we are also uncertain whether there was a difference between miscarriage rates (MR) per couple comparing a swim-up versus gradient technique (OR 0.85, 95% CI 0.28 to 2.59; I² = 44%; 3 RCTs, 330 participants; very low-quality evidence). No studies reported on ectopic pregnancy rate, fetal abnormalities or infection rate. Swim-up versus wash technique Considering the quality of evidence, we are uncertain whether there is a difference in clinical pregnancy rates after a swim-up technique versus wash and centrifugation (OR 0.41, 95% CI 0.15 to 1.13; I² = 55%; 2 RCTs, 78 participants; very low-quality evidence). The results suggest that if the chance of pregnancy after the use of a wash technique is assumed to be 38%, the chance of pregnancy after using the swim-up technique is between 9% and 41%. Considering the quality of evidence, we are uncertain whether there was a difference between multiple pregnancy rates between swim-up technique versus wash technique (OR 0.49, 95% CI 0.02 to 13.28; heterogeneity not applicable; 1 RCT, 26 participants; very low-quality evidence). Miscarriage rate was only reported by one study: no miscarriages were reported in either treatment arm. No studies reported on ongoing pregnancy rate, ectopic pregnancy rate, fetal abnormalities or infection rate. Gradient versus wash technique Considering the quality of evidence, we are uncertain whether there is a difference in clinical pregnancy rates after a gradient versus wash and centrifugation technique (OR 1.78, 95% CI 0.58 to 5.46; I² = 52%; 2 RCTs, 94 participants; very low-quality evidence). The results suggest that if the chance of pregnancy after the use of a wash technique is assumed to be 13%, the chance of pregnancy after using the gradient technique is between 8% and 46%. Considering the quality of evidence, we are uncertain whether there was a difference between multiple pregnancy rates per couple between the treatment groups (OR 0.33, 95% CI 0.01 to 8.83; very low-quality evidence). Considering the quality of evidence, we are also uncertain whether there was a difference between miscarriage rates per couple between the treatment groups (OR 6.11, 95% CI 0.27 to 138.45; very low-quality evidence). No studies reported on ongoing pregnancy rate, ectopic pregnancy rate, fetal abnormalities or infection rate. The very low quality of the available evidence means we cannot be certain about the relative effectiveness of the different semen preparation techniques: swim-up versus gradient versus wash and centrifugation technique. No studies reported on live birth rates. We are uncertain whether there is a difference in clinical pregnancy rates, ongoing pregnancy rates, multiple pregnancy rates or miscarriage rates per couple between the three sperm preparation techniques. Further randomised trials are warranted that report live birth data
We included 21 randomised studies involving 1,690 caregivers; 19 studies compared telephone support interventions and usual care, of which 18 contributed data to the analyses. Two studies compared telephone and non-telephone professional support interventions. Caregiver ages ranged from 19 years to 87 years across studies. The majority of participants were female (> 70.53%), with two trials including females only. Most caregivers were family members, educated beyond secondary or high school level or had the equivalent in years of education. All caregivers were based in the community. Overall risk of bias was high for most studies. The results demonstrated that there is probably little or no difference between telephone support interventions and usual care for the primary outcome of quality of life at the end of intervention (SMD -0.02, 95% CI -0.24 to 0.19, 4 studies, 364 caregivers) (moderate-certainty evidence) or burden at the end of intervention (SMD -0.11, 95% CI -0.30 to 0.07, 9 studies, 788 caregivers) (low-certainty evidence). For one study where quality of life at the end of intervention was reported narratively, the findings indicated that a telephone support intervention may result in slightly higher quality of life, compared with usual care. Two further studies on caregiver burden were reported narratively; one reported that telephone support interventions may decrease burden, the other reported no change in the intervention group, compared with usual care. We are uncertain about the effects of telephone support interventions on caregiver depression at the end of intervention (SMD -0.37, 95% CI -0.70 to -0.05, 9 studies, 792 caregivers) due to very low-certainty evidence for this outcome. Depression was reported narratively for three studies. One reported that the intervention may reduce caregiver depression at the end of intervention, but this effect was not sustained at short-term follow-up. The other two studies reported there may be little or no difference between telephone support and usual care for depression at the end of intervention. Six studies measured satisfaction with the intervention but did not report comparative data. All six reported high satisfaction scores with the intervention. No adverse events, including suicide or suicide ideation, were measured or reported by any of the included studies. Our analysis indicated that caregiver anxiety may be slightly reduced (MD -6.0, 95% CI -11.68 to -0.32, 1 study, 61 caregivers) and preparedness to care slightly improved (SMD 0.37, 95% CI 0.09 to 0.64, 2 studies, 208 caregivers) at the end of intervention, following telephone-only support interventions compared to usual care. Findings indicated there may be little or no difference between telephone support interventions and usual care for all of the following outcomes at the end of intervention: problem-solving, social activity, caregiver competence, coping, stress, knowledge, physical health, self-efficacy, family functioning, and satisfaction with supports (practical or social). There may also be little or no effect of telephone support interventions for quality of life and burden at short-term follow-up or for burden and depression at medium-term follow-up. Litttle or no difference was found between groups for any of the reported outcomes in studies comparing telephone and non-telephone professional support interventions. We are uncertain as to the effects of telephone support interventions compared to non-telephone support interventions for caregiver burden and depression at the end of intervention. No study reported on quality of life or satisfaction with the intervention and no adverse events were reported or noted in the two studies reporting on this comparison. Although our review indicated slight benefit may exist for telephone support interventions on some outcomes (e.g. anxiety and preparedness to care at the end of intervention), for most outcomes, including the primary outcomes, telephone-only interventions may have little or no effect on caregiver outcomes compared to usual care. The findings of the review were mainly based on studies with overall high risk of bias, and few participants. Further high-quality trials, with larger sample sizes are required.
The search yielded 19 trials including 5256 patients. The addition of CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days and at the end of follow up (RR 0.97; 95% CI 0.80 to 1.18 and RR 1.01; 95% CI 0.98 to 1.05, respectively) or in overall survival (HR 1.00; 95% 0.93 to 1.08). There was no difference in complete remission rates (RR 1.03; 95% CI 0.99 to 1.07), relapse rates (RR 0.97; 95% CI 0.89 to 1.05) and disease-free survival (HR 1.00; 95% CI 0.90 to 1.13). CSFs did not decrease the occurrence of bacteremias (RR 0.96; 95% CI 0.82 to 1.12), nor the occurrence of invasive fungal infections (RR 1.40; 95% CI 0.90 to 2.19). CSFs marginally increased adverse events requiring discontinuation of CSFs as compared to the control arm (RR 1.33; 95% CI 1.00 to 1.56). In summary, colony-stimulating factors should not be given routinely to acute myelogenous leukemia patients post-chemotherapy since they do not affect overall survival or infectious parameters including the rate of bacteremias and invasive fungal infections.
Over 4600 women were recruited into the 15 trials included in the review, however two trials did not contribute any outcome data to the review. The trials had a moderate risk of bias. Overall, prenatal TRH, in addition to corticosteroids, did not reduce the risk of death prior to hospital discharge (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.86 to 1.27, six trials, 3694 infants), neonatal respiratory distress syndrome (average RR 1.05, 95% CI 0.91 to 1.22, nine trials, 3833 infants), or chronic lung disease (RR 1.01, 95% CI 0.85 to 1.19, five trials, 2511 infants), and did not improve any of the secondary fetal, neonatal or childhood outcomes assessed by intention-to-treat analyses. Indeed, the data showed prenatal TRH to have adverse effects for women and their infants. All side effects reported (nausea, vomiting, light headedness, urgency of micturition, facial flushing) were significantly more likely to occur in women receiving TRH. In the infants, prenatal TRH increased the risk of needing respiratory support (RR 1.16, 95% CI 1.03 to 1.29, three trials, 1969 infants), and of having a low Apgar score at five minutes (RR 1.48, 95% CI 1.14 to 1.92, three trials, 1969 infants). Only three trials provided data on childhood follow-up, and while one trial suggested poorer outcomes for infants who were exposed to prenatal TRH, the other two trials, that assessed infants using an established developmental instrument, showed no clear differences between groups in follow-up outcomes. Sensitivity analyses by trial quality, or subgroups with differing times from entry to birth, or different dose regimens of TRH, did not change these findings. Prenatal TRH in addition to corticosteroids, given to women at risk of preterm birth, does not improve infant outcomes and can cause maternal side effects.
We included four trials published between 1996 to 2000 that randomized 563 children (465 evaluable) aged five months to 15 years to intermittent twice-weekly versus daily anti-TB treatment. Two trials were from India, one from South Africa, and one from Turkey. All trials used rifampicin and isoniazid, three trials used pyrazinamide, and one trial used streptomycin. The drug combination, and the duration of intermittent and daily treatments differed between trials, and no trials used drug combinations and schedules currently recommended for childhood TB. No trial reported if any child was HIV-positive. In comparisons of twice-weekly versus daily anti-TB treatment regimens, the trials did not detect differences in the number of patients cured, but trials were small, and the comparator regimens were not standard (four trials, 465 children; very low quality evidence). Trials were underpowered to provide estimates for death (two trials, 213 participants, very low quality evidence), relapse (one trial, 214 participants,very low quality evidence), and treatment limiting adverse events (four trials, 441 participants, very low quality evidence) Reported adherence to treatment was similar (87% versus 84%; four trials, 458 children, very low quality evidence) We did not find trials comparing the commonly used thrice-weekly anti-TB short-course regimen with the daily treatment regimen. Trials conducted to date are insufficient to support or refute the use of intermittent twice- or thrice-weekly, short-course treatment regimens over daily short-course treatment in children with TB. Further randomized trials conducted in high TB-transmission settings will help inform policy and practice.
Eight studies met the inclusion criteria. Three papers compared the effects of anticholinergic drugs with placebo, and a meta-analysis of these results demonstrated no statistically significant benefit of the use of anticholinergic drugs over placebo in any of the outcome measures used. The results of one of these trials could not be included in the meta-analysis but the authors did report significantly lower symptom scores with inhaled anticholinergics compared with placebo. However, there was no significant difference between ipratropium bromide and placebo in the percentage of symptom-free nights or days. Two trials studied the effects of anticholinergics on bronchial hyper responsiveness to histamine, by measuring the provocation dose of histamine needed to cause a fall of 20 % in FEV1 (PD 20). One study (comparing anticholinergics with placebo) reported a statistically significant increase in PD 20 but this was not found in another study (comparing anticholinergics with a beta-2 agonist). Both trials also examined the effect of anticholinergic drugs on diurnal variation in peak expiratory flow rate (PEFR) and reported no significant effect. Two studies compared the addition of an anticholinergic drug to a beta-2 agonist with the beta-2 agonist alone. Both trials failed to show any significant benefit from the long term use of combined anticholinergics with beta-2 agonists compared with beta-2 agonists alone. One trial compared the effects of oral and inhaled anticholinergic drugs with placebo. No statistically significant differences were found in any of the outcome measures except for a higher FEV1 / VC ratio and RV / TLC ratio with oral anticholinergic therapy when compared with placebo. The present review summarises the best evidence available to date. Although there were some small beneficial findings in favour of anticholinergic therapy, there is insufficient data to support the use of anticholinergic drugs in the maintenance treatment of chronic asthma in children.
Based on a total of 50 RCTs with 7793 patients, naltrexone reduced the risk of heavy drinking to 83% of the risk in the placebo group RR 0.83 (95% CI 0.76 to 0.90) and decreased drinking days by about 4%, MD -3.89 (95% CI -5.75 to -2.04). Significant effects were also demonstrated for the secondary outcomes of the review including heavy drinking days, MD - 3.25 (95% CI -5.51 to -0.99), consumed amount of alcohol, MD - 10.83 (95% CI -19.69 to -1.97) and gamma-glutamyltransferase, MD - 10.37 (95% CI -18.99 to -1.75), while effects on return to any drinking, RR 0.96 (95 CI 0.92 to 1.00) missed statistical significance. Side effects of naltrexone were mainly gastrointestinal problems (e.g. nausea: RD 0.10; 95% CI 0.07 to 0.13) and sedative effects (e.g. daytime sleepiness: RD 0.09; 95% CI 0.05 to 0.14). Based on a limited study sample, effects of injectable naltrexone and nalmefene missed statistical significance. Effects of industry-sponsored studies, RR 0.90 (95% CI 0.78 to 1.05) did not significantly differ from those of non-profit funded trials, RR 0.84 (95% CI 0.77 to 0.91) and the linear regression test did not indicate publication bias (P = 0.765). Naltrexone appears to be an effective and safe strategy in alcoholism treatment. Even though the sizes of treatment effects might appear moderate in their magnitudes, these should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment.
Of the 12 records retrieved by the search, three trials published in 2001, 2003 and 2007, involving 80 inpatients with schizophrenia, aged 18 to 71 years, admitted in a psychiatric facility and followed up for a period nine weeks to 26 weeks, were included. Overall, pyridoxal 5 phosphate produced a significant improvement in tardive dyskinesia symptoms when compared with placebo, assessed by a change in Extrapyramidal Symptoms Rating Scale (ESRS) scores from baseline to the end of the first phase of the included studies (2 RCTs n = 65, RR 19.97, CI 2.87 to 139.19, low quality evidence). The endpoint tardive dyskinesia score (a measure of its severity) assessed with the ESRS, was significantly lower among participants on pyridoxal 5 phosphate compared to those on placebo (2 RCTs n = 60, MD -4.07, CI -6.36 to -1.79, low quality evidence). It was unclear whether pyridoxal 5 phosphate led to more side effects (n = 65, 2 RCTs, RR 3.97, CI 0.20 to 78.59, low quality evidence) or caused deterioration in tardive dyskinesia symptoms when compared to placebo (n = 65, 2 RCTs, RR 0.16, CI 0.01 to 3.14, low quality evidence). Five participants taking pyridoxal 5 phosphate withdrew from the study because they were not willing to take more medications while none of the participants taking placebo discontinued their medications (n = 65, 2 RCTs, RR 8.72, CI 0.51 to 149.75, low quality evidence). There was no significant difference in the endpoint positive and negative psychiatric symptoms scores, measured using the Positive and Negative symptoms Scale (PANSS) between participants taking pyridoxal 5 phosphate and those taking placebo. For the positive symptoms: (n = 15, 1 RCT, MD -1.50, CI -4.80 to 1.80, low quality evidence). For negative the symptoms: (n = 15, 1 RCT, MD -1.10, CI -5.92 to 3.72, low quality evidence). Pyridoxal 5 phosphate may have some benefits in reducing the severity of tardive dyskinesia symptoms among individuals with schizophrenia. However, the quality of evidence supporting the effectiveness of pyridoxal 5 phosphate in treating tardive dyskinesia is low, based on few studies, short follow-up periods, small sample sizes and inadequate adherence to standardised reporting guidelines for randomised controlled trials among the included studies.
Only four studies met the criteria for inclusion, with a total of 274 participants. Four pharmacological agents were investigated: modafinil (51 participants); (−)-OSU6162, a monoamine stabiliser (12 participants of which six had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A meta-analysis could not be performed due to the small number and heterogeneity of the studies. All studies examined cognitive performance, with the majority of the psychometric sub-tests showing no difference between treatment and placebo (n = 274, very low quality evidence). For (−)-OSU6162 modest superiority over placebo was demonstrated on three measures, but markedly inferior performance on another. Rivastigmine was better than placebo on one primary measure, and a single cognitive outcome in a secondary analysis of a subgroup with more severe memory impairment at baseline. The study of modafinil assessed clinical global improvement (n = 51, low quality evidence), and did not find any difference between treatment and placebo. Safety, as measured by adverse events, was reported by all studies (n = 274, very low quality evidence), with significantly more nausea reported by participants who received rivastigmine compared to placebo. There were no other differences in safety between treatment and placebo. No studies reported any deaths. There is insufficient evidence to determine whether pharmacological treatment is effective in chronic cognitive impairment in TBI. Whilst there is a positive finding for rivastigmine on one primary measure, all other primary measures were not better than placebo. The positive findings for (−)-OSU6162 are interpreted cautiously as the study was small (n = 6). For modafinil and atomoxetine no positive effects were found. All four drugs appear to be relatively well tolerated, although evidence is sparse.
Two studies met the inclusion criteria. Method of generation of allocation sequence, concealment of allocation and blinding were unclear in both studies. A total of 134 children were allocated to three treatment groups comprising diazepam alone, phenobarbitone and chlorpromazine, or phenobarbitone and chlorpromazine and diazepam.   Meta-analysis of in-hospital deaths indicates that children treated with diazepam alone had a better chance of survival than those treated with combination of phenobarbitone and chlorpromazine (Relative Risk for death 0.36; 95% confidence interval 0.15 to 0.86; Risk Difference -0.22; 95% CI -0.38 to -0.06). Giving diazepam alone, or supplementing conventional anticonvulsants (phenobarbitone and chlorpromazine) with diazepam, was reported in one study to be associated with a statistically significantly milder clinical course and shorter duration of hospitalization. Although this review suggests that diazepam alone compared with combination of phenobarbitone and chlorpromazine may be more effective in treating tetanus, the small size, methodological limitations and lack of data on drug safety from available trials preclude definite conclusions to support change in current clinical practice. The application of this observation should be moderated by local needs and circumstances, pending the availability of better evidence. We recommend a reinforcement of preventive measures against tetanus infection and it is hoped that in the light of clear evidence about the preventive efficacy of tetanus toxoid immunization, concerted efforts should be made towards preventive interventions and ultimate eradication such that there will not be enough case materials for a trial. In the event of a need for a trial, a large prospective, multicenter, randomized controlled trial, which compares diazepam alone with combinations of other drugs (excluding diazepam) will be ideal.
It was not possible to extract the results from the first phases of the two crossover studies and therefore the meta-analyses are based on the two parallel group 6-month studies. There was no indication of a positive effect favouring D-cycloserine for the numbers showing improvement at 6 months as assessed by the Clinical Global Impression for any dose. The number of withdrawals for any reason before end of treatment at 6 months was significantly in favour of placebo (fewer withdrawals) compared with D-cycloserine for dose levels of 30 mg/day (OR 2.94, 95% CI 1.52, 5.70) and 100 mg/day (OR 3.23, 95% CI 1.67, 6.25). There was no significant difference between treatment, (2, 10, 30, 100, or 200 mg/day) and placebo for the number of withdrawals due to adverse events by six months. The lack of a positive effect of D-cycloserine on cognitive outcomes in controlled clinical trials with statistical power high enough to detect a clinically meaningful effect means that D-cycloserine has no place in the treatment of patients with Alzheimer's disease.
We identified two new studies for inclusion in the review update; the review now includes seven trials with 622 participants who presented to an emergency department with SVT. All included studies were RCTs, but only three described the randomisation process, and none had blinded participants, personnel, or outcome assessors to the intervention given. Moderate-quality evidence shows no differences in the number of people reverting to sinus rhythm who were treated with adenosine or CCA (89.7% vs 92.9%; OR 1.51, 95% confidence interval (CI) 0.85 to 2.68; participants = 622; studies = 7; I2 = 36%). Low-quality evidence suggests no appreciable differences in major adverse event rates between CCAs and adenosine. Researchers reported only one case of hypotension in the CCA group and none in the adenosine group (0.66% vs 0%; OR 3.09, 95% CI 0.12 to 76.71; participants = 306; studies = 3; I2 = 0%). Included trials did not report length of stay in hospital nor patient satisfaction. Moderate-quality evidence shows no differences in effects of adenosine and calcium channel antagonists for treatment of SVT on reverting to sinus rhythm, and low-quality evidence suggests no appreciable differences in the incidence of hypotension. A study comparing patient experiences and prospectively studied adverse events would provide evidence on which treatment is preferable for management of SVT.
Twelve randomised clinical trials (RCTs) met our predefined review protocol criteria for analysis. We found only one trial to be at low risk of bias, considering the remaining trials to be at high risk of bias. The risk of selection bias in nine studies was unclear due to poor reporting, leading to uncertainty in the pooled effect estimates. Five trials compared NSAIDs versus placebo, four trials compared NSAID versus opioids, and four trials compared NSAID versus spasmolytic drugs (one of the 12 trials was a three-arm study comparing NSAIDs versus both opioids and spasmolytic drugs). There were 828 randomised participants (minimum 30 and maximum 324 per trial), of whom 416 received NSAIDs and 412 received placebo, spasmolytic drugs, or opioids. Twenty-four per cent of the participants were males. The age of the participants in the trials ranged from 18 to 86 years. All people were admitted to emergency departments for acute biliary pain. There was no mortality. When compared with placebo, NSAIDs obtained a significantly lower proportion of participants without complete pain relief (RR 0.27, 95% confidence interval (CI) 0.19 to 0.40; I2 = 0%; 5 trials; moderate-quality evidence), which was confirmed by Trial Sequential Analysis, but not regarding participants with complications (RR 0.66, 95% CI 0.38 to 1.15; I2 = 26%; 3 trials; very low-quality evidence). NSAIDs showed more pain control than spasmolytic drugs (RR 0.51, 95% CI 0.37 to 0.71; I2 = 0%; 4 trials; low-quality evidence), which was not confirmed by Trial Sequential Analysis, and a significantly lower proportion of participants with complications (RR 0.27, 95% CI 0.12 to 0.57; I2 = 0%; 2 trials; low-quality evidence), which was also not confirmed by Trial Sequential Analysis. We found no difference in the proportions of participants without complete pain relief when comparing NSAIDs versus opioids (RR 0.98, 95% CI 0.47 to 2.07; I2 = 52%), suggesting moderate heterogeneity among trials (4 trials; very low-quality evidence). Only one trial comparing NSAIDs versus opioids reported results on complications, finding no significant difference between treatments. None of the included trials reported severe adverse events. Seven out of the 12 trials assessed non-severe adverse events: in two out of the seven trials, adverse events were not observed, and minor events were reported in the remaining five trials. In addition, we found one ongoing RCT assessing the analgesic efficacy of intravenous ibuprofen in biliary colic. NSAIDs have been assessed in relatively few trials including a limited number of participants for biliary colic, considering its common occurrence. We found only one trial to be at low risk of bias. There was no mortality. None of the included trials reported quality of life. The generalisability of the review is low as most of the RCTs included neither elderly people nor participants with comorbidities, who are more prone to complications as compared to others with biliary colic. The beneficial effect of NSAIDs compared with placebo on pain relief was confirmed when we applied Trial Sequential Analysis. The quality of evidence according to GRADE criteria was moderate for the comparison of NSAIDs versus placebo regarding the outcome lack of pain relief and low or very low for the other outcomes and comparisons. We found only one trial at low risk of bias, following the predefined 'Risk of bias' domains. We found the risk of selection bias to be unclear in nine studies due to poor reporting, leading to uncertainty in the pooled effect estimates.
We included 12 studies (803 children) in this review and meta-analysis. We identified three studies that are awaiting classification and two ongoing studies. Trial results show that a longer intubation time was required when indirect laryngoscopy, or videolaryngoscopy, was used instead of direct laryngoscopy (12 trials; n = 798; mean difference (MD) 5.49 seconds, 95% confidence interval (CI) 1.37 to 9.60; I2 = 90%; very low-quality evidence). Researchers found no significant differences between direct and indirect laryngoscopy on assessment of success of the first attempt at intubation (11 trials; n = 749; risk ratio (RR) 0.96, 95% CI 0.91 to 1.02; I2 = 67%; low-quality evidence) and observed that unsuccessful intubation (five trials; n = 263) was significantly increased in the indirect laryngoscopy, or videolaryngoscopy, group (RR 4.93, 95% CI 1.33 to 18.31; I2 = 0%; low-quality evidence). Five studies reported the effect of intubation on oxygen saturation (n = 272; very low-quality evidence). Five children had desaturation during intubation: one from the direct laryngoscopy group and four from the indirect laryngoscopy, or videolaryngoscopy, group. Two studies (n = 100) reported other haemodynamic responses to intubation (very low-quality evidence). One study reported a significant increase in heart rate five minutes after intubation in the indirect laryngoscopy group (P = 0.007); the other study found that the heart rate change in the direct laryngoscopy group was significantly less than the heart rate change in the indirect laryngoscopy, or videolaryngoscopy, group (P < 0.001). A total of five studies (n = 244; very low-quality evidence) looked at evidence of trauma resulting from intubation. Investigators reported that only two children from the direct laryngoscopy group had trauma compared with no children in the indirect laryngoscopy, or videolaryngoscopy, group. Use of indirect laryngoscopy, or videolaryngoscopy, improved the percentage of glottic opening (five trials; n = 256). Studies noted no significant difference in Cormack and Lehane score (C&L) grade 1 (three trials; n = 190; RR 1.06, 95% CI 0.93 to 1.21; I2 = 59%). Evidence suggests that indirect laryngoscopy, or videolaryngoscopy, leads to prolonged intubation time with an increased rate of intubation failure when compared with direct laryngoscopy (very low-quality evidence due to imprecision, inconsistency, and study limitations). Review authors had difficulty reaching conclusions on adverse haemodynamic responses and other adverse effects of intubation, as only a few children were reported to have these outcomes. Use of indirect laryngoscopy, or videolaryngoscopy, might lead to improved vocal cord view, but marked heterogeneity between studies made it difficult for review authors to reach conclusions on this outcome.
We included 63 trials that randomised 5761 women to a physical activity intervention (n = 3239) or to a control (n = 2524). The duration of interventions ranged from 4 to 24 months, with most lasting 8 or 12 weeks (37 studies). Twenty-eight studies included aerobic exercise only, 21 involved aerobic exercise and resistance training, and seven used resistance training only. Thirty studies described the comparison group as usual or standard care, no intervention, or control. One-fifth of studies reported at least 20% intervention attrition and the average physical activity adherence was approximately 77%. No data were available on effects of physical activity on breast cancer-related and all-cause mortality, or on breast cancer recurrence. Analysis of immediately postintervention follow-up values and change from baseline to end of intervention scores revealed that physical activity interventions resulted in significant small-to-moderate improvements in HRQoL (standardised mean difference (SMD) 0.39, 95% CI 0.21 to 0.57, 22 studies, 1996 women; SMD 0.78, 95% CI 0.39 to 1.17, 14 studies, 1459 women, respectively; low-quality evidence), emotional function (SMD 0.21, 95% CI 0.10 to 0.32, 26 studies, 2102 women, moderate-quality evidence; SMD 0.31, 95% CI 0.09 to 0.53, 15 studies, 1579 women, respectively; low-quality evidence), perceived physical function (SMD 0.33, 95% CI 0.18 to 0.49, 25 studies, 2129 women; SMD 0.60, 95% CI 0.23 to 0.97, 13 studies, 1433 women, respectively; moderate-quality evidence), anxiety (SMD -0.57, 95% CI -0.95 to -0.19, 7 studies, 326 women; SMD -0.37, 95% CI -0.63 to -0.12, 4 studies, 235 women, respectively; low-quality evidence), and cardiorespiratory fitness (SMD 0.44, 95% CI 0.30 to 0.58, 23 studies, 1265 women, moderate-quality evidence; SMD 0.83, 95% CI 0.40 to 1.27, 9 studies, 863 women, respectively; very low-quality evidence). Investigators reported few minor adverse events. Small improvements in physical activity interventions were sustained for three months or longer postintervention in fatigue (SMD -0.43, 95% CI -0.60 to -0.26; SMD -0.47, 95% CI -0.84 to -0.11, respectively), cardiorespiratory fitness (SMD 0.36, 95% CI 0.03 to 0.69; SMD 0.42, 95% CI 0.05 to 0.79, respectively), and self-reported physical activity (SMD 0.44, 95% CI 0.17 to 0.72; SMD 0.51, 95% CI 0.08 to 0.93, respectively) for both follow-up values and change from baseline scores. However, evidence of heterogeneity across trials was due to variation in intervention components (i.e. mode, frequency, intensity, duration of intervention and sessions) and measures used to assess outcomes. All trials reviewed were at high risk of performance bias, and most were also at high risk of detection, attrition, and selection bias. In light of the aforementioned issues, we determined that the evidence was of very low, low, or moderate quality. No conclusions regarding breast cancer-related and all-cause mortality or breast cancer recurrence were possible. However, physical activity interventions may have small-to-moderate beneficial effects on HRQoL, and on emotional or perceived physical and social function, anxiety, cardiorespiratory fitness, and self-reported and objectively measured physical activity. The positive results reported in the current review must be interpreted cautiously owing to very low-to-moderate quality of evidence, heterogeneity of interventions and outcome measures, imprecision of some estimates, and risk of bias in many trials. Future studies with low risk of bias are required to determine the optimal combination of physical activity modes, frequencies, intensities, and durations needed to improve specific outcomes among women who have undergone adjuvant therapy.
Three RCTs randomising 853 women, of whom 781 were evaluated, met the inclusion criteria. Meta-analysis of three trials for overall survival (OS) found no statistically significant difference between IDS and chemotherapy alone (hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.61 to 1.06, I² = 58%). Subgroup analysis for OS in two trials, where the primary surgery was not performed by gynaecologic oncologists or was less extensive, showed a benefit of IDS (HR = 0.68, 95% CI 0.53 to 0.87, I² = 0%). Meta-analysis of two trials for PFS found no statistically significant difference between IDS and chemotherapy alone (HR = 0.88, 95% CI 0.57 to 1.33, I² = 83%). Rates of toxic reactions to chemotherapy were similar in both arms (risk ratio = 1.19, 95% CI 0.53 to 2.66, I² = 0%), but little information was available for other adverse events or quality or life (QoL). We found no conclusive evidence to determine whether IDS between cycles of chemotherapy would improve or decrease the survival rates of women with advanced ovarian cancer, compared with conventional treatment of primary surgery followed by adjuvant chemotherapy. IDS appeared to yield benefit only in women whose primary surgery was not performed by gynaecologic oncologists or was less extensive. Data on QoL and adverse events were inconclusive.
Twelve trials (seven with duration of at least three months) met the inclusion criteria, with 19,715 participants randomised. The two largest trials that were conducted in the USA (SELECT and NPC) reported clinical events. There were no statistically significant effects of selenium supplementation on all cause mortality (RR 0.97, 95% CI 0.88 to 1.08), CVD mortality (RR 0.97, 95% CI 0.79 to 1.2), non-fatal CVD events (RR 0.96, 95% CI 0.89 to 1.04) or all CVD events (fatal and non-fatal) (RR 1.03, 95% CI 0.95 to 1.11). There was a small increased risk of type 2 diabetes with selenium supplementation but this did not reach statistical significance (RR 1.06, 95% CI 0.97 to 1.15). Other adverse effects that increased with selenium supplementation, as reported in the SELECT trial, included alopecia (RR 1.28, 95% CI 1.01 to 1.62) and dermatitis grade 1 to 2 (RR 1.17, 95% CI 1.0 to 1.35). Selenium supplementation reduced total cholesterol but this did not reach statistical significance (WMD - 0.11 mmol/L, 95% CI - 0.3 to 0.07). Mean high density lipoprotein (HDL) levels were unchanged. There was a statistically significant reduction in non-HDL cholesterol (WMD - 0.2 mmol/L, 95% CI - 0.41 to 0.00) in one trial of varying selenium dosage. None of the longer term trials examined effects on blood pressure. Overall, the included studies were regarded as at low risk of bias. The limited trial evidence that is available to date does not support the use of selenium supplements in the primary prevention of CVD.
Since only one small study (n = 40) was included, no meta-analysis could be performed. The included randomised controlled study was of parallel design and undertaken at two paediatric hospitals in Australia. The study evaluated the effects of a singing program on the quality of life and respiratory muscle strength of hospitalised children with cystic fibrosis (mean age 11.6 years, 35% male). While the singing group received eight individual singing sessions, the control group participated in preferred recreational activities, such as playing computer games or watching movies. This study was limited by a small sample size (51 participants) and a high drop-out rate (21%). There were no differences between the groups at either post-intervention or follow-up; although by the end of treatment there were some improvements in some of the domains of the quality of life questionnaire Cystic Fibrosis Questionnaire-Revised (e.g. emotional, social and vitality domains) for both singing and control groups. For the respiratory muscle strength indices, maximal expiratory pressure at follow-up (six to eight weeks post-intervention) was higher in the singing group, mean difference 25.80 (95% confidence interval 5.94 to 45.66). There was no difference between groups for any of the other respiratory function parameters (maximal inspiratory pressure, spirometry) at either post-intervention or follow-up. No adverse effects were observed in the singing group; adverse events for the control group were not reported in the paper. There is insufficient evidence to determine the effects of singing on quality of life or on the respiratory parameters in people with cystic fibrosis. However, there is growing interest in non-medical treatments for cystic fibrosis and researchers may wish to investigate the impact of this inexpensive therapy on respiratory function and psychosocial well-being further in the future.
Fifteen studies (8 parallel, 7 crossover; 352 patients) were included. Only one study enrolled women. Studies evaluated the effects of phosphodiesterase-5 inhibitors (PDE5i), zinc, vitamin E, vitamin D or bromocriptine compared to placebo. PDE5i significantly increased the overall International Index of Erectile Function-5 (IIEF-5) score (2 studies, 101 patients, MD 10.65, 95% CI 5.34 to 15.96), all its individual domains and the complete 15-item IIEF tool (1 study, 41 patients, MD 2.64, 95% CI 1.32 to 3.96). End of treatment testosterone levels were not significantly increased by addition of zinc to dialysate (2 studies, 22 patients, MD 0.21 ng/mL, 95% CI -2.14 to 2.55) but oral zinc improved end of treatment testosterone levels (1 study, 20 patients, SMD 1.62, 95% CI 0.58 to 2.66). There was no difference in plasma luteinizing and follicle-stimulating hormone levels at the end of the study period with zinc therapy. Only sparse data were available for vitamin E, bromocriptine and dihydroxycholecalciferol in CKD patients and there were no studies of intracavernous injections, transurethral injections, mechanical devices or psychosexual therapies in people with CKD. PDE5i and zinc are promising interventions for treating sexual dysfunction in men with CKD. Evidence supporting their routine use in CKD patients is limited. There is an unmet need for studying interventions for both male and female sexual dysfunction in CKD, considering the significant disease burden.
Seven studies with a total of 2422 participants were included in this systematic review. Meta-analysis could be performed with the data of four included studies, with a total of 1382 participants. The methodological quality of the included trials was relatively low. Evidence of a beneficial effect of culturing in low oxygen concentration was found for live birth rate (OR 1.39; 95% CI 1.11 to 1.76; P = 0.005; I2 = 0%); this would mean that a typical clinic could improve a 30% live birth rate using atmospheric oxygen concentration to somewhere between 32% and 43% by using a low oxygen concentration. The results were very similar for ongoing and clinical pregnancy rates. There was no evidence that culturing embryos under low oxygen concentrations resulted in higher numbers of adverse events such as multiple pregnancies, miscarriages or congenital abnormalities. The results of this systematic review and meta-analysis suggest that culturing embryos under conditions with low oxygen concentrations improves the success rates of IVF and ICSI, resulting in the birth of more healthy newborns.
Sixteen trials were included in the review and fourteen contained data in a suitable form for quantitative analysis. Most comparisons did not show differences between rTMS and other interventions. No difference was seen between rTMS and sham TMS using the Beck Depression Inventory or the Hamilton Depression Rating Scale, except for one time period (after two weeks of treatment) for left dorsolateral prefrontal cortex and high frequency; and also for right dorsolateral prefrontal cortex and low frequency, both in favour of rTMS and both using the Hamilton scale. Comparison of rTMS (left dorsolateral prefrontal cortex and high frequency) with electroconvulsive therapy showed no difference except for psychotic patients after two weeks treatment, using the Hamilton scale, which indicated that electroconvulsive therapy was more effective than rTMS. The information in this review suggests that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit.
We identified 42 eligible studies in 2433 participants: antimicrobial agents (36 studies); urokinase (4 studies), peritoneal lavage (1 study), and IP immunoglobulin (1 study). We did not identify any optimal antibiotic agent or combination of agents. IP glycopeptides (vancomycin or teicoplanin) had uncertain effects on primary treatment response, relapse rates, and need for catheter removal compared to first generation cephalosporins, although glycopeptide regimens were more likely to achieve a complete cure (3 studies, 370 episodes: RR 1.66, 95% CI 1.01 to 2.72). For relapsing or persistent peritonitis, simultaneous catheter removal and replacement was better than urokinase at reducing treatment failure rates (RR 2.35, 95% CI 1.13 to 4.91) although evidence was limited to a single small study. Continuous and intermittent IP antibiotic dosing schedules had similar treatment failure and relapse rates. IP antibiotics were superior to IV antibiotics in reducing treatment failure in one small study (RR 3.52, 95% CI 1.26 to 9.81). Longer duration treatment (21 days of IV vancomycin and IP gentamicin) had uncertain effects on risk of treatment relapse compared with 10 days treatment (1 study, 49 patients: RR 1.56, 95% CI 0.60 to 3.95) although may have increased ototoxicity. In general, review conclusions were based on a small number of studies with few events in which risk of bias was generally high; interventions were heterogeneous, and outcome definitions were often inconsistent. There were no RCTs evaluating optimal timing of catheter removal and data for automated PD were absent. Many of the studies evaluating treatment of PD-related peritonitis are small, out-dated, of poor quality, and had inconsistent definitions and dosing regimens. IP administration of antibiotics was superior to IV administration for treating PD-associated peritonitis and glycopeptides appear optimal for complete cure of peritonitis, although evidence for this finding was assessed as low quality. PD catheter removal may be the best treatment for relapsing or persistent peritonitis. Evidence was insufficient to identify the optimal agent, route or duration of antibiotics to treat peritonitis. No specific antibiotic appears to have superior efficacy for preventing treatment failure or relapse of peritonitis, but evidence is limited to few trials. The role of routine peritoneal lavage or urokinase is uncertain.
The search identified 281 trials. Only two studies involving a total of 157 participants were confirmed to be authentic RCTs (Li 2004c; Zhao 2000). Both were of poor methodological quality with a high risk of conflicted interest and potential for bias in favour of the intervention. We could not reach a definitive conclusion from the results. The pooled result showed that adding a Western medicine to CHM resulted in a significantly higher treatment success rate than with CHM alone (RR 1.33, 95% CI 1.08 to 1.63). When CHM plus Western medicine was compared to CHM alone for the time to disappearance of abdominal pain, again the results favoured the arm that included Western medicine (RR -2.09, 95% CI -4.14 to -0.04). Results were inconsistent for the time required for human chorionic gonadotropin (beta-hCG) to return to normal. One study favoured CHM plus Western medicine over Western medicine (with or without placebo) (MD -6.68, 95% CI -11.49 to -1.87); when CHM plus Western medicine was compared to CHM alone the results favoured the arm that included Western medicine (MD -8.12, 95% CI -10.89 to -5.53). We have not found any well-designed trials investigating Chinese herbal medicines in the treatment of ectopic pregnancy. We cannot support or refute any CHM preparation for clinical use on the basis of evidence from randomised controlled trials.
We included eight RCTs (474 randomised participants), which compared oral corticosteroids with placebo or no intervention. All trials only recruited adults with chronic rhinosinusitis with nasal polyps. All trials reported outcomes at two to three weeks, at the end of the short-course oral steroid treatment period. Three trials additionally reported outcomes at three to six months. Two of these studies prescribed intranasal steroids to patients in both arms of the trial at the end of the oral steroid treatment period. Oral steroids versus placebo or no intervention Disease-specific health-related quality of life  was reported by one study. This study reported improved quality of life after treatment (two to three weeks) in the group receiving oral steroids compared with the group who received placebo (standardised mean difference (SMD) -1.24, 95% confidence interval (CI) -1.92 to -0.56, 40 participants, modified RSOM-31), which corresponds to a large effect size. We assessed the evidence to be low quality (we are uncertain about the effect estimate; the true effect may be substantially different from the estimate of the effect). Disease severity  as measured by patient-reported symptom scores was reported by two studies, which allowed the four key symptoms used to define chronic rhinosinusitis (nasal blockage, nasal discharge, facial pressure, hyposmia) to be combined into one score. The results at the end of treatment (two to three weeks) showed an improvement in patients receiving oral steroids compared to placebo, both when presented as a mean final value (SMD -2.84, 95% CI -4.09 to -1.59, 22 participants) and as a change from baseline (SMD -2.28, 95% CI -2.76 to -1.80, 114 participants). These correspond to large effect sizes but we assessed the evidence to be low quality. One study (114 participants) followed patients for 10 weeks after the two-week treatment period. All patients in both arms received intranasal steroids at the end of the oral steroid treatment period. The results showed that the initial results after treatment were not sustained (SMD -0.22, 95% CI -0.59 to 0.15, 114 participants, percentage improvement from baseline). This corresponds to a small effect size and we assessed the evidence to be low quality. There was an increase in adverse events  in people receiving orals steroids compared with placebo for gastrointestinal disturbances (risk ratio (RR) 3.45, 95% CI 1.11 to 10.78; 187 participants; three studies) and insomnia (RR 3.63, 95% CI 1.10 to 11.95; 187 participants; three studies). There was no significant impact of oral steroids on mood disturbances at the dosage used in the included study (risk ratio (RR) 2.50, 95% CI 0.55 to 11.41; 40 participants; one study). We assessed the evidence to be low quality due to the lack of definitions of the adverse events and the small number of events or sample size, or both). Other comparisons No studies that compared short-course oral steroids with other treatment for chronic rhinosinusitis met the inclusion criteria. At the end of the treatment course (two to three weeks) there is an improvement in health-related quality of life and symptom severity in patients with chronic rhinosinusitis with nasal polyps taking oral corticosteroids compared with placebo or no treatment. The quality of the evidence supporting this finding is low. At three to six months after the end of the oral steroid treatment period, there is little or no improvement in health-related quality of life or symptom severity for patients taking an initial course of oral steroids compared with placebo or no treatment. The data on the adverse effects associated with short courses of oral corticosteroids indicate that there may be an increase in insomnia and gastrointestinal disturbances but it is not clear whether there is an increase in mood disturbances. All of the adverse events results are based on low quality evidence. More research in this area, particularly research evaluating patients with chronic rhinosinusitis without nasal polyps, longer-term outcomes and adverse effects, is required. There is no evidence for oral steroids compared with other treatments.
We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol 5 mg) or placebo and were of a high methodological quality. We noted no statistical differences among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.76 to 1.18). For other outcomes analysed (major vascular events, death from all causes, death from cardiovascular causes) , we observed no significant differences between the groups. There were minor blood pressure reductions in the intervention group. Neither of the included studies reported the occurrence of diabetes among their outcomes or assessed quality of life. Adverse events were significantly more frequent in participants taking atenolol than in those given placebo, and were the most common reason given for discontinuing treatment (RR 1.85, 95% CI 1.45 to 2.35). To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies with larger samples are needed.
Four trials (one on slings, three on strapping - 142 participants) met the inclusion criteria. One trial testing a hemisling versus no device reported that no participants had subluxation greater than 10 mm, the same number had lost more than 30 degrees of shoulder external rotation (Peto odds ratio (OR) 1.00, 95% confidence interval (CI) 0.1 to 9.3), and more participants in the hemisling group had pain (Peto OR 8.7, 95% CI 1.1 to 67.1). The other three showed that strapping was effective in delaying the onset of pain (weighted mean difference (WMD) 14 days, 95% CI 9.7 to 17.8), but was ineffective in reducing pain severity (WMD -0.7 cm on a visual analogue scale, 95% CI -2.0 to 0.7), increasing upper limb function (WMD 0.8, 95% CI -1.5 to 3.1) or affecting the degree of contracture (WMD -1.4 degrees, 95% CI -10.9 to 8.1) at the shoulder. There is insufficient evidence to conclude whether slings and wheelchair attachments prevent subluxation, decrease pain, increase function or adversely increase contracture in the shoulder after stroke. There is some evidence that strapping the shoulder delays the onset of pain but does not decrease it, nor does it increase function or adversely increase contracture.
We identified 1995 references and included10 RCTs (2745 workers). Two studies were assessed with low risk of bias. Most trials (N = 8) examined office workers. Few workers were sick-listed. Thus, WIs were seldom designed to improve return-to-work. Overall, there was low quality evidence that showed no significant differences between WIs and no intervention for pain prevalence or severity. If present, significant results in favour of WIs were not sustained across follow-up times. There was moderate quality evidence (1 study, 415 workers) that a four-component WI was significantly more effective in reducing sick leave in the intermediate-term (OR 0.56, 95% CI 0.33 to 0.95), but not in the short- (OR 0.83, 95% CI 0.52 to 1.34) or long-term (OR 1.28, 95% CI 0.73 to 2.26). These findings might be because only a small proportion of the workers were sick-listed. Overall, this review found low quality evidence that neither supported nor refuted the benefits of any specific WI for pain relief and moderate quality evidence that a multiple-component intervention reduced sickness absence in the intermediate-term, which was not sustained over time. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. There is an urgent need for high quality RCTs with well designed WIs.
We have added four new trials to this update. This review now includes 21 trials involving 2289 patient and 1290 carer participants. Nine trials evaluated a passive and 12 trials an active information intervention. Meta-analyses showed a significant effect in favour of the intervention on patient knowledge (standardised mean difference (SMD) 0.29, 95% confidence interval (CI) 0.12 to 0.46, P < 0.001), carer knowledge (SMD 0.74, 95% CI 0.06 to 1.43, P = 0.03), one aspect of patient satisfaction (odds ratio (OR) 2.07, 95% CI 1.33 to 3.23, P = 0.001), and patient depression scores (mean difference (MD) -0.52, 95% CI -0.93 to -0.10, P = 0.01). There was no significant effect (P > 0.05) on number of cases of anxiety or depression in patients, carer mood or satisfaction, or death. Qualitative analyses found no strong evidence of an effect on other outcomes. Post-hoc subgroup analyses showed that active information had a significantly greater effect than passive information on patient mood but not on other outcomes. There is evidence that information improves patient and carer knowledge of stroke, aspects of patient satisfaction, and reduces patient depression scores. However, the reduction in depression scores was small and may not be clinically significant. Although the best way to provide information is still unclear there is some evidence that strategies that actively involve patients and carers and include planned follow-up for clarification and reinforcement have a greater effect on patient mood.
We included five RCTs (1218 participants) in the review. Three trials focused on the prophylaxis of MRONJ. Two trials investigated options for the treatment of established MRONJ. The RCTs included only participants treated with bisphosphonates and, thus, did not cover the entire spectrum of medications associated with MRONJ. Prophylaxis of MRONJ One trial compared standard care with regular dental examinations in three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ: RR 0.10; 95% CI 0.02 to 0.39 (253 participants; low-quality evidence). Secondary outcomes were not evaluated. As dentoalveolar surgery is considered a common predisposing event for developing MRONJ, one trial investigated the effect of plasma rich in growth factors (PRGF) for preventing MRONJ in people with cancer undergoing dental extractions. There was insufficient evidence to support or refute a benefit of PRGF on MRONJ incidence when compared with standard treatment (RR 0.08, 95% CI 0.00 to 1.51; 176 participants; very low-quality evidence). Secondary outcomes were not reported. In another trial comparing wound closure by primary intention with wound closure by secondary intention after dental extractions in people treated with oral bisphosphonates (700 participants), no cases of intraoperative complications or postoperative MRONJ were observed. QoL was not investigated. Treatment of MRONJ One trial analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone. HBO in addition to standard care did not significantly improve healing from MRONJ compared with standard care alone (at last follow-up: RR 1.56; 95% CI 0.77 to 3.18; 46 participants included in the analysis; very low-quality evidence). QoL data were presented qualitatively as intragroup comparisons; hence, an effect estimate of treatment on QoL was not possible. Other secondary outcomes were not reported. The other RCT found no significant difference between autofluorescence- and tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ at any timepoint (at one-year follow-up: RR 1.05; 95% CI 0.86 to 1.30; 34 participants included in the analysis; very low-quality evidence). Secondary outcomes were not reported. Prophylaxis of MRONJ One open-label RCT provided some evidence that dental examinations in three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be low. There is insufficient evidence to either claim or refute a benefit of either of the interventions tested for prophylaxis of MRONJ (i.e. PRGF inserted into the postextraction alveolus during dental extractions, and wound closure by primary or secondary intention after dental extractions). Treatment of MRONJ Available evidence is insufficient to either claim or refute a benefit for hyperbaric oxygen therapy as an adjunct to conventional therapy. There is also insufficient evidence to draw conclusions about autofluorescence-guided versus tetracycline fluorescence-guided bone surgery.
We included four RCTs with 189 randomised participants (one RCT new for this update). None of the included studies reported the primary outcomes of alcohol withdrawal seizures, alcohol withdrawal delirium, or craving. For the comparison of baclofen and placebo (1 study, 31 participants), there was no evidence of a difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores in eight-hour periods from days one to five (very low-quality evidence). For the comparison of baclofen and diazepam (2 studies, 85 participants), there was no evidence of a difference in change from baseline to days 10 to 15 on CIWA-Ar scores (very low-quality evidence, meta-analysis was not performed due to insufficient data). In one study (37 participants), there was no evidence of a difference in participants with at least one adverse event (risk difference (RD) 0.00, 95% confidence interval (CI) –0.10 to 0.10; very low-quality evidence), dropouts (RD 0.00, 95% CI –0.10 to 0.10; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI –0.10 to 0.10; very low-quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no evidence of a difference in difference from baseline to nine-day decremental fixed-dose intervention: CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low-quality evidence), global improvement (MD 0.10, 95% CI –0.03 to 0.23; very low-quality evidence), 14/60 participants with adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low-quality of evidence), dropouts (RD 0.00, 95% CI –0.06 to 0.06; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI –0.06 to 0.06; very low-quality evidence). None of the RCTs provided information on random sequence generation or allocation concealment, therefore, we assessed them at unclear risk of bias. Two RCTs were not of double-blind design and had a high risk of bias in blinding (Addolorato 2006; Girish 2016). One RCT had more than 5% dropouts with high risk of attrition bias (Lyon 2011). We could not assess reporting bias as none of the prepublished protocols were available. No conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low-quality evidence.
We included six trials, involving a total of 636 women with a twin or triplet pregnancy (total of 1298 babies). We assessed all of the included trials as having a low risk of bias for random sequence generation. Apart from one trial with an unclear risk of bias, we judged all remaining trials to be of low risk of bias for allocation concealment. Five trials (495 women and 1016 babies) compared strict bed rest in hospital with no activity restriction at home. There was no difference in the risk of very preterm birth (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.66 to 1.58, five trials, 495 women, assuming complete correlation between twins/triplets, low-quality evidence), perinatal mortality (RR 0.65, 95% CI 0.35 to 1.21, five trials, 1016 neonates, assuming independence between twins/triplets, low-quality evidence) and low birthweight (RR 0.95, 95% CI 0.75 to 1.21, three trials, 502 neonates, assuming independence between twins/triplets, low-quality evidence). We observed no differences for the risk of small-for-gestational age (SGA) (RR 0.75, 95% CI 0.56 to 1.01, two trials, 293 women, assuming independence between twins/triplets, low-quality evidence) and prelabour preterm rupture of the membrane (PPROM) (RR 1.30, 95% CI 0.71 to 2.38, three trials, 276 women, low-quality evidence). However, strict bed rest in hospital was associated with increased spontaneous onset of labour (RR 1.05, 95% CI 1.02 to 1.09, P = 0.004, four trials, 488 women) and a higher mean birthweight (mean difference (MD) 136.99 g, 95% CI 39.92 to 234.06, P = 0.006, three trials, 314 women) compared with no activity restriction at home. Only one trial (141 women and 282 babies) compared partial bed rest in hospital with no activity restriction at home. There was no evidence of a difference in the incidence of very preterm birth (RR 2.30, 95% CI 0.84 to 6.27, 141 women, assuming complete correlation between twins, low-quality evidence) and perinatal mortality (RR 4.17, 95% CI 0.90 to 19.31, 282 neonates, assuming complete independence twins, low-quality evidence) between the intervention and control group. Low birthweight was not reported in this trial. We found no differences in the risk of PPROM and SGA between women receiving partial bed rest and the control group (low-quality evidence). Women on partial bed rest in hospital were less likely to develop gestational hypertension compared with women without activity restriction at home (RR 0.30, 95% CI 0.16 to 0.59, P = 0.0004, 141 women). Strict or partial bed rest in hospital was found to have no impact on other secondary outcomes. None of the trials reported on costs of the intervention or adverse effects such as the development of venous thromboembolism or psychosocial effects. The evidence to date is insufficient to inform a policy of routine bed rest in hospital or at home for women with a multiple pregnancy. There is a need for large-scale, multicenter randomised controlled trials to evaluate the benefits, adverse effects and costs of bed rest before definitive conclusions can be drawn.
We included 10 studies involving 632 participants. One new trial (19 participants) was added for this update. One trial was conducted in a community setting, eight in nursing homes and one in both settings. Different types of antipsychotics at varying doses were discontinued in the studies. Both abrupt and gradual withdrawal schedules were used. Reported data were predominantly from studies at low or unclear risk of bias. We included nine trials with 575 randomised participants that used a proxy outcome for overall success of antipsychotic withdrawal. Pooling data was not possible due to heterogeneity of outcome measures used. Based on assessment of seven studies, discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence). Two trials included only participants with psychosis, agitation or aggression who had responded to antipsychotic treatment. In these two trials, stopping antipsychotics was associated with a higher risk of leaving the study early due to symptomatic relapse or a shorter time to symptomatic relapse. We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline. None of the studies assessed withdrawal symptoms. Adverse effects of antipsychotics (such as falls) were not systematically assessed. Low-quality evidence showed that discontinuation may have little or no effect on adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants), or cognitive function (5 trials, 365 participants). There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence). There is low-quality evidence that antipsychotics may be successfully discontinued in older people with dementia and NPS who have been taking antipsychotics for at least three months, and that discontinuation may have little or no important effect on behavioural and psychological symptoms. This is consistent with the observation that most behavioural complications of dementia are intermittent and often do not persist for longer than three months. Discontinuation may have little or no effect on overall cognitive function. Discontinuation may make no difference to adverse events and quality of life. Based on the trials in this review, we are uncertain whether discontinuation of antipsychotics leads to a decrease in mortality. People with psychosis, aggression or agitation who responded well to long-term antipsychotic drug use, or those with more severe NPS at baseline, may benefit behaviourally from continuation of antipsychotics. Discontinuation may reduce agitation for people with mild NPS at baseline. However, these conclusions are based on few studies or small subgroups and further evidence of benefits and harms associated with withdrawal of antipsychotic is required in people with dementia and mild and severe NPS. The overall conclusions of the review have not changed since 2013 and the number of available trials remains low.
We included 65 randomised controlled trials from 12 countries involving patients undergoing a variety of procedures in hospitals. Nine thousand and twenty one patients were randomised and entered into these studies. Interventions used various designs and formats but the main data for results were from studies using written materials, audio-visual materials and decision aids. Some interventions were delivered before admission to hospital for the procedure while others were delivered on admission. Only one study attempted to measure the primary outcome, which was informed consent as a unified concept, but this study was at high risk of bias.  More commonly, studies measured secondary outcomes which were individual components of informed consent such as knowledge, anxiety, and satisfaction with the consent process.  Important but less commonly-measured outcomes were deliberation, decisional conflict, uptake of procedures and length of consultation. Meta-analyses showed statistically-significant improvements in knowledge when measured immediately after interventions (SMD 0.53 (95% CI 0.37 to 0.69) I2 73%), shortly afterwards (between 24 hours and 14 days) (SMD 0.68 (95% CI 0.42 to 0.93) I2 85%) and at a later date (15 days or more) (SMD 0.78 (95% CI 0.50 to 1.06) I2 82%). Satisfaction with decision making was also increased (SMD 2.25 (95% CI 1.36 to 3.15) I2 99%) and decisional conflict was reduced (SMD -1.80 (95% CI -3.46 to -0.14) I2 99%). No statistically-significant differences were found for generalised anxiety (SMD -0.11 (95% CI -0.35 to 0.13) I2 82%), anxiety with the consent process (SMD 0.01 (95% CI -0.21 to 0.23) I2 70%) and satisfaction with the consent process (SMD 0.12 (95% CI -0.09 to 0.32) I2 76%). Consultation length was increased in those studies with continuous data (mean increase 1.66 minutes (95% CI 0.82 to 2.50) I2 0%) and in the one study with non-parametric data (control 8.0 minutes versus intervention 11.9 minutes, interquartile range (IQR) of 4 to 11.9 and 7.2 to 15.0 respectively). There were limited data for other outcomes. In general, sensitivity analyses removing studies at high risk of bias made little difference to the overall results. Informed consent is an important ethical and practical part of patient care.  We have identified efforts by researchers to investigate interventions which seek to improve information delivery and consideration of information to enhance informed consent.  The interventions used consistently improve patient knowledge, an important prerequisite for informed consent.  This is encouraging and these measures could be widely employed although we are not able to say with confidence which types of interventions are preferable. Our results should be interpreted with caution due to the high levels of heterogeneity associated with many of the main analyses although we believe there is broad evidence of beneficial outcomes for patients with the pragmatic application of interventions. Only one study attempted to measure informed consent as a unified concept.
We included 37 studies involving a total of 4129 participants. Risk of bias across the included studies was variable. We judged the GRADE quality of evidence to be very low or low for the primary outcomes where data were available. The majority of participants were over 65 years of age with mild to moderate adult-onset hearing loss. There was a mix of new and experienced hearing aid users. Six of the studies (287 participants) assessed long-term outcomes. All 37 studies tested interventions that could be classified using the CCM as self-management support (ways to help someone to manage their hearing loss and hearing aid(s) better by giving information, practice and experience at listening/communicating or by asking people to practise tasks at home) and/or delivery system design interventions (just changing how the service was delivered). Self-management support interventions We found no studies that investigated the effect of these interventions on adherence, adverse effects or hearing aid benefit. Two studies reported daily hours of hearing aid use but we were unable to combine these in a meta-analysis. There was no evidence of a statistically significant effect on quality of life over the medium term. Self-management support reduced short- to medium-term hearing handicap (two studies, 87 participants; mean difference (MD) -12.80, 95% confidence interval (CI) -23.11 to -2.48 (0 to 100 scale)) and increased the use of verbal communication strategies in the short to medium term (one study, 52 participants; MD 0.72, 95% CI 0.21 to 1.23 (0 to 5 scale)). The clinical significance of these statistical findings is uncertain. It is likely that the outcomes were clinically significant for some, but not all, participants. Our confidence in the quality of this evidence was very low. No self-management support studies reported long-term outcomes. Delivery system design interventions These interventions did not significantly affect adherence or daily hours of hearing aid use in the short to medium term, or adverse effects in the long term. We found no studies that investigated the effect of these interventions on quality of life. There was no evidence of a statistically or clinically significant effect on hearing handicap, hearing aid benefit or the use of verbal communication strategies in the short to medium term. Our confidence in the quality of this evidence was low or very low. Long-term outcome measurement was rare. Combined self-management support/delivery system design interventions One combined intervention showed evidence of a statistically significant effect on adherence in the short term (one study, 167 participants, risk ratio (RR) 1.06, 95% CI 1.00 to 1.12). However, there was no evidence of a statistically or clinically significant effect on daily hours of hearing aid use over the long term, or the short to medium term. No studies of this type investigated adverse effects. There was no evidence of an effect on quality of life over the long term, or short to medium term. These combined interventions reduced hearing handicap in the short to medium term (14 studies, 681 participants; standardised mean difference (SMD) -0.26, 95% CI -0.50 to -0.02). This represents a small-moderate effect size but there is no evidence of a statistically significant effect over the long term. There was evidence of a statistically, but not clinically, significant effect on long-term hearing aid benefit (two studies, 69 participants, MD 0.30, 95% CI 0.02 to 0.58 (1 to 5 scale)), but no evidence of an effect over the short to medium term. There was evidence of a statistically, but not clinically, significant effect on the use of verbal communication strategies in the short term (four studies, 223 participants, MD 0.45, 95% CI 0.15 to 0.74 (0 to 5 scale)), but not the long term. Our confidence in the quality of this evidence was low or very low. We found no studies that assessed the effect of other CCM interventions (decision support, the clinical information system, community resources or health system changes). There is some low to very low quality evidence to support the use of self-management support and complex interventions combining self-management support and delivery system design in adult auditory rehabilitation. However, effect sizes are small. The range of interventions that have been tested is relatively limited. Future research should prioritise: long-term outcome assessment; development of a core outcome set for adult auditory rehabilitation; and study designs and outcome measures that are powered to detect incremental effects of rehabilitative healthcare system changes.
We included one study from the USA (re-analysed as an ITS) involving one hospital and an unknown number of nurses and patients. The study evaluated the effects of a standardised evidence-based nursing procedure on nursing care for patients at risk of developing healthcare-acquired pressure ulcers (HAPUs). If a patient's admission Braden score was below or equal to 18 (i.e. indicating a high risk of developing pressure ulcers), nurses were authorised to initiate a pressure ulcer prevention bundle (i.e. a set of evidence-based clinical interventions) without waiting for a physician order. Re-analysis of data as a time series showed that against a background trend of decreasing HAPU rates, if that trend was assumed to be real, there was no evidence of an intervention effect at three months (mean rate per quarter 0.7%; 95% confidence interval (CI) 1.7 to 3.3; P = 0.457). Given the small percentages post intervention it was not statistically possible to extrapolate effects beyond three months. Despite extensive searching of published and unpublished research we identified only one low-quality study; we excluded many studies due to non-eligible study design. If policy-makers and healthcare organisations wish to promote evidence-based nursing successfully at an organisational level, they must ensure the funding and conduct of well-designed studies to generate evidence to guide policy.
In total, 2794 participants were randomised in 13 trials included in this review. All the trials were at unclear or high risk of bias. One trial (which included 53 participants) did not contribute any data to this review. A total of 213 participants were excluded in the remaining trials after randomisation, leaving a total of 2528 randomised participants for analysis, with 1288 undergoing laparoscopic gastrectomy and 1240 undergoing open gastrectomy. All the participants were suitable for major surgery. There was no difference in the proportion of participants who died within thirty days of treatment between laparoscopic gastrectomy (7/1188: adjusted proportion = 0.6% (based on meta-analysis)) and open gastrectomy (4/1447: 0.3%) (RR 1.60, 95% CI 0.50 to 5.10; risk difference 0.00, 95% CI -0.01 to 0.01; participants = 2335; studies = 11; I2 = 0%; low quality evidence). There were no events in either group for short-term recurrence (participants = 103; studies = 3), proportion requiring blood transfusion (participants = 66; studies = 2), and proportion with positive margins at histopathology (participants = 28; studies = 1). None of the trials reported health-related quality of life, time to return to normal activity or time to return to work. The differences in long-term mortality (HR 0.94, 95% CI 0.70 to 1.25; participants = 195; studies = 3; I2 = 0%; very low quality evidence), serious adverse events within three months (laparoscopic gastrectomy (7/216: adjusted proportion = 3.6%) versus open gastrectomy (13/216: 6%) (RR 0.60, 95% CI 0.27 to 1.34; participants = 432; studies = 8; I2 = 0%; very low quality evidence), long-term recurrence (HR 0.95, 95% CI 0.70 to 1.30; participants = 162; studies = 4; very low quality evidence), adverse events within three months (laparoscopic gastrectomy (204/268: adjusted proportion = 16.1%) versus open gastrectomy (253/1222: 20.7%) (RR 0.78, 95% CI 0.60 to 1.01; participants = 2490; studies = 11; I2 = 38%; very low quality evidence), quantity of perioperative blood transfused (SMD 0.05, 95% CI -0.27 to 0.38; participants = 143; studies = 2; I2 = 0%; very low quality evidence), length of hospital stay (MD -1.82 days, 95% CI -3.72 to 0.07; participants = 319; studies = 6; I2 = 83%; very low quality evidence), and number of lymph nodes harvested (MD -0.63, 95% CI -1.51 to 0.25; participants = 472; studies = 9; I2 = 40%; very low quality evidence) were imprecise. There was no alteration in the interpretation of the results in any of the subgroups. Based on low quality evidence, there is no difference in short-term mortality between laparoscopic and open gastrectomy. Based on very low quality evidence, there is no evidence for any differences in short-term or long-term outcomes between laparoscopic and open gastrectomy. However, the data are sparse, and the confidence intervals were wide, suggesting that significant benefits or harms of laparoscopic gastrectomy cannot be ruled out. Several trials are currently being conducted and interim results of these trials have been included in this review. These trials need to perform intention-to-treat analysis to ensure that the results are reliable and report the results according to the CONSORT Statement.
From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects. Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.
This update identified one additional study for inclusion, adding data for 2305 participants. This addition more than doubled the overall number of patients eligible for the review. In total, we included four randomised controlled trials (RCTs) with a total of 4187 eligible participants. All studies compared warfarin with aspirin. One RCT additionally compared warfarin with clopidogrel. All included RCTs studied patients with heart failure with reduced ejection fraction. Analysis of all outcomes for warfarin versus aspirin was based on 3663 patients from four RCTs. All-cause mortality was similar for warfarin and aspirin (RR 1.00, 95% CI 0.89 to 1.13; 4 studies; 3663 participants; moderate quality evidence). Oral anticoagulation was associated with a reduction in non-fatal cardiovascular events, which included non-fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism (RR 0.79, 95% CI 0.63 to 1.00; 4 studies; 3663 participants; moderate quality evidence). The rate of major bleeding events was twice as high in the warfarin groups (RR 2.00, 95% CI 1.44 to 2.78; 4 studies; 3663 participants; moderate quality evidence). We generally considered the risk of bias of the included studies to be low. Analysis of warfarin versus clopidogrel was based on a single RCT (N = 1064). All-cause mortality was similar for warfarin and clopidogrel (RR 0.93, 95% CI 0.72 to 1.21; 1 study; 1064 participants; low quality evidence). There were similar rates of non-fatal cardiovascular events (RR 0.85, 95% CI 0.50 to 1.45; 1 study; 1064 participants; low quality evidence). The rate of major bleeding events was 2.5 times higher in the warfarin group (RR 2.47, 95% CI 1.24 to 4.91; 1 study; 1064 participants; low quality evidence). Risk of bias for this study can be summarised as low. There is evidence from RCTs to suggest that neither oral anticoagulation with warfarin or platelet inhibition with aspirin is better for mortality in systolic heart failure with sinus rhythm (high quality of the evidence for all-cause mortality and moderate quality of the evidence for non-fatal cardiovascular events and major bleeding events). Treatment with warfarin was associated with a 20% reduction in non-fatal cardiovascular events but a twofold higher risk of major bleeding complications (high quality of the evidence). We saw a similar pattern of results for the warfarin versus clopidogrel comparison (low quality of the evidence). At present, there are no data on the role of oral anticoagulation versus antiplatelet agents in heart failure with preserved ejection fraction with sinus rhythm. Also, there were no data from RCTs on the utility of non-vitamin K antagonist oral anticoagulants compared to antiplatelet agents in heart failure with sinus rhythm.
This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36+6 weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias. All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias. Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers) DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)). No studies reported on 'Death or neurodevelopmental impairment' in the early years'. DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty). DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty). Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty). We identified no important heterogeneity in subgroup or sensitivity analyses. Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers) There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision. Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers) There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty). Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM. The nine new reports awaiting further classification may alter the conclusions of the review once assessed.
We identified three trials in adult dialysis patients (n = 117). There were insufficient data for most outcomes for meta-analysis. In all three trials acidosis improved in the intervention group though there was variation in achieved bicarbonate level. There was no evidence of effect on blood pressure or sodium levels. Some measures of nutritional status/protein metabolism (e.g. SGA, NP NA) were significantly improved by correction in the one trial that looked in these in detail. There was heterogeneity of the effect on serum albumin in two trials. Serum PTH fell significantly in the two trials that estimated this, with no significant effect on calcium or phosphate though both fell after correction. Complex bone markers were assessed in one study, with some evidence for a reduction in bone turnover in those with initial high bone turnover and an increase in low turnover patients. The studies were underpowered to assess clinical outcomes, in the one study that did there was some evidence for a reduction in hospitalisation after correction. The evidence for the benefits and risks of correcting metabolic acidosis is very limited with no RCTs in pre-ESRD patients, none in children, and only three small trials in dialysis patients. These trials suggest there may be some beneficial effects on both protein and bone metabolism but the trials were underpowered to provide robust evidence.
No new studies were found for inclusion in this update from the latest searches. We included eight trials (1644 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10; 4 studies, 899 participants; moderate-certainly evidence) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17; 3 studies, 761 participants; moderate-certainly evidence). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups. There is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.
We identified 51 trials, including 10 cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 50 trials included a total of 84,336 participants. Twenty-four trials were in populations categorized as high burden, including nine trials in children selected because they were helminth-stool positive; 18 with intermediate burden; and nine as low burden. First or single dose of deworming drugs Fourteen trials reported on weight after a single dose of deworming drugs (4970 participants, 14 RCTs). The effects were variable. There was little or no effect in studies conducted in low and intermediate worm burden groups. In the high-burden group, there was little or no effect in most studies, except for a large effect detected from one study area in Kenya reported in two trials carried out over 30 years ago. These trials result in qualitative heterogeneity and uncertainty in the meta-analysis across all studies (I2 statistic = 90%), with GRADE assessment assessed as very low-certainty, which means we do not know if a first dose or single dose of deworming impacts on weight. For height, most studies showed little or no effect after a single dose, with one of the two trials in Kenya from 30 years ago showing a large average difference (2621 participants, 10 trials, low-certainty evidence). Single dose probably had no effect on average haemoglobin (MD 0.10 g/dL, 95% CI 0.03 lower to 0.22 higher; 1252 participants, five trials, moderate-certainty evidence), or on average cognition (1596 participants, five trials, low-certainty evidence). The data are insufficient to know if there is an effect on school attendance and performance (304 participants, one trial, low-certainty evidence), or on physical fitness (280 participants, three trials, very low-certainty evidence). No trials reported on mortality. Multiple doses of deworming drugs The effect of regularly treating children with deworming drugs given every three to six months on weight was reported in 18 trials, with follow-up times of between six months and three years; there was little or no effect on average weight in all but two trials, irrespective of worm prevalence-intensity. The two trials with large average weight gain included one in the high burden area in Kenya carried out over 30 years ago, and one study from India in a low prevalence area where subsequent studies in the same area did not show an effect. This heterogeneity causes uncertainty in any meta-analysis (I2 = 78%). Post-hoc analysis excluding trials published prior to 2000 gave an estimate of average difference in weight gain of 0.02 kg (95%CI from 0.04 kg loss to 0.08 gain, I2 = 0%). Thus we conclude that we do not know if repeated doses of deworming drugs impact on average weight, with a fewer older studies showing large gains, and studies since 2000 showing little or no average gain. Regular treatment probably had little or no effect on the following parameters: average height (MD 0.02 cm higher, 95% CI 0.09 lower to 0.13 cm higher; 13,700 participants, 13 trials, moderate-certainty evidence); average haemoglobin (MD 0.01 g/dL lower; 95% CI 0.05 g/dL lower to 0.07 g/dL higher; 5498 participants, nine trials, moderate-certainty evidence); formal tests of cognition (35,394 participants, 8 trials, moderate-certainty evidence); school performance (34,967 participants, four trials, moderate-certainty evidence). The evidence assessing an effect on school attendance is inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 5% lower to 8% higher; 20,650 participants, three trials, very low-certainty evidence). No trials reported on physical fitness. No effect was shown on mortality (1,005,135 participants, three trials, low-certainty evidence). Public health programmes to regularly treat all children with deworming drugs do not appear to improve height, haemoglobin, cognition, school performance, or mortality. We do not know if there is an effect on school attendance, since the evidence is inconsistent and at risk of bias, and there is insufficient data on physical fitness. Studies conducted in two settings over 20 years ago showed large effects on weight gain, but this is not a finding in more recent, larger studies. We would caution against selecting only the evidence from these older studies as a rationale for contemporary mass treatment programmes as this ignores the recent studies that have not shown benefit. The conclusions of the 2015 edition have not changed in this update.
Two small randomised controlled trials, involving a total of 80 participants with simple elbow dislocations, were included. Both trials were methodologically flawed and potentially biased. One trial, involving 50 participants, compared early mobilisation at three days post reduction versus cast immobilisation. At one year follow-up, the recovery of range of motion appeared better in the early mobilisation group (e.g. participants with incomplete recovery of extension: 1/24 versus 5/26; risk ratio 0.22, 95% confidence interval 0.03 to 1.72). However, the results were not statistically significant. There were no reports of instability or recurrence. One person in each group had residual pain at one year. The other trial, involving 30 participants, compared surgical repair of the torn ligaments versus conservative treatment (cast immobilisation for two weeks). At final follow-up (mean 27.5 months), there were no statistically significant differences between the two groups in the numbers of patients who considered their injured elbow to be inferior to their non-injured elbow (10/14 versus 7/14; RR 1.43, 95% CI 0.77 to 2.66) or in other patient complaints about their elbow such as weakness, pain or weather-related discomfort. There were no reports of instability or recurrence. There were no statistically significant differences between the two groups in range of motion of the elbow (extension, flexion, pronation, and supination) or grip strength at follow-up. No participants had neurological disturbances of the hand but two surgical group participants had recurrent dislocation of the ulnar nerve (no other details provided). One person in each group had radiologically detected myositis ossificans (bone formation within muscles following injury). There is insufficient evidence from randomised controlled trials to determine which method of treatment is the most appropriate for simple dislocations of the elbow in adults. Although weak and inconclusive, the available evidence from a trial comparing surgery versus conservative treatment does not suggest that the surgical repair of elbow ligaments for simple elbow dislocation improves long-term function. Future research should focus on questions relating to non-surgical treatment, such as the duration of immobilisation.
No new trials were identified in the search for this review update. In total five trials involving 365 participants were included in this review. All trials compared Padma 28 with placebo for at least 16 weeks of follow-up. Pain-free and maximum walking distances both increased significantly in the groups treated with Padma 28, with no significant change in the placebo group. In general, the studies presented results comparing the treatment arms before and after treatment but made no comparisons between the Padma 28 and placebo groups. Pooled data of maximum walking distance after treatment with Padma 28 and placebo from two studies (193 participants) indicated a higher maximum walking distance (mean difference (MD) 95.97 m, 95% confidence interval (CI) 79.07 m to 112.88 m, P < 0.00001, very low quality evidence) in the Padma 28 group compared with placebo. The clinical importance of these observed changes in walking distance is unclear as no quality of life data were reported. There was no effect on ankle brachial index (ABI): change in ABI values between baseline and six months follow up MD -0.01, 95% CI -0.07 to 0.05, 1 study, 56 participants, P = 0.72, very low quality evidence). Mild side effects, especially gastrointestinal discomfort, tiredness and skin eruption, were reported but this outcome was not different between the Padma 28 and placebo groups (odds ratio 1.09, 95% CI 0.42 to 2.83, four studies, 231 participants, P = 0.86, very low quality evidence). Some evidence exists from individual trials to suggest that Padma 28 may be effective in increasing walking distances, at least in the short term (four months), in people with IC. Side effects do not appear to be a problem. However, the longer term effects of treatment are unknown and the clinical significance of the improvements in walking distance are questionable. Moreover, the quality of the evidence is limited by the small sample size of the available trials, limited reporting of statistical analyses that compared treatment groups, and relatively high withdrawal rates that were linked to the outcome. That is, patients were withdrawn if they failed to improve walking distance. There was also evidence of publication bias. We therefore feel there is currently insufficient evidence to draw conclusions regards the effectiveness of Padma 28 in the routine management of IC. Further well-designed research would be required to determine the true effects of this herbal preparation.
We included 14 trials in this review, with 1152 randomised participants. The studies were published between 1990 and 2009 and were conducted in the United Kingdom, Egypt, Saudi Arabia, and the United States. The age of participants ranged from 2 to 40 years. Three studies were at an overall high risk of bias, seven studies were at an unclear risk of bias, and we judged four studies to be at low risk of bias. The clinical heterogeneity of the included studies precluded pooling of studies in terms of method of administration of LA (e.g., intraligamental injection, infiltration injection, or topical delivery) and variation in the use of supplementary analgesics and follow-up time. Of the seven studies where administration of LA was by infiltration injection, six studies (very low-quality body of evidence, 542 participants analysed, 1 study had overall high risk of bias, 4 studies had overall unclear risk of bias, 1 study had overall low risk of bias) measured postoperative pain. The results were equivocal. There was a decrease in bleeding and increase in soft tissue damage in the LA groups, but we did not judge this to be clinically significant. In the 2 studies where administration of LA was by intraligamental injection, there was no difference in mean pain scores, and they did not report any soft tissue damage (very low-quality body of evidence, 115 participants analysed, 1 study had overall high risk of bias, 1 study had overall unclear risk of bias). One 3-armed study (very low-quality body of evidence, 54 participants analysed, overall high risk of bias) compared the effects of intraligamental and infiltration LA injection with no treatment. There was no evidence of a mean difference in pain, distress, or postoperative anxiety among the three groups. Four studies (very low-quality body of evidence, 343 participants analysed, 2 studies had overall low risk of bias, 2 studies had overall unclear risk of bias) evaluated the effects of topical LA compared with no treatment or placebo. One study (overall unclear risk of bias) with a no-treatment comparator reported lower mean pain in the LA group; all other studies reported no difference in mean pain scores. Two studies reported on bleeding (overall unclear risk of bias): One study reported a clinically insignificant increase in bleeding with no treatment; the other reported no difference. None of the studies reported on participant or child satisfaction. In this review, it was difficult to reach firm conclusions as to the benefit of using local anaesthetic for dental treatment under general anaesthesia. The information reported in the included studies was comprehensive and applicable to the review question, but ultimately it was not sufficient to address the objective of the review. We were unable to pool the included studies in a meta-analysis because of substantial variation in outcome measures, interventions, and treatment types. The use of supplementary analgesia further obscured the effect of local anaesthetics. Based on the literature review and the results of this review, we recommend further randomised controlled trials that minimise bias through adequate allocation concealment and blinding of participants and assessors, and assess the effect of intraoperative local anaesthetic on the volume and type of anaesthetic used and on the cardiovascular system in participants receiving supplementary analgesics as well. Researchers should give consideration to the impact of any changes on the health and well-being of the participant and report baseline measures of pain or distress, or both, and preoperative anxiety.
The following statistically significant treatment effects in favour of propentofylline are reported.  Cognition at 3, 6 and 12 months including MMSE at 12 months. [MD 1.2, 95%CI 0.12 to 2.28, P=0.03]  Severity of dementia at 3, 6 and 12 months including CGI at 12 months [MD -0.21, 95%CI -0.39 to -0.03, P=0.03].  Activities of Daily Living (NAB) at 6 and 12 months [MD -1.20, 95%CI -2.22 to -0.18, P=0.02].  Global Assessment (CGI) at 3 months [MD -0.48, 95% CI -0.75 to -0.21, P=0.0006], but not at later times.  Tolerability  There were minimal data on adverse effects and drop-outs. There were a statistically significant treatment effects in favour of placebo at 12 months, for the number of dropouts [OR=1.43, 95%CI 1.04 to 1.90, P=0.03]. There is limited evidence that propentofylline might benefit cognition, global function and activities of daily living of people with Alzheimer's disease and/or vascular dementia. The meta-analyses reported here are far from satisfactory as a summary of the efficacy of propentofylline, considering the unpublished information on another 1200 patients in randomized trials that exists. Unfortunately Aventis has been unwilling to correspond with the authors, significantly limiting the scope of this review.
We included 11 trials (6 trials in high-income countries and 5 multicentre trials in high-, middle-, and low-income countries) involving 17,123 children aged 6 months to 6 years. Eight trials recruited participants from a healthcare setting. Ten trials (and all four trials that contributed to the primary outcome) declared funding from vaccine manufacturers. Four trials reported adequate allocation concealment, and 10 trials reported adequate blinding of participants and personnel. Attrition was low for eight trials included in the analysis. The primary outcome showed a small reduction in at least one episode of AOM over at least six months of follow-up (4 trials, 3134 children; RR 0.84, 95% CI 0.69 to 1.02; RD -0.04, 95% CI -0.08 to -0.00; NNTB 25, 95% CI 12.5 to 100; low-quality evidence). The subgroup analyses (i.e. number of courses and types of vaccine administered) showed no differences. There was a reduction in the use of antibiotics in vaccinated children (2 trials, 1223 children; RR 0.70, 95% CI 0.59 to 0.83; RD -0.11, 95% CI -0.16 to -0.06; moderate-quality evidence). We were unable to demonstrate whether there was any difference in the utilisation of health care. The use of influenza vaccine resulted in a significant increase in fever (7 trials, 10,615 children; RR 1.15, 95% CI 1.06 to 1.24; RD 0.02, 95% CI 0.00 to 0.04; low-quality evidence), rhinorrhoea (6 trials, 10,563 children; RR 1.17, 95% CI 1.07 to 1.29; RD 0.09, 95% CI 0.01 to 0.16; low-quality evidence), but no difference in pharyngitis. No major adverse events were reported. Differing from the protocol, the original publication of the review included a subgroup analysis of AOM episodes by season, and the secondary outcome ‘types of influenza vaccine’ was changed to a subgroup analysis. For this update, we removed the subgroup analyses for trial setting, season, and utilisation of health care due to the small number of trials involved. We removed Belshe 2000 from primary and secondary outcomes (courses of vaccine and types of vaccine) because it reported episodes of AOM per person. We did not perform a subgroup analysis by type of adverse event. We have reported each type of adverse event as a separate analysis. Influenza vaccine results in a small reduction in AOM. The observed reduction in the use of antibiotics needs to be considered in light of current recommended practices aimed at avoiding antibiotic overuse. Safety data from these trials were limited. The benefits may not justify the use of influenza vaccine without taking into account the vaccine efficacy in reducing influenza and safety data. We judged the quality of the evidence to be low to moderate. Additional research is needed.
We included 48 RCTs in the review. Of these, we assessed one as at low risk of bias, 12 as at high risk of bias and 35 as at unclear risk of bias. The results indicated a greater reduction in gingival recession for subepithelial connective tissue grafts (SCTG) + coronally advanced flap (CAF) compared to guided tissue regeneration with resorbable membranes (GTR rm) + CAF (MD -0.37 mm; 95% CI -0.60 to -0.13, P = 0.002; 3 studies; 98 participants; low-quality evidence). There was insufficient evidence of a difference in gingival recession reduction between acellular dermal matrix grafts (ADMG) + CAF and SCTG + CAF or between enamel matrix protein (EMP) + CAF and SCTG + CAF. Regarding clinical attachment level changes, GTR rm + CAF promoted additional gains compared to SCTG + CAF (MD 0.35; 95% CI 0.06 to 0.63, P = 0.02; 3 studies; 98 participants; low-quality evidence) but there was insufficient evidence of a difference between ADMG + CAF and SCTG + CAF or between EMP + CAF and SCTG + CAF. Greater gains in the keratinized tissue were found for SCTG + CAF when compared to EMP + CAF (MD -1.06 mm; 95% CI -1.36 to -0.76, P < 0.00001; 2 studies; 62 participants; low-quality evidence), and SCTG + CAF when compared to GTR rm + CAF (MD -1.77 mm; 95% CI -2.66 to -0.89, P < 0.0001; 3 studies; 98 participants; very low-quality evidence). There was insufficient evidence of a difference in keratinized tissue gain between ADMG + CAF and SCTG + CAF. Few data exist on aesthetic condition change related to patients' opinion and patients' preference for a specific procedure. Subepithelial connective tissue grafts, coronally advanced flap alone or associated with other biomaterial and guided tissue regeneration may be used as root coverage procedures for treating localised or multiple recession-type defects. The available evidence base indicates that in cases where both root coverage and gain in the width of keratinized tissue are expected, the use of subepithelial connective tissue grafts shows a slight improvement in outcome. There is also some weak evidence suggesting that acellular dermal matrix grafts appear as the soft tissue substitute that may provide the most similar outcomes to those achieved by subepithelial connective tissue grafts. RCTs are necessary to identify possible factors associated with the prognosis of each RCPPS procedure. The potential impact of bias on these outcomes is unclear.
Nineteen eligible studies involving 4096 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 to 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The risk of CLD in survivors at term equivalent gestational age was significantly reduced with the use of HFOV but this effect was inconsistent across studies, even after the meta-analysis was restricted to studies that applied a high lung volume strategy with HFOV. Subgroup analysis by HFOV strategy showed a similar effect in trials with a more strict lung volume recruitment strategy, targeting a very low fraction of inspired oxygen (FiO2), and trials with a less strict lung volume recruitment strategy and with a somewhat higher or unspecified target FiO2. Subgroup analyses by age at randomisation, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy (lung protective or not) could not sufficiently explain the heterogeneity. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial emphysema, occurred more frequently in the HFOV group, whereas the risk of severe retinopathy of prematurity was significantly reduced. Although in some studies an increased risk of severe grade intracranial haemorrhage and periventricular leukomalacia was found, the overall meta-analysis revealed no significant differences in effect between HFOV and CV. The short-term neurological morbidity with HFOV was only found in the subgroup of two trials not using a high volume strategy with HFOV. Most trials did not find a significant difference in long-term neurodevelopmental outcome, although one recent trial showed a significant reduction in the risk of cerebral palsy and poor mental development. There is evidence that the use of elective HFOV compared with CV results in a small reduction in the risk of CLD, but the evidence is weakened by the inconsistency of this effect across trials. Probably many factors, both related to the intervention itself as well as to the individual patient, interact in complex ways. In addition, the benefit could be counteracted by an increased risk of acute air leak. Adverse effects on short-term neurological outcomes have been observed in some studies but these effects are not significant overall. Most trials reporting long-term outcome have not identified any difference.
The evidence from five trials, involving 952 participants, does not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on the incidence of atopic eczema during the first 18 months of life. Data on allergic rhinitis or conjunctivitis, or both, and urticaria are limited to a single trial each and are insufficient to draw meaningful inferences. Longer-term atopic outcomes have not been reported. The restricted diet during pregnancy was associated with a slightly but statistically significantly lower mean gestational weight gain, a non-significantly higher risk of preterm birth, and a non-significant reduction in mean birthweight. The evidence from two trials, involving 523 participants, did not observe a significant protective effect of maternal antigen avoidance during lactation on the incidence of atopic eczema during the first 18 months or on positive skin-prick tests to cow milk, egg, or peanut antigen at one, two, or seven years. One crossover trial involving 17 lactating mothers of infants with established atopic eczema found that maternal dietary antigen avoidance was associated with a non-significant reduction in eczema severity. Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal or fetal nutrition, or both. Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed. Dietary antigen avoidance by lactating mothers of infants with atopic eczema may reduce the severity of the eczema, but larger trials are needed.
Five trials, which together enrolled 4965 infants, were eligible for inclusion. The investigators of these five trials had prospectively planned to combine their data as part of the NeOProM (Neonatal Oxygen Prospective Meta-analysis) Collaboration. We graded the quality of evidence as high for the key outcomes of death, major disability, the composite of death or major disability, and necrotising enterocolitis; and as moderate for blindness and retinopathy of prematurity requiring treatment. When an aligned definition of major disability was used, there was no significant difference in the composite primary outcome of death or major disability in extremely preterm infants when targeting a lower (SpO₂ 85% to 89%) versus a higher (SpO₂ 91% to 95%) oxygen saturation range (typical RR 1.04, 95% confidence interval (CI) 0.98 to 1.10; typical RD 0.02, 95% CI -0.01 to 0.05; 5 trials, 4754 infants) (high-quality evidence). Compared with a higher target range, a lower target range significantly increased the incidence of death at 18 to 24 months corrected age (typical RR 1.16, 95% CI 1.03 to 1.31; typical RD 0.03, 95% CI 0.01 to 0.05; 5 trials, 4873 infants) (high-quality evidence) and necrotising enterocolitis (typical RR 1.24, 95% 1.05 to 1.47; typical RD 0.02, 95% CI 0.01 to 0.04; 5 trials, 4929 infants; I² = 0%) (high-quality evidence). Targeting the lower range significantly decreased the incidence of retinopathy of prematurity requiring treatment (typical RR 0.72, 95% CI 0.61 to 0.85; typical RD -0.04, 95% CI -0.06 to -0.02; 5 trials, 4089 infants; I² = 69%) (moderate-quality evidence). There were no significant differences between the two treatment groups for major disability including blindness, severe hearing loss, cerebral palsy, or other important neonatal morbidities. A subgroup analysis of major outcomes by type of oximeter calibration software (original versus revised) found a significant difference in the treatment effect between the two software types for death (interaction P = 0.03), with a significantly larger treatment effect seen for those infants using the revised algorithm (typical RR 1.38, 95% CI 1.13 to 1.68; typical RD 0.06, 95% CI 0.01 to 0.10; 3 trials, 1716 infants). There were no other important differences in treatment effect shown by the subgroup analyses using the currently available data. In extremely preterm infants, targeting lower (85% to 89%) SpO₂ compared to higher (91% to 95%) SpO₂ had no significant effect on the composite outcome of death or major disability or on major disability alone, including blindness, but increased the average risk of mortality by 28 per 1000 infants treated. The trade-offs between the benefits and harms of the different oxygen saturation target ranges may need to be assessed within local settings (e.g. alarm limit settings, staffing, baseline outcome risks) when deciding on oxygen saturation targeting policies.
Five studies, 212 participants, were included. PAN showed improvement of symptoms (RR 1.35; 95% CI 1.01 to 1.79), of the amount and duration of sedative medication and of psychomotor function (WMD -8.71; 95% CI -13.71 to -3.71). At one hour post intervention, no significant differences were found for depression (WMD -2.40; 95% CI -8.70 to 3.89) and anxiety (WMD -3.70; 95% CI -10.53 to 3.12). None of the included studies reported any significant adverse effects of any treatment. Results indicate that PAN may be an effective treatment of the mild to moderate alcoholic withdrawal state. The rapidity of the therapeutic effect of PAN therapy coupled with the minimal sedative requirements, may enable patients to enter the psychological treatment phase more quickly than those on sedative regimens, accelerating the patients recovery. Our review does not provide strong evidence due to the small sample sizes of the included trials. Neither does the review indicate any causes for concern that PAN is more harmful than the benzodiazepines. Clinicians wishing to use PAN may initially wish to do so within trial settings.  Further high quality trials should be done to confirm these findings and to investigate whether the PAN therapy has fewer adverse effects than other treatments for the alcohol withdrawal states. Studies to investigate the possible cost-effectiveness of PAN by reducing costly hospital admissions and decreasing post administration supervision also need to be performed.
We identified two trials (of high risk of bias) involving 152 patients randomised to gastrojejunostomy (80 patients) and no gastrojejunostomy (72 patients). In both trials, patients were found to be unresectable during exploratory laparotomy. Most of the patients also underwent biliary-enteric drainage. There was no evidence of difference in the overall survival (HR 1.02; 95% CI 0.84 to 1.25), peri-operative mortality or morbidity, quality of life, or hospital stay (MD 0.97 days; 95%CI -0.18 to 2.12) between the two groups. The proportion of patients who developed long-term gastric outlet obstruction was significantly lower in the prophylactic gastrojejunostomy group (2/80; 2.5%) compared with no gastrojejunostomy group (20/72; 27.8%) (RR 0.10; 95%CI 0.03 to 0.37). The operating time was significantly longer in the gastrojejunostomy group compared with no gastrojejunostomy group (MD 45.00 minutes; 95%CI 21.39 to 68.61). Routine prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary cancer undergoing exploratory laparotomy (with or without hepaticojejunostomy).
Four trials met the inclusion criteria. Three had losses to follow-up > 20% and only one provided an adequate description of allocation concealment. Three included a treatment population (0.5 to 2 g/day of strontium ranelate) and one a prevention population (0.125, 0.5 and 1 g/day). A 37% reduction in vertebral fractures (RR 0.63, 95% CI 0.56, 0.71), and a 14% reduction in non-vertebral fractures with the upper boundary of the confidence interval approaching one (RR 0.86, 95% CI 0.75, 0.98), were demonstrated over three years with 2 g of strontium ranelate daily in a treatment population. An increase in BMD was shown at all sites after two to three years of treatment in both populations. Lower doses of strontium ranelate were superior to placebo and the highest dose demonstrated the greatest reduction in vertebral fractures and increase in BMD. An increased risk of diarrhea with 2 g of strontium ranelate daily was found; however, adverse events did not affect the risk of discontinuing treatment nor did it increase the risk of serious side effects, gastritis or death. Additional data suggests that the risk of vascular and nervous system side-effects is increased with taking 2 g of strontium ranelate daily over three to four years. There is silver level evidence (www.cochranemsk.org) to support the efficacy of strontium ranelate for the reduction of fractures (vertebral and to a lesser extent, non-vertebral) in postmenopausal osteoporotic women and an increase in BMD in postmenopausal women with/without osteoporosis. Diarrhea may occur, however, adverse events leading to study withdrawal were not significantly increased. Potential vascular and neurological side-effects need to be further explored.
Seven eligible studies were identified from a total of 2314 references. One new study with 600 patients was added to the original review. Four trials compared IABP to standard treatment and three to other percutaneous left assist devices (LVAD). Data from a total of 790 patients with acute myocardial infarction and cardiogenic shock were included in the updated meta-analysis: 406 patients were treated with IABP and 384 patients served as controls; 339 patients were treated without assisting devices and 45 patients with other LVAD. The HR for all-cause 30-day mortality of 0.95 (95% CI 0.76 to 1.19) provided no evidence for a survival benefit. Different non-fatal cardiovascular events were reported in five trials. During hospitalisation, 11 and 4 out of 364 patients from the intervention groups suffered from reinfarction or stroke, respectively. Altogether 5 out of 363 patients from the control group suffered from reinfarction or stroke. Reocclusion was treated with subsequent re-revascularization in 6 out of 352 patients from the intervention group and 13 out of 353 patients of the control group. The high incidence of complications such as moderate and severe bleeding or infection in the control groups has to be attributed to interventions with other LVAD. Possible reasons for bias were more frequent in small studies with high cross-over rates, early stopping and the inclusion of patients with IABP at randomisation. Available evidence suggests that IABP may have a beneficial effect on some haemodynamic parameters. However, this did not result in survival benefits so there is no convincing randomised data to support the use of IABP in infarct-related cardiogenic shock.
We included in this review eight RCTs conducted in an outpatient setting, in Italy, the United Kingdom, the United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate versus placebo, and four studies compared methotrexate versus other DMARDs. The average age of participants varied across studies (26 to 52 years), as did the average duration of psoriatic arthritis (one to nine years). Doses of methotrexate varied from 7.5 mg to 25 mg orally per week, but most studies administered approximately 15 mg or less orally per week. Risk of bias was generally unclear or high across most domains for all studies. We considered only one study to have low risk of selection and detection bias. The main study informing results of the primary comparison (methotrexate vs placebo up to six months) was at low risk of bias for all domains except attrition bias and reporting bias. We restricted reporting of results to the comparison of methotrexate versus placebo for up to six months. Low-quality evidence (downgraded due to bias and imprecision) from a single study (221 participants; methotrexate dose 15 mg orally or less per week) informed results for disease response, function, and disease activity. Disease response, measured by the proportion who responded to treatment according to PsARC (response indicates improvement), was 41/109 in the methotrexate group and 24/112 in the placebo group (risk ratio (RR) 1.76, 95% confidence interval (CI) 1.14 to 2.70). This equates to an absolute difference of 16% more responders with methotrexate (4% more to 28% more), and a number needed to treat for an additional beneficial outcome (NNTB) of 6 (95% CI 5 to 25). Mean function, measured by the HAQ (scale 0 to 3; 0 meaning no functional impairment; minimum clinically important difference 0.22), was 1.0 points with placebo and 0.3 points better (95% 0.51 better to 0.09 better) with methotrexate; absolute improvement was 10% (3% better to 17% better), and relative improvement 30% (9% better to 51% better). Mean disease activity as measured by the DAS28-ESR (scale of 0 to 10; lower score means lower disease activity; minimum clinically important difference unknown) was 3.8 points in the methotrexate group and 4.06 points in the placebo group; mean difference was -0.26 points (95% CI -0.65 to 0.13); absolute improvement was 3% (7% better to 1% worse), and relative improvement 6% (16% better to 3% worse). Low-quality evidence (downgraded due to risk of bias and imprecision) from three studies (n = 293) informed our results for serious adverse events and withdrawals due to adverse events. Due to low event rates, we are uncertain if methotrexate results show increased risk of serious adverse events or withdrawals due to adverse events compared to placebo. Results show 1/141 serious adverse events in the methotrexate group and 4/152 in the placebo group: RR 0.26 (95% CI 0.03 to 2.26); absolute difference was 2% fewer events with methotrexate (5% fewer to 1% more). In all, 9/141 withdrawals in the methotrexate group were due to adverse events and 7/152 in the placebo group: RR 1.32 (95% CI 0.51 to 3.42); absolute difference was 1% more withdrawals (4% fewer to 6% more). One study measured health-related quality of life but did not report these results. No study measured radiographic progression. Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for six months; however we are uncertain if it is more harmful. Effects of methotrexate on health-related quality of life, radiographic progression, enthesitis, dactylitis, and fatigue; its benefits beyond six months; and effects of higher-dose methotrexate have not been measured or reported in a randomised placebo-controlled trial.
One non-randomised study met our inclusion criteria. It analysed retrospective data for 194 women with stage IIIC advanced epithelial ovarian cancer who underwent either ultra-radical (extensive) or standard surgery and reported disease specific overall survival and perioperative mortality. Multivariate analysis, adjusted for prognostic factors, identified better disease specific survival among women receiving ultra-radical surgery, although this was not statistically significant (Hazard ratio (HR) = 0.64, 95% confidence interval (CI): 0.40 to 1.04). In a subset of 144 women with carcinomatosis, those who underwent ultra-radical surgery had significantly better disease specific survival than women who underwent standard surgery (adjusted HR = 0.64, 95% CI 0.41 to 0.98). Progression-free survival and quality of life (QoL) were not reported and adverse events were incompletely documented. The study was at high risk of bias. We found only low quality evidence comparing ultra-radical and standard surgery in women with advanced ovarian cancer and carcinomatosis. The evidence suggested that ultra-radical surgery may result in better survival.  It was unclear whether there were any differences in progression-free survival, QoL and morbidity between the two groups. The cost-effectiveness of this intervention has not been investigated. We are, therefore, unable to reach definite conclusions about the relative benefits and adverse effects of the two types of surgery. In order to determine the role of ultra-radical surgery in the management of advanced stage ovarian cancer, a sufficiently powered randomised controlled trial comparing ultra-radical and standard surgery or well-designed non-randomised studies would be required.
Nineteen randomised trials on banding ligation versus non-selective beta-blockers for primary prevention in oesophageal varices were included. Most trials specified that only patients with large or high-risk oesophageal varices were included. Bias control was unclear in most trials. In total, 176 of 731 (24%) of the patients randomised to banding ligation and 177 of 773 (23%) of patients randomised to non-selective beta-blockers died. The difference was not statistically significant in a random-effects meta-analysis (RR 1.09; 95% CI 0.92 to 1.30; I2 = 0%). There was no evidence of bias or small study effects in regression analysis (Egger's test P = 0.997). Trial sequential analysis showed that the heterogeneity-adjusted low-bias trial relative risk estimate required an information size of 3211 patients, that none of the interventions showed superiority, and that the limits of futility have not been reached. When all trials were included, banding ligation reduced upper gastrointestinal bleeding and variceal bleeding compared with non-selective beta-blockers (RR 0.69; 95% CI 0.52 to 0.91; I2 = 19% and RR 0.67; 95% CI 0.46 to 0.98; I2 = 31% respectively). The beneficial effect of banding ligation on bleeding was not confirmed in subgroup analyses of trials with adequate randomisation or full paper articles. Bleeding-related mortality was not different in the two intervention arms (29/567 (5.1%) versus 37/585 (6.3%); RR 0.85; 95% CI 0.53 to 1.39; I2 = 0%). Both interventions were associated with adverse events. This review found a beneficial effect of banding ligation on primary prevention of upper gastrointestinal bleeding in patient with oesophageal varices. The effect on bleeding did not reduce mortality. Additional evidence is needed to determine whether our results reflect that non-selective beta-blockers have other beneficial effects than on bleeding.
Three trials met the inclusion criteria, with a total of 107 participants in three different health-care settings: A USA veterans administration nursing home; a geriatric centre in Israel; and a community nursing service in Hong Kong. Data were available for three of the pre-stated comparisons. Priefer and colleagues evaluated different time intervals between catheter replacement (n = 17); Firestein and colleagues evaluated the use of antibiotic prophylaxis at the time of replacement (n = 70); and Cheung and colleagues compared two different types of cleaning solutions (n = 20). All the included trials were small and under-powered. The reporting of the trials was inadequate and as a result, risk of bias assessment was judged to be unclear for the majority of the domains in two out of the three trials. There was insufficient evidence to indicate that (i) there was a lower incidence of symptomatic UTI in people whose catheter was changed both monthly and when clinically indicated (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.13 to 0.95; very low quality evidence) compared to only when clinically indicated, (ii) there was not enough evidence to assess the effect of antibiotic prophylaxis on reducing: positive urine cultures at 7 days (RR 0.91, 95% CI 0.79 to 1.04); infection (RR 1.41, 95% CI 0.55 to 3.65); or death (RR 2.12, 95% CI 0.20 to 22.30; very low quality evidence), (iii) there was no statistically significant difference in the incidence of asymptomatic bacteruria at 7 days (RR 0.80, 95% CI 0.42 to 1.52) between people receiving water or chlorhexidine solution for periurethral cleansing at the time of catheter replacement. However, none of the 16 participants developed a symptomatic catheter-associated urinary tract infection (CAUTI) at day 14. The following outcomes were considered critical for decision-making and were also selected for the 'Summary of findings' table: (i) participant satisfaction, (ii) condition-specific quality of life, (iii) urinary tract trauma, and (iv) formal economic analysis. However, none of the trials reported these outcomes. None of the trials compared the following comparisons: (i) replacing catheter versus other policy e.g. washouts, (ii) replacing in the home environment versus clinical environment, (iii) clean versus aseptic technique for replacing catheter, (iv) lubricant A versus lubricant B or no lubricant, and (v) catheter user versus carer versus health professional performing the catheter replacement procedure. There is currently insufficient evidence to assess the value of different policies for replacing long-term urinary catheters on patient outcomes. In particular, there are a number of policies for which there are currently no trial data; and a number of important outcomes which have not been assessed, including patient satisfaction, quality of life, urinary tract trauma, and economic outcomes. There is an immediate need for rigorous, adequately powered randomised controlled trials which assess important clinical outcomes and abide by the principles and recommendations of the CONSORT statement.
Four trials involving 132 people were included. Two studies compared nasal mask with the Oracle oral mask and showed no significant difference in compliance at one month (mean difference (MD) 0.17 hours per night, 95%CI 0.54 to 0.87). There were also no significant differences in any of the physiological parameters (e.g. AHI, arousal index, minimum oxygen saturation), Epworth Sleepiness Scale (ESS), or symptoms of OSA. A single study comparing nasal mask with nasal pillows showed a significant difference in compliance when expressed as the percentage of days used in favour of nasal pillows (nasal pillows mean 94.1± SD 8.3%; nasal mask 85.7 ± 23.5%, P = 0.02), however there were no significant differences in the mean daily use for all days or when use was greater than 0 minutes per day. Nasal pillows were also associated with fewer overall adverse effects (P < 0.001) and greater interface satisfaction (P = 0.001). One study comparing nasal mask with face mask showed that compliance was significantly greater with use of a nasal mask (MD 1.0 hour per night,95% CI 0.3 to 1.8). Nasal mask was also associated with significantly lower ESS scores and was the preferred interface in almost all patients. Due to the limited number of studies available comparing various interface types, the optimum form of CPAP delivery interface remains unclear. The results of our review suggest that nasal pillows or the Oracle oral mask may be useful alternatives when a patient is unable to tolerate conventional nasal masks. The face mask can not be recommended as a first line interface, but may be considered if nasal obstruction or dryness limits the use of a nasal mask. Further randomised studies comparing the different forms of CPAP delivery interface now available for the treatment of OSA, in larger groups of patients and for longer durations, are required.
Forty nine studies (12,067 patients) were identified. Thirty eight compared ACEi with placebo, four compared AIIRA with placebo and seven compared ACEi and AIIRA directly. There was no significant difference in the risk of all-cause mortality for ACEi versus placebo (RR 0.91, 95% CI 0.71 to 1.17) and AIIRA versus placebo (RR 0.99, 95% CI 0.85 to 1.17). A subgroup analysis of studies using full-dose ACEi versus studies using half or less than half the maximum tolerable dose of ACEi showed a significant reduction in the risk of all-cause mortality with the use of full-dose ACEi (RR 0.78, 95% CI 0.61 to 0.98). Baseline mortality rates were similar in the ACEi and AIIRA studies. The effects of ACEi and AIIRA on renal outcomes (ESKD, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) were similarly beneficial. Reliable estimates of effect of ACEi versus AIIRA could not be obtained from the three studies in which they were compared directly because of their small sample size. Although the survival benefits of ACEi are known for patients with DKD, the relative effects on survival of ACEi with AIIRA are unknown due to the lack of adequate direct comparison studies. In placebo controlled studies, only ACEi (at the maximum tolerable dose, but not lower so-called renal doses) were found to significantly reduce the risk of all-cause mortality. Renal and toxicity profiles of these two classes of agents were not significantly different.
Three crossover studies (Korner 1978; Tuck 1982; Jirapaet 1993) were identified that compared a form of kinesthetic stimulation to control for the treatment of apnea of prematurity. No study reported a clinically important reduction (> 50%) in apnea. Using a lower threshold (> 25%), Korner 1978 reported less apnea and bradycardia in infants while on an oscillating water bed. Tuck 1982 demonstrated a reduction in frequency of apneas (> 12 seconds) associated with bradycardia (< 100 bpm), apneas associated with hypoxia (TcP02 < 50 mmHg), and apneas requiring stimulation in infants on a rocking bed. Individual patient data were not available from the author to determine if there was an important reduction in clinical apnea. No outcome could be extracted from the study using a 'vertical pulsating stimulus' by Jirapaet 1993 that was consistent with the definition of clinically important apnea. Jirapaet 1993 reported no infants required resuscitation or ventilation. Adverse events such as death, intraventricular hemorrhage and neurodevelopmental disability were not reported. There is insufficient evidence to recommend kinesthetic stimulation as treatment for clinically significant apnea of prematurity. Previous reviews have suggested that kinesthetic stimulation is not effective at preventing apnea of prematurity (Henderson-Smart 2005) and is not as effective as theophylline at treating clinically significant apnea of prematurity (Osborn 2005).
Only one trial with only eight participants met all the inclusion criteria and provided the primary outcome measure for this review. In this trial, four participants treated with neurotrophin-3 had more improvement after six months on the Neuropathy Impairment Score, mean difference -9.50 (95% CI -13.77 to -5.23), than those four treated with placebo. Small trials of exercise training, creatine monohydrate, orthoses and purified bovine brain ganglioside injections (Cronassial) showed no significant benefit in people with genetically undefined CMT1 or CMT2. Small trials of exercise, creatine, purified brain gangliosides, and orthoses have been performed. None showed significant benefit. A very small trial of neurotrophin-3 showed possible minor benefit which needs to be replicated in a larger trial. None of the two trials were large enough to detect moderate benefit or harm. Larger RCTs are needed for any form of pharmacological intervention as well as as for any form of physical intervention. Outcome measures should include a validated composite scale such as the Charcot-Marie-Tooth neuropathy scale.
In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age. Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference. Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD. MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence. Maintenance therapy Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.
Sixteen studies (enrolling 809 children) were identified. Risk of bias assessment indicated that study quality was poor or poorly reported with only four and five studies respectively reporting adequate allocation concealment or blinding of study participants and investigators. Treatment with rhGH (28 IU/m²/wk) compared with placebo or no specific therapy resulted in a significant increase in height standard deviation score (HSDS) at one year (8 studies, 391 children: MD 0.82, 95% CI 0.56 to 1.07), and a significant increase in height velocity at six months (2 studies, 27 children: MD 2.85 cm/6 mo, 95% CI 2.22 to 3.48) and one year (7 studies, 287 children: MD 3.88 cm/y, 95% CI 3.32 to 4.44). Height velocity, though reduced, remained significantly greater than untreated children during the second year of therapy (1 study, 82 children: MD 2.30 cm/y, 95% CI 1.39 to 3.21). Compared to the 14 IU/m²/wk group, there was a 1.18 cm/y increase in height velocity in the 28 IU/m²/wk group (3 studies, 150 children: 1.18 cm/y, 95% CI 0.52 to 1.84) . The frequency of reported side effects of rhGH was generally similar to that of the control group. One year of 28 IU/m²/wk rhGH in children with CKD resulted in a 3.88 cm increase in height velocity above that of untreated patients. Studies were too short to determine if continuing treatment resulted in an increase in final adult height.
Out of 14,717 citations, only one study met the inclusion criteria. The included RCT recruited women and girl children who received post-exposure prophylaxis (PEP) after rape from sexual assault services in South Africa between August 2007 and May 2008. Participants (n (number) =274) were randomised into a telephone support (n=136) and control (n=138) group. Control group participants received usual care (an interactive information session) from the sexual assault service during the 28 days in which they had to take PEP, with no further contact from the study staff. Telephone support group participants received standard care and phone calls from a counsellor throughout the 28 days when they had to take PEP. Overall, adherence to PEP was not significantly (P=0.13) different between the intervention (38.2%) and control (31.9 %) groups. Also, the proportion of participants who read a pamphlet, did not return to collect medication or with a depression were not significantly different between the intervention and control groups (P=0.006, P=0.42, P=0.72 respectively). The proportion of participants who used a diary was significantly (P=0.001) higher in the intervention group (78.8%) versus the control group (69.9%). The study authors reported that there were no recorded adverse events. The RCT did not provide information about participants’ and providers’ evaluation outcomes, or economic outcomes. The study had a moderate risk of bias. We found only one RCT, with a moderate risk of bias, which showed that providing PEP support by phone calls did not result in higher adherence to PEP. However, the RCT was conducted in an upper-middle-income country with high HIV prevalence, on a high-risk population and the applicability of its results on other settings and contexts is unclear. There is a need for robust evidence from various settings on the effectiveness of using phone calls for providing PEP support and for other HIV prevention interventions.
We included 27 studies (3003 participants) that were followed up for a median of six months. Study interventions included alternative anticoagulant locking solutions (19 studies, 2216 patients), systemic agents (6 studies, 664 patients) and low or no dose heparin (2 studies, 123 patients). The most common comparison treatment was a locking solution of heparin 5000 IU/mL, used in 17 studies. No significant effect on catheter malfunction was observed for alternative anticoagulant locking solutions (RR 0.96, 95% CI 0.74 to 1.26), systemic agents (RR 0.59, 95% CI 0.28 to 1.23), or low or no dose heparin (RR 0.90, 95% CI 0.10 to 8.31). A significant reduction on incidence of catheter-related bacteraemia was observed for alternative anticoagulant locking solutions (RR 0.46, 95% CI 0.32 to 0.66) but not systemic agents (RR 2.41, 95% CI 0.89 to 6.55), and could not be assessed in reports of low or no dose heparin studies. No significant effect on all-cause mortality was observed for alternative anticoagulant locking solutions (RR 0.88, 95% CI 0.54 to 1.43) or systemic agents (RR 0.78, 95% CI 0.37 to 1.65), and was not reported in studies of low or no dose heparin. Bleeding events were only reported in eight studies, including only 2/5 studies of systemic warfarin, with no clear effect demonstrated (RR 1.43, 95% CI 0.86 to 2.39). For individual agents, recombinant tissue plasminogen (rt-PA) was the only locking solution shown to reduce catheter malfunction (RR 0.58, 95% CI 0.37 to 0.91) based on the results of a single study. No significant on catheter malfunction was observed for other individual classes of alternative anticoagulant locking solutions (citrate: RR 1.14, 95% CI 0.76 to 1.69; antibiotic: RR 1.48, 95% CI 0.79 to 2.77; ethanol: RR 0.88, 95% CI 0.21 to 3.67). On the other hand, all individual classes of alternative anticoagulant locking solutions, except ethanol, reduced catheter-related bacteraemia (citrate: RR 0.49, 95% CI 0.36 to 0.68; antibiotic: RR 0.27, 95% CI 0.11 to 0.70; rt-PA: RR 0.35, 95% CI 0.13 to 0.93; ethanol: RR 0.33, 95% CI 0.03 to 4.05). No significant effect on all-cause mortality was observed for any individual agent within the class of alternative locking solutions. Studies were mainly of low quality and underpowered with an average participant number of 75 and study duration of six months. The interpretation of the study evidence was further limited by the variation in tested interventions and outcome reporting. The relative net benefit of anticoagulant therapies for prevention of catheter malfunction remains uncertain. Multiple agents appear to reduce catheter-related bacteraemia although the lack of clear assessment of harms and the limitations of study quality mean these results should be interpreted with caution. Methodological approaches can be used to avoid methods of reporting unduly affecting on the results of meta-analyses incorporating studies employed mixed reporting methods. Further high quality randomised studies, including safety outcomes, are needed.
We identified 20 studies that had analyzed a total of 1947 eyes of 1866 participants (individual studies ranged from 8 to 346 participants who were randomized). The studies were conducted in eight different countries: one in Brazil, three in China, three in Cuba, one in Egypt, two in Iran, two in Thailand, seven in Turkey, and one in Venezuela. Overall risk of bias was unclear, as many studies did not provide information on randomization methods or masking to prevent performance and detection bias. The risk ratio for recurrence of pterygium using conjunctival autograft versus amniotic membrane transplant was 0.87 (95% confidence interval (CI) 0.43 to 1.77) and 0.53 (95% CI 0.33 to 0.85) at 3 months and 6 months, respectively. These estimates include participants with primary and recurrent pterygia. We performed a subgroup analysis to compare participants with primary pterygia with participants with recurrent pterygia. For participants with primary pterygia, the risk ratio was 0.92 (95% CI 0.37 to 2.30) and 0.58 (95% CI 0.27 to 1.27) at 3 months and 6 months, respectively. We were only able to estimate the recurrence of pterygia at 6 months for participants with recurrent pterygia, and the risk ratio comparing conjunctival autograft with amniotic membrane transplant was 0.45 (95% CI 0.21 to 0.99). One included study was a doctoral thesis and did not use allocation concealment. When this study was excluded in a sensitivity analysis, the risk ratio for pterygium recurrence at 6 months' follow-up was 0.43 (95% CI 0.30 to 0.62) for participants with primary and recurrent pterygium. One of the secondary outcomes, the proportion of participants with clinical improvement, was analyzed in only one study. This study reported clinical outcome as the risk of non-recurrence, which was seen in 93.8% of participants in the conjunctival limbal autograft group and 93.3% in the amniotic membrane transplant group at 3 months after surgery. We did not analyze data on the need for repeat surgery, vision-related quality of life, and direct and indirect costs of surgery due to an insufficient number of studies reporting these outcomes. Thirteen studies reported adverse events associated with conjunctival autograft surgery and amniotic membrane transplant surgery. Adverse events that occurred in more than one study were granuloma and pyogenic granuloma and increased intraocular pressure. None of the included studies reported that participants had developed induced astigmatism. In association with pterygium excision, conjunctival autograft is associated with a lower risk of recurrence at six months' after surgery than amniotic membrane transplant. Participants with recurrent pterygia in particular have a lower risk of recurrence when they receive conjunctival autograft surgery compared with amniotic membrane transplant. There are few studies comparing the two techniques with respect to visual acuity outcomes, and we identified no studies that reported on vision-related quality of life or direct or indirect costs. Comparison of these two procedures in such outcome measures bears further investigation. There were an insufficient number of studies that used adjunctive mitomycin C to estimate the effects on pterygium recurrence following conjunctival autograft or amniotic membrane transplant.
Two randomised controlled studies were eligible for inclusion in the review. Both studies were of moderate quality and used active control comparisons (another type of meditation, relaxation, biofeedback). Anti-anxiety drugs were used as standard treatment. The duration of trials ranged from 3 months (12 weeks) to 18 weeks. In one study transcendental meditation showed a reduction in anxiety symptoms and electromyography score comparable with electromyography-biofeedback and relaxation therapy. Another study compared Kundalini Yoga (KY), with Relaxation/Mindfulness Meditation. The Yale-Brown Obsessive Compulsive Scale showed no statistically significant difference between groups. The overall dropout rate in both studies was high (33-44%). Neither study reported on adverse effects of meditation. The small number of studies included in this review do not permit any conclusions to be drawn on the effectiveness of meditation therapy for anxiety disorders. Transcendental meditation is comparable with other kinds of relaxation therapies in reducing anxiety, and Kundalini Yoga did not show significant effectiveness in treating obsessive-compulsive disorders compared with Relaxation/Meditation. Drop out rates appear to be high, and adverse effects of meditation have not been reported. More trials are needed.
We included two small trials (involving a total of 99 pregnant women) that compared guided imagery with quiet rest. The trials were conducted in Canada and the USA. We assessed both trials as at high risk of performance bias, and low risk of attrition bias; one trial was at low risk for selection, detection, and reporting bias, while the other was at unclear risk for the same domains. We could not perform a meta-analysis because the two included studies reported different outcomes, and the frequency of the intervention was slightly different between the two studies. One study performed guided imagery for 15 minutes at least twice daily for four weeks, or until the baby was born (whichever came first). In the other study, the intervention included guided imagery, self-monitoring of blood pressure, and thermal biofeedback-assisted relaxation training for four total hours; the participants were instructed to practice the procedures twice daily and complete at least three relief relaxation breaks each day. The control groups were similar - one was quiet rest, and the other was quiet rest as bed rest. None of our primary outcomes were reported in the included trials: severe hypertension (either systolic blood pressure of 160 mmHg or higher, or diastolic blood pressure of 110 mmHg or higher); severe pre-eclampsia, or perinatal death (stillbirths plus deaths in the first week of life). Only one of the secondary outcomes was measured. Low-certainty evidence from one trial (69 women) suggests that guided imagery may make little or no difference in the use of antihypertensive drugs (risk ratio 1.27, 95% confidence interval 0.72 to 2.22). There is insufficient evidence to inform practice about the use of guided imagery for hypertension in pregnancy. The available evidence for this review topic is sparse, and the effect of guided imagery for treating hypertension during pregnancy (compared with quiet rest) remains unclear. There was low-certainty evidence that guided imagery made little or no difference to the use of antihypertensive drugs, downgraded because of imprecision. The two included trials did not report on any of the primary outcomes of this review. We did not identify any trials comparing guided imagery with no intervention, or with another non-pharmacological method for hypertension. Large and well-designed RCTs are needed to identify the effects of guided imagery on hypertension during pregnancy and on other relevant outcomes associated with short-term and long-term maternal and neonatal health. Trials could also consider utilisation and costs of health service.
We found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. We found one trial (18 participants) that fulfilled the selection criteria, comparing different doses of alglucosidase alfa. The trial provided low-quality evidence (this was a small trial, there were no numerical results available by dose group, random sequence generation and allocation concealment were unclear, and there was a lack of blinding). The duration of alglucosidase alfa treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extended phase of the trial), with a median duration of treatment being 2.3 years. The trial only reported that clinical responses including cardiac function and motor development, as well as the proportion of children that were free of invasive ventilation, were similar in the 20 mg/kg every two weeks and the 40 mg/kg every two weeks groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between dose groups, risk ratio 0.83 (95% confidence interval 0.40 to 1.76) (low-quality of evidence). However, of note, at 52 weeks, five children in the 20 mg/kg every two weeks dose group experienced a total of 41 mild or moderate (none severe) infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 123 infusion-related events. By the end of the extended phase of the trial, five children in the 20 mg/kg every two weeks dose group experienced a total of 47 infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 177 infusion-related events. The trial was supported by the Genzyme Corporation. The search found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. One small randomized controlled trial provided no robust evidence for which dosing schedule of alglucosidase alfa was more effective to treat infantile-onset Pompe disease. It is not deemed ethical to proceed with new placebo-controlled trials, therefore a randomized controlled trial with a large sample size comparing different dosing schedules of enzyme replacement therapy is needed. The main clinical outcomes (i.e. cardiac function, invasive ventilation, survival, motor development, adverse events (e.g. the development of antibodies)) should be standardized when evaluated and reported.
We identified 16 trials, of which six were eligible for inclusion. The six included studies randomized 546 women with singleton gestations and threatened preterm labor (PTL) at 23 0/7 to 34 6/7 weeks. A total of 277 women were randomized to knowledge and 269 to no knowledge of FFN. No trials were identified on asymptomatic women or multiple gestations. The risk of bias of included studies was mixed. For selected important outcomes, preterm birth before 37, 34, and 32 weeks, and maternal hospitalization, we graded the quality of the evidence and created a 'Summary of findings' table. For these outcomes, the evidence was graded as mainly low quality due to the imprecision of effect estimates. Management based on knowledge of FFN results may reduce preterm birth before 37 weeks (20.7%) versus controls without such knowledge (29.2%) (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.52 to 1.01; 5 trials; 434 women; low-quality evidence). However, management based on knowledge of FFN results may make little or no difference to preterm birth before 34 (RR 1.09, 95% CI 0.54 to 2.18; 4 trials; 357 women; low-quality evidence) or maternal hospitalization (RR 1.06, 95% CI 0.79 to 1.43; 5 trials; 441 women; low-quality evidence). The evidence for preterm birth before 32 weeks is uncertain because the quality was found to be very low (average RR 0.79, 95% CI 0.16 to 3.96; 4 trials; 357 women; very low-quality evidence). For all other outcomes, for which there were available data (preterm birth less than 28 weeks; gestational age at delivery (weeks); birthweight less than 2500 g; perinatal death; tocolysis; steroids for fetal lung maturity; time to evaluate; respiratory distress syndrome; neonatal intensive care unit (NICU) admission; and NICU days), knowledge of FFN results may make little or no difference to the outcomes. The evidence from this review suggests that management based on knowledge of FFN results may reduce preterm birth before 37 weeks. However, our confidence in this result is limited as the evidence was found to be of low quality. Effects on other substantive outcomes are uncertain due to serious concerns in study design, inconsistency, and imprecision of effect estimates. No trials were identified on asymptomatic women, or multiple gestations. Future studies are needed that include specific populations (e.g. singleton gestations with symptoms of preterm labor), a study group managed with a protocol based on the FFN results, and that report not only maternal but also important perinatal outcomes. Cost-effectiveness analyses are also needed.
Three trials met the inclusion criteria and these randomised 579 women, of whom all were assessed at the end of the trials. Two trials assessing 373 participants with stage III to IV persistent or recurrent disease, found that women who received combination therapy had a significantly lower risk of death and disease progression than women who received single agent ifosfamide, after adjustment for performance status (HR = 0.75, 95% confidence interval (CI): 0.60 to 0.94 and HR = 0.72, 95% CI: 0.58 to 0.90 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of nausea and vomiting, where significantly more women experienced these ailments in the combination therapy group than the Ifosamide group (RR = 3.53, 95% CI: 1.33 to 9.37). In one trial there was no statistically significant difference in the risk of death and disease progression in women who received whole body irradiation and chemotherapy, after adjustment for age and FIGO stage (HR = 0.71, 95% CI: 0.48 to 1.05 and HR = 0.79, 95% CI: 0.53 to 1.18 for OS and PFS respectively). There was no statistically significant difference in all reported adverse events, with the exception of haematological and neuropathy morbidities, where significantly less women experienced these morbidities in the whole body irradiation group than the chemotherapy group (RR= 0.02, 95% CI: 0.00 to 0.16) for haematological morbidity and all nine women in the trial experiencing neuropathy morbidity were in the chemotherapy group). In advanced stage metastatic uterine carcinosarcoma as well as recurrent disease adjuvant combination, chemotherapy with ifosfamide should be considered. Combination chemotherapy with ifosfamide and paclitaxel is associated with lower risk of death compared with ifosfamide alone. In addition, radiotherapy to the abdomen is not associated with improved survival.
We included 13 RCTs (839 people). Studies were at risk of selection, performance, and detection bias (owing to lack of blinding for self-reported outcomes) and had low risk of attrition and reporting bias. We prioritized the findings when aerobic exercise was compared with no exercise control and present them fully here. Eight trials (with 456 participants) provided low-quality evidence for pain intensity, fatigue, stiffness, and physical function; and moderate-quality evidence for withdrawals and HRQL at completion of the intervention (6 to 24 weeks). With the exception of withdrawals and adverse events, major outcome measures were self-reported and were expressed on a 0 to 100 scale (lower values are best, negative mean differences (MDs)/standardized mean differences (SMDs) indicate improvement). Effects for aerobic exercise versus control were as follows: HRQL: mean 56.08; five studies; N = 372; MD -7.89, 95% CI -13.23 to -2.55; absolute improvement of 8% (3% to 13%) and relative improvement of 15% (5% to 24%); pain intensity: mean 65.31; six studies; N = 351; MD -11.06, 95% CI -18.34 to -3.77; absolute improvement of 11% (95% CI 4% to 18%) and relative improvement of 18% (7% to 30%); stiffness: mean 69; one study; N = 143; MD -7.96, 95% CI -14.95 to -0.97; absolute difference in improvement of 8% (1% to 15%) and relative change in improvement of 11.4% (21.4% to 1.4%); physical function: mean 38.32; three studies; N = 246; MD -10.16, 95% CI -15.39 to -4.94; absolute change in improvement of 10% (15% to 5%) and relative change in improvement of 21.9% (33% to 11%); and fatigue: mean 68; three studies; N = 286; MD -6.48, 95% CI -14.33 to 1.38; absolute change in improvement of 6% (12% improvement to 0.3% worse) and relative change in improvement of 8% (16% improvement to 0.4% worse). Pooled analysis resulted in a risk ratio (RR) of moderate quality for withdrawals (17 per 100 and 20 per 100 in control and intervention groups, respectively; eight studies; N = 456; RR 1.25, 95%CI 0.89 to 1.77; absolute change of 5% more withdrawals with exercise (3% fewer to 12% more). Three trials provided low-quality evidence on long-term effects (24 to 208 weeks post intervention) and reported that benefits for pain and function persisted but did not for HRQL or fatigue. Withdrawals were similar, and investigators did not assess stiffness and adverse events. We are uncertain about the effects of one aerobic intervention versus another, as the evidence was of low to very low quality and was derived from single trials only, precluding meta-analyses. Similarly, we are uncertain of the effects of aerobic exercise over active controls (ie, education, three studies; stress management training, one study; medication, one study) owing to evidence of low to very low quality provided by single trials. Most studies did not measure adverse events; thus we are uncertain about the risk of adverse events associated with aerobic exercise. When compared with control, moderate-quality evidence indicates that aerobic exercise probably improves HRQL and all-cause withdrawal, and low-quality evidence suggests that aerobic exercise may slightly decrease pain intensity, may slightly improve physical function, and may lead to little difference in fatigue and stiffness. Three of the reported outcomes reached clinical significance (HRQL, physical function, and pain). Long-term effects of aerobic exercise may include little or no difference in pain, physical function, and all-cause withdrawal, and we are uncertain about long-term effects on remaining outcomes. We downgraded the evidence owing to the small number of included trials and participants across trials, and because of issues related to unclear and high risks of bias (performance, selection, and detection biases). Aerobic exercise appears to be well tolerated (similar withdrawal rates across groups), although evidence on adverse events is scarce, so we are uncertain about its safety.
We included a single study in this review comparing lumbar sympathectomy with prostanoids for the treatment of CLI in people with non-reconstructable PAD. The single study included 200 participants with Buerger's disease, a form of PAD, 100 in each treatment group, but only 162 were actually included in the analyses. The study compared an open surgical technique for lumbar sympathectomy with the prostanoid, iloprost, and followed participants for 24 weeks. Risk of bias was low for most evaluated domains. Due to the nature of the treatment, blinding of the participants and those providing the treatment would be impossible as a surgical procedure was compared with intravenous injections. It was not mentioned if blinded assessors evaluated the study outcomes, therefore, we judged subjective outcomes (i.e. pain reduction) to be at unclear risk of detection bias and objective outcomes (i.e. ulcer healing, amputation and mortality) at low risk of detection bias. We also rated the risk of attrition bias as unclear; 38 out of 200 (19%) participants were not included in the analysis without clear explanation (16 of 100 in the iloprost arm and 22 of 100 in the sympathectomy arm). The quality of evidence was low due to serious imprecision because the study numbers were low and there was only one study included. The single included study reported on the outcome of complete healing without pain or major amputation, which fell under three separate outcomes for our review: relief of rest pain, complete ulcer healing and avoidance of major amputation. We chose to keep the outcome as a singularly reported outcome in order to not introduce bias into the outcomes, which may have been the case if reported separately. The limited evidence suggests participants who received prostaglandins had improved complete ulcer healing without rest pain or major amputation when compared with those who received lumbar sympathectomy (RR 1.63, 95% CI 1.30 to 2.05), but as it was the only included study, we rated the data as low-quality and could not draw any overall conclusions. The study authors stated that more participants who received prostaglandins reported adverse effects, such as headache, flushing, nausea and abdominal discomfort, but only one participant experienced severe enough adverse effects to drop out. Five participants who underwent lumbar sympathectomy reported minor wound infection (low-quality evidence). There was no reported mortality in either of the treatment groups (low-quality evidence). The included study did not report on claudication distances, quality of life or functional status, ankle brachial pressure index (ABPI), tissue oxygenation or toe pressures, or progression to minor amputation, complications or provide any cost-effectiveness data. Low-quality evidence from a single study in a select group of participants (people with Buerger's disease) suggests that prostaglandins are superior to open surgical lumbar sympathectomy for complete ulcer healing without rest pain or major amputation, but possibly incur more adverse effects. Further studies are needed to better understand if prostaglandins truly are more efficacious than open surgical lumbar sympathectomy and if there are any concerns with adverse effects. It would be of great importance for future studies to include other forms of PAD (as Buerger's disease is a select type of PAD), other methods of sympathectomy as well as data on quality of life, complications and cost-effectiveness.
Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 μmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 μmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. There is evidence of short-term benefit from using sapropterin in some people with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term. There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.
Seven trials were included, but only six trials (919 participants) contributed data. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.30 to 1.46; two trials, 241 pregnancies, low quality evidence). Although the data suggest an effect in reducing pneumococcal colonization in infants by 16 months of age (average RR 0.33; 95% CI 0.11 to 0.98; one trial, 56 pregnancies), there was no evidence of this effect in infants at two to three months of age (average RR 1.13; 95% CI 0.46 to 2.78; two trials, 146 pregnancies, low quality evidence) or by six to seven months of age (average RR 0.67, 95% CI 0.22 to 2.08; two trials, 148 pregnancies, low quality evidence). None of the trials included in this review reported neonatal death as a result of pneumococcal infection. Neonatal antibody levels were reported as geometric mean and 95% CI. There were inconsistent results between studies. Two studies showed significantly higher immunoglobulin G (IgG) levels in cord blood in the pneumococcal vaccine group when compared with the control group for all serotypes. In contrast, another trial showed no difference in neonatal antibody levels between the pneumococcal vaccine group and the control group. Maternal antibody levels were also reported as geometric mean and 95% CI. One study showed significantly higher IgG levels in maternal serum in women immunized with pneumococcal vaccine when compared with control vaccine regardless of any serotypes. Another study showed significantly higher maternal antibody levels only for serotype 14, but no evidence of an effect for other serotypes. The percentage of women with seroprotection was measured in one trial at delivery and at 12 months post-delivery. At delivery, results favored the intervention group for serotype 6 (RR 1.49, 95% CI 1.31 to 1.69), serotype 14 (RR 1.40, 95% CI 1.25 to 1.56) and serotype 19 (RR 2.29, 95% CI 1.89 to 2.76). There were no group differences seen at 12 months post-delivery for serotypes 6 or 14 (RR 1.06, 95% CI 1.00 to 1.12 and RR 1.06, 95% CI 0.98 to 1.15, respectively), but results favored the intervention group for serotype 19 (RR 1.59, 95% CI 1.37 to 1.85). No significant difference for tenderness at the injection site between women who received pneumococcal vaccine and those who received control vaccine (average RR 3.20; 95% CI 0.32 to 31.54; two trials, 130 women). The overall quality of evidence is low for primary outcomes. Most outcomes had wide confidence intervals crossing the line of no effect, and most of the included trials had small numbers of participants and few events which led to downgrading evidence for imprecision of findings. There is insufficient evidence to assess whether pneumococcal vaccination during pregnancy could reduce infant infections.
Four trials (1429 participants) comparing PDT with verteporfin to PDT with 5% dextrose in water were included in this review. Participants received on average five treatments over two years. The risk ratio of losing 3 or more lines of visual acuity at 24 months comparing the intervention with the control group was 0.80 (95% confidence interval (CI) 0.73 to 0.88). The risk ratio of losing 6 or more lines of visual acuity at 24 months comparing the intervention with the control group was 0.66 (95% CI 0.56 to 0.83). The results at 12 months were similar to those at 24 months. The most serious adverse outcome, severe visual acuity decrease within one week of treatment, occurred in 11 per 1000 patients (95% CI 3 to 48). Infusion related back pain was experienced by 20 per 1000 (95% CI 6 to 70). Two further trials compared different treatment regimens: standard versus delayed light application; retreatment every two months versus every three months. Neither trial demonstrated differences in effectiveness. The overall quality of the evidence included in this review was considered to be high. Five out of the six trials were funded by the manufacturers of verteporfin. Photodynamic therapy in people with choroidal neovascularisation due to AMD is effective in preventing clinically significant visual loss with a relative risk reduction of approximately 20%. Modified treatment regimens have not convincingly shown increased effectiveness. There was no evidence on quality of life and little on cost.
Seventy-four studies enrolling 7049 infants were included. Results from only a few studies could be combined in meta-analyses and for most analyses the GRADE assessments indicated low- or moderate-quality evidence. There was high-quality evidence for the beneficial effect of sucrose (24%) with non-nutritive sucking (pacifier dipped in sucrose) or 0.5 mL of sucrose orally in preterm and term infants: Premature Infant Pain Profile (PIPP) 30 s after heel lance WMD -1.70 (95% CI -2.13 to -1.26; I2 = 0% (no heterogeneity); 3 studies, n = 278); PIPP 60 s after heel lance WMD -2.14 (95% CI -3.34 to -0.94; I2 = 0% (no heterogeneity; 2 studies, n = 164). There was high-quality evidence for the use of 2 mL 24% sucrose prior to venipuncture: PIPP during venipuncture WMD -2.79 (95% CI -3.76 to -1.83; I2 = 0% (no heterogeneity; 2 groups in 1 study, n = 213); and intramuscular injections: PIPP during intramuscular injection WMD -1.05 (95% CI -1.98 to -0.12; I2 = 0% (2 groups in 1 study, n = 232). Evidence from studies that could not be included in RevMan-analyses supported these findings. Reported adverse effects were minor and similar in the sucrose and control groups. Sucrose is not effective in reducing pain from circumcision. The effectiveness of sucrose for reducing pain/stress from other interventions such as arterial puncture, subcutaneous injection, insertion of nasogastric or orogastric tubes, bladder catherization, eye examinations and echocardiography examinations are inconclusive. Most trials indicated some benefit of sucrose use but that the evidence for other painful procedures is of lower quality as it is based on few studies of small sample sizes. The effects of sucrose on long-term neurodevelopmental outcomes are unknown. Sucrose is effective for reducing procedural pain from single events such as heel lance, venipuncture and intramuscular injection in both preterm and term infants. No serious side effects or harms have been documented with this intervention. We could not identify an optimal dose due to inconsistency in effective sucrose dosage among studies. Further investigation of repeated administration of sucrose in neonates is needed. There is some moderate-quality evidence that sucrose in combination with other non-pharmacological interventions such as non-nutritive sucking is more effective than sucrose alone, but more research of this and sucrose in combination with pharmacological interventions is needed. Sucrose use in extremely preterm, unstable, ventilated (or a combination of these) neonates needs to be addressed. Additional research is needed to determine the minimally effective dose of sucrose during a single painful procedure and the effect of repeated sucrose administration on immediate (pain intensity) and long-term (neurodevelopmental) outcomes.
Thirty-three trials were included. They recruited 2293 participants with insomnia, aged 15 to 98 years, some with medical conditions contributing to insomnia (stroke, end-stage renal disease, perimenopause, pregnancy, psychiatric diseases). They evaluated needle acupuncture, electroacupuncture, acupressure or magnetic acupressure. Compared with no treatment (two studies, 280 participants) or sham/placebo (two studies, 112 participants), acupressure resulted in more people with improvement in sleep quality (compared to no treatment: OR 13.08, 95% confidence interval (CI) 1.79 to 95.59; compared to sham/placebo: OR 6.62, 95% CI 1.78 to 24.55). However, when assuming that dropouts had a worse outcome in sensitivity analysis the beneficial effect of acupuncture was inconclusive. Compared with other treatment alone, acupuncture as an adjunct to other treatment might marginally increase the proportion of people with improved sleep quality (13 studies, 883 participants, OR 3.08, 95% CI 1.93 to 4.90). On subgroup analysis, only needle acupuncture but not electroacupuncture showed benefits. All trials had high risk of bias and were heterogeneous in the definition of insomnia, participant characteristics, acupoints and treatment regimen. The effect sizes were generally small with wide confidence intervals. Publication bias was likely present. Adverse effects were rarely reported and they were minor. Due to poor methodological quality, high levels of heterogeneity and publication bias, the current evidence is not sufficiently rigorous to support or refute acupuncture for treating insomnia. Larger high-quality clinical trials are required.
Nine trials met the inclusion criteria. Live birth rate per woman was significantly lower after IVF/ICSI with PGS compared to IVF/ICSI without PGS in women of advanced maternal age and in women with repeated IVF failure (OR 0.59; 95% CI 0.44 to 0.81 and OR 0.41, 95% CI 0.20 to 0.88 respectively). In good prognosis patients a similar trend was seen, albeit not significant (OR 0.50, 95% CI 0.20 to 1.26, random effects model). PGS as currently performed significantly decreases live birth rates in women of advanced maternal age and those with repeated IVF failure. Trials in which PGS was offered to women with a good prognosis suggested similar outcomes. PGS technique development is still ongoing in an effort to increase its efficacy. This involves biopsy at other stages of development (polar body or trophectoderm biopsy) and other methods of analysis (comparative genome hybridisation (CGH) or array-based technologies) than used by the trials included in this review. These new developments should be properly evaluated before their routine clinical application. Until such trials have been performed, PGS should not be offered as routine patient care in any form.
We identified 11 studies for potential inclusion. Of those, we included three studies involving 97 women. Two additional studies are ongoing. Two trials examined in-utero fetal tracheal occlusion with standard (postnatal) care in fetuses with severe diaphragmatic hernia. Whilst the trials utilised fetal interventions that were similar, there were important differences in how access was gained to the fetus and in the timing and mode of delivery. Therefore, we did not combine these trials in meta-analysis and the results are examined in separate comparisons. One trial examined the effect of antenatal corticosteroids versus placebo. Overall, the methodological quality of the trials was variable and no data were available for a number of this review's secondary outcomes. In-utero fetal occlusion by maternal laparotomy versus standard postnatal management (one trial, 24 women) For the primary infant outcome (perinatal mortality), there were no data suitable for inclusion in the analysis. There was no difference between groups in terms of long-term infant survival (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.66 to 1.69). In-utero fetal occlusion by minimally invasive fetoscopy versus standard postnatal management (one trial, 41 women) The primary infant outcome (perinatal mortality) was not reported. Minimally invasive fetoscopy was associated with a small reduction in the mean gestational age at birth (mean difference (MD) -1.80 weeks, 95% CI -3.13 to -0.47), but there was no clear difference in the risk of preterm birth before 37 weeks (RR 1.75, 95% CI 0.78 to 3.92). Long-term infant survival (three to six months) (RR 10.50, 95% CI 1.48 to 74.71) was increased with the intervention when compared with standard management, and there was a corresponding reduction in pulmonary hypertension (RR 0.58, 95% CI 0.36 to 0.93) associated with the intervention. There was no difference between groups in terms of preterm ruptured membranes (< 37 weeks) (RR 1.47, 95% CI 0.56 to 3.88) or maternal infectious morbidity (RR 3.14, 95% CI 0.14 to 72.92), and there were no maternal blood transfusions. Antenatal corticosteroids versus placebo (one trial, 32 women) We also included one trial (involving 32 women) examining the effect of antenatal corticosteroids versus placebo. There was no clear difference in the incidence of perinatal mortality (our primary infant outcome) between the group of women who received antenatal corticosteroids and the placebo control (RR 1.24, 95% CI 0.50 to 3.08). Data (mean only) were reported for two of our secondary outcomes (mechanical ventilation and days of hospital admission) but standard deviations (SDs) were not provided. For the purposes of this review and to permit further analysis we have estimated the SDs based on the reported P values reported in the trial report, although our estimation does assume that the SD is the same in both the intervention and control groups. There were no differences between the antenatal corticosteroid group and the placebo control in terms of days of mechanical ventilation (MD 18.00 days, 95% CI -14.77 to 50.77) or days of hospital admission (MD 17.00 days, 95% CI -13.93 to 47.93) . There is currently insufficient evidence to recommend in-utero intervention for fetuses with CDH as a part of routine clinical practice. We identified three small studies, with only one study adequately reporting on the primary outcome of this review - perinatal mortality, and there were few data pertaining to many of this review's secondary outcomes. WIth regard to the administration of antenatal corticosteroids, there remains a gap in current research, and a large multicentre trial with adequate statistical power should be undertaken to answer this unresolved question. More studies are needed to further examine the effect of in-utero fetal tracheal occlusion on important neonatal outcomes and long-term infant survival and health. Long-term follow-up is of particular importance, and should include morbidity and mortality measures. Further studies should examine the benefits of an in-utero intervention on subgroups with moderate and severe congenital diaphragmatic hernia. Indeed, there are three ongoing studies, being conducted by European, North and South American fetal medicine centres, which will contribute to this gap. Ongoing research and any implementation into clinical practice should include standardisation of the procedure, inclusion criteria and long-term childhood follow-up.
We included two trials, but data were available for only 339 men in one trial, of whom 188 underwent invasive urodynamic studies. We found evidence of risk of bias, such as lack of outcome information for 24 men in one arm of the trial. Statistically significant evidence suggests that the tests did change clinical decision making. Men in the invasive urodynamics arm were more likely to have their management changed than men in the control arm (proportion with change in management 24/188 (13%) vs 0/151 (0%), risk ratio (RR) 39.41, 95% confidence interval (CI) 2.42 to 642.74). However, the quality of the evidence was low. Low-quality evidence indicates that men in the invasive urodynamics group were less likely to undergo surgery as treatment for voiding LUTS (164/188 (87%) vs 151/151 (100%), RR 0.87, 95% CI 0.83 to 0.92). Investigators observed no difference in urine flow rates before and after surgery for LUTS (mean percentage increase in urine flow rate, 140% in invasive urodynamic group vs 149% in immediate surgery group, P value = 0.13). Similarly, they found no differences between groups with regards to International Prostate Symptom Score (IPSS) (mean percentage decrease in IPSS score, 58% in invasive urodynamics group vs 59% in immediate surgery group, P value = 0.22). No evidence was available to demonstrate whether differences in management equated to improved health outcomes, such as relief of symptoms of voiding dysfunction or improved quality of life. No evidence from randomised trials revealed the adverse effects associated with invasive urodynamic studies. Although invasive urodynamic testing did change clinical decision making, we found no evidence to demonstrate whether this led to reduced symptoms of voiding dysfunction after treatment. Larger definitive trials of better quality are needed, in which men are randomly allocated to management based on invasive urodynamic findings or to management based on findings obtained by other diagnostic means. This research will show whether performance of invasive urodynamics results in reduced symptoms of voiding dysfunction after treatment.
Two studies are included, which involved a total of 114 people with penetrating abdominal injuries. Both studies are at moderate risk of bias because the randomisation methods are not fully described, and the original study protocols are no longer available. The studies were undertaken in Finland between 1992 and 2002, by the same two researchers. In one study, 51 people were randomised to surgery or an observation protocol. None of the participants in the study died. Seven people had complications: 5 (18.5%) in the surgical group and 2 (8.3%) in the observation group; the difference was not statistically significant (P = 0.42; Fischer's exact). Among the 27 people who had surgery, 6 (22.2%) surgeries were negative laparotomies, and 15 (55.6%) were non-therapeutic. In the other study, 63 people were randomised to diagnostic laparoscopy (surgery) or an observation protocol. There were no deaths and no unnecessary surgeries in either group. Four people did not receive the intervention they were assigned. There was no difference in therapeutic operations between the two groups: 3 of 28 in the diagnostic laparoscopy group versus 1 of 31 in the observation protocol group (P = 0.337). Based on the findings of 2 studies involving a total of 114 people, there is no evidence to support the use of surgery over an observation protocol for people with penetrating abdominal trauma who have no signs of peritonitis and are stable.
We found 11 RCTs (1884 women) suitable for inclusion in the review. Most studies were at unclear or high risk of bias. The main limitations in the overall quality of the evidence were high risk of bias, unexplained heterogeneity and serious imprecision and indirectness. There were no data on our primary outcome — live birth per woman randomised — in any review comparisons. NSAIDs vs. placebo/no treatment We are uncertain of an effect on ongoing pregnancy when NSAIDs were compared to placebo/no treatment (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.71 to 1.59; 4 studies, 1159 participants; I² = 53%; very low quality evidence). Results suggest that if the chance of ongoing pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of NSAIDs is estimated to be between 12% and 24%. Subgroup analysis according to the type of NSAID yielded similar results. We are also uncertain of an effect on miscarriage rates when NSAIDs were compared to placebo/no treatment (RR 0.62, 95% CI 0.33 to 1.16; 4 studies, 525 participants; I² = 43%; very low quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 21%, the chance following the use of NSAIDs is estimated to be between 7% and 27%. The results were similar when two studies were excluded due to high risk of bias. Concerning the secondary outcomes, we are uncertain of an effect on clinical pregnancy rates (RR 1.23, 95% CI 1.00 to 1.52; 6 studies, 1570 participants; I² = 49%; low-quality evidence); on ectopic pregnancy (RR 0.56, 95% CI 0.05 to 5.89; 1 study, 72 participants); on multiple pregnancy (RR 2.00, 95% CI 0.18 to 21.67; 1 study, 180 participants); and on side effects (RR 1.39, 95% CI 0.02 to 119.35; 3 studies, 418 participants; I² = 79%). The evidence suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 30%, the chance following the use of NSAIDs is estimated to be between 31% and 45%. If the chance of ectopic pregnancy following placebo or no treatment is assumed to be 5%, the chance following the use of NSAIDs is estimated to be between 0.3% and 31%. If the chance of multiple pregnancy following placebo or no treatment is assumed to be 1%, the chance following the use of NSAIDs is estimated to be between 0.2 % and 24%. There were no cases of congenital anomalies during antenatal ultrasound screening of the women in one study. NSAID vs. another NSAID Only one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy (RR 1.12, 95% CI 0.63 to 2.00; 1 study, 170 participants; very low quality evidence); and on miscarriage (RR 1.00, 95% CI 0.44 to 2.28; 1 study, 170 participants; very low quality evidence). The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%. Similar results were reported for clinical pregnancy (RR 1.07, 95% CI 0.71 to 1.63; 1 study, 170 participants; very low quality evidence). There were no data for the other outcomes specified in this review. NSAID vs. aspirin No study reported this comparison. Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve ongoing pregnancy and miscarriage rates. This is based on available data from RCTs, where very low quality evidence showed that there is no single outcome measure demonstrating a benefit with their use. Further large, well-designed randomised placebo-controlled trials reporting on live births are required to clarify the exact role of NSAIDs.
We identified two trials of GCS that included 2615 patients and two small studies of IPC that included 177 patients. Overall, physical methods were not associated with a significant reduction in DVTs during the treatment period (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.70 to 1.04) or deaths (OR 1.12, 95% CI 0.87 to 1.45). Use of GCS was not associated with any significant reduction in risk of DVT (OR 0.88, 95% CI 0.72 to 1.08) or death (OR 1.13, 95% CI 0.87 to 1.47) at the end of follow up. IPC was associated with a non-significant trend towards a lower risk of DVTs (OR 0.45, 95% CI 0.19 to 1.10) with no evidence of an effect on deaths (OR 1.04, 95% CI 0.37 to 2.89). Evidence from randomised trials does not support the routine use of GCS to reduce the risk of DVT after acute stroke. There is insufficient evidence to support the routine use of IPC to reduce the risk of DVT in acute stroke and further larger randomised studies of IPC are needed to reliably assess the balance of risks and benefits of this intervention.
Eleven randomized controlled trials met our criteria for inclusion, representing 7695 patients in the United States, China, India and Sweden. Advance provision did not decrease pregnancy rates (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.76 to 1.25 in studies for which we included twelve-month follow-up data; OR 0.48, 95% CI 0.18 to 1.29 in a study with seven-month follow-up data; OR 0.92, 95% CI 0.70 to 1.20 in studies for which we included six-month follow-up data; OR 0.49, 95% CI 0.09 to 2.74 in a study with three-month follow-up data), despite reported increased use (single use: OR 2.47, 95% CI 1.80 to 3.40; multiple use: OR 4.13, 95% CI 1.77 to 9.63) and faster use (weighted mean difference (WMD) -12.98 hours, 95% CI -16.66 to -9.31 hours). Advance provision did not lead to increased rates of sexually transmitted infections (OR 1.01, 95% CI 0.75 to 1.37), increased frequency of unprotected intercourse, or changes in contraceptive methods. Women who received emergency contraception in advance were equally likely to use condoms as other women. Advance provision of emergency contraception did not reduce pregnancy rates when compared to conventional provision. Results from primary analyses suggest that advance provision does not negatively impact sexual and reproductive health behaviors and outcomes. Women should have easy access to emergency contraception, because it can decrease the chance of pregnancy. However, the interventions tested thus far have not reduced overall pregnancy rates in the populations studied.
No new studies were identified for this update. A single RCT with a total of 30 PAAs met the inclusion criteria. There was a low risk of selection bias and detection bias. However, the risks of performance bias, attrition bias and reporting bias were unclear from the study. Despite being an RCT, the certainty of the evidence was downgraded to moderate due to the small sample size, resulting in wide confidence intervals (CIs); only 30 PAAs were randomised over a period of five years (15 PAAs each in the groups receiving endovascular stent graft and undergoing conventional open surgery). The primary patency rate at one year was 93.3% in the endovascular group and 100% in the surgery group (RR 0.94, 95% CI 0.78 to 1.12; moderate-certainty evidence). The assisted patency rate at one year was similar in both groups (RR 1.00, 95% CI 0.88 to 1.13; moderate-certainty evidence). There was no clear evidence of a difference between the two groups in the primary or assisted patency rates at four years (13 grafts were patent from 15 PAA treatments in each group; RR 1.00, 95% CI 0.76 to 1.32; moderate-certainty evidence); the effects were imprecise and compatible with the benefit of either endovascular stent graft or surgery or no difference. Mean hospital stay was shorter in the endovascular group (4.3 days for the endovascular group versus 7.7 days for the surgical group; mean difference (MD) -3.40 days, 95% CI -4.42 to -2.38; P < 0.001; moderate-certainty evidence). Mean operating time was also reduced in the endovascular group (75.4 minutes in the endovascular group versus 195.3 minutes in the surgical group; MD -119.90 minutes, 95% CI -137.71 to -102.09; P < 0.001; moderate-certainty evidence). Limb salvage was 100% in both groups. Data on local wound complications were not published in the trial report. Evidence to determine the effectiveness of endovascular stent graft versus conventional open surgery for the treatment of asymptomatic PAAs is limited to data from one small study. At one year there is moderate-certainty evidence that primary patency may be improved in the surgery group but assisted primary patency rates were similar between groups. At four years there was no clear benefit from either endovascular stent graft or surgery to primary or assisted primary patency (moderate-certainty evidence). As both operating time and hospital stay were reduced in the endovascular group (moderate-certainty evidence), it may represent a viable alternative to open repair of PAA. A large multicenter RCT may provide more information in the future. However, difficulties in recruiting enough patients are likely, unless it is an international collaboration including a number of high volume vascular centres.
Six trials, all from the USA, involving 2343 participants, were included. A meta-analysis of four trials comparing CBT with a no-intervention control (1771 participants) reported that the relative risk of violence was 0.86 (favouring the intervention group) with a 95% confidence interval (CI) of 0.54 to 1.38. This is a small effect size, and the width of the CI suggests no clear evidence for an effect. One study (Wisconsin Study) compared CBT with process-psychodynamic group treatment and reported a relative risk of new violence of 1.07 (95% CI 0.68 to 1.68). Even though the process-psychodynamic treatment did marginally better than CBT, this result is equivocal. Finally, one small study (N = 64) compared a combined CBT treatment for substance abuse and domestic violence (SADV) with a Twelve-Step Facilitation (TSF) group. An analysis involving 58 participants investigated the effect on reduction in frequency of physical violence episodes. The effect size was 0.30 (favouring TSF) with 95% CI from -0.22 to 0.81. There are still too few randomised controlled trials to draw conclusions about the effectiveness of cognitive behaviour therapy for male perpetrators of domestic violence.
We identified 1432 references; after screening, we included 60 studies in the final qualitative analyses. Among these, 54 (including 3021 patients) were also included in the quantitative analyses. With respect to the analyses for the first of our primary outcomes, (short-term remission), the most studied of the included psychological therapies was CBT (32 studies), followed by BT (12 studies), PT (10 studies), CT (three studies), SP (three studies) and PD (two studies). The quality of the evidence for the entire network was found to be low for all outcomes. The quality of the evidence for CBT vs NT, CBT vs SP and CBT vs PD was low to very low, depending on the outcome. The majority of the included studies were at unclear risk of bias with regard to the randomisation process. We found almost half of the included studies to be at high risk of attrition bias and detection bias. We also found selective outcome reporting bias to be present and we strongly suspected publication bias. Finally, we found almost half of the included studies to be at high risk of researcher allegiance bias. Overall the networks appeared to be well connected, but were generally underpowered to detect any important disagreement between direct and indirect evidence. The results showed the superiority of psychological therapies over the WL condition, although this finding was amplified by evident small study effects (SSE). The NMAs for ST-remission, ST-response and ST-improvement on a continuous scale showed well-replicated evidence in favour of CBT, as well as some sparse but relevant evidence in favour of PD and SP, over other therapies. In terms of ST-dropouts, PD and 3W showed better tolerability over other psychological therapies in the short term. In the long term, CBT and PD showed the highest level of remission/response, suggesting that the effects of these two treatments may be more stable with respect to other psychological therapies. However, all the mentioned differences among active treatments must be interpreted while taking into account that in most cases the effect sizes were small and/or results were imprecise. There is no high-quality, unequivocal evidence to support one psychological therapy over the others for the treatment of panic disorder with or without agoraphobia in adults. However, the results show that CBT - the most extensively studied among the included psychological therapies - was often superior to other therapies, although the effect size was small and the level of precision was often insufficient or clinically irrelevant. In the only two studies available that explored PD, this treatment showed promising results, although further research is needed in order to better explore the relative efficacy of PD with respect to CBT. Furthermore, PD appeared to be the best tolerated (in terms of ST-dropouts) among psychological treatments. Unexpectedly, we found some evidence in support of the possible viability of non-specific supportive psychotherapy for the treatment of panic disorder; however, the results concerning SP should be interpreted cautiously because of the sparsity of evidence regarding this treatment and, as in the case of PD, further research is needed to explore this issue. Behaviour therapy did not appear to be a valid alternative to CBT as a first-line treatment for patients with panic disorder with or without agoraphobia.
We identified two RCTs (160 participants) that fulfilled our inclusion criteria. As these two trials evaluated different diet supplements (enriched skim milk powder (SMP) and vitamin C) with different outcomes (gout flare prevention for enriched SMP and sUA reduction for vitamin C), we reported the results separately. One trial including 120 participants, at moderate risk of bias, compared SMP enriched with glycomacropeptides (GMP) with unenriched SMP and with lactose over three months. Participants were predominantly men aged in their 50's who had severe gout. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the study period. The effects of enriched SMP (SMP/GMP/G600) compared with the combined control groups (SMP and lactose powder) at three months in terms of mean number of gout flares per month were uncertain (mean ± standard deviation (SD) flares per month: 0.49 ± 1.52 in SMP/GMP/G60 group versus 0.70 ± 1.28 in control groups; mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34; low-quality evidence). The number of withdrawals due to adverse effects was similar in both groups although again the results were imprecise (7/40 in SMP/GMP/G600 group versus 11/80 in control groups; risk ratio (RR) 1.27, 95% CI 0.53 to 3.03; low-quality evidence). The findings for adverse events were also uncertain (2/40 in SMP/GMP/G600 group versus 3/80 in control groups; RR 1.33, 95% CI 0.23 to 7.66; low-quality evidence). Gastrointestinal events were the most commonly reported adverse effects. Pain from self reported gout flares (measured on a 10-point Likert scale) improved slightly more in the SMP/GMP/G600 group compared with controls (mean ± SD reduction -1.97 ± 2.28 points in SMP/GMP/G600 group versus -0.94 ± 2.25 in control groups; MD -1.03, 95% CI -1.96 to -0.10; low-quality evidence). This was an absolute reduction of 10% (95% CI 20% to 1% reduction), which may not be of clinical relevance. Results were imprecise for the outcome improvement in physical function (mean ± SD Health Assessment Questionnaire (HAQ)-II (scale 0 to 3, 0 = no disability): 0.08 ± 0.23 in SMP/GMP/G60 group versus 0.11 ± 0.31 in control groups; MD -0.03, 95% CI -0.14 to 0.08; low-quality evidence). Similarly, results for sUA reduction were imprecise (mean ± SD reduction: -0.025 ± 0.067 mmol/L in SMP/GMP/G60 group versus -0.010 ± 0.069 in control groups; MD -0.01, 95% CI -0.04 to 0.01; low-quality evidence). The study did not report tophus regression and health-related quality of life impact. One trial including 40 participants, at moderate to high risk of bias, compared vitamin C alone with allopurinol and with allopurinol plus vitamin C in a three-arm trial. We only compared vitamin C with allopurinol in this review. Participants were predominantly middle-aged men, and their severity of gout was representative of gout in general. The effect of vitamin C on the rate of gout attacks was not assessed. Vitamin C did not lower sUA as much as allopurinol (-0.014 mmol/L in vitamin C group versus -0.118 mmol/L in allopurinol group; MD 0.10, 95% CI 0.06 to 0.15; low-quality evidence). The study did not assess tophus regression, pain reduction or disability or health-related quality of life impact. The study reported no adverse events and no participant withdrawal due to adverse events. While dietary supplements may be widely used for gout, this review has shown a paucity of high-quality evidence assessing dietary supplementation.
Two trials met the inclusion criteria. Both trials commenced prior to the widespread availability of prostate-specific antigen (PSA) screening; hence the results may not be applicable to men with PSA-detected disease. One trial (N = 142), conducted in the US, was judged to be of poor quality. All cause (overall) mortality was not significantly different between RP and WW groups after fifteen years of follow up (Hazard Ratio (HR) 0.9 (95% Confidence Interval (CI) 0.56 to 1.43). The second trial (N = 695), conducted in Scandinavia, was judged to be of good quality. After 12 years of follow up, the trial results were compatible with a beneficial effect of RP on the risks of overall mortality, prostate cancer mortality and distant metastases compared with WW but the precise magnitude of the effect is uncertain as indicated by the width of the confidence intervals for all estimates (risk difference (RD) -7.1% (95% CI -14.7 to 0.5); RD -5.4% (95% CI -11.1 to 0.2); RD -6.7% (95% CI -13.2 to -0.2), respectively). Compared to WW, RP increased the absolute risks of erectile dysfunction (RD 35% (95% CI 25 to 45)) and urinary leakage (RD 27% (95% CI 17 to 37)). These estimates must be interpreted cautiously as they are derived from data obtained from a self-administered questionnaire survey of a sample of the trial participants (N = 326), no baseline quality of life data were obtained and nerve-sparing surgery was not routinely performed on trial participants undergoing RP. The existing trials provide insufficient evidence to allow confident statements to be made about the relative beneficial and harmful effects of RP and WW for patients with localised prostate cancer. The results of ongoing trials should help to inform treatment decisions for men with screen-detected localised prostate cancer.
Twenty-four new trials were identified since the 2009 update, bringing the total number of included trials to 90. There were 65 trials of bupropion and ten trials of nortriptyline, with the majority at low or unclear risk of bias. There was high quality evidence that, when used as the sole pharmacotherapy, bupropion significantly increased long-term cessation (44 trials, N = 13,728, risk ratio [RR] 1.62, 95% confidence interval [CI] 1.49 to 1.76). There was moderate quality evidence, limited by a relatively small number of trials and participants, that nortriptyline also significantly increased long-term cessation when used as the sole pharmacotherapy (six trials, N = 975, RR 2.03, 95% CI 1.48 to 2.78). There is insufficient evidence that adding bupropion (12 trials, N = 3487, RR 1.19, 95% CI 0.94 to 1.51) or nortriptyline (4 trials, N = 1644, RR 1.21, 95% CI 0.94 to 1.55) to nicotine replacement therapy (NRT) provides an additional long-term benefit. Based on a limited amount of data from direct comparisons, bupropion and nortriptyline appear to be equally effective and of similar efficacy to NRT (bupropion versus nortriptyline 3 trials, N = 417, RR 1.30, 95% CI 0.93 to 1.82; bupropion versus NRT 8 trials, N = 4096, RR 0.96, 95% CI 0.85 to 1.09; no direct comparisons between nortriptyline and NRT). Pooled results from four trials comparing bupropion to varenicline showed significantly lower quitting with bupropion than with varenicline (N = 1810, RR 0.68, 95% CI 0.56 to 0.83). Meta-analyses did not detect a significant increase in the rate of serious adverse events amongst participants taking bupropion, though the confidence interval only narrowly missed statistical significance (33 trials, N = 9631, RR 1.30, 95% CI 1.00 to 1.69). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation. There was no evidence of a significant effect for selective serotonin reuptake inhibitors on their own (RR 0.93, 95% CI 0.71 to 1.22, N = 1594; 2 trials fluoxetine, 1 paroxetine, 1 sertraline) or as an adjunct to NRT (3 trials of fluoxetine, N = 466, RR 0.70, 95% CI 0.64 to 1.82). Significant effects were also not detected for monoamine oxidase inhibitors (RR 1.29, 95% CI 0.93 to 1.79, N = 827; 1 trial moclobemide, 5 selegiline), the atypical antidepressant venlafaxine (1 trial, N = 147, RR 1.22, 95% CI 0.64 to 2.32), the herbal therapy St John's wort (hypericum) (2 trials, N = 261, RR 0.81, 95% CI 0.26 to 2.53), or the dietary supplement SAMe (1 trial, N = 120, RR 0.70, 95% CI 0.24 to 2.07). The antidepressants bupropion and nortriptyline aid long-term smoking cessation. Adverse events with either medication appear to rarely be serious or lead to stopping medication. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Evidence also suggests that bupropion is less effective than varenicline, but further research is needed to confirm this finding. Evidence suggests that neither selective serotonin reuptake inhibitors (e.g. fluoxetine) nor monoamine oxidase inhibitors aid cessation.
Five randomised trials met our inclusion criteria (n = 302). Three studies objectively measured infant breastfeeding using standardised assessment tools. Pooled analysis of two studies (n = 155) showed no change on a 10-point feeding scale following frenotomy (mean difference (MD) -0.1, 95% confidence interval (CI) -0.6 to 0.5 units on a 10-point feeding scale). A third study (n = 58) showed objective improvement on a 12-point feeding scale (MD 3.5, 95% CI 3.1 to 4.0 units of a 12-point feeding scale). Four studies objectively assessed maternal pain. Pooled analysis of three studies (n = 212) based on a 10-point pain scale showed a reduction in maternal pain scores following frenotomy (MD -0.7, 95% CI -1.4 to -0.1 units on a 10-point pain scale). A fourth study (n = 58) also showed a reduction in pain scores on a 50-point pain scale (MD -8.6, 95% CI -9.4 to -7.8 units on a 50-point pain scale). All studies reported no adverse effects following frenotomy. These studies had serious methodological shortcomings. They included small sample sizes, and only two studies blinded both mothers and assessors; one did not attempt blinding for mothers nor for assessors. All studies offered frenotomy to controls, and most controls underwent the procedure, suggesting lack of equipoise. No study was able to report whether frenotomy led to long-term successful breastfeeding. Frenotomy reduced breastfeeding mothers’ nipple pain in the short term. Investigators did not find a consistent positive effect on infant breastfeeding. Researchers reported no serious complications, but the total number of infants studied was small. The small number of trials along with methodological shortcomings limits the certainty of these findings. Further randomised controlled trials of high methodological quality are necessary to determine the effects of frenotomy.
The risk of bias in the included studies was low. The overall quality of the evidence based on the GRADE approach was moderate. No statistically significant differences were found between interleukin 10 and placebo for complete remission (CDAI < 150 with a 100 point decrease in CDAI from baseline; RR=1.43; 95% CI 0.62 to 3.29; I2=40%) or clinical remission (CDAI < 150; RR=1.29; 95% CI 0.79 to 2.11; I2= 0%). Patients treated with interleukin 10 were significantly more likely to withdraw from the studies due to adverse events (RR=13.50; 95% CI 3.89 to 46.79; I2=0%). Interleukin 10 does not appear to provide any benefit for the treatment of active Crohn's disease. This systematic review shows that interleukin 10 does not increase the number of remissions (complete or clinical), but increases the rate of withdrawal due to adverse events relative to placebo. The quality of the evidence regarding the efficacy of IL-10 is moderate and although further research may have an impact on point estimates of efficacy further randomized trials are unlikely to be undertaken.
We included 21 trials and identified eight ongoing trials. The included trials evaluated metformin (11 trials), sibutramine (six trials), orlistat (four trials), and one trial arm investigated the combination of metformin and fluoxetine. The ongoing trials evaluated metformin (four trials), topiramate (two trials) and exenatide (two trials). A total of 2484 people participated in the included trials, 1478 participants were randomised to drug intervention and 904 to comparator groups (91 participants took part in two cross-over trials; 11 participants not specified). Eighteen trials used a placebo in the comparator group. Two trials had a cross-over design while the remaining 19 trials were parallel RCTs. The length of the intervention period ranged from 12 weeks to 48 weeks, and the length of follow-up from baseline ranged from six months to 100 weeks. Trials generally had a low risk of bias for random sequence generation, allocation concealment and blinding (participants, personnel and assessors) for subjective and objective outcomes. We judged approximately half of the trials as having a high risk of bias in one or more domain such as selective reporting. The primary outcomes of this review were change in body mass index (BMI), change in weight and adverse events. All 21 trials measured these outcomes. The secondary outcomes were health-related quality of life (only one trial reported results showing no marked differences; very low certainty evidence), body fat distribution (measured in 18 trials), behaviour change (measured in six trials), participants' views of the intervention (not reported), morbidity associated with the intervention (measured in one orlistat trial only reporting more new gallstones following the intervention; very low certainty evidence), all-cause mortality (one suicide in the orlistat intervention group; low certainty evidence) and socioeconomic effects (not reported). Intervention versus comparator for mean difference (MD) in BMI change was -1.3 kg/m2 (95% confidence interval (CI) -1.9 to -0.8; P < 0.00001; 16 trials; 1884 participants; low certainty evidence). When split by drug type, sibutramine, metformin and orlistat all showed reductions in BMI in favour of the intervention. Intervention versus comparator for change in weight showed a MD of -3.9 kg (95% CI -5.9 to -1.9; P < 0.00001; 11 trials; 1180 participants; low certainty evidence). As with BMI, when the trials were split by drug type, sibutramine, metformin and orlistat all showed reductions in weight in favour of the intervention. Five trials reported serious adverse events: 24/878 (2.7%) participants in the intervention groups versus 8/469 (1.7%) participants in the comparator groups (risk ratio (RR) 1.43, 95% CI 0.63 to 3.25; 1347 participants; low certainty evidence). A total 52/1043 (5.0%) participants in the intervention groups versus 17/621 (2.7%) in the comparator groups discontinued the trial because of adverse events (RR 1.45, 95% CI 0.83 to 2.52; 10 trials; 1664 participants; low certainty evidence). The most common adverse events in orlistat and metformin trials were gastrointestinal (such as diarrhoea, mild abdominal pain or discomfort, fatty stools). The most frequent adverse events in sibutramine trials included tachycardia, constipation and hypertension. The single fluoxetine trial reported dry mouth and loose stools. No trial investigated drug treatment for overweight children. This systematic review is part of a series of associated Cochrane reviews on interventions for obese children and adolescents and has shown that pharmacological interventions (metformin, sibutramine, orlistat and fluoxetine) may have small effects in reduction in BMI and bodyweight in obese children and adolescents. However, many of these drugs are not licensed for the treatment of obesity in children and adolescents, or have been withdrawn. Trials were generally of low quality with many having a short or no post-intervention follow-up period and high dropout rates (overall dropout of 25%). Future research should focus on conducting trials with sufficient power and long-term follow-up, to ensure the long-term effects of any pharmacological intervention are comprehensively assessed. Adverse events should be reported in a more standardised manner specifying amongst other things the number of participants experiencing at least one adverse event. The requirement of regulatory authorities (US Food and Drug Administration and European Medicines Agency) for trials of all new medications to be used in children and adolescents should drive an increase in the number of high quality trials.
We included 15 trials (39,908 participants) that evaluated antihypertensive pharmacotherapy for a mean duration of follow-up of 4.2 years. This review provides moderate-quality evidence to show that antihypertensive drugs do not reduce sudden death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.81 to 1.15) but do reduce both non-fatal myocardial infarction (RR 0.85, 95% CI 0.74, 0.98; absolute risk reduction (ARR) 0.3% over 4.2 years) and fatal myocardial infarction (RR 0.75, 95% CI 0.62 to 0.90; ARR 0.3% over 4.2 years). Withdrawals due to adverse effects were increased in the drug treatment group to 12.8%, as compared with 6.2% in the no treatment group. Although antihypertensive drugs reduce the incidence of fatal and non-fatal myocardial infarction, they do not appear to reduce the incidence of sudden death. This suggests that sudden cardiac death may not be caused primarily by acute myocardial infarction. Continued research is needed to determine the causes of sudden cardiac death.
A total of 13 studies involving 906 participants are included in the review. The trials were different from one another in terms of type of breathing exercise performed, number of participants enrolled, number and duration of sessions completed, outcomes reported and statistical presentation of data. Asthma severity in participants from the included studies ranged from mild to moderate, and the samples consisted solely of outpatients. The following outcomes were measured: quality of life, asthma symptoms, number of acute exacerbations and lung function. Eleven studies compared breathing exercise with inactive control, and two with asthma education control groups. All eight studies that assessed quality of life reported an improvement in this outcome. An improvement in the number of acute exacerbations was observed by the only study that assessed this outcome. Six of seven included studies showed significant differences favouring breathing exercises for asthma symptoms. Effects on lung function were more variable, with no difference reported in five of the eleven studies that assessed this outcome, while the other six showed a significant difference for this outcome, which favoured breathing exercises. As a result of substantial heterogeneity among the studies, meta-analysis was possible only for asthma symptoms and changes in the Asthma Quality of Life Questionnaire (AQLQ). Each meta-analysis included only two studies and showed a significant difference favouring breathing exercises (MD -3.22, 95% CI -6.31 to -0.13 for asthma symptoms; MD 0.79, 95% CI 0.50 to 1.08 for change in AQLQ). Assessment of risk of bias was impaired by incomplete reporting of methodological aspects of most of the included trials. Even though individual trials reported positive effects of breathing exercises, no reliable conclusions could be drawn concerning the use of breathing exercises for asthma in clinical practice. This was a result of methodological differences among the included studies and poor reporting of methodological aspects in most of the included studies. However, trends for improvement are encouraging, and further studies including full descriptions of treatment methods and outcome measurements are required.
In this Cochrane Review update we did not include any new RCT compared with the first review version. Accordingly, four RCTs (388 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included trials reported data on mortality and bleeding. The studies were conducted in Japan, Italy and the Netherlands. We classified the included trials as: 1) including patients with or without leukemia which did not report data for the leukemia subgroup (366 participants); and 2) only including patients with leukemia (22 participants). Overall, the risk of bias of the included trials was high, since the trial authors did not provide a detailed description about trial design and execution. According to the GRADE recommendations, we judged the overall quality of the body of evidence for all prefixed outcomes as 'very low', due to methodological limitations and very small sample size. One trial, including 10 participants with leukemia and comparing dermatan sulphate with heparin, reported no deaths during trial treatment. In terms of bleeding data, we were unable to pool results from two studies that were only conducted with leukemia patients due to the inconsistency in the measurement and reporting of this outcome. One trial, including 12 participants with leukemia, found very low quality evidence that tranexamic acid can reduce the cumulative hemorrhagic score in participants compared with those assigned to placebo (P = 0.0015, very low quality evidence). On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis (1/5 (20%) versus 2/5 (40%); RR 0.50; 95% CI 0.06 to 3.91; P = 0.51, very low quality evidence). No thromboembolic complications were reported in either trial that included patients with leukemia only (very low quality evidence). The safety profile was inconclusive. The included trials did not assess overall mortality, resolution of respiratory failure, renal failure or shock. Due to a lack of new RCTs, our conclusions in this Cochrane Review update are the same as the previous review version. We included four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The quality of the evidence was low to very low. Therefore, prescription of these interventions for treating DIC in patients with acute and chronic leukemia can neither be supported nor rejected, unless new evidence from a large high-quality trial alters this conclusion.
We included five RCTs involving 825 participants. The studies were carried out in the USA and Europe, and were published between 1987 and 2017. Risk of bias across the studies varied. Most had low risk for selection, reporting and attrition bias, and a high risk for performance and detection bias because blinding was inadequate or absent. All participants had mild to moderate hearing loss. The average age across all five studies was between 69 and 83 years. The duration of the studies ranged between six weeks and six months. There was a large beneficial effect of hearing aids on hearing-specific health-related quality of life associated with participation in daily life as measured using the Hearing Handicap Inventory for the Elderly (HHIE, scale range 1 to 100) compared to the unaided/placebo condition (mean difference (MD) -26.47, 95% confidence interval (CI) -42.16 to -10.77; 722 participants; three studies) (moderate-quality evidence). There was a small beneficial effect of hearing aids on general health-related quality of life (standardised mean difference (SMD) -0.38, 95% CI -0.55 to -0.21; 568 participants; two studies) (moderate-quality evidence). There was a large beneficial effect of hearing aids on listening ability (SMD -1.88, 95% CI -3.24 to -0.52; 534 participants; two studies) (moderate-quality evidence). Adverse effects were measured in only one study (48 participants) and none were reported (very low-quality evidence). The available evidence concurs that hearing aids are effective at improving hearing-specific health-related quality of life, general health-related quality of life and listening ability in adults with mild to moderate hearing loss. The evidence is compatible with the widespread provision of hearing aids as the first-line clinical management in those who seek help for hearing difficulties. Greater consistency is needed in the choice of outcome measures used to assess benefits from hearing aids. Further placebo-controlled studies would increase our confidence in the estimates of these effects and ascertain whether they vary according to age, gender, degree of hearing loss and type of hearing aid.
We included one randomised controlled trial involving 2782 participants. The study investigated the effects of mobile phone messaging in alleviating anxiety in women waiting for prenatal biochemical screening results for Down syndrome, by providing fast reporting of results before a follow-up appointment. The study measured health outcomes using the Spielberger State-Trait Anxiety Inventory (STAI), which includes a scale (20 to 80 points, higher score indicates higher anxiety) to describe how the respondent feels at a particular moment in time (state anxiety). The study, which was at high risk of bias, found that women who had received their test result early by text message had a mean anxiety score 2.48 points lower than women who had not yet received their result (95% CI - 8.79 to 3.84). Women with a serum-negative test result receiving their result early had a mean anxiety score 5.3 points lower (95% CI - 5.99 to -4.61) than women in the control group. Women with a serum-positive test result receiving their result early by text message had a mean anxiety score 1.2 points higher (95% CI - 3.48 to 5.88) than women in the control group.The evidence was of low quality due to high risk of bias in the included study, and the fact that the evidence comes from one study only. The study did not report on other outcomes of interest, such as patient satisfaction, adverse events or cost. We found very limited evidence of low quality that communicating results of medical investigations by mobile phone messaging may make little or no difference to women's anxiety overall or in women with positive test results, but may reduce anxiety in women with negative test results. However, with only one study included in this review, this evidence is insufficient to inform recommendations at this time. More research is needed on the effectiveness and user evaluation of these interventions. In particular, more research should be conducted into the potential risks and limitations of these interventions.
We included three studies, enrolling 1158 participants. Each study reported an increased rate of recovery with intraoperative mild hypothermia, but the effect sizes were not sufficient for certainty. A total of 1086 of the 1158 participants (93.8%) had good grade aneurysmal subarachnoid haemorrhage. Seventy-six of 577 participants (13.1%) who received hypothermia and 93 of 581 participants (16.0%) who did not receive hypothermia were dead or dependent (RR 0.82; 95% CI 0.62 to 1.09; RD -0.03; 95% CI -0.07 to 0.01, moderate-quality evidence) after three months. Reported unfavourable outcomes did not differ between participants with or without hypothermia. The quality of evidence for these outcomes remains unclear because the outcomes were reported in a variety of ways. No decompressive craniectomy or corticectomy was reported. Thirty-six of 577 (6.2%) participants with hypothermia and 40 of 581 (6.9%) participants without hypothermia had infarction. Thirty-four of 577 (6%) participants with hypothermia and 32 of the 581 (5.5%) participants without hypothermia had clinical vasospasm (temporary deficits). Duration of hospital stay was not reported. Only one study with 112 participants reported discharge destinations: 43 of 55 (78.2%) participants with hypothermia and 39 of 57 (68.4%) participants in the control group were discharged home. The remaining participants were discharged to other facilities. Thirty-nine of 577 (6.8%) participants with hypothermia and 39 of 581 (6.7%) participants without hypothermia had infections. Six of 577 (1%) participants with hypothermia and 6 of 581 (1%) participants without hypothermia had cardiac arrhythmia. It remains possible that intraoperative mild hypothermia could prevent death or dependency in activities of daily living in people with good grade aneurysmal subarachnoid haemorrhage. However, the confidence intervals around this estimate include the possibility of both benefit and harm. There was insufficient information to draw any conclusions about the effects of intraoperative mild hypothermia in people with poor grade aneurysmal subarachnoid haemorrhage or without subarachnoid haemorrhage. We did not identify any reliable evidence to support the routine use of intraoperative mild hypothermia. A high-quality randomised clinical trial of intraoperative mild hypothermia for postoperative neurological deficits in people with poor grade aneurysmal subarachnoid haemorrhage might be feasible.
Five trials on gabapentin and one trial on its prodrug gabapentin enacarbil met the inclusion criteria; no reports on pregabalin were identified. In total, data from 1009 patients were considered. One trial each of gabapentin 900 mg (53 patients), and gabapentin titrated to 1200 mg (63 patients) and 1800 mg (122 patients) failed to show a statistically significant reduction in headache frequency in the active treatment group as compared to the placebo group, whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (MD -0.80; 95% confidence interval (CI) -1.55 to -0.05). The pooled results of these four studies (MD -0.44; 95% CI -1.43 to 0.56; 351 patients) do not demonstrate a significant difference between gabapentin and placebo. One trial of gabapentin titrated to 1800 mg (122 patients) failed to demonstrate a significant difference between active treatment and placebo in the proportion of responders (OR 0.97; 95% CI 0.45 to 2.11), whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (OR 2.79; 95% CI 1.09 to 7.17). The pooled results of these two studies (OR 1.59; 95% CI 0.57 to 4.46; 235 patients) do not demonstrate a significant difference between gabapentin and placebo. Comparisons from one study (135 patients) suggest that gabapentin 2000 mg is no more effective than gabapentin 1200 mg. One trial of gabapentin enacarbil (523 participants) failed to demonstrate a significant difference versus placebo or between doses for gabapentin enacarbil titrated to between 1200 mg and 3000 mg with regard to proportion of responders; there was also no evidence of a dose-response trend. Adverse events, most notably dizziness and somnolence, were common with gabapentin. The pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults.
Five studies including 523 participants reported the diagnostic accuracy of ultrasound. One studies (262 participants) compared the accuracy of ultrasound, serum bilirubin and serum alkaline phosphatase in the same participants. All the studies included people with symptoms. One study included only participants without previous cholecystectomy but this information was not available from the remaining studies. All the studies were of poor methodological quality. The sensitivities for ultrasound ranged from 0.32 to 1.00, and the specificities ranged from 0.77 to 0.97. The summary sensitivity was 0.73 (95% CI 0.44 to 0.90) and the specificity was 0.91 (95% CI 0.84 to 0.95). At the median pre-test probability of common bile duct stones of 0.408, the post-test probability (95% CI) associated with positive ultrasound tests was 0.85 (95% CI 0.75 to 0.91), and negative ultrasound tests was 0.17 (95% CI 0.08 to 0.33). The single study of liver function tests reported diagnostic accuracy at two cut-offs for bilirubin (greater than 22.23 μmol/L and greater than twice the normal limit) and two cut-offs for alkaline phosphatase (greater than 125 IU/L and greater than twice the normal limit). This study also assessed ultrasound and reported higher sensitivities for bilirubin and alkaline phosphatase at both cut-offs but the specificities of the markers were higher at only the greater than twice the normal limit cut-off. The sensitivity for ultrasound was 0.32 (95% CI 0.15 to 0.54), bilirubin (cut-off greater than 22.23 μmol/L) was 0.84 (95% CI 0.64 to 0.95), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.92 (95% CI 0.74 to 0.99). The specificity for ultrasound was 0.95 (95% CI 0.91 to 0.97), bilirubin (cut-off greater than 22.23 μmol/L) was 0.91 (95% CI 0.86 to 0.94), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.79 (95% CI 0.74 to 0.84). No study reported the diagnostic accuracy of a combination of bilirubin and alkaline phosphatase, or combinations with ultrasound. Many people may have common bile duct stones in spite of having a negative ultrasound or liver function test. Such people may have to be re-tested with other modalities if the clinical suspicion of common bile duct stones is very high because of their symptoms. False-positive results are also possible and further non-invasive testing is recommended to confirm common bile duct stones to avoid the risks of invasive testing. It should be noted that these results were based on few studies of poor methodological quality and the results for ultrasound varied considerably between studies. Therefore, the results should be interpreted with caution. Further studies of high methodological quality are necessary to determine the diagnostic accuracy of ultrasound and liver function tests.
We included five trials involving 1350 participants in the original review. The updated review identified no new trials. The evidence from two small trials (one trial including infants and one including adolescents) was insufficient to allow any definitive statements to be made about the effects of the needles evaluated in the trials on vaccine immunogenicity and reactogenicity. The remaining three trials (1135 participants) contributed data to comparisons between 25 G 25 mm, 23 G 25 mm, and 25 G 16 mm needles. These trials included infants predominantly aged from two to six months undergoing intramuscular vaccination in the anterolateral thigh using the World Health Organization (WHO) injection technique (skin stretched flat, needle inserted at a 90° angle and up to the needle hub in healthy infants). The vaccines administered were combination vaccines containing diphtheria, tetanus, and whole-cell pertussis antigens (DTwP). In some trials, the vaccines also contained Haemophilus influenzae type b (DTwP-Hib) and hepatitis B (DTwP-Hib-Hep B) antigen components. Primary outcomes Incidence of vaccine-preventable diseases: No trials reported this outcome. Procedural pain and crying: Using a wider gauge 23 G 25 mm needle may slightly reduce procedural pain (low-quality evidence) and probably leads to a slight reduction in the duration of crying time immediately after vaccination (moderate-quality evidence) compared with a narrower gauge 25 G 25 mm needle (one trial, 320 participants). The effects are probably not large enough to be clinically relevant. Secondary outcomes Immune response: There is probably little or no difference in immune response, defined in terms of the proportion of seroprotected infants, between use of 25 G 25 mm, 23 G 25 mm, or 25 G 16 mm needles to administer a series of three doses of a DTwP-Hib vaccine at ages two, three, and four months (moderate-quality evidence, one trial, numbers of participants in analyses range from 309 to 402. The immune response to the pertussis antigen was not measured). Severe and non-severe local reactions: 25 mm needles (either 25 G or 23 G) probably lead to fewer severe and non-severe local reactions after DTwP-Hib vaccination compared with 25 G 16 mm needles (moderate-quality evidence, one trial, 447 to 458 participants in analyses). We estimate that one fewer infant will experience a severe local reaction (extensive redness and swelling) after the first vaccine dose for every 25 infants vaccinated with the longer rather than the shorter needle (number needed to treat for an additional beneficial outcome (NNTB) with a 25 G 25 mm needle: 25 (95% confidence interval (CI) 15 to 100); NNTB with a 23 G 25 mm needle: 25 (95% CI 17 to 100)). We estimate that one fewer infant will experience a non-severe local reaction (any redness, swelling, tenderness, or hardness (composite outcome)) at 24 hours after the first vaccine dose for every 5 or 6 infants vaccinated with a 25 mm rather than a 16 mm needle (NNTB with a 25 G 25 mm needle: 5 (95% CI 4 to 10); NNTB with a 23 G 25 mm needle: 6 (95% CI 4 to 13)). The results are similar after the second and third vaccine doses. Using a narrow gauge 25 G 25 mm needle may produce a small reduction in the incidence of local reactions after each dose of a DTwP vaccine compared with a wider gauge 23 G 25 mm needle, but the effect estimates are imprecise (low-quality evidence, two trials, 100 to 459 participants in analyses). Systemic reactions: The comparative effects of 23 G 25 mm, 25 G 25 mm, and 25 G 16 mm needles on the incidence of postvaccination fever and other systemic events such as drowsiness, loss of appetite, and vomiting are uncertain due to the very low quality of the evidence. Using 25 mm needles (either 23 G or 25 G) for intramuscular vaccination procedures in the anterolateral thigh of infants using the WHO injection technique probably reduces the occurrence of local reactions while achieving a comparable immune response to 25 G 16 mm needles. These findings are applicable to healthy infants aged two to six months receiving combination DTwP vaccines with a reactogenic whole-cell pertussis antigen component. These vaccines are predominantly used in low- and middle-income countries. The applicability of the findings to vaccines with acellular pertussis components and other vaccines with different reactogenicity profiles is uncertain.
We included 28 trials (3 of which are new trials since the original review), involving 9140 children and adolescents. Most of these trials recruited participants from schools. Most of the studies (20) were at high risk of bias, with 8 at unclear risk of bias. Twenty-five trials (8479 participants) contributed data for meta-analysis on permanent tooth surfaces: the D(M)FS pooled prevented fraction (PF) estimate was 28% (95% confidence intervals (CI) 19% to 36%; P < 0.0001; with substantial heterogeneity (P < 0.0001; I2 = 82%); moderate quality evidence). Subgroup and metaregression analyses suggested no significant association between estimates of D(M)FS prevented fractions and the prespecified trial characteristics. However, the effect of fluoride gel varied according to the type of control group used, with D(M)FS PF on average being 17% (95% CI 3% to 31%; P = 0.018) higher in non-placebo-controlled trials (the reduction in caries was 38% (95% CI 24% to 52%; P < 0.0001, 2808 participants) for the 10 trials with no treatment as control group, and 21% (95% CI 15% to 28%; P < 0.0001, 5671 participants) for the 15 placebo-controlled trials. A funnel plot of the 25 trials in the D(M)FS PF meta-analysis indicated a relationship between prevented fraction and study precision, with an apparent lack of small studies with statistically significant large effects. The d(e/m)fs pooled prevented fraction estimate for the three trials (1254 participants) that contributed data for the meta-analysis on primary teeth surfaces was 20% (95% CI 1% to 38%; P = 0.04; with no heterogeneity (P = 0.54; I2 = 0%); low quality evidence). There was limited reporting of adverse events. Only two trials reported information on acute toxicity signs and symptoms during the application of the gel (risk difference 0.01, 95% CI -0.01 to 0.02; P = 0.36; with no heterogeneity (P = 36; I2 = 0%); 490 participants; very low quality evidence). None of the trials reported information on tooth staining, mucosal irritation or allergic reaction. The conclusions of this updated review remain the same as those when it was first published. There is moderate quality evidence of a large caries-inhibiting effect of fluoride gel in the permanent dentition. Information concerning the caries-preventive effect of fluoride gel on the primary dentition, which also shows a large effect, is based on low quality evidence from only three placebo-controlled trials. There is little information on adverse effects or on acceptability of treatment. Future trials should include assessment of potential adverse effects.
Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67). There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.
Eleven studies (835 participants) compared exercise to usual care. No studies compared exercise with no treatment or non-exercise interventions. The quality of the evidence was very low for the primary outcome rates of falls, and very low to low for the secondary outcomes. We downgraded the evidence due to study limitations (risk of bias), and issues of imprecision due to small sample sizes, inconsistency and indirectness. All studies were at high risk of bias for blinding of participants and personnel due to inability to blind participants to an exercise intervention. Risk of bias was generally low or unclear for other categories. There was generally little information on the important outcomes comparing exercise to usual care. Rates of falls and number of fallers: one study (223 participants) measured accidental falls, but reported neither the rate of falls or the number of fallers; there was no difference in the number of falls between exercise and usual care (very low-quality evidence). Strength: 10 studies (813 participants) reported on strength outcomes. Two analyses favoured exercise over usual care: quadriceps strength (2 studies, 72 participants; mean difference (MD) 8.99 kg, 95% confidence interval (CI) 1.29 to 16.70; low-quality evidence), and leg press (4 studies, 388 participants; MD 21.1 kg, 95% CI 8.47 to 33.74; low-quality evidence). In one analysis of the Sit-to-Stand Test, there was no difference between exercise and usual care (4 studies, 214 participants; standardised mean difference (SMD) –0.45, 95% CI –1.05 to 0.14; very low-quality evidence). Flexibility: one study (21 participants) reported on flexibility for Sit-and-Reach Distance (MD 2.05 cm, 95% CI 0.59 to 3.51; very low-quality evidence). Balance: five studies (350 participants) measured three different balance outcomes. Two analyses favoured exercise over usual care: postural balance (4 studies, 127 participants; standardised mean difference (SMD) 0.44, 95% CI 0.08 to 0.79; very low-quality evidence), and Backward Walk Test (2 studies, 280 participants; SMD –0.24, 95% CI –0.48 to –0.01; low-quality evidence). There was no difference between exercise and usual care for the Timed Up-and-Go Test (1 study, 15 participants; MD –0.35 seconds, 95% CI –1.47 to 0.77; low-quality evidence). Number of people sustaining a fall-related fracture: the quality of the evidence for exercise reducing fall-related fractures was very low. Adverse events: a single study (223 participants) noted some temporary muscle soreness on initiation of exercise or when there was an increase in the weight lifted. As no occurrence data were reported, we could not assess this variable further. No studies reported musculoskeletal injury. Analysis indicated that there was very low-quality evidence that exercise did not increase fatigue. There is a paucity of evidence for exercise training to reduce fall rates in people living with and beyond cancer. Exercise training may improve strength, flexibility and balance for people in this population, but the evidence is very low quality.
We included two eligible studies with a total of 287 participants; both had good methodological quality. There was no difference in the duration of catheter patency between heparin-bonded and non-heparin bonded catheters (median duration seven days versus six days) reported in one study. There was no difference in the risk of catheter-related thrombosis (two studies, RR 0.34, 95% CI 0.01 to 7.68; I2 = 80%; RD -0.06, 95% CI -0.17 to 0.06). Data from one study revealed a statistically significant reduction in the risk of catheter occlusion (RR 0.06, 95% CI 0.00 to 1.07; RD -0.08, 95% CI -0.13 to -0.02; NNT 13, 95% CI 8 to 50), catheter-related blood stream infections (RR 0.06, 95% CI 0.01 to 0.41; RD -0.17, 95% CI -0.25 to -0.10; NNT 6, 95% CI 4 to 10) and catheter colonization (RR 0.21, 95% CI 0.06 to 0.71; RD -0.11, 95% CI -0.19 to -0.04; NNT 9, 95% CI 5 to 25) in the heparin-bonded catheter group. The second study did not report on these outcomes. There was no significant difference in risk of thrombocytopenia after catheter placement (RR 0.73, 95% CI 0.38 to 1.39; RD -0.02, 95% CI -0.10 to 0.07). Two eligible studies on the use of heparin-bonded catheters versus placebo in children were identified. Meta-analysis of the two studies revealed no reduction in catheter-related thrombosis with heparin-bonded catheters. One study reported a reduction in catheter-related blood stream infection and colonization following the use of heparin-bonded catheters. The strength of evidence is low and further well-designed multicenter randomized controlled trials are warranted.
We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers. However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses. There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.
We identified two randomised controlled trials that met our inclusion criteria, and we found no new trials when we updated the searches in 2012. The first, a study with overall unclear risk of bias, examined the effects of a twice-daily exercise program of moderate load endurance exercise versus "usual activities" in 25 people with ALS. The second, a study with overall low risk of bias, examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined (43 participants), there was a significant mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in favour of the exercise groups (mean difference 3.21, 95% confidence interval 0.46 to 5.96). No statistically significant differences in quality of life, fatigue or muscle strength were found. In both trials adverse effects, investigators reported no adverse effects such as increased muscle cramping, muscle soreness or fatigue The included studies were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.
Two RCTs were identified. One compared warfarin, aspirin and no antithrombotic therapy and the second compared warfarin with placebo in patients with idiopathic dilated cardiomyopathy. Three small prospective controlled studies of warfarin in heart failure were also identified, but they were over 50 years old with methods not considered reliable by modern standards. In both WASH 2004 and HELAS 2006, there were no significant differences in the incidence of myocardial infarction, non-fatal stroke and death between patients taking oral anticoagulation and those taking placebo. Four retrospective non-randomised cohort analyses and four observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients and reported contradictory results. Based on the two major randomised trials (HELAS 2006; WASH 2004), there is no convincing evidence that oral anticoagulant therapy modifies mortality or vascular events in patients with heart failure and sinus rhythm. Although oral anticoagulation is indicated in certain groups of patients with heart failure (for example those with atrial fibrillation), the available data does not support the routine use of anticoagulation in heart failure patients who remain in sinus rhythm.
This review examined 16 trials lasting four weeks to two years involving 1391 participants receiving 15 different Chinese herbal medicines in eight different comparisons. No trial reported on mortality, morbidity or costs. No serious adverse events like severe hypoglycaemia were observed. Meta-analysis of eight trials showed that those receiving Chinese herbal medicines combined with lifestyle modification were more than twice as likely to have their fasting plasma glucose levels return to normal levels (i.e. fasting plasma glucose <7.8 mmol/L and 2hr blood glucose <11.1 mmol/L) compared to lifestyle modification alone (RR 2.07; 95% confidence intervall (CI) 1.52 to 2.82). Those receiving Chinese herbs were less likely to progress to diabetes over the duration of the trial (RR 0.33; 95% CI 0.19 to 0.58). However, all trials had a considerable risk of bias and none of the specific herbal medicines comparison data was available from more than one study. Moreover, results could have been confounded by rates of natural reversion to normal glucose levels. The positive evidence in favour of Chinese herbal medicines for the treatment of IGT or IFG is constrained by the following factors: lack of trials that tested the same herbal medicine, lack of details on co-interventions, unclear methods of randomisation, poor reporting and other risks of bias.
Fourteen trials compared escitalopram with another SSRI and eight compared escitalopram with a newer antidepressive agent (venlafaxine, bupropion and duloxetine). Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR 0.67, 95% CI 0.50 to 0.87). Escitalopram was also more effective than citalopram in terms of remission (OR 0.53, 95% CI 0.30 to 0.93). Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to duloxetine, for discontinuation due to any cause (OR 0.62, 95% CI 0.38 to 0.99). Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression were found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to detect a difference between escitalopram and other antidepressants in early response to treatment (after two weeks of treatment). Cost-effectiveness information is also needed in the field of antidepressant trials. Furthermore, as with most standard systematic reviews, the findings rely on evidence from direct comparisons. The potential for overestimation of treatment effect due to sponsorship bias should also be borne in mind.
We included eight studies in the review and seven in the meta-analysis. Of those seven studies, only two were judged to be at low risk of bias. Overall, no strong evidence exists that etomidate increases mortality in critically ill patients when compared to other bolus dose induction agents (odds ratio (OR) 1.17; 95% confidence interval (CI) 0.86 to 1.60, 6 studies, 772 participants, moderate quality evidence). Due to a large number of participants lost to follow-up, we performed a post hoc sensitivity analysis. This gave a similar result (OR 1.15; 95% CI 0.86 to 1.53). There was evidence that the use of etomidate in critically ill patients was associated with a positive adrenocorticotropic hormone (ACTH) stimulation test, and this difference was more pronounced at between 4 to 6 hours (OR 19.98; 95% CI 3.95 to 101.11) than after 12 hours (OR 2.37; 95% CI 1.61 to 3.47) post-dosing. Etomidate's use in critically ill patients was associated with a small increase in SOFA score, indicating a higher risk of multisystem organ failure (mean difference (MD) 0.70; 95% CI 0.01 to 1.39, 2 studies, 591 participants, high quality evidence), but this difference was not clinically meaningful. Etomidate use did not have an effect on ICU LOS (MD 1.70 days; 95% CI -2.00 to 5.40, 4 studies, 621 participants, moderate quality evidence), hospital LOS (MD 2.41 days; 95% CI -7.08 to 11.91, 3 studies, 152 participants, moderate quality evidence), duration of mechanical ventilation (MD 2.14 days; 95% CI -1.67 to 5.95, 3 studies, 621 participants, moderate quality evidence), or duration of vasopressor use (MD 1.00 day; 95% CI -0.53 to 2.53, 1 study, 469 participants). Although we have not found conclusive evidence that etomidate increases mortality or healthcare resource utilization in critically ill patients, it does seem to increase the risk of adrenal gland dysfunction and multi-organ system dysfunction by a small amount. The clinical significance of this finding is unknown. This evidence is judged to be of moderate quality, owing mainly to significant attrition bias in some of the smaller studies, and new research may influence the outcomes of our review. The applicability of these data may be limited by the fact that 42% of the patients in our review were intubated for "being comatose", a population less likely to benefit from the haemodynamic stability inherent in etomidate use, and less at risk from its potential negative downstream effects of adrenal suppression.
We included 10 trials that involved 390 children with ASD. The age range was three to 18 years and the treatment duration ranged from four weeks to nine months. The studies were carried out in Hong Kong, mainland China and Egypt. Two trials compared needle acupuncture with sham acupuncture and found no difference in the primary outcome of core autistic features (RFRLRS total score: MD 0.09; 95% CI -0.03 to 0.21, P = 0.16), although results suggested needle acupuncture might be associated with improvement in some aspects of the secondary outcomes of communication and linguistic ability, cognitive function and global functioning. Six trials compared needle acupuncture plus conventional treatment with conventional treatment alone. The trials used different primary outcome measures and most could not demonstrate effectiveness of acupuncture in improving core autistic features in general, though one trial reported patients in the acupuncture group were more likely to have improvement on the Autism Behavior Checklist (RR 1.53; 95% CI 1.09 to 2.16, P = 0.02) and had slightly better post-treatment total scores (MD -5.53; 95% CI -10.76 to -0.31, P = 0.04). There was no evidence that acupuncture was effective for the secondary outcome of communication and linguistic ability, though there seemed to be some benefit for the secondary outcomes of cognitive function and global functioning. Two trials compared acupressure plus conventional treatment with conventional treatment alone and did not report on the primary outcome. Individual study results suggested there may be some benefit from acupressure for certain aspects of the secondary outcomes of communication and linguistic ability, cognitive function and global functioning. Four trials reported some adverse effects, though there was little quantitative information, and at times both intervention and control groups experienced them. Adverse effects noted included bleeding, crying due to fear or pain, irritability, sleep disturbance and increased hyperactivity. None of the trials reported on quality of life. There are a number of problems with the evidence base: the trials were few in number and included only children; six of the trials were at high risk of bias; they were heterogeneous in terms of participants and intervention; they were of short duration and follow-up; they reported inconsistent and imprecise results, and, due to carrying out large numbers of analyses, they were at risk of false positivity. Current evidence does not support the use of acupuncture for treatment of ASD. There is no conclusive evidence that acupuncture is effective for treatment of ASD in children and no RCTs have been carried out with adults. Further high quality trials of larger size and longer follow-up are needed.
For this update we included one RCT with 17,802 participants that assessed rosuvastatin compared with placebo for the prevention of VTE. The quality of the evidence was moderate because of imprecision, as the required sample size for the outcomes of this review was not achieved. Analysis showed that when compared with placebo rosuvastatin reduced the incidence of VTE (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37 to 0.86) and deep vein thrombosis (DVT) (OR 0.45, 95% CI 0.25 to 0.79), the risk of any (fatal and non-fatal) myocardial infarction (MI) (OR 0.45, 95% CI 0.30 to 0.69), and any (fatal and non-fatal) stroke (OR 0.51, 95% CI 0.34 to 0.78). There was no difference in the incidence of pulmonary embolism (PE) (OR 0.77, 95% CI 0.41 to 1.46), fatal MI (OR 1.50, 95% CI 0.53 to 4.22), fatal stroke (OR 0.30, 95% CI 0.08 to 1.09) or death after VTE (OR 0.50, 95% CI 0.20 to 1.24). The incidence of any serious adverse events was no different between the rosuvastatin and placebo groups (OR 1.07, 95% CI 0.95 to 1.20). Available evidence showed that rosuvastatin was associated with a reduced incidence of VTE, but the evidence was limited to a single RCT and any firm conclusions and suggestions could be not drawn. Randomised controlled trials of statins (including rosuvastatin) are needed to evaluate their efficacy in the prevention of VTE.
Three cohort studies were included in the review. They examined 484 patients with HIV infection who received YF immunisation. Patients with HIV infection developed significantly lower concentrations of neutralising antibodies in the first year post immunisation compared to uninfected patients, though decay patterns were similar for recipients regardless of HIV infection. No study patient with HIV infection suffered serious adverse events as a result of YF vaccination. YF vaccination can produce protective levels of neutralising antibodies in HIV patients. Immunogenicity of YF vaccine is slightly less in HIV-infected patients compared to HIV-uninfected patients. No serious adverse events related to YF vaccine were observed in HIV-infected study participants. At time of immunisation, higher CD4 cell counts and lower HIV RNA levels in patients with HIV infection seem to be key determinants for development of protective titres of neutralising antibodies. The quality of the evidence for all outcomes was low to very low. YF vaccine may potentially be used safely in HIV-infected patients, although our conclusions are limited by small numbers of patients who have been reported. To assure maximum effectiveness YF vaccine should be given to HIV-infected patients after HIV replication has been suppressed.
Only one randomised trial was identified and included in the review. The bias risk in the trial was high. The trial compared chlorambucil versus no intervention in 24 patients with primary biliary cirrhosis. Fisher's exact test did not show a significant reduction of mortality when comparing chlorambucil with no treatment (0/13 (0%) versus (2/11 (18.2%); P = 0.20). There was no significant difference regarding adverse events for chlorambucil compared with no treatment, but all patients receiving chlorambucil experienced adverse events (13/13 (100%) versus (3/11 (27%); P = 0.1). According to the authors of the trial, chlorambucil led to a significant improvement in mean serum levels of bilirubin (P < 0.05), albumin (P < 0.05), immunoglobulin M (P < 0.01), serum aspartate aminotransferase activity (P < 0.01), and hepatic inflammatory infiltrates (P < 0.01). There is not sufficient evidence to support or reject the use of chlorambucil for patients with primary biliary cirrhosis. Chlorambucil may show benefit in some unvalidated surrogate outcome measures (for example, serum bilirubin and immunoglobulin M levels). Chlorambucil is, however, connected with a number of adverse events. Bone marrow suppression should be noted in particular. Further randomised clinical trials are necessary to assess the benefits and harms of chlorambucil in this indication.
We included 23 trials (8 parallel-group and 15 cross-over trials), with 2675 children aged three years to 17 years. All studies compared amphetamines to placebo. Study durations ranged from 14 days to 365 days, with the majority lasting less than six months. Most studies were conducted in the United States; three studies were conducted across Europe. We judged 11 included studies to be at a high risk of bias due to insufficient blinding methods, failing to account for dropouts and exclusions from the analysis, and failing to report on all outcomes defined a priori. We judged the remaining 12 studies to be at unclear risk of bias due to inadequate reporting. Amphetamines improved total ADHD core symptom severity according to parent ratings (SMD -0.57; 95% confidence interval (CI) -0.86 to -0.27; 7 studies; 1247 children/adolescents; very low quality evidence), teacher ratings (SMD -0.55; 95% CI -0.83 to -0.27; 5 studies; 745 children/adolescents; low quality evidence), and clinician ratings (SMD -0.84; 95% CI -1.32 to -0.36; 3 studies; 813 children/adolescents; very low quality evidence). In addition, the proportion of responders as rated by the Clinical Global Impression - Improvement (CGI-I) scale was higher when children were taking amphetamines (RR 3.36; 95% CI 2.48 to 4.55; 9 studies; 2207 children/adolescents; very low quality evidence). The most commonly reported adverse events included decreased appetite, insomnia/trouble sleeping, abdominal pain, nausea/vomiting, headaches, and anxiety. Amphetamines were associated with a higher proportion of participants experiencing decreased appetite (RR 6.31; 95% CI 2.58 to 15.46; 11 studies; 2467 children/adolescents), insomnia (RR 3.80; 95% CI 2.12 to 6.83; 10 studies; 2429 children/adolescents), and abdominal pain (RR 1.44; 95% CI 1.03 to 2.00; 10 studies; 2155 children/adolescents). In addition, the proportion of children who experienced at least one adverse event was higher in the amphetamine group (RR 1.30; 95% CI 1.18 to 1.44; 6 studies; 1742 children/adolescents; low quality evidence). We performed subgroup analyses for amphetamine preparation (dexamphetamine, lisdexamphetamine, mixed amphetamine salts), amphetamine release formulation (long acting versus short acting), and funding source (industry versus non industry). Between-group differences were observed for proportion of participants experiencing decreased appetite in both the amphetamine preparation (P < 0.00001) and amphetamine release formulation (P value = 0.008) subgroups, as well as for retention in the amphetamine release formulation subgroup (P value = 0.03). Most of the included studies were at high risk of bias and the overall quality of the evidence ranged from low to very low on most outcomes. Although amphetamines seem efficacious at reducing the core symptoms of ADHD in the short term, they were associated with a number of adverse events. This review found no evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting amphetamine preparations. Future trials should be longer in duration (i.e. more than 12 months), include more psychosocial outcomes (e.g. quality of life and parent stress), and be transparently reported.
We included 1 RCT and 9 CCTs (total number of participants = 770). None of the included studies reported clinical outcomes. All included studies reported on influenza immunity and adverse reactions to vaccination. In five studies, immune responses to influenza vaccine were compared in 272 children receiving chemotherapy and 166 children not receiving chemotherapy. In four studies, responses to influenza vaccine were assessed in 236 children receiving chemotherapy compared with responses in 142 healthy children. Measures used to assess immune responses included a four-fold rise in antibody titre after vaccination, development of a haemagglutination inhibition (HI) titre > 32 and pre- and post-vaccination geometric mean titres (GMTs). Immune responses in children receiving chemotherapy were consistently weaker (four-fold rise of 38% to 65%) than those in children who had completed chemotherapy (50% to 86%) and in healthy children (53% to 89%). In terms of adverse effects, 391 paediatric oncology patients received influenza vaccine, and the adverse effects described included mild local reactions and low-grade fever. No life-threatening or persistent adverse effects were reported. Paediatric oncology patients receiving chemotherapy are able to generate an immune response to the influenza vaccine, but it remains unclear whether this immune response protects them from influenza infection or its complications. We are awaiting results from well-designed RCTs addressing the clinical benefit of influenza vaccination in these patients.
Eleven studies met the inclusion criteria of the review (1021 participants). Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health-related quality of life (mean difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive. Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available. There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function. It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease
Nine studies involving 804 participants (IM = 402 participants; oral = 402 participants) met our review inclusion criteria. Four studies enrolled children (n = 245 participants), while five studies enrolled adults (n = 559 participants). All of the studies recruited participants presenting to an ED, except one study which recruited participants attending a primary care clinic. All of the paediatric studies compared intramuscular (IM) dexamethasone to oral prednisone/prednisolone. In the adult studies, the IM corticosteroid provided ranged from methylprednisolone, betamethasone, dexamethasone, or triamcinolone, while the regimen of oral corticosteroids provided consisted of prednisone, methylprednisolone, or dexamethasone. Only five studies were placebo controlled. For the purposes of this review, we did not take corticosteroid dose equivalency into account in the analysis. The most common co-intervention provided to participants during the acute care visit included short-acting beta₂-agonists (SABA), methylxanthines, and ipratropium bromide. In some instances, some studies reported providing some participants with supplemental oral or IV corticosteroids during their stay in the ED. Co-interventions provided to participants at discharge consisted primarily of SABA, methylxanthine, long-acting beta₂-agonists (LABA), and ipratropium bromide. The risk of bias of the included studies ranged from unclear to high across various domains. The primary outcome of interest was relapse to additional care defined as an unscheduled visit to a health practitioner for worsening asthma symptoms, or requiring subsequent treatment with corticosteroids which may have occurred at any time point after discharge from the ED. We found intramuscular and oral corticosteroids to be similarly effective in reducing the risk for relapse (RR 0.94, 95% CI 0.72 to 1.24; 9 studies, 804 participants; I² = 0%; low-quality evidence). We found no subgroup differences in relapse rates between paediatric and adult participants (P = 0.71), relapse occurring within or after 10 days post-discharge (P = 0.22), or participants with mild/moderate or severe exacerbations (P = 0.35). While we found no statistical difference between participants receiving IM versus oral corticosteroids regarding the risk for adverse events (RR 0.83, 95% CI 0.64 to 1.07; 5 studies, 404 participants; I² = 0%; moderate-quality evidence), an estimated 50 fewer patients per 1000 receiving IM corticosteroids reported experiencing adverse events (95% from 106 fewer to 21 more). We found inconsistent reporting of specific adverse events across the studies. There were no differences in the frequency of specific adverse events including nausea and vomiting, pain, swelling, redness, insomnia, or personality changes. We did not seek additional adverse events data. Participants receiving IM corticosteroids or oral corticosteroids both reported decreases in peak expiratory flow (MD −7.78 L/min, 95% CI −38.83 L/min to 23.28 L/min; 4 studies, 272 participants; I² = 33%; moderate-quality evidence), similar symptom persistence (RR 0.41, 95% CI 0.14 to 1.20; 3 studies, 80 participants; I² = 44%; low-quality evidence), and 24-hour beta-agonist use (RR 0.54, 95% CI 0.21 to 1.37; 2 studies, 48 participants; I² = 0%; low-quality evidence). There is insufficient evidence to identify whether IM corticosteroids are more effective in reducing relapse compared to oral corticosteroids among children or adults discharged from an ED or equivalent acute care setting for acute asthma. While we found no statistical differences, patients receiving IM corticosteroids reported fewer adverse events. Additional studies comparing the effectiveness of IM versus oral corticosteroids could provide further evidence clarity. Furthermore, there is a need for studies comparing different IM corticosteroids (e.g. IM dexamethasone versus IM methylprednisone) and different oral corticosteroids (e.g. oral dexamethasone versus oral prednisone), with consideration for dosing and pharmacokinetic properties, to better identify the optimal IM or oral corticosteroid regimens to improve patient outcomes. Other factors, such as patient preference and potential issues with adherence, may dictate practitioner prescribing.
For the purpose of this review, STI strategies were classified either as a timed-cycle STI strategy or a CD4-guided STI strategy. In timed-cycle STI strategy, a predetermined period of fixed duration (e.g. one week, one month) off ART was attempted followed by resumption of ART, while closely monitoring changes in CD4 levels and viral load levels. Predetermined criteria for interruption and resumption were laid out in this strategy. Timed-cycle STI fell out of favor due to reports of development of resistance in many studies. Moreover, there were no significant immunological and virological benefits, and no reduction in toxicities, reported in these studies. In CD4-guided STI strategy, ART was interrupted for variable durations guided by CD4 levels. Participants with high nadir CD4 levels qualified for this approach. A reduction in costs of ART, a reduction in mutation, and a better tolerability of this CD4-guided STI strategy was reported. However, concerns about long-term safety of this strategy on immunological, virological, and clinical outcomes were also raised. Timed-cycle STI have not been proven to be safe in the short term. Although CD4-guided STI strategy has reported favorable outcomes in the short term, the long-term safety, efficacy and tolerability of this strategy has not been fully investigated. Based on the studies we reviewed, the evidence to support the use of timed-cycle STI and CD4-guided STI cycles as a standard of care in the management of chronic suppressed HIV infection is inconclusive.
Overall, 102 studies have been included in this review. Interventions explored were: 'positive distracters', to include aromas (two studies), audiovisual distractions (five studies), decoration (one study), and music (85 studies); interventions to reduce environmental stressors through physical changes, to include air quality (three studies), bedroom type (one study), flooring (two studies), furniture and furnishings (one study), lighting (one study), and temperature (one study); and multifaceted interventions (two studies). We did not find any studies meeting the inclusion criteria to evaluate: art, access to nature for example, through hospital gardens, atriums, flowers, and plants, ceilings, interventions to reduce hospital noise, patient controls, technologies, way-finding aids, or the provision of windows. Overall, it appears that music may improve patient-reported outcomes such as anxiety; however, the benefit for physiological outcomes, and medication consumption has less support. There are few studies to support or refute the implementation of physical changes, and except for air quality, the included studies demonstrated that physical changes to the hospital environment at least did no harm. Music may improve patient-reported outcomes in certain circumstances, so support for this relatively inexpensive intervention may be justified. For some environmental interventions, well designed research studies have yet to take place.
Twenty trials were included. These involved a total of 2562 mostly young active adult males. All trials had methodological weaknesses. Specifically, concealment of allocation was confirmed in only one trial. Data for pooling individual outcomes were only available for a maximum of 12 trials and under 60% of participants. The findings of statistically significant differences in favour of the surgical treatment group for the four primary outcomes (non-return to pre-injury level of sports; ankle sprain recurrence; long-term pain; subjective or functional instability) when using the fixed-effect model were not robust when using the random-effects model, nor on the removal of one low quality (quasi-randomised) trial that had more extreme results. A corresponding drop in the I² statistics showed the remaining trials to be more homogeneous. The functional implications of the statistically significantly higher incidence of objective instability in conservatively treated trial participants are uncertain. There was some limited evidence for longer recovery times, and higher incidences of ankle stiffness, impaired ankle mobility and complications in the surgical treatment group. There is insufficient evidence available from randomised controlled trials to determine the relative effectiveness of surgical and conservative treatment for acute injuries of the lateral ligament complex of the ankle. High quality randomised controlled trials of primary surgical repair versus the best available conservative treatment for well-defined injuries are required.
The 2011 update search yielded three further randomised controlled trials. The review currently includes 34 studies with 2657 participants. Most studies were characterised by a small sample size, short duration, and incomplete outcome data reporting. Benzodiazepine monotherapy is compared with placebo in eight trials. The proportion of participants with no clinically important response did not significantly differ between those given benzodiazepines or placebo (N = 382, 6 RCTs, RR 0.67 CI 0.44 to 1.02). The results from the various rating scales applied to assess global and mental state were inconsistent. Fourteen studies examined benzodiazepine monotherapy in comparison with antipsychotic monotherapy. Clinically important treatment response assessment revealed no statistically significant difference between the study groups (30 minutes: N = 44, 1 RCT, RR 0.91 CI 0.58 to 1.43; 60 minutes: N = 44,1 RCT, RR 0.61 CI 0.20 to 1.86; 12 hours: N = 66, 1 RCT, RR 0.75 CI 0.44 to 1.30; pooled short-term studies: N = 112, 2 RCTs, RR 1.48 CI 0.64 to 3.46). Desired sedation occurred significantly more often among participants in the benzodiazepine group than in the antipsychotic group at 20 and 40 minutes. No significant between-group differences could be identified for global and mental state or occurrence of adverse effects. Twenty trials compared benzodiazepine augmentation of antipsychotics with antipsychotic monotherapy. Referring to clinically important response, statistically significant improvement could be demonstrated only for the first 30 minutes of augmentation treatment (30 minutes: 1 RCT, N = 45, RR 0.38 CI 0.18 to 0.80; 60 minutes: N = 45,1 RCT, RR 0.07 CI 0.00 to 1.13; 12 hour: N = 67,1 RCT, RR 0.85 CI 0.51 to 1.41; pooled short-term studies: N = 511, 6 RCTs, RR 0.87 CI 0.49 to 1.54). Analyses of the global and mental state yielded no between-group differences except for desired sedation at 30 as well as 60 minutes (30 minutes: N = 45, 1 RCT, RR 2.25 CI 1.18 to 4.30; 60 minutes: N = 45, 1 RCT, RR 1.39 CI 1.06 to 1.83). There is currently no convincing evidence to confirm or refute the practise of administering benzodiazepines as monotherapy or in combination with antipsychotics for the pharmacological treatment of schizophrenia and schizophrenia-like psychosis. Low-quality evidence suggests that benzodiazepines are effective for very short-term sedation and could be considered for calming acutely agitated people with schizophrenia. Measured by the overall attrition rate, the acceptability of benzodiazepine treatment appears to be adequate. Adverse effects were generally poorly reported. High-quality future research projects with large sample sizes are required to clarify the evidence of benzodiazepine treatment in schizophrenia, especially regarding long-term augmentation strategies.
We included one quasi-RCT (with data from 73 women) in the review. The trial, which was conducted in a public hospital in Brazil, compared oral chloramphenicol 500 mg four times daily for 72 hours after episiotomy repair (N = 34) and no treatment (N = 39). We assessed most of the domains at high risk of bias because women were randomised according to even and odd numbers, allocation concealment was based on protocol number, there was no treatment or placebo administered in the control group, we were unclear about the blinding of outcome assessments, and outcomes were incompletely reported. We considered the other domains to be at low risk of bias. We downgraded the quality of the evidence for very serious design limitations (related to lack of random sequence generation, allocation concealment, and blinding) and imprecision of effect estimates (small sample sizes and wide confidence intervals (CI) of effect estimates). We found very low-quality evidence, from one trial of 73 women, that there was no clear indication that prophylactic antibiotics reduced the incidence of episiotomy wound dehiscence with infection (risk ratio (RR) 0.13, 95% CI 0.01 to 2.28), or without infection (RR 0.82, 95% CI 0.29 to 2.34). No cases of other puerperal infections (e.g. endometritis) were reported in either the antibiotic or control group. The trial did not report on any of the secondary outcomes of interest for this review, including severe maternal infectious morbidity, discomfort or pain at the episiotomy wound site, sexual function postpartum, adverse effects of antibiotics, costs of care, women's satisfaction with care, and individual antimicrobial resistance. There was insufficient evidence to assess the clinical benefits or harms of routine antibiotic prophylaxis for episiotomy repair after normal birth. The only trial included in this review had several methodological limitations, with very serious limitations in design, and imprecision of effect estimates. In addition, the trial tested an antibiotic with limited application in current clinical practice. There is a need for a careful and rigorous assessment of the comparative benefits and harms of prophylactic antibiotics on infection morbidity after episiotomy, in well-designed randomised controlled trials, using common antibiotics and regimens in current obstetric practice.
The search update identified 273 new references, of which none fulfilled our inclusion criteria. We included four studies (643 participants) in this updated review, which were all included in the previous (2004) update. The quality of the evidence was very low for all outcomes. As data were too clinically heterogeneous to be pooled, we described individual trial results. The results indicate that there is very low quality evidence that back schools are no more effective than a placebo (or sham or attention control) or another treatment (physical therapies, myofascial therapy, joint manipulations, advice) on pain, disability, work status and adverse events at short-term, intermediate-term and long-term follow-up. There is very low quality evidence that shows a statistically significant difference between back schools and a placebo (or sham or attention control) for return to work at short-term follow-up in favour of back school. Very low quality evidence suggests that back school added to a back care programme is more effective than a back care programme alone for disability at short-term follow-up. Very low quality evidence also indicates that there is no difference in terms of adverse events between back school and myofascial therapy, joint manipulation and combined myofascial therapy and joint manipulation. It is uncertain if back schools are effective for acute and subacute non-specific LBP as there is only very low quality evidence available. While large well-conducted studies will likely provide more conclusive findings, back schools are not widely used interventions for acute and subacute LBP and further research into this area may not be a priority.
We included in the review 37 studies representing 6128 adult and adolescent participants (most with mild to moderate asthma). Investigators in these studies used three leukotriene receptor antagonists (LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies lasted from four weeks to five years. Anti-leukotrienes and ICS versus same dose of ICS Of 16 eligible studies, 10 studies, representing 2364 adults and adolescents, contributed data. Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants; four studies; moderate quality); this is equivalent to a number needed to treat for additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75). Only one trial including 368 participants reported mortality and serious adverse events, but events were too infrequent for researchers to draw a conclusion. Four trials reported all adverse events, and the pooled result suggested little difference between groups (RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality). Investigators noted between-group differences favouring the addition of anti-leukotrienes for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), asthma symptoms and night-time awakenings, but not for reduction in β2-agonist use or evening PEFR. Anti-leukotrienes and ICS versus higher dose of ICS Of 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed data. Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779 participants; four studies; moderate quality) nor in all adverse events between groups (RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three trials reported no deaths among 834 participants. Results showed no statistically significant differences in lung function tests including morning PEFR and FEV1 nor in asthma control measures including use of rescue β2-agonists or asthma symptom scores. Anti-leukotrienes and ICS versus tapering dose of ICS Seven studies, representing 1150 adults and adolescents, evaluated the combination of anti-leukotrienes and tapering-dose of ICS compared with tapering-dose of ICS alone and contributed data. Investigators observed no statistically significant difference in % change from baseline ICS dose (mean difference (MD) -3.05, 95% CI -8.13 to 2.03; 930 participants; four studies; moderate quality), number of participants with exacerbations requiring oral corticosteroids (RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate quality). Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too infrequent for researchers to draw any conclusions about mortality. Data showed no improvement in lung function nor in asthma control measures. For adolescents and adults with persistent asthma, with suboptimal asthma control with daily use of ICS, the addition of anti-leukotrienes is beneficial for reducing moderate and severe asthma exacerbations and for improving lung function and asthma control compared with the same dose of ICS. We cannot be certain that the addition of anti-leukotrienes is superior, inferior or equivalent to a higher dose of ICS. Scarce available evidence does not support anti-leukotrienes as an ICS sparing agent, and use of LTRAs was not associated with increased risk of withdrawals or adverse effects, with the exception of an increase in serious adverse events when the ICS dose was tapered. Information was insufficient for assessment of mortality.
Three trials met the inclusion criteria. Two trials (n = 20,451) assessed the effect of TXA. The larger of these (CRASH-2, n = 20,211) was conducted in 40 countries and included patients with a variety of types of trauma; the other (n = 240) restricted itself to those with traumatic brain injury (TBI) only. One trial (n = 77) assessed aprotinin in participants with major bony trauma and shock. The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, 95% CI 0.85 to 0.96; P = 0.002) (quality of evidence: high). This estimate is based primarily on data from the CRASH-2 trial of TXA, which contributed 99% of the data. There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events (quality of evidence: moderate), need for surgical intervention or receipt of blood transfusion (quality of evidence: high). There is no evidence for a difference in the effect by type of antifibrinolytic (TXA versus aprotinin) however, as the pooled analyses were based predominantly on trial data concerning the effects of TXA, the results can only be confidently applied to the effects of TXA. The effects of aprotinin in this patient group remain uncertain. There is some evidence from pooling data from one study (n = 240) and a subset of data from CRASH-2 (n = 270) in patients with TBI which suggest that TXA may reduce mortality although the estimates are imprecise, the quality of evidence is low, and uncertainty remains. Stronger evidence exists for the possibility of TXA reducing intracranial bleeding in this population. TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.  TXA should be given as early as possible and within three hours of injury, as further analysis of the CRASH-2 trial showed that treatment later than this is unlikely to be effective and may be harmful. Although there is some promising evidence for the effect of TXA in patients with TBI, substantial uncertainty remains. Two ongoing trials being conducted in patients with isolated TBI should resolve these remaining uncertainties.
We included 13 trials (1135 participants, 1923 eyes) in this review. Nine of these trials randomised eyes to treatment, two trials randomised people to treatment and treated both eyes, and two trials randomised people to treatment and treated one eye. None of the paired trials reported an appropriate paired analysis. We considered the overall quality of evidence to be low for most outcomes because of the risk of bias in the included trials. There was evidence that LASIK gives a faster visual recovery than PRK and is a less painful technique. Results at one year after surgery were comparable: most analyses favoured LASIK but they were not statistically significant. LASIK gives a faster visual recovery and is a less painful technique than PRK. The two techniques appear to give similar outcomes one year after surgery. Further trials using contemporary techniques are required to determine whether LASIK and PRK as currently practised are equally safe. Randomising eyes to treatment is an efficient design, but only if analysed properly. In future trials, more efforts could be made to mask the assessment of outcome.
We included 14 studies with 2966 randomised men across five comparisons. The studies recruited from urology outpatients clinics and defined nocturia as two or more voids per night. The average age of study participants ranged between 57 and 74 years. Desmopressin versus placebo: based on short-term follow-up (up to three months), desmopressin may result in a small, possibly unimportant effect on the number of nocturnal voids (mean difference (MD) -0.61, 95% confidence interval (CI) -0.96 to -0.27; low-quality evidence). We are uncertain about the effect of desmopressin on major adverse events at short-term follow-up (risk ratio (RR) 0.97, 95% CI 0.10 to 9.03; very low-quality evidence). For intermediate-term follow-up (three to 12 months), desmopressin may reduce the number of nocturnal voids in an appreciable number of men (MD -0.85, 95% CI -1.17 to -0.53; low-quality evidence). There was one major adverse event in the desmopressin group at intermediate-term follow-up in one trial of 115 men (RR 3.05, 95% CI 0.13 to 73.39 for both outcomes; low-quality evidence). We found no evidence on quality of life. Subgroup analyses suggest a larger effect on nocturnal voiding with oral, higher-dose formulations of desmopressin and in men with documented nocturnal polyuria. Desmopressin versus behaviour modification: there were no data regarding the effect on the number of nocturnal voids, quality of life, or major adverse events. Desmopressin versus alpha-blocker: based on short-term follow-up in one small trial, desmopressin likely has a similar effect on the number of nocturnal voids (MD 0.30, 95% CI -0.20 to 0.80; moderate-quality evidence) and quality of life measured on the International Prostate Symptom Score (IPSS) scale (MD 0.00, 95% CI -0.35 to 0.35; moderate-quality evidence). There were no major adverse events in either group. Desmopressin plus alpha-blocker versus alpha-blocker alone: based on short-term follow-up, combination therapy likely results in a small, unimportant effect on the number of nocturnal voids (MD -0.47, 95% CI -0.73 to -0.21; moderate-quality evidence) and quality of life (MD -0.29, 95% CI -0.51 to -0.07; moderate-quality evidence). The risk of major adverse events may be similar (0.5% versus 0.3%; RR 0.30, 95% CI 0.01 to 7.32; low-quality evidence). Desmopressin plus alpha-blocker versus alpha-blocker plus an anticholinergic: based on short-term follow-up, combination therapy likely results in little or no difference in the number of nocturnal voids (MD -0.43, 95% CI -0.97 to 0.11; moderate-quality evidence). We found no evidence on quality of life or sleep duration. There were no major adverse events in either study group. Desmopressin may reduce the number of nocturnal voids by a small amount compared to placebo in intermediate-term (three to 12 months) follow-up without increasing major adverse events. We found insufficient evidence to determine the effects of desmopressin when compared with behaviour modification. The effect on the number of nocturnal voids in the short term is likely to be similar to that of alpha-blockers, with very infrequent major adverse events. There appears to be little added benefit in the combined use of desmopressin with an alpha-blocker. The findings of this review were limited by short-term follow-up, study limitations, and imprecision.
Nineteen studies of 2033 initially randomly assigned participants were included, of which 11 used a second injected agent, five used a mechanical method (haemoclips) and three employed thermal methods. The risk of further bleeding after initial haemostasis was lower in the combination therapy groups than in the epinephrine alone group, regardless of which second procedure was applied (RR 0.53, 95% CI 0.35 to 0.81). Adding any second procedure significantly reduced the overall bleeding rate (persistent and recurrent bleeding) (RR 0.57, 95% CI 0.43 to 0.76) and the need for emergency surgery (RR 0.68, 95% CI 0.50 to 0.93). Mortality rates were not significantly different when either method was applied. Rebleeding in the 10 studies that scheduled a reendoscopy showed no difference between epinephrine and combined therapy; without second-look endoscopy, a statistically significant difference was observed between epinephrine and epinephrine and any second endoscopic method, with fewer participants rebleeding in the combined therapy group (nine studies) (RR 0.32, 95% CI 0.21 to 0.48). For ulcers of the Forrest Ia or Ib type (oozing or spurting), the addition of a second therapy significantly reduced the rebleeding rate (RR 0.66, 95% CI 0.49 to 0.88); this difference was not seen for type IIa (visible vessel) or type IIb (adherent clot) ulcers. Few procedure-related adverse effects were reported, and this finding was not statistically significantly different between groups. Few adverse events occurred, and no statistically significant difference was noted between groups. The addition of a second injected method reduced recurrent and persistent rebleeding rates and surgery rates in the combination therapy group, but these findings were not statistically significantly different. Significantly fewer participants died in the combined therapy group (RR 0.50, 95% CI 0.25 to 1.00). Epinephrine and a second mechanical method decreased recurrent and persistent bleeding (RR 0.31, 95% CI 0.18 to 0.54) and the need for emergency surgery (RR 0.20, 95% CI 0.06 to 0.62) but did not affect mortality rates. Epinephrine plus thermal methods decreased the rebleeding rate (RR 0.49, 95% CI 0.30 to 0.78) and the surgery rate (RR 0.20, 95% CI 0.06 to 0.62) but did not affect the mortality rate. Our risk of bias estimates show that risk of bias was low, as, although the type of study did not allow a double-blind trial, rebleeding, surgery and mortality were not dependent on subjective observation. Although some studies had limitations in their design or implementation, most were clear about important quality criteria, including randomisation and allocation concealment, sequence generation and blinding. Additional endoscopic treatment after epinephrine injection reduces further bleeding and the need for surgery in patients with high-risk bleeding peptic ulcer. The main adverse events include risk of perforation and gastric wall necrosis, the rates of which were low in our included studies and favoured neither epinephrine therapy nor combination therapy. The main conclusion is that combined therapy seems to work better than epinephrine alone. However, we cannot conclude that a particular form of treatment is equal or superior to another.
We included 24 studies (2,610 patients) in this review. Teicoplanin reduced the risk of nephrotoxicity compared to vancomycin (RR 0.66, 95% CI 0.48 to 0.90).The effects of teicoplanin or vancomycin were similar for clinical cure (RR 1.03, 95% CI 0.98 to 1.08), microbiological cure (RR 0.98, 95% CI 0.93 to 1.03) and mortality (RR 1.02, 95% CI 0.79 to1.30). Six studies reported no cases of acute kidney injury (AKI) needing dialysis. Adverse events were less frequent with teicoplanin including cutaneous rash (RR 0.57, 95% CI 0.35 to 0.92), red man syndrome (RR 0.21, 95% CI 0.08 to 0.59) and total adverse events (RR 0.73, 95% CI 0.53 to 1.00). A lower risk of nephrotoxicity with teicoplanin was observed in patients either with (RR 0.51, 95% CI 0.30 to 0.88) or without aminoglycosides (RR 0.31, 95% 0.07 to 1.50), and also when vancomycin dosing was guided by serum levels (RR 0.22, 95% CI 0.10 to 0.52). Teicoplanin and vancomycin are both effective in treating those with proven or suspected infection; however the incidence of adverse effects including nephrotoxicity was lower with teicoplanin. There were no cases of AKI needing dialysis. It remains unclear whether the differential effect on kidney function should influence which antibiotic be prescribed, although it may be reasonable to consider teicoplanin for patients at higher risk for AKI needing dialysis.
Seven low quality randomised trials were included. All studies included a total of 310 patients, but due to selective outcome reporting bias, less patients could be included in our analyses. Pooled analysis of three homogenous trials showed that needle aspiration did not significantly increase the proportion of patients with fever resolution (RR 0.60, 95% confidence interval (CI) 0.22 to 1.61). Sensitivity analysis according to trial quality preserved these findings. Trials that evaluated resolution of abdominal pain, days to resolution of fever, pain, resolution of abscess cavities, reduction in liver size, and duration of hospitalisation were heterogeneous. The benefits in the number of days to resolution of pain (MD -1.59, 95%CI -2.73 to -0.42), number of days to resolution of abdominal tenderness (MD -1.70, 95%CI -2.86 to -0.54), and duration of hospitalisation (MD -1.31, 95%CI -2.05 to -0.57) were observed in the needle aspiration group only. Therapeutic aspiration in addition to metronidazole to hasten clinical or radiologic resolution of uncomplicated amoebic liver abscesses cannot be supported or refuted by the present evidence. The trials lack methodological rigour and adequate sample size to conclude on the presence of effectiveness of adjunctive image-guided aspiration plus metronidazole versus metronidazole alone. Further randomised trials are necessary.
Forty-nine RCTs were included of which 33 trials investigated smoking cessation interventions with specific mood management components for depression. In smokers with current depression, meta-analysis showed a significant positive effect for adding psychosocial mood management to a standard smoking cessation intervention when compared with standard smoking cessation intervention alone (11 trials, N = 1844, RR 1.47, 95% CI 1.13 to 1.92). In smokers with past depression we found a similar effect (13 trials, N = 1496, RR 1.41, 95% CI 1.13 to 1.77). Meta-analysis resulted in a positive effect, although not significant, for adding bupropion compared with placebo in smokers with current depression (5 trials, N = 410, RR 1.37, 95% CI 0.83 to 2.27). There were not enough trial data to evaluate the effectiveness of fluoxetine and paroxetine for smokers with current depression. Bupropion (4 trials, N = 404, RR 2.04, 95% CI 1.31 to 3.18) might significantly increase long-term cessation among smokers with past depression when compared with placebo, but the evidence for bupropion is relatively weak due to the small number of studies and the post hoc subgroups for all the studies. There were not enough trial data to evaluate the effectiveness of fluoxetine, nortriptyline, paroxetine, selegiline, and sertraline in smokers with past depression. Twenty-three of the 49 trials investigated smoking cessation interventions without specific components for depression. There was heterogeneity between the trials which compared psychosocial interventions with standard smoking cessation counselling for both smokers with current and past depression. Therefore, we did not estimate a pooled effect. One trial compared nicotine replacement therapy (NRT) versus placebo in smokers with current depression and found a positive, although not significant, effect (N = 196, RR 2.64, 95% CI 0.93 to 7.45). Meta-analysis also found a positive, although not significant, effect for NRT versus placebo in smokers with past depression (3 trials, N = 432, RR 1.17, 95% CI 0.85 to 1.60). Three trials compared other pharmacotherapy versus placebo and six trials compared other interventions in smokers with current or past depression. Due to heterogeneity between the interventions of the included trials we did not estimate pooled effects. Evidence suggests that adding a psychosocial mood management component to a standard smoking cessation intervention increases long-term cessation rates in smokers with both current and past depression when compared with the standard intervention alone. Pooled results from four trials suggest that use of bupropion may increase long-term cessation in smokers with past depression. There was no evidence found for the use of bupropion in smokers with current depression. There was not enough evidence to evaluate the effectiveness of the other antidepressants in smokers with current or past depression. There was also not enough evidence to evaluate the group of trials that investigated interventions without specific mood management components for depression, including NRT and psychosocial interventions.
The 13 included trials involved 2498 older, usually female, patients who had undergone hip fracture surgery. Though generally well conducted, some trials were at risk of bias such as from imbalances in key baseline characteristics. There was substantial clinical heterogeneity in the trial interventions and populations. Multidisciplinary rehabilitation was provided primarily in an inpatient setting in 11 trials. Pooled results showed no statistically significant difference between intervention and control groups for poor outcome (risk ratio 0.89; 95% confidence interval 0.78 to 1.01), mortality (risk ratio 0.90, 95% confidence interval 0.76 to 1.07) or hospital readmission. Individual trials found better results, often short-term only, in the intervention group for activities of daily living and mobility. There was considerable heterogeneity in length of stay and cost data. Three trials reporting carer burden showed no evidence of detrimental effect from the intervention. Overall, the evidence indicates that multidisciplinary rehabilitation is not harmful. The trial comparing primarily home-based multidisciplinary rehabilitation with usual inpatient care found marginally improved function and a clinically significantly lower burden for carers in the intervention group. Participants of this group had shorter hospital stays, but longer periods of rehabilitation. One trial found no significant effect from doubling the number of weekly contacts at the patient's home from a multidisciplinary rehabilitation team. While there was a tendency to a better overall result in patients receiving multidisciplinary inpatient rehabilitation, these results were not statistically significant. Future trials of multidisciplinary rehabilitation should aim to establish both effectiveness and cost effectiveness of multidisciplinary rehabilitation overall, rather than evaluate its components.
This review included only one trial (21 participants), which compared fish oil-derived (n-3) fatty acid-based lipid emulsion (50 mL per infusion (1.05 g eicosapentaenoic and 10.5 g docosahexaenoic acid)) (10 participants) to soya oil-derived (n-6) fatty acid-based lipid emulsion (50 mL per infusion (1.05 g eicosapentaenoic and 10.5 g docosahexaenoic acid)) (11 participants) administered intravenously twice daily for 10 days, with a total follow-up of 40 days. The study was conducted in a single centre in Germany in 18 men and three women, aged between 21 and 65 years, who were in hospital with acute guttate psoriasis and had mean total body surface involvement of 25.7% ± 20.4% (range 10 to 90). The study was funded by a company that produces the oil emulsions. We found no other evidence regarding non-antistreptococcal interventions used in clinical practice for guttate psoriasis, such as topical treatments (corticosteroids, vitamin D₃ analogues), systemic drugs, biological therapy, and phototherapy. The primary outcomes of the review were not measured, and only one of our secondary outcomes was measured: improvement in participant satisfaction measures and quality of life assessment measures. However, the study authors did report that there was rare skin irritation at the site of peripheral intravenous route, but the number of affected participants was not provided. Improvement between baseline and day 10, using a non-validated score assessed by participants themselves daily based on five items (appearance of lesions, impairment of daily life, pruritus, burning, and pain), was greater in the group that received the fish oil-derived (n-3) fatty acid-based lipid emulsion (75%) than in the group receiving the soya oil-derived (n-6) fatty acid-based lipid emulsion (18%) (one trial, 21 participants). However, these results are uncertain as they are based on very low-quality evidence. There is no evidence regarding topical and systemic drugs, biotherapy, or phototherapy in guttate psoriasis (we did not consider drugs that aimed to eradicate streptococcal infection because these are assessed in another Cochrane Review). We are uncertain of the effect of intravenously administered lipid emulsion on guttate psoriasis because the quality of the evidence is very low, due to risk of bias (unclear risk of bias for all domains), indirectness (the trial only included adults, and the follow-up from baseline was only 10 days), and imprecision (small number of participants). This review highlights the need for trials assessing the efficacy and safety of phototherapy and topical and systemic drugs for guttate psoriasis. There is also a need for studies that clearly distinguish the specific population with guttate psoriasis from the larger group of people with chronic plaque psoriasis, and children and young adults should be assessed as a distinct group.
We included 11 studies that randomised 343 people. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, participants and outcome assessors were not clearly blinded. For some studies we were unsure if data were complete, and data were often poorly or selectively reported. Data from six trials showed that there may be a clinically important improvement in TD symptoms after GABA agonist treatment compared with placebo at six to eight weeks follow-up (6 RCTs, n = 258, RR 0.83, CI 0.74 to 0.92; low-quality evidence). Data from five studies showed no difference between GABA agonist treatment and placebo for deterioration of TD symptoms (5 RCTs, n = 136, RR 1.90, CI 0.70 to 5.16; very low-quality evidence). Studies reporting adverse events found a significant effect favouring placebo compared with baclofen, sodium valproate or progabide for dizziness/confusion (3 RCTs, n = 62 RR 4.54, CI 1.14 to 18.11; very low-quality evidence) and sedation/drowsiness (4 RCTS, n = 144, RR 2.29, CI 1.08 to 4.86; very low-quality evidence). Studies reporting on akathisia (RR 1.05, CI 0.32 to 3.49, 2 RCTs, 80 participants), ataxia (RR 3.25, CI 0.36 to 29.73, 2 RCTs, 95 participants), nausea/vomiting (RR 2.61, CI 0.79 to 8.67, 2 RCTs, 64 participants), loss of muscle tone (RR 3.00, CI 0.15 to 59.89, 1 RCT, 10 participants), seizures (RR 3.00, CI 0.24 to 37.67, 1 RCT, 2 participants), hypotension (RR 3.04, CI 0.33 to 28.31, 2 RCTs, 119 participants) found no significant difference between GABA drug and placebo (very low-quality evidence). Evidence on mental state also showed no effect between treatment groups (6 RCTS, n = 121, RR 2.65, CI 0.71 to 9.86; very low-quality evidence) as did data for leaving the study early (around 10% in both groups, 6 RCTS, n = 218, RR 1.47, CI 0.69 to 3.15; very low-quality evidence). No study reported on social confidence, social inclusion, social networks, or personalised quality of life, a group of outcomes selected as being of particular importance to patients. We are uncertain about the evidence of the effects of baclofen, progabide, sodium valproate or tetrahydroisoxazolopyridinol (THIP) for people with antipsychotic-induced TD. Evidence is inconclusive and unconvincing. The quality of data available for main outcomes ranges from very low to low. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.
Thirty-two RCTs and two cluster-RCTs that randomised 3554 people satisfied criteria for inclusion. Only one study examined the effects of early warning signs interventions without additional psychological interventions, and many of the outcomes for this review were not reported or poorly-reported. Significantly fewer people relapsed with early warning signs interventions than with usual care (23% versus 43%; RR 0.53, 95% CI 0.36 to 0.79; 15 RCTs, 1502 participants; very low quality evidence). Time to relapse did not significantly differ between intervention groups (6 RCTs, 550 participants; very low quality evidence). Risk of re-hospitalisation was significantly lower with early warning signs interventions compared to usual care (19% versus 39%; RR 0.48, 95% CI 0.35 to 0.66; 15 RCTS, 1457 participants; very low quality evidence). Time to re-hospitalisation did not significantly differ between intervention groups (6 RCTs; 1149 participants; very low quality evidence). Participants' satisfaction with care and economic costs were inconclusive because of a lack of evidence. This review indicates that early warning signs interventions may have a positive effect on the proportions of people re-hospitalised and on rates of relapse, but not on time to recurrence. However, the overall quality of the evidence was very low, indicating that we do not know if early warning signs interventions will have similar effects outside trials and that it is very likely that further research will alter these estimates. Moreover, the early warning signs interventions were used along side other psychological interventions, and we do not know if they would be effective on their own. They may be cost-effective due to reduced hospitalisation and relapse rates, but before mental health services consider routinely providing psychological interventions involving the early recognition and prompt management of early warning signs to adults with schizophrenia, further research is required to provide evidence of high or moderate quality regarding the efficacy of early warning signs interventions added to usual care without additional psychological interventions, or to clarify the kinds of additional psychological interventions that might aid its efficacy. Future RCTs should be adequately-powered, and designed to minimise the risk of bias and be transparently reported. They should also systematically evaluate resource costs and resource use, alongside efficacy outcomes and other outcomes that are important to people with serious mental illness and their carers.
We found three eligible randomized controlled trials, with a total of 2081 participants. One of the three included studies did not mention the amount of participants and presented no outcome data. The 'Risk of bias' assessment indicated that there was a high risk of detection bias owing to lack of blinding of outcomes assessors, but we assessed all other domains to be at low risk of bias. Trial design and conduct were generally adequate, with the most common areas of weakness in blinding. The majority of participants were included in centres across North America. The mean age of participants ranged from 61 to 64 years, and the mean duration of intubation was between 3.2 and 7.7 days. One trial comparing silver-coated ETTs versus non-coated ETTs showed a statistically significant decrease in VAP in favour of the silver-coated ETT (1 RCT, 1509 participants; 4.8% versus 7.5%, risk ratio (RR) 0.64, 95% confidence interval (CI) 0.43 to 0.96; number needed to treat for an additional beneficial outcome (NNTB) = 37; low-quality evidence). The risk of VAP within 10 days of intubation was significantly lower with the silver-coated ETTs compared with non-coated ETTs (1 RCT, 1509 participants; 3.5% versus 6.7%, RR 0.51, 95% CI 0.31 to 0.82; NNTB = 32; low-quality evidence). Silver-coated ETT was associated with delayed time to VAP occurrence compared with non-coated ETT (1 RCT, 1509 participants; hazard ratio 0.55, 95% CI 0.37 to 0.84). The confidence intervals for the results of the following outcomes did not exclude potentially important differences with either treatment. There were no statistically significant differences between groups in hospital mortality (1 RCT, 1509 participants; 30.4% versus 26.6%, RR 1.09, 95% CI 0.93 to 1.29; low-quality evidence); device-related adverse events (2 RCTs, 2081 participants; RR 0.65, 95% CI 0.37 to 1.16; low-quality evidence); duration of intubation; and length of hospital and ICU stay. We found no clinical studies evaluating the cost-effectiveness of silver-coated ETTs. This review provides limited evidence that silver-coated ETT reduces the risk of VAP, especially during the first 10 days of mechanical ventilation.
Randomised evidence was sparse. Only four trials were eligible for inclusion, one comparing the efficacy of real ECT versus simulated ECT, two comparing the efficacy of unilateral versus bilateral ECT and the other comparing the efficacy of ECT once a week with ECT three times weekly. All trials had major methodological shortcomings; reports were mostly lacking essential information to perform a quantitative analysis. Although the findings from one study (35 participants) concluded that real ECT was superior to simulated ECT, these conclusions need to be interpreted cautiously. Only results from one of the trials (29 participants) comparing unilateral versus bilateral ECT could be analysed, and did not show convincing efficacy of unilateral ECT over bilateral ECT, WMD 6.06 (CI -5.20 to 17.32). Randomised evidence on the efficacy and safety of ECT in depressed elderly with concomitant dementia, cerebrovascular disorders or Parkinson's disease was lacking completely. Possible side-effects could not be adequately examined because of the lack of randomised evidence and methodological shortcomings. None of the objectives of this review could be adequately tested because of the lack of firm, randomised evidence. Given the specific problems in the treatment of depressed elderly, a well designed randomised controlled trial should be conducted in which the efficacy of ECT is compared to one or more antidepressants.
Seven RCTs were included in the review, involving a total of 393 participants. All of the included studies assessed psychoeducational methods, and one study also assessed a type of systems psychotherapy. In all trials, participants continued to receive pharmacotherapy treatment. Due to the diversity of interventions, outcome measures and endpoints used across studies, it was not possible to perform meta-analyses for primary outcomes. Five studies compared a variety of family interventions, involving carers, families or spouses, against no intervention, with individual findings indicating no significant added effect for family interventions. Three studies compared one type or modality of family intervention against another family intervention, with inconsistent findings. To date there is only a small and heterogeneous body of evidence on the effectiveness of family oriented approaches for bipolar disorder, and it is not yet possible to draw any definite conclusions to support their use as an adjunctive treatment for bipolar disorder. Further well designed RCTs should be a research priority.
We found six RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs included 937 participants and compared outcomes at six months to sham injection for four anti-VEGF agents: aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) and ranibizumab (Lucentis). Three trials were conducted in Norway, Sweden and the USA, and three trials were multicentre, one including centres in the USA, Canada, India, Israel, Argentina and Columbia, a second including centres in the USA, Australia, France, Germany, Israel, and Spain, and a third including centres in Austria, France, Germany, Hungary, Italy, Latvia, Australia, Japan, Singapore and South Korea. We performed meta-analysis on three key visual outcomes, using data from up to six trials. High-quality evidence from six trials revealed that participants receiving intravitreal anti-VEGF treatment were 2.71 times more likely to gain at least 15 letters of visual acuity at six months compared to participants treated with sham injections (risk ratio (RR) 2.71; 95% confidence intervals (CI) 2.10 to 3.49). High-quality evidence from five trials suggested anti-VEGF treatment was associated with an 80% lower risk of losing at least 15 letters of visual acuity at six months compared to sham injection (RR 0.20; 95% CI 0.12 to 0.34). Moderate-quality evidence from three trials (481 participants) revealed that the mean reduction from baseline to six months in central retinal thickness was 267.4 µm (95% CI 211.4 µm to 323.4 µm) greater in participants treated with anti-VEGF than in participants treated with sham. The meta-analyses demonstrate that treatment with anti-VEGF is associated with a clinically meaningful gain in vision at six months. One trial demonstrated sustained benefit at 12 months compared to sham. No significant ocular or systemic safety concerns were identified in this time period. Compared to no treatment, repeated intravitreal injection of anti-VEGF agents in eyes with CRVO macular oedema improved visual outcomes at six months. All agents were relatively well tolerated with a low incidence of adverse effects in the short term. Future trials should address the relative efficacy and safety of the anti-VEGF agents and other treatments, including intravitreal corticosteroids, for longer-term outcomes.
We included six trials (n = 698; most participants were women approximately 40 years of age). All studies evaluated psychotherapy plus usual care (with antidepressants) versus usual care (with antidepressants). Three studies addressed the addition of cognitive-behavioural therapy (CBT) to usual care (n = 522), and one each evaluated intensive short-term dynamic psychotherapy (ISTDP) (n = 60), interpersonal therapy (IPT) (n = 34), or group dialectical behavioural therapy (DBT) (n = 19) as the intervention. Most studies were small (except one trial of CBT was large), and all studies were at high risk of detection bias for the main outcome of self-reported depressive symptoms. A random-effects meta-analysis of five trials (n = 575) showed that psychotherapy given in addition to usual care (vs usual care alone) produced improvement in self-reported depressive symptoms (MD -4.07 points, 95% confidence interval (CI) -7.07 to -1.07 on the Beck Depression Inventory (BDI) scale) over the short term (up to six months). Effects were similar when data from all six studies were combined for self-reported depressive symptoms (SMD -0.40, 95% CI -0.65 to -0.14; n = 635). The quality of this evidence was moderate. Similar moderate-quality evidence of benefit was seen on the Patient Health Questionnaire-9 Scale (PHQ-9) from two studies (MD -4.66, 95% CI 8.72 to -0.59; n = 482) and on the Hamilton Depression Rating Scale (HAMD) from four studies (MD -3.28, 95% CI -5.71 to -0.85; n = 193). High-quality evidence shows no differential dropout (a measure of acceptability) between intervention and comparator groups over the short term (RR 0.85, 95% CI 0.58 to 1.24; six studies; n = 698). Moderate-quality evidence for remission from six studies (RR 1.92, 95% CI 1.46 to 2.52; n = 635) and low-quality evidence for response from four studies (RR 1.80, 95% CI 1.2 to 2.7; n = 556) indicate that psychotherapy was beneficial as an adjunct to usual care over the short term. With the addition of CBT, low-quality evidence suggests lower depression scores on the BDI scale over the medium term (12 months) (RR -3.40, 95% CI -7.21 to 0.40; two studies; n = 475) and over the long term (46 months) (RR -1.90, 95% CI -3.22 to -0.58; one study; n = 248). Moderate-quality evidence for adjunctive CBT suggests no difference in acceptability (dropout) over the medium term (RR 0.98, 95% CI 0.66 to 1.47; two studies; n = 549) and lower dropout over long term (RR 0.80, 95% CI 0.66 to 0.97; one study; n = 248). Two studies reported serious adverse events (one suicide, two hospitalisations, and two exacerbations of depression) in 4.2% of the total sample, which occurred only in the usual care group (no events in the intervention group). An economic analysis (conducted as part of an included study) from the UK healthcare perspective (National Health Service (NHS)) revealed that adjunctive CBT was cost-effective over nearly four years. Moderate-quality evidence shows that psychotherapy added to usual care (with antidepressants) is beneficial for depressive symptoms and for response and remission rates over the short term for patients with TRD. Medium- and long-term effects seem similarly beneficial, although most evidence was derived from a single large trial. Psychotherapy added to usual care seems as acceptable as usual care alone. Further evidence is needed on the effectiveness of different types of psychotherapies for patients with TRD. No evidence currently shows whether switching to a psychotherapy is more beneficial for this patient group than continuing an antidepressant medication regimen. Addressing this evidence gap is an important goal for researchers.
We could not identify any studies in which the only difference between the treatment groups was the use of intracystic bleomycin. We did identify a RCT comparing intracystic bleomycin with intracystic phosphorus32 (32P) (seven children). In this update we identified no additional studies. The included study had a high risk of bias. Survival could not be evaluated. There was no clear evidence of a difference between the treatment groups in cyst reduction (MD -0.15, 95% confidence interval (CI) -0.69 to 0.39, P value = 0.59, very low quality of evidence), neurological status (Fisher's exact P value = 0.429, very low quality of evidence), third nerve paralysis (Fischer's exact P value = 1.00, very low quality of evidence), fever (RR 2.92, 95% CI 0.73 to 11.70, P value = 0.13, very low quality of evidence) or total adverse effects (RR 1.75, 95% CI 0.68 to 4.53, P value = 0.25, very low quality of evidence). There was a significant difference in favour of the 32P group for the occurrence of headache and vomiting (Fischer's exact P value = 0.029, very low quality of evidence for both outcomes). Since we identified no RCTs, quasi-randomised trials or CCTs of the treatment of cystic craniopharyngiomas in children in which only the use of intracystic bleomycin differed between the treatment groups, no definitive conclusions could be made about the effects of intracystic bleomycin in these patients. Only one low-power RCT comparing intracystic bleomycin with intracystic 32P treatment was available, but no definitive conclusions can be made about the effectiveness of these agents in children with cystic craniopharyngiomas. Based on the currently available evidence, we are not able to give recommendations for the use of intracystic bleomycin in the treatment of cystic craniopharyngiomas in children. High-quality RCTs are needed.
The methodological quality of primary studies was generally unsatisfying and the results were reported inadequately in many aspects. Additional information was not available from primary trialists. The meta-analysis results showed that patients who had been given G. lucidum alongside with chemo/radiotherapy were more likely to respond positively compared to chemo/radiotherapy alone (RR 1.50; 95% CI 0.90 to 2.51, P = 0.02). G. lucidum treatment alone did not demonstrate the same regression rate as that seen in combined therapy. The results for host immune function indicators suggested that G. lucidum simultaneously increases the percentage of CD3, CD4 and CD8 by 3.91% (95% CI 1.92% to 5.90%, P < 0.01), 3.05% (95% CI 1.00% to 5.11%, P < 0.01) and 2.02% (95% CI 0.21% to 3.84%, P = 0.03), respectively. In addition, leukocyte, NK-cell activity and CD4/CD8 ratio were marginally elevated. Four studies showed that patients in the G. lucidum group had relatively improved quality of life in comparison to controls. One study recorded minimal side effects, including nausea and insomnia. No significant haematological or hepatological toxicity was reported. Our review did not find sufficient evidence to justify the use of G. lucidum as a first-line treatment for cancer. It remains uncertain whether G. lucidum helps prolong long-term cancer survival. However, G. lucidum could be administered as an alternative adjunct to conventional treatment in consideration of its potential of enhancing tumour response and stimulating host immunity. G. lucidum was generally well tolerated by most participants with only a scattered number of minor adverse events. No major toxicity was observed across the studies. Although there were few reports of harmful effect of G. lucidum, the use of its extract should be judicious, especially after thorough consideration of cost-benefit and patient preference. Future studies should put emphasis on the improvement in methodological quality and further clinical research on the effect of G. lucidum on cancer long-term survival are needed. An update to this review will be performed every two years.
Seven studies enrolling a total of 669 participants were eligible for inclusion in this review. Moderately early steroid treatment (vs placebo or nothing) reduced mortality by 28 days, chronic lung disease at 28 days and 36 weeks, and death or chronic lung disease at 28 days or 36 weeks. Earlier extubation was facilitated. There was no significant effect on the rates of pneumothorax, severe ROP, or NEC. Adverse effects included hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection. Steroid-treated infants were less likely to need late rescue with dexamethasone. There were limited data from four studies of long term follow-up; these did not show evidence of an increase in adverse neurological outcomes. Moderately early corticosteroid therapy (started at 7-14 days) reduces neonatal mortality and CLD, but at the cost of important short term adverse effects. Limited evidence concerning long term effects is provided by the trials included in this review. The methodological quality of the studies determining the long-term outcome is limited in some cases, the children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. Therefore, given the risk:benefit ratio of short-term effects and the limited long-term follow-up data, it seems appropriate to reserve moderately early corticosteroid treatment to infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of therapy. More research is urgently needed, including long term follow-up of survivors included in previous and any future trials, before the benefits and risks of postnatal steroid treatment, including initiation at 7-14 days, can be reliably assessed (See DART study; Doyle 2000a).
We found 14 studies that included siblings amongst other family members in receipt of psychoeducational interventions. However, we were only able to include one small trial with relevant and available data (n = 9 siblings out of n = 84 family member/carer-participants) comparing psychoeducational intervention with standard care in a community care setting, over a duration of 21 months. There was insufficient evidence to determine the effects of psychoeducational interventions compared with standard care on 'siblings' quality of life' (n = 9, MD score 3.80 95% CI -0.26 to 7.86, low quality of evidence), coping with (family) burden (n = 9, MD -8.80 95% CI -15.22 to -2.34, low quality of evidence). No sibling left the study early by one year (n = 9, RD 0.00 CI -0.34 to 0.34, low quality of evidence). Low quality and insufficient evidence meant we were unable to determine the effects of psychoeducational interventions compared with standard care on service users' global mental state (n = 9, MD -0.60 CI -3.54 to 2.38, low quality of evidence), their frequency of re-hospitalisation (n = 9, MD -0.70 CI -2.46 to 1.06, low quality of evidence) or duration of inpatient stay (n = 9, MD -2.60 CI -6.34 to 1.14, low quality of evidence), whether their siblings received psychoeducation or not. No study data were available to address the other primary outcomes: 'siblings' psychosocial wellbeing', 'siblings' distress' and adverse effects. Most studies evaluating psychoeducational interventions recruited siblings along with other family members. However, the proportion of siblings in these studies was low and outcomes for siblings were not reported independently from those of other types of family members. Indeed, only data from one study with nine siblings were available for the review. The limited study data we obtained provides no clear good quality evidence to indicate psychoeducation is beneficial for siblings' wellbeing or for clinical outcomes of people affected by SMI. More randomised studies are justified and needed to understand the role of psychoeducation in addressing siblings' needs for information and support.
We found four double-blind, double-dummy trials comparing LAMA to placebo, including 1197 people with asthma taking combination LABA/ICS. One of the trials was designed to study glycopyrronium bromide but was withdrawn prior to enrolment, and the other three all studied tiotropium bromide (mostly 5 µg once daily via Respimat) over 48 to 52 weeks. People in the trials had a mean forced expiratory volume in one second (FEV1) of 55% of their predicted value, indicating severe asthma. People randomised to take tiotropium add-on had fewer exacerbations requiring oral corticosteroids than those continuing to take LABA/ICS alone, but the confidence intervals did not rule out no difference (OR 0.76, 95% CI 0.57 to 1.02; moderate quality evidence). Over 48 weeks, 328 out of 1000 people taking their usual LABA/ICS would have to take oral corticosteroids for an exacerbation compared with 271 if they took tiotropium as well (95% CI 218 to 333 per 1000). Analyses comparing the number of exacerbations per patient in each group (rate ratio) and the time until first exacerbation (hazard ratio) were in keeping with the main result. Quality of life, as measured by the Asthma Quality of Life Questionnaire (AQLQ) was no better for those taking tiotropium add-on than for those taking LABA/ICS alone when considered in light of the 0.5 minimal clinically important difference on the scale (MD 0.09, 95% CI − 0.03 to 0.20), and evidence for whether tiotropium increased or decreased serious adverse events in this population was inconsistent (OR 0.60, 95% CI 0.24 to 1.47; I2 = 76%). Within the secondary outcomes, exacerbations requiring hospital admission were too rare to tell whether tiotropium was beneficial over LABA/ICS alone. There was high quality evidence showing benefits to lung function (trough FEV1 and forced vital capacity (FVC)) and potentially small benefits to asthma control. People taking tiotropium add-on were less likely to experience non-serious adverse events. Tiotropium add-on may have additional benefits over LABA/ICS alone in reducing the need for rescue oral steroids in people with severe asthma. The effect was imprecise, and there was no evidence for other LAMA preparations. Possible benefits on quality of life were negligible, and evidence for the effect on serious adverse events was inconsistent. There are likely to be small added benefits for tiotropium Respimat 5 µg daily on lung function and asthma control over LABA/ICS alone and fewer non-serious adverse events. The benefit of tiotropium add-on on the frequency of hospital admission is still unknown, despite year-long trials. Ongoing and future trials should clearly describe participants' background medications to help clinicians judge how the findings relate to stepwise care. If studies test LAMAs other than tiotropium Respimat for asthma, they should be at least six months long and use accepted and validated outcomes to allow comparisons of the safety and effectiveness between different preparations.
Fourteen trials (590 participants) were included. No overall difference was found for the primary outcome of response to treatment compared with placebo (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.91 to 1.26; 9 trials, N = 454). There was a small reduction in depression symptoms (standardised mean difference (SMD) -0.32, 95% CI -0.59 to -0.04; 13 trials, N = 533), but the evidence was of low quality. Subgroup analyses suggested a small reduction in depression symptoms among adolescents (SMD -0.45, 95% CI -0.83 to -0.007), and negligible change among children (SMD 0.15, 95% CI -0.34 to 0.64). Treatment with a tricyclic antidepressant caused more vertigo (RR 2.76, 95% CI 1.73 to 4.43; 5 trials, N = 324), orthostatic hypotension (RR 4.86, 95% CI 1.69 to 13.97; 5 trials, N = 324), tremor (RR 5.43, 95% CI 1.64 to 17.98; 4 trials, N = 308) and dry mouth (RR 3.35, 95% CI 1.98 to 5.64; 5 trials, N = 324) than did placebo, but no differences were found for other possible adverse effects. Wide CIs and the probability of selective reporting mean that there was very low-quality evidence for adverse events. There was heterogeneity across the studies in the age of participants, treatment setting, tricyclic drug administered and outcome measures. Statistical heterogeneity was identified for reduction in depressive symptoms, but not for rates of remission or response. As such, the findings from analyses of pooled data should be interpreted with caution. We judged none of these trials to be at low risk of bias, with limited information about many aspects of risk of bias, high dropout rates, and issues regarding measurement instruments and the clinical usefulness of outcomes, which were often variously defined across trials. Data suggest tricyclic drugs are not useful in treating depression in children. There is marginal evidence to support the use of tricyclic drugs in the treatment of depression in adolescents.
We identified 15 eligible trials enrolling a total of 1690 infants. Ten trials (1371 infants) compared systemic antifungal prophylaxis versus placebo or no drug. These trials were generally of good methodological quality. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection (typical risk ratio (RR) 0.43, 95% confidence interval (CI) 0.31 to 0.59; risk difference (RD) −0.09, 95% CI −0.12 to −0.06). The average incidence of invasive fungal infection in the control groups of the trials (16%) was much higher than that generally reported from large cohort studies. Meta-analysis did not find a statistically significant difference in the risk of death prior to hospital discharge (typical RR 0.79, 95% CI 0.61 to 1.02; typical RD −0.04, 95% CI −0.07 to 0.00). Very limited data on long-term neurodevelopmental outcomes were available. Three trials that compared systemic versus oral or topical non-absorbed antifungal prophylaxis did not detect any statistically significant effects on invasive fungal infection or mortality. Two trials that compared different dose regimens of prophylactic intravenous fluconazole did not detect any significant differences in infection rates or mortality. Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very preterm or very low birth weight infants. This finding should be interpreted and applied cautiously since the incidence of invasive fungal infection was very high in the control groups of many of the included trials. Meta-analysis does not demonstrate a statistically significant effect on mortality. There are currently only limited data on the long-term neurodevelopmental consequences for infants exposed to this intervention. In addition, there is a need for further data on the effect of the intervention on the emergence of organisms with antifungal resistance.
Forty RCTs and two QRCTs were identified, including 17 new trials since the first edition of this review in 1999. Many of the early trials were of some form of chemonucleolysis, whereas the majority of the later studies either compared different techniques of discectomy or the use of some form of membrane to reduce epidural scarring. Despite the critical importance of knowing whether surgery is beneficial for disc prolapse, only four trials have directly compared discectomy with conservative management and these give suggestive rather than conclusive results. However, other trials show that discectomy produces better clinical outcomes than chemonucleolysis and that in turn is better than placebo. Microdiscectomy gives broadly comparable results to standard discectomy. Recent trials of an inter-position gel covering the dura (five trials) and of fat (four trials) show that they can reduce scar formation, though there is limited evidence about the effect on clinical outcomes. There is insufficient evidence on other percutaneous discectomy techniques to draw firm conclusions. Three small RCTs of laser discectomy do not provide conclusive evidence on its efficacy, There are no published RCTs of coblation therapy or trans-foraminal endoscopic discectomy. Surgical discectomy for carefully selected patients with sciatica due to lumbar disc prolapse provides faster relief from the acute attack than conservative management, although any positive or negative effects on the lifetime natural history of the underlying disc disease are still unclear. Microdiscectomy gives broadly comparable results to open discectomy. The evidence on other minimally invasive techniques remains unclear (with the exception of chemonucleolysis using chymopapain, which is no longer widely available).
Two new trials reporting three comparisons were found in the update. Nineteen trials are included in the review, reporting 22 oral versus intra-vaginal anti-fungal comparisons. No statistically significant differences were shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short term (OR 0.94, 95% CI, 0.75 to 1.17) and long term (OR 1.07, 95% CI, 0.82 to 1.41) follow-up. No statistically significant differences for mycological cure were observed between oral and intra-vaginal treatment at short term (OR 1.15, 95% CI, 0.94 to 1.42). There was a statistically significant difference for long term follow-up (OR 1.29, 95% CI, 1.05 to 1.60) in favour of oral treatment, however the clinical significance of this result is uncertain. Two trials each reported one withdrawal from treatment due to an adverse reaction. Treatment preference data were poorly reported. No statistically significant differences were observed in clinical cure rates of anti-fungals administered by the oral and intra-vaginal routes for the treatment of uncomplicated vaginal candidiasis. No definitive conclusion can be made regarding the relative safety of oral and intra-vaginal anti-fungals for uncomplicated vaginal candidiasis. The decision to prescribe or recommend the purchase of an anti-fungal for oral or intra-vaginal administration should take into consideration: safety, cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications, women who are purchasing their own treatment should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of some oral anti-fungals is worth the gain in convenience, if this is the patient's preference.
Fifty-six studies, with a total of 4076 participants, met the inclusion criteria. Comparing anticonvulsants with placebo, no statistically significant differences for the six outcomes considered. Comparing anticonvulsant versus other drug, 19 outcomes considered, results favour anticonvulsants only in the comparison carbamazepine versus benzodiazepine (oxazepam and lorazepam) for  alcohol withdrawal symptoms (CIWA-Ar score): 3 studies, 262 participants, MD -1.04 (-1.89 to -0.20),  none of the other comparisons reached statistical significance. Comparing different anticonvulsants no statistically significant differences in the two outcomes considered. Comparing anticonvulsants plus other drugs versus other drugs (3 outcomes considered), results from one study, 72 participants, favour paraldehyde plus chloral hydrate versus chlordiazepoxide, for the severe-life threatening side effects, RR 0.12 (0.03 to 0.44). Results of this review do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS. There are some suggestions that carbamazepine may actually be more effective in treating some aspects of alcohol withdrawal when compared to benzodiazepines, the current first-line regimen for alcohol withdrawal syndrome. Anticonvulsants seem to have limited side effects, although adverse effects are not rigorously reported in the analysed trials.
We included four studies with 1684 participants. Three parallel-group placebo comparisons were in painful diabetic neuropathy (1643 participants), and one cross-over study with diphenhydramine as an active placebo (41 participants) was in lumbar radiculopathy. Doses of topiramate were titrated up to 200 mg/day or 400 mg/day. All studies had one or more sources of potential major bias, as they either used LOCF imputation or were of small size. No study provided first tier evidence for an efficacy outcome. There was no convincing evidence for efficacy of topiramate at 200 to 400 mg/day over placebo. Eighty-two per cent of participants taking topiramate 200 to 400 mg/day experienced at least one adverse event, as did 71% with placebo, and the number needed to treat for an additional harmful effect (NNTH) was 8.6 (95% confidence interval (CI) 4.9 to 35). There was no difference in serious adverse events recorded (6.6% versus 7.5%). Adverse event withdrawals with 400 mg daily were much more common with topiramate (27%) than with placebo (8%), with an NNTH of 5.4 (95% CI 4.3 to 7.1). Lack of efficacy withdrawal was less frequent with topiramate (12%) than placebo (18%). Weight loss was a common event in most studies. No deaths attributable to treatment were reported. Topiramate is without evidence of efficacy in diabetic neuropathic pain, the only neuropathic condition in which it has been adequately tested. The data we have includes the likelihood of major bias due to LOCF imputation, where adverse event withdrawals are much higher with active treatment than placebo control. Despite the strong potential for bias, no difference in efficacy between topiramate and placebo was apparent.
Two trials were included in the review, totaling 104 participants. One trial assessed additional (four times a day) versus once daily stretching and the other assessed exercise for movement dysfunction versus stretching and strengthening. The first trial, involving 80 elite athletes, suggested additional stretching could reduce time to return to full activity (mean difference (MD) -1.8 days, 95% confidence interval (CI) -2.1 to -1.5, P < 0.001). The second trial, involving 24 participants from a diverse sporting background, did not find conclusive evidence of a difference (MD -14.5 days, 95% CI -30.64 to 1.64, P = 0.08). It did, however, report reduced re-injury rates using exercise for movement dysfunction of 8% versus 64% (odds ratio (OR) 0.05, 95% CI 0.00 to 0.52, P = 0.01). No other outcomes relevant to this review were reported by either study: most notably pain and participant satisfaction. Most proposed physiotherapy techniques for rehabilitation of hamstring injuries have not been assessed using randomised trials. Those that have only have single studies with a limited range of participants and outcomes. There is limited evidence to suggest that time to recovery for elite athletes can be reduced with an increased daily frequency of hamstring stretching exercises. There is preliminary evidence from another small study of mixed ability athletes to suggest that exercise to correct movement dysfunction could reduce time to return to full activity and the risk of re-injury. Further studies are required to check these findings. Until further evidence is available, current practice and widely published rehabilitation protocols cannot either be supported or refuted.
In this update, review authors added one study to the study from the original review. The first relevant study involved 62 adults with recent-onset dilated cardiomyopathy randomly assigned to receive IVIG or an equivalent volume of 0.1% albumin in a blinded fashion. The overall risk of bias was unclear. The incidence of death or the requirement for cardiac transplant or placement of a left ventricular assist device was low in both groups (odds ratio (OR) for event-free survival 0.52, 95% confidence interval (CI) 0.12 to 2.30). Follow-up at six months and at 12 months showed equivalent improvement in LVEF (mean difference (MD) 0.00, 95% CI -0.07 to 0.07 at six months; MD 0.01, 95% CI -0.06 to 0.08 at 12 months). Functional capacity as assessed by peak oxygen consumption was equivalent in the two groups at 12 months (MD -0.80, 95% CI -4.57 to 2.97). Infusion-related side effects were more common in the treated group, but all were reported to be mild (OR 30.16, 95% CI 1.69 to 539.42). The second study added at this update included 83 children in India with suspected viral encephalitis and myocarditis. The overall risk of bias was high. The odds ratio for event-free survival was 7.39 (95% CI 0.91 to 59.86). Follow-up occurred only until hospital discharge, and LVEF was 49.5% in the treated group versus 35.9% in the placebo group (risk difference 13.6%, 95% CI 5.1 to 22.1%; P value = 0.001). Evidence from one trial does not support the use of IVIG for the treatment of adults with presumed viral myocarditis. The only paediatric trial had high risk of bias but suggested that benefit may be seen in the select group of children beyond the neonatal period who have viral encephalitis with myocarditis. Until higher-quality studies have demonstrated benefit in a particular group of patients, IVIG for presumed viral myocarditis should not be provided as routine practice in any situation. Further studies of the pathophysiology of myocarditis would lead to improved diagnostic criteria, which would facilitate future research.
We identified 10 completed RCTs, most of which were relatively recent (2007 or later) and were conducted with at least some involvement from the intervention developer or the FAST organisation. Nine of the 10 trials were from the USA; the other was from the UK. Children were young (five to nine years old; mean age approximately six years), and therefore, whilst not so named in the reports, evaluations consisted of what is sometimes referred to as 'Kids FAST' and sometimes 'Elementary Level FAST'). Among the USA-based studies, at least 62% of participants were members of a racial/ethnic minority group (most commonly, African American or Latino). FAST was usually delivered in schools after the school day. Trials lasted about eight weeks and usually examined the effects of FAST relative to no additional intervention. Most studies were funded by agencies in the US federal government. We judged the certainty of evidence in the included studies to be moderate or low for the main review outcomes. Failure to include all families in outcome analyses (attrition) and possible bias in recruitment of families into the trials were the main limitations in the evidence. We included over 9000 children and their families in at least one meta-analysis. The follow results relate to meta-analyses of data at long-term follow-up. Primary outcomes Four studies (approximately 6276 children) assessed child school performance at long-term follow-up. The effect size was very small, and the CI did not include effects that, if real, suggest possibly important positive or negative effects if viewed from an individual perspective (SMD -0.02, 95% CI -0.11 to 0.08). We assessed the certainty of evidence for this outcome as moderate. No studies assessed child adverse events, parental substance use, or parental stress. Secondary outcomes Parent reports of child internalising behaviour (SMD -0.03, 95% CI -0.11 to 0.17; 4 RCTs, approximately 908 children; low-certainty evidence) and family relationships (SMD 0.08, 95% CI -0.03 to 0.19; 4 RCTs, approximately 2569 children; moderate-certainty evidence) also yielded CIs that did not include effects that, if real, suggest possibly important positive or negative effects. The CI for parent reports of child externalising behaviour, however, did include effects that, if real, were possibly large enough to be important (SMD -0.19, 95% CI -0.32 to -0.05; 4 RCTs, approximately 754 children; low-certainty evidence). Given these results, it is hard to support the assertion that assignment to FAST is associated with important positive outcomes for children and their parents.
For this update, we identified three new studies and therefore included in the Review four studies with a total of 459 participants who received subcutaneous injections of LMWH into the abdomen. Only one trial reported the injected drug volume (0.4 mL). Owing to the nature of the intervention, it was not possible to blind participants and care givers (personnel) in any included study. Two studies described blinding of outcome assessors; therefore overall, the methodological quality of included studies was moderate. The duration of the fast injection was 10 seconds and the duration of the slow injection was 30 seconds in all included studies. Three studies reported site pain intensity after each injection at different time points. Two studies assessed site pain intensity immediately after each injection, and meta-analysis on 140 participants showed no clear difference in site pain intensity immediately post slow injection when compared to fast injection (low-quality evidence; P = 0.15). In contrast, meta-analysis of two studies with 59 participants showed that 48 hours after the heparin injection, slow injection was associated with less pain intensity compared to fast injection (low-quality evidence; P = 0.007). One study (40 participants) reported pain intensity at 60 and 72 hours after injection. This study described no clear difference in site pain intensity at 60 and 72 hours post slow injection compared to fast injection. All four included studies assessed bruise size at 48 hours after each injection. Meta-analysis on 459 participants showed no difference in bruise size after slow injection compared to fast injection (low-quality evidence; P = 0.07). None of the included studies measured the incidence of haematoma as an outcome. We found four RCTs that evaluated the effect of subcutaneous heparin injection duration on pain intensity and bruise size. Owing to the small numbers of participants, we found insufficient evidence to determine any effect on pain intensity immediately after injection or at 60 and 72 hours post injection. However, slow injection may reduce site pain intensity 48 hours after injection (low-quality evidence). We observed no clear difference in bruise size after slow injection compared to fast injection (low-quality evidence). We judged this evidence to be of low quality owing to imprecision and inconsistency.
The original review was based on nineteen trials (17 published and two unpublished) including 4580 patients. This update includes twenty four trials (21 published, 3 unpublished) and 4921 patients, although due to patient exclusion and differential reporting 61% to 75% were available for the analyses. The review strongly suggests chemoradiation improves overall survival and progression free survival, whether or not platinum was used with absolute benefits of 10% and 13% respectively. There was, however, statistical heterogeneity for these outcomes. There was some evidence that the effect was greater in trials including a high proportion of stage I and II patients. Chemoradiation also showed significant benefit for local recurrence and a suggestion of a benefit for distant recurrence. Acute haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group. Late effects of treatment were not well reported and so the impact of chemoradiation on these effects could not be determined adequately. Treatment-related deaths were rare. Concomitant chemoradiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also appears to reduce local and distant recurrence suggesting concomitant chemotherapy may afford radiosensitisation and systemic cytotoxic effects. Some acute toxicity is increased, but the long-term side effects are still not clear.
A total of 40 randomised or quasi-randomised controlled trials (10 new in this update) met the inclusion criteria, with a total of 1780 out of 2440 children who enrolled receiving an active drug other than desmopressin or a tricyclic. In all, 31 different drugs or classes of drugs were tested. The trials were generally small or of poor methodological quality. There was an overall paucity of data regarding outcomes after treatment was withdrawn. For drugs versus placebo, when compared to placebo indomethacin (risk ratio [RR] 0.36, 95% CI 0.16 to 0.79), diazepam (RR 0.22, 95% CI 0.11 to 0.46), mestorelone (RR 0.32, 95% CI 0.17 to 0.62) and atomoxetine (RR 0.81, 95% CI 0.70 to 0.94) appeared to reduce the number of children failing to have 14 consecutive dry nights. Although indomethacin and diclofenac were better than placebo during treatment, they were not as effective as desmopressin and there was a higher chance of adverse effects. None of the medications were effective in reducing relapse rates, although this was only reported in five placebo controlled trials. For drugs versus drugs, combination therapy with imipramine and oxybutynin was more effective than imipramine monotherapy (RR 0.68, 95% CI 0.50 to 0.94) and also had significantly lower relapse rates than imipramine monotherapy (RR 0.35, 95% CI 0.16 to 0.77). There was an overall paucity of data regarding outcomes after treatment was withdrawn. For drugs versus behavioural therapy, bedwetting alarms were found to be better than amphetamine (RR 2.2, 95% CI 1.12 to 4.29), oxybutynin (RR 3.25, 95% CI 1.77 to 5.98), and oxybutynin plus holding exercises (RR 3.3, 95% CI 1.84 to 6.18) in reducing the number of children failing to achieve 14 consecutive dry nights. Adverse effects of drugs were seen in 19 trials while 17 trials did not adequately report the occurrence of side effects. There was not enough evidence to judge whether or not the included drugs cured bedwetting when used alone. There was limited evidence to suggest that desmopressin, imipramine and enuresis alarms therapy were better than the included drugs to which they were compared. In other reviews, desmopressin, tricyclics and alarm interventions have been shown to be effective during treatment. There was also evidence to suggest that combination therapy with anticholinergic therapy increased the efficacy of other established therapies such as imipramine, desmopressin and enuresis alarms by reducing the relapse rates, by about 20%, although it was not possible to identify the characteristics of children who would benefit from combination therapy. Future studies should evaluate the role of combination therapy against established treatments in rigorous and adequately powered trials.
We included eight studies in the review involving a total of 1338 low-risk women in the first stage of spontaneous labour at term. Two comparisons were made; 1) the use of oxytocin versus placebo or no treatment (three trials); 2) the early use of oxytocin versus its delayed use (five trials). There were no significant differences in the rates of caesarean section or instrumental vaginal delivery in either comparison. Early use of oxytocin resulted in an increase in uterine hyperstimulation associated with fetal heart changes. However, the early use of oxytocin versus its delayed use resulted in no significant differences in a range of neonatal and maternal outcomes. Use of early oxytocin resulted in a statistically significant reduction in the mean duration in labour of approximately two hours but did not increase the normal delivery rate. There was significant heterogeneity for this analysis and we carried out a random-effects meta-analysis; however, all of the trials are strongly in the same direction so it is reasonable to conclude that this is the true effect. We also performed a random-effects meta-analysis for the four other analyses which showed substantial heterogeneity in the review. For women making slow progress in spontaneous labour, treatment with oxytocin as compared with no treatment or delayed oxytocin treatment did not result in any discernable difference in the number of caesarean sections performed. In addition there were no detectable adverse effects for mother or baby. The use of oxytocin was associated with a reduction in the time to delivery of approximately two hours which might be important to some women. However, if the primary goal of this treatment is to reduce caesarean section rates, then doctors and midwives may have to look for alternative options.
We found one eligible trial. Participants were 210 newborn infants with birth weight less than 1251 grams. The trial was unblinded but otherwise of good methodological quality. This trial compared removal of an umbilical venous catheter within 10 days after insertion (and replacement with a peripheral cannula or a percutaneously inserted central catheter as required) versus expectant management (UVC in place up to 28 days). More infants in the early planned removal group than in the expectant management group (83 vs 33) required percutaneous insertion of a central catheter (PICC). Trial results showed no difference in the incidence of catheter-related bloodstream infection (RR 0.65, 95% CI 0.35 to 1.22), in hospital mortality (RR 1.12, 95% CI 0.42 to 2.98), in catheter-associated thrombus necessitating removal (RR 0.33, 95% confidence interval 0.01 to 7.94), or in other morbidity. GRADE assessment indicated that the quality of evidence was "low" at outcome level principally as the result of imprecision and risk of surveillance bias due to lack of blinding in the included trial. Currently available trial data are insufficient to show whether early planned removal of umbilical venous catheters reduces risk of infection, mortality, or other morbidity in newborn infants. A large, simple, and pragmatic randomised controlled trial is needed to resolve this ongoing uncertainty.
Forty-three randomized trials met the inclusion criteria, of which 29 are new in this update. In most of the studies, training interventions were directed at primary care physicians (general practitioners, internists, paediatricians or family doctors) or nurses practising in community or hospital outpatient settings. Some studies trained specialists. Patients were predominantly adults with general medical problems, though two studies included children with asthma. Descriptive and pooled analyses showed generally positive effects on consultation processes on a range of measures relating to clarifying patients' concerns and beliefs; communicating about treatment options; levels of empathy; and patients' perception of providers' attentiveness to them and their concerns as well as their diseases. A new finding for this update is that short-term training (less than 10 hours) is as successful as longer training. The analyses showed mixed results on satisfaction, behaviour and health status. Studies using complex interventions that focused on providers and patients with condition-specific materials generally showed benefit in health behaviour and satisfaction, as well as consultation processes, with mixed effects on health status. Pooled analysis of the fewer than half of included studies with adequate data suggests moderate beneficial effects from interventions on the consultation process; and mixed effects on behaviour and patient satisfaction, with small positive effects on health status. Risk of bias varied across studies. Studies that focused only on provider behaviour frequently did not collect data on patient outcomes, limiting the conclusions that can be drawn about the relative effect of intervention focus on providers compared with providers and patients. Interventions to promote patient-centred care within clinical consultations are effective across studies in transferring patient-centred skills to providers. However the effects on patient satisfaction, health behaviour and health status are mixed. There is some indication that complex interventions directed at providers and patients that include condition-specific educational materials have beneficial effects on health behaviour and health status, outcomes not assessed in studies reviewed previously. The latter conclusion is tentative at this time and requires more data. The heterogeneity of outcomes, and the use of single item consultation and health behaviour measures limit the strength of the conclusions.
We included eight trials (1563 patients). The drug was IFN alfa-2b in six trials and alfa-2a in two. Trials were heterogeneous in terms of diagnosis of FL, using several classification systems. IFN had been compared with placebo/no intervention in five trials and other chemotherapy in three. The effect of IFN was similar to that of placebo on overall survival (hazard ratio (HR) 0.90, 95% CI 0.61 to 1.34) whereas IFN was more effective when added to chemotherapy (HR 0.68, 95% confidence interval (CI) 0.52 to 0.90). Considering IFN versus all comparators, IFN was effective in prolonging progression-free survival (HR 0.66, 95% CI 0.57 to 0.77) and overall survival (fixed effects HR 0.79, 95% CI 0.67 to 0.94, I2 = 52%). After adjustment for heterogeneity this statistically significance disappeared (random effects HR 0.82, 95% CI 0.63 to 1.08). Toxicity and patients lost to follow up were significantly higher in the IFN groups. There is evidence that addition of IFN as maintenance therapy for FL improves progression-free survival. A net benefit for overall survival is less evident. In the included studies, IFN was associated with significant toxicities that may have a major impact on a patient's quality of life.
Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the seven trials that reported progression-free survival (time to first progression in the sequential arm), 637 women progressed out of the 846 women randomised. There was weak evidence of a higher risk of progression in the combination arm (HR 1.11; 95% CI 0.99 to 1.25; P = 0.08) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.16; 95% CI 1.06 to 1.28; P = 0.001) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome. There is weak evidence that sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.
Three RCTs (1713 participants) fulfilled the selection criteria and we included them in the review. All three trials compared alemtuzumab versus subcutaneous interferon beta-1a for patients with relapsing–remitting MS. Patients were treatment-naive in the CARE-MS and CAMMS223 studies. The CARE-MS II study included patients with at least one relapse while being treated with interferon beta or glatiramer acetate. Alemtuzumab was given for 12 or 24 months; for some outcomes, the follow-up period reached 36 months. The regimens were (a) 12 mg or 24 mg per day administered intravenously, once a day for five consecutive days at month 0 and 12 or (b) 24 mg per day, intravenously, once a day for three consecutive days at month 12 and 24. The patients in the other arm of the trials received interferon beta-1a 44 μg subcutaneously three times weekly after dose titration. At 24 months, alemtuzumab 12 mg was associated with: (a) higher relapse-free survival (hazard ratio (HR) 0.50, 95% CI 0.41 to 0.60; 1248 participants, two studies, moderate quality evidence); (b) higher sustained disease progression-free survival (HR 0.62, 95% CI 0.44 to 0.87; 1191 participants; two studies; moderate quality evidence); (c) a slightly higher number of participants with at least one adverse event (RR 1.04, 95% CI 1.01 to 1.06; 1248 participants; two studies; moderate quality evidence); (d) a lower number of participants with new or enlarging T2-hyperintense lesions on magnetic resonance imaging (MRI) (RR 0.74, 95% CI 0.59 to 0.91; 1238 participants; two studies; I2 = 80%); and (e) a lower number of dropouts (RR 0.31, 95% CI 0.23 to 0.41; 1248 participants; two studies, I2 = 29%; low quality evidence). At 36 months, alemtuzumab 24 mg was associated with: (a) higher relapse-free survival (45 versus 17; HR 0.21, 95% CI 0.11 to 0.40; one study; 221 participants); (b) a higher sustained disease progression-free survival (HR 0.33, 95% CI 0.16 to 0.69; one study; 221 participants); and (c) no statistical difference in the rate of participants with at least one adverse event. We did not find any study that reported any of the following outcomes: rate of participants free of clinical disease activity, quality of life, fatigue or change in the numbers of MRI T2- and T1-weighted lesions after treatment. It was not possible to perform subgroup analyses according to disease type and disability at baseline due to lack of data. In patients with relapsing-remitting MS, alemtuzumab 12 mg was better than subcutaneous interferon beta-1a for the following outcomes assessed at 24 months: relapse-free survival, sustained disease progression-free survival, number of participants with at least one adverse event and number of participants with new or enlarging T2-hyperintense lesions on MRI. The quality of the evidence for these results was low to moderate. Alemtuzumab 24 mg seemed to be better than subcutaneous interferon beta-1a for relapse-free survival and sustained disease progression-free survival, at 36 months. More randomised clinical trials are needed to evaluate the effects of alemtuzumab on other forms of MS and compared with other therapeutic options. These new studies should assess additional relevant outcomes such as the rate of participants free of clinical disease activity, quality of life, fatigue and adverse events (individual rates, serious adverse events and long-term adverse events). Moreover, these new studies should evaluate other doses and durations of alemtuzumab course.
We included 24 trials involving 7099 participants. Using the Cochrane 'Risk of bias' tool, we assessed no study as being at low risk of bias for all domains. Many studies were poorly reported, so the risk of selection and detection biases were often unclear. Most studies reported important outcomes incompletely, and we judged them to be at high risk of reporting bias. All but one study enrolled oral poisoning patients in an emergency department; the remaining study was conducted in a pre-hospital setting. Fourteen studies included multiple toxic syndromes or did not specify, while the other studies specifically investigated paracetamol (2 studies), carbamazepine (2 studies), tricyclic antidepressant (2 studies), yellow oleander (2 studies), benzodiazepine (1 study), or toxic berry intoxication (1 study). Twenty-one trials investigated the effects of activated charcoal (AC), administered as a single dose (SDAC) or in multiple doses (MDAC), alone or in combination with other first aid interventions (a cathartic) and/or hospital treatments. Six studies investigated syrup of ipecac plus other first aid interventions (SDAC + cathartic) versus ipecac alone. The collected evidence was mostly of low to very low certainty, often downgraded for indirectness, risk of bias or imprecision due to low numbers of events. First aid interventions that limit or delay the absorption of the poison in the body We are uncertain about the effect of SDAC compared to no intervention on the incidence of adverse events in general (zero events in both treatment groups; 1 study, 451 participants) or vomiting specifically (Peto odds ratio (OR) 4.17, 95% confidence interval (CI) 0.30 to 57.26, 1 study, 25 participants), ICU admission (Peto OR 7.77, 95% CI 0.15 to 391.93, 1 study, 451 participants) and clinical deterioration (zero events in both treatment groups; 1 study, 451 participants) in participants with mixed types or paracetamol poisoning, as all evidence for these outcomes was of very low certainty. No studies assessed SDAC for mortality, duration of symptoms, drug absorption or hospitalization. Only one study compared SDAC to syrup of ipecac in participants with mixed types of poisoning, providing very low-certainty evidence. Therefore we are uncertain about the effects on Glasgow Coma Scale scores (mean difference (MD) −0.15, 95% CI −0.43 to 0.13, 1 study, 34 participants) or incidence of adverse events (risk ratio (RR) 1.24, 95% CI 0.26 to 5.83, 1 study, 34 participants). No information was available concerning mortality, duration of symptoms, drug absorption, hospitalization or ICU admission. This review also considered the added value of SDAC or MDAC to hospital interventions, which mostly included gastric lavage. No included studies investigated the use of body positioning in oral poisoning patients. First aid interventions that evacuate the poison from the gastrointestinal tract We found one study comparing ipecac versus no intervention in toxic berry ingestion in a pre-hospital setting. Low-certainty evidence suggests there may be an increase in the incidence of adverse events, but the study did not report incidence of mortality, incidence or duration of symptoms of poisoning, drug absorption, hospitalization or ICU admission (103 participants). In addition, we also considered the added value of syrup of ipecac to SDAC plus a cathartic and the added value of a cathartic to SDAC. No studies used cathartics as an individual intervention. First aid interventions that neutralize or dilute the poison No included studies investigated the neutralization or dilution of the poison in oral poisoning patients. The studies included in this review provided mostly low- or very low-certainty evidence about the use of first aid interventions for acute oral poisoning. A key limitation was the fact that only one included study actually took place in a pre-hospital setting, which undermines our confidence in the applicability of these results to this setting. Thus, the amount of evidence collected was insufficient to draw any conclusions.
Nine trials in which a total of 754 very preterm or very low birth weight infants participated were eligible for inclusion. Few participants were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 grams) or growth restricted. These trials did not provide any evidence that early trophic feeding affected feed tolerance or growth rates. Meta-analysis did not detect a statistically significant effect on the incidence of necrotising enterocolitis: typical risk ratio 1.07 (95% confidence interval 0.67 to 1.70); risk difference 0.01 (-0.03 to 0.05). The available trial data do not provide evidence of important beneficial or harmful effects of early trophic feeding for very preterm or very low birth weight infants. The applicability of these findings to extremely preterm, extremely low birth weight or growth restricted infants is limited. Further randomised controlled trials would be needed to determine how trophic feeding compared with enteral fasting affects important outcomes in this population.
The searches identified 9900 titles and, after excluding duplicates, 6433 titles were initially screened. After the initial title screen, 6266 were excluded. Abstracts were screened for 167 studies and 33 articles were identified as meeting the inclusion criteria, of which 13 were included in the review after an assessment of the complete manuscripts. Seven trials evaluating IE nutrition were included in the review, of which 6 were combined in a meta-analysis. These studies showed a low to moderate level of heterogeneity and significantly reduced total post-operative complications (risk ratio (RR) 0.67 CI 0.53 to 0.84). Three trials evaluating PN were included in a meta-analysis and a significant reduction in post-operative complications was demonstrated (RR 0.64 95% CI 0.46 to 0.87) with low heterogeneity, in predominantly malnourished participants. Two trials evaluating enteral nutrition (RR 0.79, 95% CI 0.56 to 1.10) and 3 trials evaluating standard oral supplements (RR 1.01 95% CI 0.56 to 1.10) were included, neither of which showed any difference in the primary outcomes. There have been significant benefits demonstrated with pre-operative administration of IE nutrition in some high quality trials. However, bias was identified which may limit the generalizability of these results to all GI surgical candidates and the data needs to be placed in context with other recent innovations in surgical management (eg-ERAS). Some unwanted effects have also been reported with components of IE nutrition in critical care patients and it is unknown whether there would be detrimental effects by administering IE nutrition to patients who could require critical care support after their surgery. The studies evaluating PN demonstrated that the provision of PN to predominantly malnourished surgical candidates reduced post-operative complications; however, these data may not be applicable to current clinical practice, not least because they have involved a high degree of 'hyperalimentation'. Trials evaluating enteral or oral nutrition were inconclusive and further studies are required to select GI surgical patients for these nutritional interventions.
We included 51 studies that analysed a total of 5345 participants. One study was assessed as being at unclear risk of bias, with the remaining 50 being at high risk of bias, however, this did not affect the quality assessments for gingivitis and plaque as we believe that further research is very unlikely to change our confidence in the estimate of effect. Gingivitis After 4 to 6 weeks of use, chlorhexidine mouthrinse reduced gingivitis (Gingival Index (GI) 0 to 3 scale) by 0.21 (95% CI 0.11 to 0.31) compared to placebo, control or no mouthrinse (10 trials, 805 participants with mild gingival inflammation (mean score 1 on the GI scale) analysed, high-quality evidence). A similar effect size was found for reducing gingivitis at 6 months. There were insufficient data to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 (moderate or severe levels of gingival inflammation). Plaque Plaque was measured by different indices and the SMD at 4 to 6 weeks was 1.45 (95% CI 1.00 to 1.90) standard deviations lower in the chlorhexidine group (12 trials, 950 participants analysed, high-quality evidence), indicating a large reduction in plaque. A similar large reduction was found for chlorhexidine mouthrinse use at 6 months. Extrinsic tooth staining There was a large increase in extrinsic tooth staining in participants using chlorhexidine mouthrinse at 4 to 6 weeks. The SMD was 1.07 (95% CI 0.80 to 1.34) standard deviations higher (eight trials, 415 participants analysed, moderate-quality evidence) in the chlorhexidine mouthrinse group. There was also a large increase in extrinsic tooth staining in participants using chlorhexidine mouthrinse at 7 to 12 weeks and 6 months. Calculus Results for the effect of chlorhexidine mouthrinse on calculus formation were inconclusive. Effect of concentration and frequency of rinsing There were insufficient data to determine whether there was a difference in effect for either chlorhexidine concentration or frequency of rinsing. Other adverse effects The adverse effects most commonly reported in the included studies were taste disturbance/alteration (reported in 11 studies), effects on the oral mucosa including soreness, irritation, mild desquamation and mucosal ulceration/erosions (reported in 13 studies) and a general burning sensation or a burning tongue or both (reported in nine studies). There is high-quality evidence from studies that reported the Löe and Silness Gingival Index of a reduction in gingivitis in individuals with mild gingival inflammation on average (mean score of 1 on the 0 to 3 GI scale) that was not considered to be clinically relevant. There is high-quality evidence of a large reduction in dental plaque with chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for 4 to 6 weeks and 6 months. There is no evidence that one concentration of chlorhexidine rinse is more effective than another. There is insufficient evidence to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 indicating moderate or severe levels of gingival inflammation. Rinsing with chlorhexidine mouthrinse for 4 weeks or longer causes extrinsic tooth staining. In addition, other adverse effects such as calculus build up, transient taste disturbance and effects on the oral mucosa were reported in the included studies.
Two RCTs were included, involving 2667 adult patients with RRMS to evaluate the efficacy and safety of two dosages of dimethyl fumarate (240 mg orally three times daily or twice daily) by direct comparison with placebo for two years. Among them, a subsample of 1221 (45.8%) patients were selected to participate in MRI evaluations by each study site with MRI capabilities itself. No powered head-to-head study with an active treatment comparator has been found. Meta-analyses showed that dimethyl fumarate both three times daily and twice daily reduced the number of patients with a relapse (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.50 to 0.66, P < 0.00001 and 0.64, 95% CI 0.54 to 0.77, P < 0.00001, respectively) or disability worsening (RR 0.70, 95% CI 0.57 to 0.87, P = 0.0009 and 0.65, 95% CI 0.53 to 0.81, P = 0.0001, respectively) over two years, compared to placebo. The treatment effects were decreased in the likely-case scenario analyses taking the effect of dropouts into consideration. Both dosages also reduced the annualised relapse rate. Data of active lesions on MRI scans were not combined because there was a high risk of selection bias for MRI outcomes and imprecision of MRI data in both studies, as well as an obvious heterogeneity between the studies. In terms of safety profile, both dosages increased the risk for adverse events and the risk for drug discontinuation due to adverse events. The most common adverse events included flushing and gastrointestinal events (upper abdominal pain, nausea and diarrhoea). Uncommon adverse events included lymphopenia and leukopenia, but they were more likely to happen with dimethyl fumarate than with placebo (high dosage: RR 5.25, 95% CI 2.20 to 12.51, P = 0.0002 and 5.23, 95% CI 2.47 to 11.07, P < 0.0001, respectively; low dosage: RR 5.69, 95% CI 2.40 to 13.46, P < 0.0001 and 6.53, 95% CI 3.13 to 13.64, P < 0.00001, respectively). Both studies had a high attrition bias resulting from the unbalanced reasons for dropouts among groups. Quality of evidence for relapse outcome was moderate, but for disability worsening was low. There is moderate-quality evidence to support that dimethyl fumarate at a dose of 240 mg orally three times daily or twice daily reduces both the number of patients with a relapse and the annualised relapse rate over two years of treatment in comparison with placebo. However, the quality of the evidence to support the benefit in reducing the number of patients with disability worsening is low. There is no high-quality data available to evaluate the benefit on MRI outcomes. The common adverse effects such as flushing and gastrointestinal events are mild-to-moderate for most patients. Lymphopenia and leukopenia are uncommon adverse events but significantly associated with dimethyl fumarate. Both dosages of dimethyl fumarate have similar benefit and safety profile, which supports the option of low-dose administration. New studies of high quality and long-term follow-up are needed to evaluate the benefit of dimethyl fumarate on prevention of disability worsening and to observe the long-term adverse effects including progressive multifocal leukoencephalopathy.
We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) −0.02, 95% CI −0.09 to 0.09); I² = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD −0.06, 95% CI −0.09 to −0.02); I² = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence). Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD −0.21 (95% CI −0.41 to −0.02); I² = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence). Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I² = 11%; typical RD −0.01, 95% CI −0.09 to 0.08; I² = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group. Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made.
We included nine RCTs involving 2888 participants without occupational irritant hand dermatitis (OIHD) at baseline. Six studies, including 1533 participants, investigated the effects of barrier creams, moisturisers, or both. Three studies, including 1355 participants, assessed the effectiveness of skin protection education on the prevention of OIHD. No studies were eligible that investigated the effects of protective gloves. Among each type of intervention, there was heterogeneity concerning the criteria for assessing signs and symptoms of OIHD, the products, and the occupations. Selection bias, performance bias, and reporting bias were generally unclear across all studies. The risk of detection bias was low in five studies and high in one study. The risk of other biases was low in four studies and high in two studies. The eligible trials involved a variety of participants, including: metal workers exposed to cutting fluids, dye and print factory workers, gut cleaners in swine slaughterhouses, cleaners and kitchen workers, nurse apprentices, hospital employees handling irritants, and hairdressing apprentices. All studies were undertaken at the respective work places. Study duration ranged from four weeks to three years. The participants' ages ranged from 16 to 67 years. Meta-analyses for barrier creams, moisturisers, a combination of both barrier creams and moisturisers, or skin protection education showed imprecise effects favouring the intervention. Twenty-nine per cent of participants who applied barrier creams developed signs of OIHD, compared to 33% of the controls, so the risk may be slightly reduced with this measure (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.72 to 1.06; 999 participants; 4 studies; low-quality evidence). However, this risk reduction may not be clinically important. There may be a clinically important protective effect with the use of moisturisers: in the intervention groups, 13% of participants developed symptoms of OIHD compared to 19% of the controls (RR 0.71, 95% CI 0.46 to 1.09; 507 participants; 3 studies; low-quality evidence). Likewise, there may be a clinically important protective effect from using a combination of barrier creams and moisturisers: 8% of participants in the intervention group developed signs of OIHD, compared to 13% of the controls (RR 0.68, 95% CI 0.33 to 1.42; 474 participants; 2 studies; low-quality evidence). We are uncertain whether skin protection education reduces the risk of developing signs of OIHD (RR 0.76, 95% CI 0.54 to 1.08; 1355 participants; 3 studies; very low-quality evidence). Twenty-one per cent of participants who received skin protection education developed signs of OIHD, compared to 28% of the controls. None of the studies addressed the frequency of treatment discontinuation due to adverse effects of the products directly. However, in three studies of barrier creams, the reasons for withdrawal from the studies were unrelated to adverse effects. Likewise, in one study of moisturisers plus barrier creams, and in one study of skin protection education, reasons for dropout were unrelated to adverse effects. The remaining studies (one to two in each comparison) reported dropouts without stating how many of them may have been due to adverse reactions to the interventions. We judged the quality of this evidence as moderate, due to the indirectness of the results. The investigated interventions to prevent OIHD probably cause few or no serious adverse effects. Moisturisers used alone or in combination with barrier creams may result in a clinically important protective effect, either in the long- or short-term, for the primary prevention of OIHD. Barrier creams alone may have slight protective effect, but this does not appear to be clinically important. The results for all of these comparisons were imprecise, and the low quality of the evidence means that our confidence in the effect estimates is limited. For skin protection education, the results varied substantially across the trials, the effect was imprecise, and the pooled risk reduction was not large enough to be clinically important. The very low quality of the evidence means that we are unsure as to whether skin protection education reduces the risk of developing OIHD. The interventions probably cause few or no serious adverse effects. We conclude that at present there is insufficient evidence to confidently assess the effectiveness of interventions used in the primary prevention of OIHD. This does not necessarily mean that current measures are ineffective. Even though the update of this review included larger studies of reasonable quality, there is still a need for trials which apply standardised measures for the detection of OIHD in order to determine the effectiveness of the different prevention strategies.
Nine randomised (Banner 2000; Baum 2000; Goldman 1990; Kilmann 1987; Kockott 1975; Melnik 2005; Munjack 1984; Price 1981; Wylie 2003) and two quasi-randomised trials (Ansari 1976; Van Der Windt 2002), involving 398 men with ED (141 in psychotherapy group, 109 received medication, 68 psychotherapy plus medication, 20 vacuum devices and 59 control group) met the inclusion criteria. In data pooled from five randomised trials (Kockott 1975; Ansari 1976; Price 1981; Munjack 1984; Kilmann 1987), group psychotherapy was more likely than the control group (waiting list - a group of participants who did not receive any active intervention) to reduce the number of men with "persistence of erectile dysfunction" at post-treatment (RR 0.40, 95% CI 0.17 to 0.98, N = 100; NNT 1.61, 95% CI 0.97 to 4.76).   At six months follow up there was continued maintenance of reduction of men with "persistence of ED" in favour of group psychotherapy (RR 0.43, 95% CI 0.26 to 0.72, N = 37; NNT 1.58, 95% CI 1.17 to 2.43). In data pooled from two randomised trials (Price 1981; Kilmann 1987), sex-group psychotherapy reduced the number of men with "persistence of erectile dysfunction" in post-treatment (RR 0.13, 95% CI 0.04 to 0.43, N = 37), with a 95% response rate for sex therapy and 0% for the control group (waiting list - no treatment) (NNT 1.07, 95% CI 0.86 to 1.44). Treatment response appeared to vary between patient subgroups, although there was no significant difference in improvement in erectile function according to mean group age, type of relationship, and severity of ED. In two trials (Melnik 2005; Banner 2000) that compared group therapy plus sildenafil citrate versus sildenafil, men randomised to receive group therapy plus sildenafil showed significant reduction of "persistence of ED" (RR 0.46, 95% CI 0.24 to 0.88; NNT 3.57, 95% CI 2 to 16.7, N = 71), and were less likely than those receiving only sildenafil to drop out (RR 0.29, 95% CI 0.09 to 0.93). One small trial (Melnik 2005) directly compared group therapy and sildenafil citrate. It found a significant difference favouring group therapy versus sildenafil in the mean difference of the IIEF (WMD -12.40, 95% CI -20.81 to -3.99, N = 20). No differences in effectiveness were found between psychosocial interventions versus local injection and vacuum devices. There was evidence that group psychotherapy may improve erectile function. Treatment response varied between patient subgroups, but focused sex-group therapy showed greater efficacy than control group (no treatment). In a meta-analysis that compared group therapy plus sildenafil citrate versus sildenafil, men randomised to receive group therapy plus sildenafil showed significant improvement of successful intercourse, and were less likely than those receiving only sildenafil to drop out. Group psychotherapy also significantly improved ED compared to sildenafil citrate alone. Regarding the effectiveness of psychosocial interventions for the treatment of ED compared to local injection, vacuum devices and other psychosocial techniques, no differences were found.
Seven trials with a total of 2144 participants were included. Four studies (1959 participants) addressed subjective change in severity of rhinorrhoea. All studies were consistent in reporting statistically significant changes in favour of IB. Nasal congestion was reported in four studies and was found to have no significant change between the two groups. Two studies found a positive response in the IB group for the global assessment of overall improvement. Side effects were more frequent in the IB group, odds ratio (OR) 2.09 (95% confidence interval (CI) 1.40 to 3.11). Commonly encountered side effects included nasal dryness, blood tinged mucus and epistaxis. The overall risk of bias in the included studies was moderate. For people with the common cold, the existing evidence, which has some limitations, suggests that IB is likely to be effective in ameliorating rhinorrhoea. IB had no effect on nasal congestion and its use was associated with more side effects compared to placebo or no treatment although these appeared to be well tolerated and self limiting. There is a need for larger, high-quality trials to determine the effectiveness of IB in relieving common cold symptoms.
Psychological interventions as a group  The SMD for symptom score improvement at 2 and 3 months was 0.97 (95% CI 0.29 to 1.65) and 0.62 (95% CI 0.45 to 0.79) respectively compared to usual care. Against placebo, the SMDs were 0.71 (95% CI 0.08 to 1.33) and -0.17 (95% CI -0.45 to 0.11) respectively. For improvement of abdominal pain, the SMDs at 2 and 3 months were 0.54 (95%CI 0.10 to 0.98) and 0.26 (95% CI 0.07 to 0.45) compared to usual care. The SMD from placebo at 3 months was 0.31 (95% CI -0.16 to 0.79). For improvement in quality of life, the SMD from usual care at 2 and 3 months was 0.47 (95%CI 0.11 to 0.84) and 0.31 (95%CI -0.16 to 0.77) respectively.   Cognitive behavioural therapy  The SMD for symptom score improvement at 2 and 3 months was 0.75 (95% CI -0.20 to 1.70) and 0.58 (95% CI 0.36 to 0.79) respectively compared to usual care. Against placebo, the SMDs were 0.68 (95% CI -0.01 to 1.36) and -0.17 (95% CI -0.45 to 0.11) respectively. For improvement of abdominal pain, the SMDs at 2 and 3 months were 0.45 (95% CI 0.00 to 0.91) and 0.22 (95% CI -0.04 to -0.49) compared to usual care. Against placebo the SMD at 3 months was 0.33 (95% CI -0.16 to 0.82). For improvement in quality of life, the SMDs at 2 and 3 months compared to usual care were 0.44 (95% CI 0.04 to 0.85) and 0.92 (95% CI 0.07 to 1.77) respectively. Interpersonal psychotherapy  The RR for adequate relief of symptoms was 2.02 (95% CI 1.13 to 3.62), RD 0.30 (95% CI 0.13 to 0.46), NNT 4 for comparison with care as usual. The SMD for improvement of symptom score was 0.35 (95% CI -0.75 to 0.05) compared with usual care.   Relaxation/Stress management  The SMD in symptom score improvement at 2 months was 0.50 (95%CI 0.02 to 0.98) compared with usual care. The SMD in improvement of abdominal pain at 3 months was 0.02 (95%CI -0.56 to 0.61) compared with usual care.   Long term results  Very few long term follow-up results were available. There was no convincing evidence that treatment effects were sustained following completion of treatment for any treatment modality. Psychological interventions may be slightly superior to usual care or waiting list control conditions at the end of treatment although the clinical significance of this is debatable. Except for a single study, these therapies are not superior to placebo and the sustainability of their effect is questionable. The meta-analysis was significantly limited by issues of validity, heterogeneity, small sample size and outcome definition. Future research should adhere to current recommendations for IBS treatment trials and should focus on the long-term effects of treatment.
Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo. Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups. This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
Twenty studies (986 participants; 966 MS participants and 20 healthy controls) fulfilled the inclusion criteria. The mean age of the participants was 44.6 years, mean length of education was 12.3 years and 70% of the participants were women. Most of the participants had a relapsing-remitting course of disease. The mean Expanded Disability Status Scale score was 3.2 and the mean duration of disease was 14.0 years. On the basis of these studies, we found low-level evidence that neuropsychological rehabilitation reduces cognitive symptoms in MS. Cognitive training was found to improve memory span (standardised mean difference (SMD) 0.54, 95% confidence interval (CI) 0.20 to 0.88, P = 0.002) and working memory (SMD 0.33, 95% CI 0.09 to 0.57, P = 0.006). Cognitive training combined with other neuropsychological rehabilitation methods was found to improve attention (SMD 0.15, 95% CI 0.01 to 0.28, P = 0.03), immediate verbal memory (SMD 0.31, 95% CI 0.08 to 0.54, P = 0.008) and delayed memory (SMD 0.22, 95% CI 0.02 to 0.42, P = 0.03). There was no evidence of an effect of neuropsychological rehabilitation on emotional functions. The overall quality, as well as the comparability of the included studies, was relatively low due to methodological limitations and heterogeneity of interventions and outcome measures. Although most of the pooled results in the meta-analyses yielded no significant findings, 18 of the 20 studies showed some evidence of positive effects when the studies were individually analysed. This review found low-level evidence for positive effects of neuropsychological rehabilitation in MS. The interventions and outcome measures included in the review were heterogeneous, which limited the comparability of the studies. New trials may therefore change the strength and direction of the evidence.
Five randomised or quasi-randomised double-blind trials fulfilled the selection criteria, but were not sufficiently comparable to undertake a meta-analysis. The drugs studied were verapamil (8 participants), diltiazem (56 participants), nifedipine (105 participants) and flunarizine (27 participants). There were limitations in the description of blinding and randomisation, and definition of outcome measures. One trial, using verapamil, showed a difference between groups in muscle force measured by ergometry, but also revealed cardiac side effects. The numbers of people included in the trials were low, and so the studies may not have included enough people for sufficient power to detect small differences in muscle force or function between placebo and control groups. In addition, calcium antagonists were in an early stage of development and some of the second generation drugs that have a better side effect profile, such as amlodipine, have not been studied. There is no evidence to show a significant beneficial effect of calcium antagonists on muscle function in DMD.
Nine Cochrane reviews were selected for this overview. Their scores on the Overview Quality Assessment Questionnaire varied from four to six of a maximal possible score of seven. Compared with general anaesthesia, neuraxial blockade reduced the zero to 30-day mortality (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53 to 0.94; I2 = 0%) based on 20 studies that included 3006 participants. Neuraxial blockade also decreased the risk of pneumonia (RR 0.45, 95% CI 0.26 to 0.79; I2 = 0%) based on five studies that included 400 participants. No difference was detected in the risk of myocardial infarction between the two techniques (RR 1.17, 95% CI 0.57 to 2.37; I2 = 0%) based on six studies with 849 participants. Compared with general anaesthesia alone, the addition of a neuraxial block to general anaesthesia did not affect the zero to 30-day mortality (RR 1.07, 95% CI 0.76 to 1.51; I2 = 0%) based on 18 studies with 3228 participants. No difference was detected in the risk of myocardial infarction between combined neuraxial blockade-general anaesthesia and general anaesthesia alone (RR 0.69, 95% CI 0.44 to 1.09; I2 = 0%) based on eight studies that included 1580 participants. The addition of a neuraxial block to general anaesthesia reduced the risk of pneumonia (RR 0.69, 95% CI 0.49 to 0.98; I2 = 9%) after adjustment for publication bias and based on nine studies that included 2433 participants. The quality of the evidence was judged as moderate for all six comparisons. No serious adverse events (seizure or cardiac arrest related to local anaesthetic toxicity, prolonged central or peripheral neurological injury lasting longer than one month or infection secondary to neuraxial blockade) were reported. The quality of the reporting score of complications related to neuraxial blocks was nine (four to 12 (median range)) of a possible maximum score of 14. Compared with general anaesthesia, a central neuraxial block may reduce the zero to 30-day mortality for patients undergoing surgery with intermediate to high cardiac risk (level of evidence, moderate). Further research is required.
Six RCTs with 456 participants and variable treatment and follow-up periods were included. From the limited data, the live birth rate per couple randomly assigned (27% vs 0%; Peto odds ratio (OR) 9.31, 95% confidence interval (CI) 1.17 to 73.75, one study, 30 participants, very low-quality evidence) and the spontaneous pregnancy rate per couple randomly assigned (16% vs 7%; Peto OR 4.94, 95% CI 2.13 to 11.44, five studies, 412 participants, I2 = 0%, moderate-quality evidence) were significantly higher in men receiving gonadotrophin treatment than in men receiving placebo or no treatment. No significant difference between groups was noted when intracytoplasmic sperm injection (ICSI) or intrauterine insemination (IUI) was performed. None of the included studies reported miscarriage rates, and adverse events data were sparse. Encouraging preliminary data suggest a beneficial effect on live birth and pregnancy of gonadotrophin treatment for men with idiopathic male factor subfertility, but because the numbers of trials and participants are small, evidence is insufficient to allow final conclusions. Large multi-centre trials with adequate numbers of participants are needed.
One trial (46 participants) was eligible for inclusion. After randomization eight participants were withdrawn, mainly because they declined to participate in the trial. Data were analysed for 38 participants at the end of the trial. After a mean follow-up of three years, hip core decompression and physical therapy did not show clinical improvement when compared with physical therapy alone using the score from the original trial (an improvement of 18.1 points for those treated with intervention therapy versus an improvement of 15.7 points with control therapy). We are very uncertain whether there is any difference between groups regarding major complications (hip pain, risk ratio 0.95 (95% confidence interval 0.56 to 1.60; vaso-occlusive crises, risk ratio 1.14 (95% confidence interval 0.72 to 1.80; very low quality of evidence); and acute chest syndrome, risk ratio 1.06 (95% confidence interval 0.44 to 2.56; very low quality of evidence)). This trial did not report results on mortality or quality of life. We found no evidence that adding hip core decompression to physical therapy achieves clinical improvement in people with sickle cell disease with avascular necrosis of bone compared to physical therapy alone. However, we highlight that our conclusion is based on one trial with high attrition rates. Further randomized controlled trials are necessary to evaluate the role of hip-core depression for this clinical condition. Endpoints should focus on participants' subjective experience (e.g. quality of life and pain) as well as more objective 'time-to-event' measures (e.g. mortality, survival, hip longevity). The availability of participants to allow adequate trial power will be a key consideration for endpoint choice.
We included in the analysis one small sham-controlled randomised trial of 173 women performed in the United States. Participants enrolled in this study had been diagnosed with stress UI and were randomly assigned to transurethral radiofrequency collagen denaturation (treatment) or a sham surgery using a non-functioning catheter (no treatment). Mean age of participants in the 12-month multi-centre trial was 50 years (range 22 to 76 years). Of three patient-important primary outcomes selected for this systematic review, the number of women reporting UI symptoms after intervention was not reported. No serious adverse events were reported for the transurethral radiofrequency collagen denaturation arm or the sham treatment arm during the 12-month trial. Owing to high risk of bias and imprecision, we downgraded the quality of evidence for this outcome to low. The effect of transurethral radiofrequency collagen denaturation on the number of women with an incontinence quality of life (I-QOL) score improvement ≥ 10 points at 12 months was as follows: RR 1.11, 95% CI 0.77 to 1.62; participants = 142, but the confidence interval was wide. For this outcome, the quality of evidence was also low as the result of high risk of bias and imprecision. We found no evidence on the number of women undergoing repeat continence surgery. The risk of other adverse events (pain/dysuria (RR 5.73, 95% CI 0.75 to 43.70; participants = 173); new detrusor overactivity (RR 1.36, 95% CI 0.63 to 2.93; participants = 173); and urinary tract infection (RR 0.95, 95% CI 0.24 to 3.86; participants = 173) could not be established reliably as the trial was small. Evidence was insufficient for assessment of whether use of transurethral radiofrequency collagen denaturation was associated with an increased rate of urinary retention, haematuria and hesitancy compared with sham treatment in 173 participants. The GRADE quality of evidence for all other adverse events with available evidence was low as the result of high risk of bias and imprecision. We found no evidence to inform comparisons of transurethral radiofrequency collagen denaturation with conservative physical treatment, mechanical devices, drug treatment, injectable treatment for UI or other surgery for UI. It is not known whether transurethral radiofrequency collagen denaturation, as compared with sham treatment, improves patient-reported symptoms of UI. Evidence is insufficient to show whether the procedure improves disease-specific quality of life. Evidence is also insufficient to show whether the procedure causes serious adverse events or other adverse events in comparison with sham treatment, and no evidence was found for comparison with any other method of treatment for UI.
Only two eligible trials were included (593 patients), both of reasonable quality although one was unblinded. Both trials compared selegiline with a dopamine agonist, whilst one also compared selegiline with levodopa. MAO-B inhibitors were not associated with a significant increase or decrease in deaths compared with levodopa (odds ratio (OR) 0.96; 95% confidence interval (CI) 0.52 to 1.76) or dopamine agonists (OR 1.30; 95% CI 0.69 to 2.45). Those receiving MAO-B inhibitors were more likely to require add-on therapy during follow-up than those receiving levodopa (OR 12.02; 95% CI 6.78 to 21.31) or dopamine agonist (OR 2.00; 95% CI 1.05 to 3.81). There was a reduction in motor fluctuations with MAO-B inhibitors compared with levodopa (OR 0.55; 95% CI 0.32 to 0.94) but not dopamine agonists (OR 1.15; 95% CI 0.65 to 2.05). Withdrawals due to adverse events were less common with MAO-B inhibitors than with dopamine agonists (OR 0.11; 95% CI 0.01 to 0.99). MAO-B inhibitors are one option for the early treatment of PD although they have weaker symptomatic effects than levodopa and dopamine agonists. They may reduce the rate of motor fluctuations compared with initial levodopa therapy and may have fewer significant adverse effects than the older agonists but data are too few to provide reliable conclusions.
We included seven trials involving a total of 75 people with mild to moderate asthma. The studies were all of cross-over design. Six trials involving 55 people showed that in comparison with placebo, caffeine, even at a 'low dose' (less than 5 mg/kg body weight), appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one second (FEV1) showed a small improvement up to two hours after caffeine ingestion (standardised mean difference 0.72; 95% confidence interval 0.25 to 1.20), which translates into a 5% mean difference in FEV1. However in two studies the mean differences in FEV1 were 12% and 18% after caffeine. Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours. One trial involving 20 people examined the effect of drinking coffee versus a decaffeinated variety on the exhaled nitric oxide levels in patients with asthma and concluded that there was no significant effect on this outcome. Caffeine appears to improve airways function modestly, for up to four hours, in people with asthma. People may need to avoid caffeine for at least four hours prior to lung function testing, as caffeine ingestion could cause misinterpretation of the results. Drinking caffeinated coffee before taking exhaled nitric oxide measurements does not appear to affect the results of the test, but more studies are needed to confirm this.
Six studies (reported in 50 publications) were included with a total of 784 participants. Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population. Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality. For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF. For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations. In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa). There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa. The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.
Forty seven randomised controlled trials involving 3448 children (of whom 2210 received desmopressin) met the inclusion criteria. The quality of many of the trials was poor. Desmopressin was effective in reducing bed-wetting during treatment, compared with placebo (e.g. 20 µg: 1.34 fewer wet nights per week; 95% confidence interval (CI) 1.11 to 1.57), and children were more likely to become dry (e.g. 118/146, 81% versus 140/142, 98% still wet; relative risk (RR) for failure to achieve 14 dry nights with 20 µg was 0.84; 95% CI 0.79 to 0.91). However, there was no difference between the two patient groups after treatment was finished. There was no clear dose-related effect of desmopressin, but the evidence was limited. Data which compared oral and nasal administration were too few to be conclusive. In four small trials, there were no significant differences between desmopressin and alarms during treatment when these were used separately, but the chance of failure or relapse after treatment stopped was lower after an alarm in two small trials (40/62, 65% versus 26/57, 46%; RR 1.42, 95% CI 1.05 to 1.91). Although children had fewer wet nights during treatment when they used desmopressin combined with alarm treatment compared with alarms alone (WMD -0.83, 95% CI -1.11 to -0.55), there were no significant differences either in failure rates during treatment (RR 0.88; 95% CI 0.73 to 1.05) or for relapse after treatment stopped (105/213, 49% versus 118/214, 55%: RR 0.91, 95% CI 0.76 to 1.08). Comparison with some tricyclic drugs (e.g. amitriptyline) suggested that they might be as effective as desmopressin, although in two trials children were less likely to achieve 14 dry nights with imipramine than desmopressin (RR 0.44, 95% CI 0.27 to 0.73) but there was not enough information about subsequent relapse. There were more side effects with the tricyclics. Desmopressin may be better than diclofenac or indomethacin. There was not enough information to evaluate the relative effects of behavioural or complementary treatments against desmopressin. Desmopressin rapidly reduced the number of wet nights per week experienced by children, but the limited evidence available suggested that this was not sustained after treatment stopped. Comparison with alternative treatments suggested that desmopressin and tricyclics had similar clinical effects during treatment, but that alarms may produce more sustained benefits. However, based on the available limited evidence, these conclusions are only tentative. Children should be advised not to drink more than 240 ml (8 ounces) of fluid during the evening before desmopressin treatment in order to avoid the possible risk of water intoxication.
Three RCTs were identified, comprising a total of 847 participants. One trial compared silver-containing foam (Contreet®) with hydrocellular foam (Allevyn®) in patients with leg ulcers. The second trial compared a silver-containing alginate (Silvercel®) with an alginate alone (Algosteril®). The third trial compared a silver-containing foam dressing (Contreet®)) with best local practice in patients with chronic wounds. The data from these trials show that silver-containing foam dressings did not significantly increase complete ulcer healing as compared with standard foam dressings or best local practice after up to four weeks of follow-up, although a greater reduction of ulcer size was observed with the silver-containing foam. The use of antibiotics was assessed in two trials, but no significant differences were found. Data on pain, patient satisfaction, length of hospital stay, and costs were limited and showed no differences. Leakage occurred significantly less frequently in patients with leg ulcers and chronic wounds treated with a silver dressing than with a standard foam dressing or best local practice in one trial. Only three trials with a short follow-up duration were found. There is insufficient evidence to recommend the use of silver-containing dressings or topical agents for treatment of infected or contaminated chronic wounds.
Eleven studies involving 496 participants met some of the inclusion criteria stated in the protocol. One hundred and eighty patients in five studies had peripheral interventions, 229 patients in five studies had percutaneous interventions applied to the Gasserian ganglion, and 87 patients in one study underwent two modalities of stereotactic radiosurgery (Gamma Knife) treatment. No studies addressing microvascular decompression (which is the only non-ablative procedure) met the inclusion criteria. All but two of the identified studies had a high to medium risk of bias because of either missing data or methodological inconsistency. It was not possible to undertake meta-analysis because of differences in the intervention modalities and variable outcome measures. Three studies had sufficient outcome data for analysis. One trial, which involved 40 participants, compared two techniques of radiofrequency thermocoagulation (RFT) of the Gasserian ganglion at six months. Pulsed RFT resulted in return of pain in all participants by three months. When this group were converted to conventional (continuous) treatment these participants achieved pain control comparable to the group that had received conventional treatment from the outset. Sensory changes were common in the continuous treatment group. In another trial, of 87 participants, investigators compared radiation treatment to the trigeminal nerve at one or two isocentres in the posterior fossa. There were insufficient data to determine if one technique was superior to another. Two isocentres increased the incidence of sensory loss. Increased age and prior surgery were predictors for poorer pain relief. Relapses were nonsignificantly reduced with two isocentres (risk ratio (RR) 0.72, 95% confidence intervaI (CI) 0.30 to 1.71). A third study compared two techniques for RFT in 54 participants for 10 to 54 months. Both techniques produced pain relief (not significantly in favour of neuronavigation (RR 0.70, 95% CI 0.46 to 1.04) but relief was more sustained and side effects fewer if a neuronavigation system was used. The remaining eight studies did not report outcomes as predetermined in our protocol. There is very low quality evidence for the efficacy of most neurosurgical procedures for trigeminal neuralgia because of the poor quality of the trials. All procedures produced variable pain relief, but many resulted in sensory side effects. There were no studies of microvascular decompression which observational data suggests gives the longest pain relief. There is little evidence to help comparative decision making about the best surgical procedure. Well designed studies are urgently needed.
Seven evaluable studies randomised 404 patients. There was no statistically significant effect on reduction of mortality with therapy: 8.4% versus controls 14.4%, and infected pancreatic necrosis rates: 19.7% versus controls 24.4%. Non-pancreatic infection rates and the incidence of overall infections were not significantly reduced with antibiotics: 23.7% versus 36%; 37.5% versus 51.9% respectively. Operative treatment and fungal infections were not significantly different. Insufficient data were provided concerning antibiotic resistance. With beta-lactam antibiotic prophylaxis there was less mortality (9.4% treatment, 15% controls), and less infected pancreatic necrosis (16.8% treatment group, 24.2% controls) but this was not statistically significant. The incidence of non-pancreatic infections was non-significantly different (21% versus 32.5%), as was the incidence of overall infections (34.4% versus 52.8%), and operative treatment rates. No significant differences were seen with quinolone plus imidazole in any of the end points measured. Imipenem on its own showed no difference in the incidence of mortality, but there was a significant reduction in the rate of pancreatic infection (p=0.02; RR 0.34, 95% CI 0.13 to 0.84). No benefit of antibiotics in preventing infection of pancreatic necrosis or mortality was found, except for when imipenem (a beta-lactam) was considered on its own, where a significantly decrease in pancreatic infection was found. None of the studies included in this review were adequately powered. Further better designed studies are needed if the use of antibiotic prophylaxis is to be recommended.
Searches identified 23 trials; nine trials (255 participants) are included, of these seven trials are more than 10 years old. Three trials of nebulized thiol derivatives were identified (one compared 20% N-acetylcysteine to 2% N-acetylcysteine; another compared sodium-2-mercaptoethane sulphonate to 7% hypertonic saline; and another compared glutathione to 4% hypertonic saline). Although generally well-tolerated with no significant adverse effects, there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments. Six trials of oral thiol derivatives were identified. Three trials compared N-acetylcysteine to placebo; one compared N-acetylcysteine, ambroxol and placebo; one compared carbocysteine to ambroxol; and one compared low and high-dose N-acetylcysteine. Oral thiol derivatives were generally well-tolerated with no significant adverse effects, however there was no evidence of significant clinical benefit in our primary outcomes in participants receiving these treatments. We found no evidence to recommend the use of either nebulized or oral thiol derivatives in people with cystic fibrosis. There are very few good quality trials investigating the effect of these medications in cystic fibrosis, and further research is required to investigate the potential role of these medications in improving the outcomes of people with cystic fibrosis.
No new studies were identified for this 2018 update. In total, four studies with 1644 participants are included. Two studies assessed the effect of extensive tests including computed tomography (CT) scanning versus tests at the physician's discretion, while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/CT scanning versus standard testing alone. For extensive tests including CT versus tests at the physician's discretion, the quality of the evidence, as assessed according to GRADE, was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the quality of evidence was moderate due to a risk of detection bias. The quality of the evidence was downgraded further as detection bias was present in one study with a low number of events. When comparing extensive tests including CT versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; P = 0.26; low-quality evidence). One study (201 participants) showed that, overall, malignancies were less advanced at diagnosis in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; P = 0.04; low-quality evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; P = 0.22; low-quality evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; P = 0.50; low-quality evidence). Neither study measured all-cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either benefit or no benefit on all-cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; P = 0.66; moderate-quality evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; P = 0.25; moderate-quality evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; P = 0.96; moderate-quality evidence). Regarding stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; P = 0.37; low-quality evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; P = 1.00; low-quality evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; P = 0.09; moderate-quality evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. Specific testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer- or VTE-related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made.
Seventeen potentially eligible RCTs were identified but only six trials with 138 patients in total could be included. One study was at low risk of bias, two studies were judged to be at unclear risk of bias and three at high risk of bias. Two trials (56 patients) compared flapless placement of dental implants with conventional flap elevation, one trial (10 patients) compared crestal versus vestibular incisions, one trial (20 patients) Erbium:YAG laser versus flap elevation at the second-stage surgery for implant exposure, one split-mouth trial (10 patients) evaluated whether connective tissue graft at implant placement could be effective in augmenting peri-implant tissues, and one trial (40 patients) compared autograft with an animal-derived collagen matrix to increase the height of the keratinised mucosa. On a patient, rather than per implant basis, implants placed with a flapless technique and implant exposures performed with laser induced statistically significantly less postoperative pain than flap elevation. Sites augmented with soft tissues connective grafts showed a better aesthetic and thicker tissues. Both palatal autografts or the use of a porcine-derived collagen matrix are effective in increasing the height of keratinised mucosa at the price of a 0.5 mm recession of peri-implant soft tissues. There were no other statistically significant differences for any of the remaining analyses. There is limited weak evidence suggesting that flapless implant placement is feasible and has been shown to reduce patient postoperative discomfort in adequately selected patients, that augmentation at implant sites with soft tissue grafts is effective in increasing soft tissue thickness improving aesthetics and that one technique to increase the height of keratinised mucosa using autografts or an animal-derived collagen matrix was able to achieve its goal but at the price of a worsened aesthetic outcome (0.5 mm of recession). There is insufficient reliable evidence to provide recommendations on which is the ideal flap design, the best soft tissue augmentation technique, whether techniques to increase the width of keratinised/attached mucosa are beneficial to patients or not, and which are the best incision/suture techniques/materials. Properly designed and conducted RCTs, with at least 6 months of follow-up, are needed to provide reliable answers to these questions.
We included four studies that compared SDM versus control and included a total of 1342 participants. Three studies recruited children with asthma and their care-givers, and one recruited adults with asthma. Three studies took place in the United States, and one in the Netherlands. Trial duration was between 6 and 24 months. One trial delivered the SDM intervention to the medical practitioner, and three trials delivered the SDM intervention directly to the participant. Two paediatric studies involved use of an online portal, followed by face-to-face consultations. One study delivered an SDM intervention or a clinical decision-making intervention through a mixture of face-to-face consultations and telephone calls. The final study randomised paediatric general practice physicians to receive a seminar programme promoting application of SDM principles. All trials were open-label, although one study, which delivered the intervention to physicians, stated that participants were unaware of their physicians' involvement in the trial. We had concerns about selection and attrition bias and selective reporting, and we noted that one study substantially under-recruited participants. The four included studies used different approaches to measure fidelity/intervention adherence and to report study findings. One study involving adults with poorly controlled asthma reported improved quality of life (QOL) for the SDM group compared with the control group, using the Asthma Quality of Life Questionnaire (AQLQ) for assessment (mean difference (MD) 1.90, 95% confidence interval (CI) 1.24 to 2.91), but two other trials did not identify a benefit. Patient/parent satisfaction with the performance of paediatricians was greater in the SDM group in one trial involving children. Medication adherence was better in the SDM group in two studies - one involving adults and one involving children (all medication adherence: MD 0.21, 95% CI 0.11 to 0.31; mean number of controlled medication prescriptions over 26 weeks: 1.1 in the SDM group (n = 26) and 0.7 in the control group (n = 27)). In one study, asthma-related visit rates were lower in the SDM group than in the usual care group (1.0/y vs 1.4/y; P = 0.016), but two other studies did not report a difference in exacerbations nor in prescriptions for short courses of oral steroids. Finally, one study described better odds of reporting no asthma problems in the SDM group than in the usual care group (odds ratio (OR) 1.90, 95% CI 1.26 to 2.87), although two other studies reporting asthma control did not identify a benefit with SDM. We found no information about acceptability of the intervention to the healthcare professional and no information on adverse events. Overall, our confidence in study results ranged from very low to moderate, and we downgraded outcomes owing to risk of bias, imprecision, and indirectness. Substantial differences between the four included randomised controlled trials (RCTs) indicate that we cannot provide meaningful overall conclusions. Individual studies demonstrated some benefits of SDM over control, in terms of quality of life; patient and parent satisfaction; adherence to prescribed medication; reduction in asthma-related healthcare visits; and improved asthma control. Our confidence in the findings of these individual studies ranges from moderate to very low, and it is important to note that studies did not measure or report adverse events. Future trials should be adequately powered and of sufficient duration to detect differences in patient-important outcomes such as exacerbations and hospitalisations. Use of core asthma outcomes and validated scales when possible would facilitate future meta-analysis. Studies conducted in lower-income settings and including an economic evaluation would be of interest. Investigators should systematically record adverse events, even if none are anticipated. Studies identified to date have not included adolescents; future trials should consider their inclusion. Measuring and reporting of intervention fidelity is also recommended.
We included one trial comparing oral dextrose gel versus placebo in 416 infants at risk of hypoglycaemia. We judged this trial to be at low risk of bias. Using the GRADE method, we determined that evidence ranged from high quality to moderate quality. For outcomes selected for the GRADE analysis, we found the following. • Oral dextrose gel prophylaxis (any dose) is associated with reduced risk of neonatal hypoglycaemia compared with placebo (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.62 to 0.94; one RCT; n = 415 infants; high-quality evidence). The risk difference (RD) is -0.13 (95% CI -0.23 to -0.03), and on average, 8.3 infants would have to receive prophylactic dextrose gel to prevent one additional case of neonatal hypoglycaemia. • Investigators found no statistically significant differences between dextrose gel and placebo groups in the number of adverse events (RR 1.09, 95% CI 0.55 to 2.17; one RCT; n = 413 infants; moderate-quality evidence); separation from mother for treatment of hypoglycaemia (RR 0.46, 95% CI 0.21 to 1.01; one RCT, n = 415 infants; moderate-quality evidence); exclusive breastfeeding at discharge (RR 1.00, 95% CI 0.86 to 1.15; one RCT; n = 415 women; moderate-quality evidence); or breastfeeding at six weeks postpartum (RR 1.06, 95% CI 0.88 to 1.29; one RCT; n = 386 women; moderate-quality evidence). • Researchers provided no data for the other prespecified GRADE outcomes for this review (major neurological disability at two years of age or older; receipt of treatment for hypoglycaemia during initial hospital stay; receipt of intravenous treatment for hypoglycaemia). Oral dextrose gel reduced the risk of neonatal hypoglycaemia in at-risk infants in a single trial. Results showed no statistically significant differences in the number of adverse events or in risk of separation of infant from mother for treatment of hypoglycaemia between babies who received oral dextrose gel and those given placebo. Caution is suggested in interpreting data for the latter two outcomes owing to low event rates. Available evidence is limited to a cohort of at-risk infants, most of whom were infants of diabetic mothers and were treated on the postnatal ward. Minimal data available for many of the prespecified outcomes of this review showed no long-term neurodevelopmental and disability outcomes. Additional evidence is needed to assess the efficacy and safety of dextrose gel for prevention of neonatal hypoglycaemia.
We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full. There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm. There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only. We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review. Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence. Only four trials analysed HRQoL and the data could not be meta-analysed. Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy. This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.
Eight trials involving around 1100 people were included but data were only available for 1036 women in seven trials, of whom 526 received urodynamics. There was some evidence of risk of bias. The four deaths and 12 dropouts in the control arm of one trial were unexplained. There was significant evidence that the tests did change clinical decision making. Women in the urodynamic arms of three trials were more likely to have their management changed (proportion with change in management compared with the control arm 17% versus 3%, risk ratio (RR) 5.07, 95% CI 1.87 to 13.74), although there was statistical heterogeneity. There was evidence from two trials that women treated after urodynamic investigations were more likely to receive drugs (RR 2.09, 95% CI 1.32 to 3.31). On the other hand, in five trials women undergoing treatment following urodynamic investigation were not more likely to undergo surgery (RR 0.99, 95% CI 0.88 to 1.12). There was no statistically significant difference however in the number of women with urinary incontinence if they received treatment guided by urodynamics (37%) compared with those whose treatment was based on history and clinical findings alone (36%) (for example, RR for the number with incontinence after the first year 1.02, 95% CI 0.86 to 1.21). It was calculated that the number of women needed to treat was 100 women (95% CI 86 to 114 women) undergoing urodynamics to prevent one extra individual being incontinent at one year. One trial reported adverse effects and no significant difference was found (RR 1.10, 95% CI 0.81 to 1.50). While urodynamic tests did change clinical decision making, there was some evidence that this did not result in better outcomes in terms of a difference in urinary incontinence rates after treatment. There was no evidence about their use in men, children, or people with neurological diseases. Larger definitive trials are needed in which people are randomly allocated to management according to urodynamic findings or to management based on history and clinical examination to determine if performance of urodynamics results in higher continence rates after treatment.
We found 14 relevant studies, mostly of short duration, poorly reported and conducted in the 1970s (total n=794 participants). Nine of these compared oral formulations of both compounds, and five compared intramuscular formulations. Haloperidol was associated with significantly fewer people leaving the studies early (13 RCTs, n=476, RR 0.26 CI 0.08 to 0.82). The efficacy outcome 'no significant improvement' tended to favour haloperidol, but this difference was not statistically significant (9 RCTs, n=400, RR 0.81 CI 0.64 to 1.04). Movement disorders were more frequent in the haloperidol groups ('at least one extrapyramidal side effect': 6 RCTs, n=37, RR 2.2 CI 1.1 to 4.4, NNH 5 CI 3 to 33), while chlorpromazine was associated with more frequent hypotension (5 RCTs, n=175, RR 0.31 CI 0.11 to 0.88, NNH 7 CI 4 to 25). Similar trends were found when studies comparing intramuscular formulations and studies comparing oral formulations were analysed separately. Given that haloperidol and chlorpromazine are global standard antipsychotic treatments for schizophrenia, it is surprising that less than 800 people have been randomised to a comparison and that incomplete reporting still makes it difficult for anyone to draw clear conclusions on the comparative effects of these drugs. However, it seems that haloperidol causes more movement disorders than chlorpromazine, while chlorpromazine is significantly more likely to lead to hypotonia. We are surprised to have to say that we feel further, large, well designed, conducted and reported studies are required.
The searches identified 17 trials; four are included (287 participants aged five to 39 years; maximum follow-up of four years) and one is currently awaiting classification pending publication of the full trial report and two are ongoing. Three trials compared ibuprofen to placebo (two from the same center with some of the same participants); one trial assessed piroxicam versus placebo. The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a lower annual rate of decline for lung function, % predicted forced expiratory volume in one second (FEV1), mean difference (MD) 1.32 (95% confidence interval (CI) 0.21 to 2.42) (moderate-quality evidence); forced vital capacity (FVC), MD 1.27 (95% CI 0.26 to 2.28) (moderate-quality evidence); forced expiratory flow (FEF25%-75%), MD 1.80 (95% CI 0.15 to 3.45). The post hoc analysis of data from two trials split by age showed a slower rate of annual decline of FEV1 % predicted and FVC in the ibuprofen group in younger children, MD 1.41% (95% CI 0.03 to 2.80) (moderate-quality evidence) and MD 1.32% (95% CI 0.04 to 2.60) (moderate-quality evidence) respectively. Data from four trials demonstrated the proportion of participants with at least one hospitalization may be slightly lower in the ibuprofen group compared to placebo, Peto odds ratio 0.61 (95% CI 0.37 to 1.01) (moderate-quality evidence). In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low. We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyze in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analyzable data were available for any other review outcome. High-dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.
Seventy-eight studies met the inclusion criteria, and we assessed all evidence to be of low or very low quality based on GRADE assessment. We judged nine studies to be at low risk of bias, 35 to have unclear overall risk of bias, and 34 to have high risk of bias. Twenty-one interventions targeted populations or community settings, 27 studies were conducted in the well-child healthcare setting and 26 in the ill-child healthcare setting. Two further studies conducted in paediatric clinics did not make clear whether visits were made to well- or ill-children, and another included visits to both well- and ill-children. Forty-five studies were reported from North America, 22 from other high-income countries, and 11 from low- or middle-income countries. Only 26 of the 78 studies reported a beneficial intervention effect for reduction of child ETS exposure, 24 of which were statistically significant. Of these 24 studies, 13 used objective measures of children's ETS exposure. We were unable to pinpoint what made these programmes effective. Studies showing a significant effect used a range of interventions: nine used in-person counselling or motivational interviewing; another study used telephone counselling, and one used a combination of in-person and telephone counselling; three used multi-component counselling-based interventions; two used multi-component education-based interventions; one used a school-based strategy; four used educational interventions, including one that used picture books; one used a smoking cessation intervention; one used a brief intervention; and another did not describe the intervention. Of the 52 studies that did not show a significant reduction in child ETS exposure, 19 used more intensive counselling approaches, including motivational interviewing, education, coaching, and smoking cessation brief advice. Other interventions consisted of brief advice or counselling (10 studies), feedback of a biological measure of children's ETS exposure (six studies), nicotine replacement therapy (two studies), feedback of maternal cotinine (one study), computerised risk assessment (one study), telephone smoking cessation support (two studies), educational home visits (eight studies), group sessions (one study), educational materials (three studies), and school-based policy and health promotion (one study). Some studies employed more than one intervention. 35 of the 78 studies reported a reduction in ETS exposure for children, irrespective of assignment to intervention and comparison groups. One study did not aim to reduce children's tobacco smoke exposure but rather sought to reduce symptoms of asthma, and found a significant reduction in symptoms among the group exposed to motivational interviewing. We found little evidence of difference in effectiveness of interventions between the well infant, child respiratory illness, and other child illness settings as contexts for parental smoking cessation interventions. A minority of interventions have been shown to reduce children's exposure to environmental tobacco smoke and improve children's health, but the features that differentiate the effective interventions from those without clear evidence of effectiveness remain unclear. The evidence was judged to be of low or very low quality, as many of the trials are at a high risk of bias, are small and inadequately powered, with heterogeneous interventions and populations.
Twenty one trials involving 7243 participants were included. Equal daily doses of ciclesonide and beclomethasone (BDP) or budesonide (BUD) gave similar results for peak expiratory flow rates (PEF), although forced vital capacity (FVC) was higher with ciclesonide. Data on forced expired volume in one second (FEV1) were inconsistent. Withdrawal data and symptoms were similar between treatments. Compared with the same dose of fluticasone (FP), data on lung function parameters (FEV1, FVC and PEF) did not differ significantly. Paediatric quality of life score favoured ciclesonide. Candidiasis was less frequent with ciclesonide, although other side-effect outcomes did not give significant differences in favour of either treatment. When lower doses of ciclesonide were compared to BDP or BUD, the difference in FEV1 did not reach significance but we cannot exclude a significant effect in favour of BDP/BUD. Other lung function outcomes did not give significant differences between treatments. Paediatric quality of life scores did not differ between treatments. Adverse events occurred with similar frequency between ciclesonide and BDP/BUD. Comparison with FP at half the nominal dose was undertaken in three studies, which indicated that FEV1 was not significantly different, but was not equivalent between the treatments (per protocol: -0.05 L 95% confidence intervals -0.11 to 0.01). The results of this review give some support to ciclesonide as an equivalent therapy to other ICS at similar nominal doses. The studies assessed low doses of steroids, in patients whose asthma required treatment with low doses of steroids. At half the dose of FP and BDP/BUD, the effects of ciclesonide were more inconsistent The effect on candidiasis may be of importance to people who find this to be problematic. The role of ciclesonide in the management of asthma requires further study, especially in paediatric patients. Further assessment against FP at a dose ratio of 1:2 is a priority.
For this update, 12 trials (1557 women and 1661 infants) were included. Dexamethasone was associated with a reduced risk of intraventricular haemorrhage (IVH) compared with betamethasone (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.21 to 0.92; four trials, 549 infants). No statistically significant differences were seen for other primary outcomes: respiratory distress syndrome (RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials, 753 infants) and perinatal death (neonatal death RR 1.41, 95% CI 0.54 to 3.67; four trials, 596 infants). Similarly, very few differences were seen for secondary outcomes such as rate of admission to the neonatal intensive care unit (NICU) although in one trial, those infants exposed to dexamethasone, compared with betamethasone, had a significantly shorter length of NICU admission (mean difference (MD) -0.91 days, 95% CI -1.77 to -0.05; 70 infants). Results for biophysical parameters were inconsistent, but mostly no clinically important differences were seen. Compared with intramuscular dexamethasone, oral dexamethasone significantly increased the incidence of neonatal sepsis (RR 8.48, 95% CI 1.11 to 64.93) in one trial of 183 infants. No statistically significant differences were seen for other outcomes reported. Apart from a reduced maternal postpartum length of stay for women who received betamethasone at 12-hourly intervals compared to 24-hourly intervals in one trial (MD -0.73 days, 95% CI -1.28 to -0.18; 215 women), no differences in maternal or neonatal outcomes were seen between the different betamethasone dosing intervals assessed. Similarly, no significant differences in outcomes were seen when betamethasone acetate and phosphate was compared with betamethasone phosphate in one trial. It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another. Dexamethasone may have some benefits compared with betamethasone such as less IVH, and a shorter length of stay in the NICU. The intramuscular route may have advantages over the oral route for dexamethasone, as identified in one small trial. Apart from the suggestion that 12-hour dosing may be as effective as 24-hour dosing of betamethasone based on one small trial, few other conclusions about optimal antenatal corticosteroid regimens were able to be made. No long-term results were available except for a small subgroup of 18 month old children in one trial. Trials comparing the commonly used corticosteroids are most urgently needed, as are trials of dosages and other variations in treatment regimens.
Administration of dexamethasone prior to extubation significantly reduced the need for reintubation of the trachea. This result applies to both the high-risk group and to the total population of infants enrolled. However, the incidence of extubation failure was zero in the trial that attempted to exclude infants at high risk of airway edema. The side effects of higher blood sugar levels and glycosuria were found in the two trials where these were sought. Implications for practice  Dexamethasone reduces the need for endotracheal reintubation of neonates after a period of IPPV. In view of the lack of effect in low-risk infants and the documented and potential side effects, it appears reasonable to restrict its use to infants at increased risk for airway edema and obstruction, such as those who have received repeated or prolonged intubations. Implications for research  Issues of dosage and applicability to the extremely low birthweight population could be addressed in future trials. Outcomes such as chronic lung disease, duration of assisted ventilation and length of hospital stay as well as long-term neurodevelopment should also be examined.
We included 12 new RCTs for this update, giving a total of 39 RCTs (6013 participants). These additional 12 RCTs have not changed the original conclusions about the clinical efficacy of minocycline. The identified RCTs were generally small and poor quality. Meta-analysis was rarely possible because of the lack of data and different outcome measures and trial durations. Although minocycline was shown to be an effective treatment for moderate to moderately-severe acne vulgaris, there was no evidence that it is better than any of the other commonly-used acne treatments. One company-sponsored RCT found minocycline to be less effective than combination treatment with topical erythromycin and zinc. No trials have been conducted using minocycline in those participants whose acne is resistant to other therapies. Also, there is no evidence to guide what dose should be used. The adverse effects studies must be interpreted with caution. The evidence suggests that minocycline is associated with more severe adverse effects than doxycycline. Minocycline, but not other tetracyclines, is associated with lupus erythematosus, but the risk is small: 8.8 cases per 100,000 person-years. The risk of autoimmune reactions increases with duration of use. The evidence does not support the conclusion that the more expensive extended-release preparation is safer than standard minocycline preparations. Minocycline is an effective treatment for moderate to moderately-severe inflammatory acne vulgaris, but there is still no evidence that it is superior to other commonly-used therapies. This review found no reliable evidence to justify the reinstatement of its first-line use, even though the price-differential is less than it was 10 years ago. Concerns remain about its safety compared to other tetracyclines.
We included 15 trials with 6515 patients. The median follow up was six years. Tumour sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (UICC 2002). There was a significant survival benefit with altered fractionation radiotherapy, corresponding to an absolute benefit of 3.4% at five years (hazard ratio (HR) 0.92, 95% CI 0.86 to 0.97; P = 0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at five years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at five years, P = 0.02). There was a benefit in locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at five years; P < 0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (under 50 year old) (HR 0.78, 95% CI 0.65 to 0.94), 0.95 (95% CI 0.83 to 1.09) for 51 to 60 year olds, 0.92 (95% CI 0.81 to 1.06) for 61 to 70 year olds, and 1.08 (95% CI 0.89 to 1.30) for those over 70 years old; test for trends P = 0.007). Altered fractionation radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit. An update of this IPD meta-analysis (MARCH 2), which will increase the power of this analysis and allow for other comparisons, is currently in progress.
Five primary studies that collectively researched a total of 725 women living with HIV were analysed. When compared to standard care or minimal HIV support intervention, meta-analysis showed that behavioral interventions had no effect on increasing condom use among HIV-positive women. This finding was consistent at 3 (OR= 0.72; 95% CI 0.43-1.20; p=0.21), 6 (OR= 0.96; 95% CI 0.66-1.40; p=0.83) and 12-months follow-up meetings (OR= 0.75; 95% CI 0.51-1.11; p=0.15). Only one study presented adequate data to analyze the relationship between behavioral interventions and STI incidence. Studies included in this analysis demonstrated low risk of bias based on the risk of bias criteria. However, sample size was considered inadequate across all studies. Meta-analysis shows that behavioral interventions have little effect on increasing condom use among HIV-positive women. However, these findings should be used with caution since results were based on a few small trials that were targeted specifically towards HIV-positive women. To decrease sexual transmission of HIV among this population, we recommend interventions that combine condom promotion, family planning provision and counselling, and efforts to reduce viral loads among HIV-positive women and their partners (e.g., HAART treatment provision). New research is needed to address the needs of HIV-positive women, including an assessment of the impact of interventions that combine safer sexual behavior and harm reduction approaches.
Eight randomised controlled trials with 856 patients were included. Three studies used a mixed intervention (including either aerobic exercises or breathing exercises); five studies used inspiratory muscle training. Only one study used sham training in the controls. Patients that received preoperative physical therapy had a reduced risk of postoperative atelectasis (four studies including 379 participants, relative risk (RR) 0.52; 95% CI 0.32 to 0.87; P = 0.01) and pneumonia (five studies including 448 participants, RR 0.45; 95% CI 0.24 to 0.83; P = 0.01) but not of pneumothorax (one study with 45 participants, RR 0.12; 95% CI 0.01 to 2.11; P = 0.15) or mechanical ventilation for > 48 hours after surgery (two studies with 306 participants, RR 0.55; 95% CI 0.03 to 9.20; P = 0.68). Postoperative death from all causes did not differ between groups (three studies with 552 participants, RR 0.66; 95% CI 0.02 to 18.48; P = 0.81). Adverse events were not detected in the three studies that reported on them. The length of postoperative hospital stay was significantly shorter in experimental patients versus controls (three studies with 347 participants, mean difference -3.21 days; 95% CI -5.73 to -0.69; P = 0.01). One study reported an increased physical function measure on the six-minute walking test in experimental patients compared to controls. One other study reported a better health-related quality of life in experimental patients compared to controls. Postoperative death from respiratory causes did not differ between groups (one study with 276 participants, RR 0.14; 95% CI 0.01 to 2.70; P = 0.19). Cost data were not reported on. Evidence derived from small trials suggests that preoperative physical therapy reduces postoperative pulmonary complications (atelectasis and pneumonia) and length of hospital stay in patients undergoing elective cardiac surgery. There is a lack of evidence that preoperative physical therapy reduces postoperative pneumothorax, prolonged mechanical ventilation or all-cause deaths.
A total of 3309 records were identified, examined and the trials subjected to selection criteria; 30 trials were included in the review. No significant effects were observed for QoL at 6-month follow up (in 9 studies, SMD 0.11; 95% CI -0.00 to 0.22); however, a small improvement in QoL was observed when QoL was measured using cancer-specific measures (in 6 studies, SMD 0.16; 95% CI 0.02 to 0.30). General psychological distress as assessed by 'mood measures' improved also (in 8 studies, SMD - 0.81; 95% CI -1.44 to - 0.18), but no significant effect was observed when measures of depression or anxiety were used to assess distress (in 6 studies, depression SMD 0.12; 95% CI -0.07 to 0.31; in 4 studies, anxiety SMD 0.05; 95% CI -0.13 to 0.22). Psychoeducational and nurse-delivered interventions that were administered face to face and by telephone with breast cancer patients produced small positive significant effects on QoL (in 2 studies, SMD 0.23; 95% CI 0.04 to 0.43). The significant variation that was observed across participants, mode of delivery, discipline of 'trained helper' and intervention content makes it difficult to arrive at a firm conclusion regarding the effectiveness of psychosocial interventions for cancer patients. It can be tentatively concluded that nurse-delivered interventions comprising information combined with supportive attention may have a beneficial impact on mood in an undifferentiated population of newly diagnosed cancer patients.
We identified one new trial from the updated searches. Seven trials (347 participants) met the selection criteria. The interventions varied but had common components: interventions that increased the intensity and frequency of service delivery (4 trials, 200 participants), community-based specialist behaviour therapy (1 trial, 63 participants), and outreach treatment (1 trial, 50 participants). Another trial compared two active arms (traditional counselling and integrated intervention for bereavement, 34 participants). The included studies investigated interventions dealing with the mental health problems of persons with an intellectual disability; none focused on physical health problems. Four studies assessed the effect of organisational interventions on behavioural problems for persons with an intellectual disability, three assessed care giver burden, and three assessed the costs associated with the interventions. None of the included studies reported data on the effect of organisational interventions on adverse events. Most studies were assessed as having low risk of bias. It is uncertain whether interventions that increase the frequency and intensity of delivery or outreach treatment decrease behavioural problems for persons with an intellectual disability (two and one trials respectively, very low certainty evidence). Behavioural problems were slightly decreased by community-based specialist behavioural therapy (one trial, low certainty evidence). Increasing the frequency and intensity of service delivery probably makes little or no difference to care giver burden (MD 0.03, 95% CI -3.48 to 3.54, two trials, moderate certainty evidence). It is uncertain whether outreach treatment makes any difference for care giver burden (one trial, very low certainty evidence). There was very limited evidence regarding costs, with low to very low certainty evidence for the different interventions. There is very limited evidence on the organisation of healthcare services for persons with an intellectual disability. There are currently no well-designed studies focusing on organising the health services of persons with an intellectual disability and concurrent physical problems. There are very few studies of organisational interventions targeting mental health needs and the results of those that were found need corroboration. There is an urgent need for high-quality health services research to identify optimal health services for persons with an intellectual disability and concurrent physical problem.
One randomised controlled trial (91 participants) was included in this review. We judged the trial to have a low risk of bias for method of randomisation and outcome reporting, and an unclear risk of bias for other criteria. No non-randomised controlled trials meeting our inclusion criteria were identified. The included study measured change in tinnitus severity (primary measure of interest) using a tinnitus questionnaire measure, and change in tinnitus loudness (secondary measure of interest) on a visual analogue scale. Other secondary outcome measures of interest, namely change in the psychoacoustic characteristics of tinnitus, change in self reported anxiety, depression and quality of life, and change in neurophysiological measures, were not investigated in this study. The included study compared hearing aid use to sound generator use. The estimated effect on change in tinnitus loudness or severity as measured by the Tinnitus Handicap Inventory score was compatible with benefits for both hearing aids or sound generators but no difference was found between the two alternative treatments (MD -0.90, 95% confidence interval (CI) -7.92 to 6.12) (100-point scale); moderate quality evidence. No negative or adverse events were reported. The current evidence base for hearing aid prescription for tinnitus is limited. To be useful, future studies should make appropriate use of blinding and be consistent in their use of outcome measures. Whilst hearing aids are sometimes prescribed as part of tinnitus management, there is currently no evidence to support or refute their use as a more routine intervention for tinnitus.
Only three trials tested the efficacy of interferon (IFN) beta including a total of 1160 participants (639 treatment, 521 placebo); no trial tested the efficacy of glatiramer acetate (GA). The metanalyses showed that the proportion of patients converting to CDMS was significantly lower in IFN beta-treated than in placebo-treated patients both after one year (pooled OR 0.53; 95% CI, 0.40 to 0.71; p <0.0001) as well as after two years of follow-up (pooled OR 0.52; 95% CI, 0.38 to 0.70; p <0.0001). Early treatment with IFN beta was associated with the side effect profile reported by the randomised controlled trials with this drug. Since side effects were reported with some heterogeneity in the three studies the metanalysis was possible only for the frequency of serious adverse events, not significantly different in IFN beta-treated or placebo-treated patients. The efficacy of IFN beta treatment on preventing the conversion from CIS to CDMS was confirmed over two years of follow-up. Since patients had some clinical heterogeneity (length of follow-up, clinical findings of initial attack), it could be useful for the clinical practice to further analyse the efficacy of IFN beta treatment in different patient subgroups.
For the original version of the review, 17 studies met the inclusion criteria and examined either brachytherapy, laser or photodynamic therapy (eight studies) or a variety of pharmacological therapies (nine studies). Overall, there was an absence of credible evidence and the majority of studies were of low methodological quality and at high risk of bias. Brachytherapy in a variety of doses seemed to improve cough in selected participants, suggesting that possibly the lowest effective dose should be used to minimise side effects. Photodynamic therapy was examined in one study and, while improvements in cough were observed, its role in relationship to other therapies for cough was unclear. Some indication of positive effect was observed with morphine, codeine, dihydrocodeine, levodropropizine, sodium cromoglycate and butamirate citrate linctus (cough syrup), although all studies had significant risk of bias. For this update, we did not identify any additional trials for inclusion. Two ongoing trials were identified but no study results were available. No new trials were included since the publication of the original version of this review, while 11 new studies that were identified were eventually excluded from this review. Therefore, our conclusions remain unchanged. No practice recommendations could be drawn from this review. There is an urgent need to increase the number and quality of studies evaluating the effects of interventions for the management of cough in cancer.
We included four trials (two cluster-randomised trials reported in three articles and two non-randomised cluster trials). Three trials assessed retail sector ACT subsidies combined with supportive interventions (retail outlet provider training, community awareness and mass media campaigns). One trial assessed vouchers provided to households to purchase subsidised ACTs. Price subsidies ranged from 80% to 95%. One trial enrolled children under five years of age; the other three trials studied people of all age groups. The studies were done in rural districts in East Africa (Kenya, Uganda and Tanzania). In this East Africa setting, these ACT subsidy programmes increased the percentage of children under five years of age receiving ACTs on the day, or following day, of fever onset by 25 percentage points (95% confidence interval (CI) 14.1 to 35.9 percentage points; 1 study, high certainty evidence). This suggests that in practice, among febrile children under five years of age with an ACT usage rate of 5% without a subsidy, subsidy programmes would increase usage by between 19% and 41% over a one year period. The ACT subsidy programmes increased the percentage of retail outlets stocking ACTs for children under five years of age by 31.9 percentage points (95% CI 26.3 to 37.5 percentage points; 1 study, high certainty evidence). Effects on ACT stocking for patients of any age is unknown because the certainty of evidence was very low. The ACT subsidy programmes decreased the median cost of ACTs for children under five years of age by US$ 0.84 (median cost per ACT course without subsidy: US$ 1.08 versus with subsidy: US$ 0.24; 1 study, high certainty evidence). The ACT subsidy programmes increased the market share of ACTs for children under five years of age by between 23.6 and 63.0 percentage points (1 study, high certainty evidence). The ACT subsidy programmes decreased the use of older antimalarial drugs (such as amodiaquine and sulphadoxine-pyrimethamine) among children under five years of age by 10.4 percentage points (95% CI 3.9 to 16.9 percentage points; 1 study, high certainty evidence). None of the three studies of ACT subsidies reported the number of patients treated who had confirmed malaria. Vouchers increased the likelihood that an illness is treated with an ACT by 16 to 23 percentage points; however, vouchers were associated with a high rate of over-treatment of malaria (only 56% of patients taking ACTs from the drug shop tested positive for malaria under the 92% subsidy; 1 study, high certainty evidence). Programmes that include substantive subsidies for private sector retailers combined with training of providers and social marketing improved use and availability of ACTs for children under five years of age with suspected malaria in research studies from three countries in East Africa. These programmes also reduced prices of ACTs, improved market share of ACTs and reduced the use of older antimalarial drugs among febrile children under five years of age. The research evaluates drug delivery but does not assess whether the patients had confirmed (parasite-diagnosed) malaria. None of the included studies assessed patient outcomes; it is therefore not known whether the effects seen in the studies would translate to an impact on health.
We included 13 trials in this review and IPD were available for 836 individuals out of 1455 eligible individuals from six trials, 57% of the potential data. For remission outcomes, a HR of less than 1 indicates an advantage for phenobarbitone and for first seizure and treatment failure outcomes a HR of less than 1 indicates an advantage for carbamazepine. Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 676 participants: 0.66, 95% CI 0.50 to 0.86, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 619 participants: 0.69, 95% CI 0.49 to 0.97, low-quality evidence), time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 487 participants: 0.54, 95% CI 0.38 to 0.78, moderate-quality evidence), showing a statistically significant advantage for carbamazepine compared to phenobarbitone. For our secondary outcomes, we did not find any statistically significant differences between carbamazepine and phenobarbitone: time to first seizure post-randomisation (pooled HR adjusted for seizure type for 822 participants: 1.13, 95% CI 0.93 to 1.38, moderate-quality evidence), time to 12-month remission (pooled HR adjusted for seizure type for 683 participants: 1.09, 95% CI 0.84 to 1.40, low-quality evidence), and time to six-month remission pooled HR adjusted for seizure type for 683 participants: 1.01, 95% CI 0.81 to 1.24, low-quality evidence). Results of these secondary outcomes suggest that there may be an association between treatment effect in terms of efficacy and seizure type; that is, that participants with focal onset seizures experience seizure recurrence later and hence remission of seizures earlier on phenobarbitone than carbamazepine, and vice versa for individuals with generalised seizures. It is likely that the analyses of these outcomes were confounded by several methodological issues and misclassification of seizure type, which could have introduced the heterogeneity and bias into the results of this review. Limited information was available regarding adverse events in the trials and we could not compare the rates of adverse events between carbamazepine and phenobarbitone. Some adverse events reported on both drugs were abdominal pain, nausea, and vomiting, drowsiness, motor and cognitive disturbances, dysmorphic side effects (such as rash), and behavioural side effects in three paediatric trials. Moderate-quality evidence from this review suggests that carbamazepine is likely to be a more effective drug than phenobarbitone in terms of treatment retention (treatment failures due to lack of efficacy or adverse events or both). Moderate- to low-quality evidence from this review also suggests an association between treatment efficacy and seizure type in terms of seizure recurrence and seizure remission, with an advantage for phenobarbitone for focal onset seizures and an advantage for carbamazepine for generalised onset seizures. However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies that may have impacted upon the results of this review. Therefore, we do not suggest that results of this review alone should form the basis of a treatment choice for a patient with newly onset seizures. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.
We included 25 RCTs (1688 participants) in this review (23 trials combined within meta-analyses). In 18 studies, participants underwent total knee arthroplasty (TKA), whereas seven trials investigated patients undergoing arthroscopic knee surgery. We identified 11 studies awaiting classification and 11 ongoing studies. We investigated the following comparisons. ACB versus sham treatment We included eight trials for this comparison. We found no significant differences in postoperative pain intensity at rest (2 hours: standardized mean difference (SMD) -0.56, 95% confidence interval (CI) -1.20 to 0.07, 4 trials, 208 participants, low-quality evidence; 24 hours: SMD -0.49, 95% CI -1.05 to 0.07, 6 trials, 272 participants, low-quality evidence) or during movement (2 hours: SMD -0.59, 95% CI -1.5 to 0.33; 3 trials, 160 participants, very low-quality evidence; 24 hours: SMD 0.03, 95% CI -0.26 to 0.32, 4 trials, 184 participants, low-quality evidence). Furthermore, they noted no evidence of a difference in postoperative nausea between groups (24 hours: risk ratio (RR) 1.91, 95% CI 0.48 to 7.58, 3 trials, 121 participants, low-quality evidence). One trial reported that no accidental falls occurred 24 hours postoperatively (low-quality evidence). ACB versus femoral nerve block We included 15 RCTs for this comparison. We found no evidence of a difference in postoperative pain intensity at rest (2 hours: SMD -0.74, 95% CI -1.76 to 0.28, 5 trials, 298 participants, low-quality evidence; 24 hours: SMD 0.04, 95% CI -0.09 to 0.18, 12 trials, 868 participants, high-quality evidence) or during movement (2 hours: SMD -0.47, 95% CI -1.86 to 0.93, 2 trials, 88 participants, very low-quality evidence; 24 hours: SMD 0.56, 95% CI -0.00 to 1.12, 9 trials, 576 participants, very low-quality evidence). They noted no evidence of a difference in postoperative nausea (24 hours: RR 1.22, 95% CI 0.42 to 3.54, 2 trials, 138 participants, low-quality evidence) and no evidence that the rate of accidental falls during postoperative care was significantly different between groups (24 hours: RR 0.20, 95% CI 0.04 to 1.15, 3 trials, 172 participants, low-quality evidence). We are currently uncertain whether patients treated with ACB suffer from lower pain intensity at rest and during movement, fewer opioid-related adverse events, and fewer accidental falls during postoperative care compared to patients receiving sham treatment. The same holds true for the comparison of ACB versus femoral nerve block focusing on postoperative pain intensity. The overall evidence level was mostly low or very low, so further research might change the conclusion. The 11 studies awaiting classification and the 11 ongoing studies, once assessed, may alter the conclusions of this review.
We identified five high quality studies with a total of 366 participants. All measured pain or disability levels at six months, and four measured the proportion of participants reporting a greater than 50% reduction in pain or disability scores. Three randomised controlled trials (206 participants) found that prolotherapy injections alone are no more effective than control injection for chronic low-back pain and disability. At six months, there was no difference between groups in mean pain or disability scores (2 RCTs; 184 participants) and no difference in proportions who reported over 50% improvement in pain or disability (3 RCTs; 206 participants). These trials could not be pooled due to clinical heterogeneity. Two RCTs (160 participants) found that prolotherapy injections, given with spinal manipulation, exercise, and other therapies, are more effective than control injections for chronic low-back pain and disability. At six months, one study reported a significant difference between groups in mean pain and disability scores, whereas the other study did not. Both studies reported a significant difference in the proportion of individuals who reported over 50% reduction in disability or pain. Co-interventions confounded interpretation of results and clinical heterogeneity in the trials prevented pooling. There is conflicting evidence regarding the efficacy of prolotherapy injections for patients with chronic low-back pain. When used alone, prolotherapy is not an effective treatment for chronic low-back pain. When combined with spinal manipulation, exercise, and other co-interventions, prolotherapy may improve chronic low-back pain and disability. Conclusions are confounded by clinical heterogeneity amongst studies and by the presence of co-interventions.
The review included four trials (186 women) that hugely differed in terms of the diversity of the intervention modalities and outcomes measured. Most trials assessed the effects of electromyographic biofeedback in women who were pregnant for the first time. The trials were judged to be at a high risk of bias due to the lack of data describing the sources of bias assessed. There was no significant evidence of a difference between biofeedback and control groups in terms of assisted vaginal birth, caesarean section, augmentation of labour and the use of pharmacological pain relief. The results of the included trials showed that the use of biofeedback to reduce the pain in women during labour is unproven. Electromyographic biofeedback may have some positive effects early in labour, but as labour progresses there is a need for additional pharmacological analgesia. Despite some positive results shown in the included trials, there is insufficient evidence that biofeedback is effective for the management of pain during labour.
Three new studies were added in this update, resulting in a total of six included studies (five in adults and one involving children/adolescents). These six studies were clinically and methodologically heterogeneous (use of medications, cut-off for percentage of sputum eosinophils and definition of asthma exacerbation). Of 374 participants randomised, 333 completed the trials. In the meta-analysis, there was a significant reduction in the occurrence of any exacerbations when treatment was based on sputum eosinophil counts, compared to that based on clinical symptoms with or without lung function; pooled odds ratio (OR) was 0.57 (95% confidence interval (CI) 0.38 to 0.86). The risk of having one or more exacerbations over 16 months was 82% in the control arm and 62% (95% CI 49% to 74%) in the sputum strategy arm, resulting in a number needed to treat to benefit (NNTB) of 6 (95% CI 4 to 13). There were also differences between the groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids and hospitalisations: the risk of one or more hospitalisations over 16 months was 24% in controls compared to 8% (95% CI 3% to 21%) in the sputum arm. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was also similar in both groups. However sputum induction was not always possible. The included studies did not record any adverse events. One study was not blinded and thus was considered to have a high risk of bias. However, when this study was removed in a sensitivity analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant between groups. The GRADE quality of the evidence ranged from moderate (for the outcomes 'Occurrence of any exacerbation' and 'Hospitalisation' ) to low (for the outcome 'Mean dose of inhaled corticosteroids per person per day') due to the inconsistency in defining exacerbations and the small number of hospital admissions. In this updated review, tailoring asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. Adults with frequent exacerbations and severe asthma may derive the greatest benefit from this additional monitoring test, although we were unable to confirm this through subgroup analysis. There is insufficient data available to assess tailoring asthma medications based on sputum eosinophilia in children. Further robust RCTs need to be undertaken and these should include participants with different underlying asthma severities and endotypes.
We included eight RCTs (with a total of 559 participants) in this review. The studies recruited outpatients aged between 17 and 76 years who were referred to endoscopy centres in several different countries. The certainty of evidence was reduced for most outcomes due to the poor methodological quality of included studies; issues mainly related to the generation of allocation sequence, allocation concealment, and blinding (this last domain related specifically to adverse outcomes). We are uncertain whether the addition of NAC to antibiotics improves H pylori eradication rates, compared with the addition of placebo or no NAC (38.8% versus 49.1%, risk ratio (RR) 0.74, 95% confidence interval (CI) 0.51 to 1.08; participants = 559; studies = eight; very low-certainty evidence). A post-hoc sensitivity analysis, in which we removed studies that tested antibiotic regimens no longer recommended in clinical practice, showed that the addition of NAC may improve eradication rates compared to control (27.2% versus 37.6%, RR 0.71, 95% CI 0.53 to 0.94; participants = 397; published studies = five). We are uncertain whether NAC is associated with a higher risk of gastrointestinal adverse events compared to control (23.9% versus 18.9%, RR 1.25, 95% CI 0.85 to 1.85; participants = 336; studies = five; very low-certaintyevidence), or allergic adverse events (2% versus 0%, RR 2.98, 95% CI 0.32 to 27.74; participants = 336; studies = five; very low-certainty evidence). There were no reports of toxic adverse events amongst included studies. We are uncertain whether the addition of NAC to antibiotics improves H pylori eradication rates compared with the addition of placebo or no NAC. Due to the clinical, statistical and methodological heterogeneity found in included studies, and the uncertainty observed when analysing therapy subgroups, any possible beneficial effect of NAC should be regarded cautiously. We are uncertain whether NAC is associated with a higher risk of gastrointestinal or allergic adverse events compared with placebo or no NAC. There were no reports of toxic adverse events amongst the included studies. Further large, well-designed, randomised clinical studies should be conducted, with good reporting standards and appropriate collection of efficacy and safety outcomes, especially for current recommended antibiotic regimens.
We included four randomised clinical trials analysing a total of 1892 women comparing a freeze-all strategy with a conventional IVF/ICSI strategy. The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules. There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.91 to 1.31; 4 trials; 1892 women; I2 = 0%; moderate-quality evidence). This suggests that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%. The prevalence of OHSS was lower after the freeze-all strategy compared to the conventional IVF/ICSI strategy (OR 0.24, 95% CI 0.15 to 0.38; 2 trials; 1633 women; I2 = 0%; low-quality evidence). This suggests that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%. The freeze-all strategy was associated with fewer miscarriages (OR 0.67, 95% CI 0.52 to 0.86; 4 trials; 1892 women; I2 = 0%; low-quality evidence) and a higher rate of pregnancy complications (OR 1.44, 95% CI 1.08 to 1.92; 2 trials; 1633 women; low-quality evidence). There was no difference in multiple pregnancies per woman after the first transfer (OR 1.11, 95% CI 0.85 to 1.44; 2 trials; 1630 women; low-quality evidence), and no data were reported for time to pregnancy. We found moderate-quality evidence showing that one strategy is not superior to the other in terms of cumulative live birth rates. Time to pregnancy was not reported, but it can be assumed to be shorter using a conventional IVF/ICSI strategy in the case of similar cumulative live birth rates, as embryo transfer is delayed in a freeze-all strategy. Low-quality evidence suggests that not performing a fresh transfer lowers the OHSS risk for women at risk of OHSS.
One RCT was identified that compared different platelet transfusion thresholds prior to insertion of a CVC in people with chronic liver disease. This study is still recruiting participants (expected recruitment: up to 165 participants) and is due to be completed in December 2017. There were no completed studies. There were no studies that compared no platelet transfusions to a platelet transfusion threshold. There is no evidence from RCTs to determine whether platelet transfusions are required prior to central line insertion in patients with thrombocytopenia, and, if a platelet transfusion is required, what is the correct platelet transfusion threshold. Further randomised trials with robust methodology are required to develop the optimal transfusion strategy for such patients. The one ongoing RCT involving people with cirrhosis will not be able to answer this review's questions, because it is a small study that assesses one patient group and does not address all of the comparisons included in this review. To detect an increase in the proportion of participants who had major bleeding from 1 in 100 to 2 in 100 would require a study containing at least 4634 participants (80% power, 5% significance).
Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.
We included 67 trials with 5438 participants that comprised 79 comparisons. Forty-five RCTs compared ABSW versus control, whereas 18 compared two different types of ABSW, and 10 compared two different techniques to administer the same type of ABSW. Forced-air warming (FAW) was by far the most studied intervention. Trials varied widely regarding whether the interventions were applied alone or in combination with other active (based on a different mechanism of heat transfer) and/or passive methods of maintaining normothermia. The type of participants and surgical interventions, as well as anaesthesia management, co-interventions and the timing of outcome measurement, also varied widely. The risk of bias of included studies was largely unclear due to limitations in the reports. Most studies were open-label, due to the nature of the intervention and the fact that temperature was usually the principal outcome. Nevertheless, given that outcome measurement could have been conducted in a blinded manner, we rated the risk of detection and performance bias as high. The comparison of ABSW versus control showed a reduction in the rate of surgical site infection (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.20 to 0.66; 3 RCTs, 589 participants, low-quality evidence). Only one study at low risk of bias observed a beneficial effect with forced-air warming on major cardiovascular complications (RR 0.22, 95% CI 0.05 to 1.00; 1 RCT with 12 events, 300 participants, low-quality evidence) in people at high cardiovascular risk. We found no beneficial effect for mortality. ABSW also reduced blood loss during surgery but the magnitude of this effect seems to be irrelevant (MD -46.17 mL, 95% CI -82.74 to -9.59; I² = 78%; 20 studies, 1372 participants). The same conclusion applies to total fluids infused during surgery (MD -144.49 mL, 95% CI -221.57 to -67.40; I² = 73%; 24 studies, 1491 participants). These effects did not translate into a significant reduction in the number of participants being transfused or the average amount of blood transfused. ABSW was associated with a reduction in shivering (RR 0.39, 95% CI 0.28 to 0.54; 29 studies, 1922 participants) and in thermal comfort (standardized mean difference (SMD) 0.76, 95% CI 0.29 to 1.24; I² = 77%, 4 trials, 364 participants). For the comparison between different types of ABSW system or modes of administration of a particular type of ABSW, we found no evidence for the superiority of any system in terms of clinical outcomes, except for extending systemic warming to the preoperative period in participants undergoing major abdominal surgery (one study at low risk of bias). There were limited data on adverse effects (the most relevant being thermal burns). While some trials included a narrative report mentioning that no adverse effects were observed, the majority made no reference to it. Nothing so far suggests that ABSW involves a significant risk to patients. Forced-air warming seems to have a beneficial effect in terms of a lower rate of surgical site infection and complications, at least in those undergoing abdominal surgery, compared to not applying any active warming system. It also has a beneficial effect on major cardiovascular complications in people with substantial cardiovascular disease, although the evidence is limited to one study. It also improves patient's comfort, although we found high heterogeneity among trials. While the effect on blood loss is statistically significant, this difference does not translate to a significant reduction in transfusions. Again, we noted high heterogeneity among trials for this outcome. The clinical relevance of blood loss reduction is therefore questionable. The evidence for other types of ABSW is scant, although there is some evidence of a beneficial effect in the same direction on chills/shivering with electric or resistive-based heating systems. Some evidence suggests that extending systemic warming to the preoperative period could be more beneficial than limiting it only to during surgery. Nothing suggests that ABSW systems pose a significant risk to patients. The difficulty in observing a clinically-relevant beneficial effect with ABSW in outcomes other than temperature may be explained by the fact that many studies applied concomitant procedures that are routinely in place as co-interventions to prevent hypothermia, whether passive or active warming systems based in other physiological mechanisms (e.g. irrigation fluid or gas warming), as well as a stricter control of temperature in the context of the study compared with usual practice. These may have had a beneficial effect on the participants in the control group, leading to an underestimation of the net benefit of ABSW.
Three studies, with a combined total of 496 patients, matched the inclusion criteria for this review. All three included studies evaluated the role of KL and TL in thromboprophylaxis among a group of postoperative patients. These studies showed no significant difference in the ability of the two modalities of leg compression to reduce the incidence of deep vein thrombosis in postoperative patients. In both the fixed-effect model (odds ratio (OR) 1.55, 95% confidence interval (CI) 0.78 to 3.07, P = 0.21) and random-effects model (OR 1.32, 95% CI 0.43 to 4.06, P = 0.63) KL graduated compression stockings were as effective as TL stockings in thromboprophylaxis. However, there was significant heterogeneity (Tau2 = 0.50; Chi2 = 4.12, df = 2 (P = 0.13); I2 = 51%) among trials. Results of this review may be considered weak because there was significant heterogeneity among included trials resulting from inadequate randomisation techniques, allocation concealment, power calculations and the absence of intention-to-treat analysis. This review found that there is insufficient high quality evidence to determine whether or not KL and TL GCS differ in their effectiveness in terms of reducing the incidence of deep vein thrombosis (DVT) in hospitalised patients.  A major multicentre RCT is required to address this issue. In the meantime, the decision on which type of stocking to use in clinical practice is likely to be influenced by factors such as patient compliance, ease of use and cost implications.
We included three trials randomising 295 participants: 147 to T-tube drainage versus 148 to primary closure. All trials had a high risk of bias. No one died during the follow-up period. There was no significant difference in the proportion of patients with serious morbidity (17/147 (weighted percentage 11.3%) in the T-tube drainage versus 9/148 (6.1%) in the primary closure group; RR 1.86; 95% CI 0.87 to 3.96; three trials), and no significant difference was found in the serious morbidity rates (weighted serious morbidity rate = 97 events per 1000 patients) in participants randomised to T-tube drainage versus serious morbidity rate = 61 events per 1000 patients in the primary closure group; RR 1.59; 95% CI 0.66 to 3.83; three trials). Quality of life was not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 21.22 minutes; 95% CI 12.44 minutes to 30.00 minutes; three trials). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 3.26 days; 95% CI 2.49 days to 4.04 days; three trials). According to one trial, the participants randomised to T-tube drainage returned to work approximately eight days later than the participants randomised to the primary closure group (P < 0.005). T-tube drainage appears to result in significantly longer operating time and hospital stay as compared with primary closure without any evidence of benefit after laparoscopic common bile duct exploration. Based on currently available evidence, there is no justification for the routine use of T-tube drainage after laparoscopic common bile duct exploration in patients with common bile duct stones. More randomised trials comparing the effects of T-tube drainage versus primary closure after laparoscopic common bile duct exploration may be needed. Such trials should be conducted with low risk of bias, assessing the long-term beneficial and harmful effects including long-term complications such as bile stricture and recurrence of common bile duct stones.
We identified two studies with a total of 100 participants for inclusion in the review. We found the overall risk of bias to be unclear in a number of domains. Neither study reported the time taken to the first INR in range. Only one study (70 participants) reported the mean time in therapeutic range as a percentage. This study found that in the group of participants deemed to have poor INR control, the addition of 150 micrograms (mcg) oral vitamin K significantly improved anticoagulation control in those with unexplained instability of response to warfarin. The second study (30 participants) reported the effect of 175 mcg oral vitamin K versus placebo on participants with high variability in their INR levels. The study concluded that vitamin K supplementation did not significantly improve the stability of anticoagulation for participants on chronic anticoagulation therapy. However, the study was only available in abstract form, and communication with the lead author confirmed that there were no further publications. Therefore, we interpreted this conclusion with caution. Neither study reported any thromboembolic events, haemorrhage, or death from the addition of vitamin K supplementation. Two included studies in this review compared whether the addition of a low dose (150 to 175 mcg) of vitamin K given to participants with a high-variability response to warfarin improved their INR control. One study demonstrated a significant improvement, while another smaller study (published in abstract only) suggested no overall benefit. Currently, there are insufficient data to suggest an overall benefit. Larger, higher quality trials are needed to examine if low-dose vitamin K improves INR control in those starting or already taking warfarin.
We included 26 trials with 2435 randomised participants aged between 2 and 16 years. Studies were carried out between 2002 and 2019 in dental clinics in the UK, USA, the Netherlands, Iran, India, France, Egypt, Saudi Arabia, Syria, Mexico, and Korea. Studies included equipment interventions (using several LA delivery devices for injection or audiovisual aids used immediately prior to or during LA delivery or both) and dentist interventions (psychological behaviour interventions delivered in advance of LA (video modelling), or immediately prior to or during delivery of LA or both (hypnosis, counter-stimulation). We judged one study to be at low risk and the rest at high risk of bias. Clinical heterogeneity of the included studies rendered it impossible to pool data into meta-analyses. None of the studies reported on our primary outcome of acceptance of LA. No studies reported on the following secondary outcomes: completion of dental treatment, successful LA/painless treatment, patient satisfaction, parent satisfaction, and adverse events. Audiovisual distraction compared to conventional treatment: the evidence was uncertain for the outcome pain-related behaviour during delivery of LA with a reduction in negative behaviour when 3D video glasses where used in the audiovisual distraction group (risk ratio (RR) 0.13, 95% confidence interval (CI) 0.03 to 0.50; 1 trial, 60 participants; very low-certainty evidence). The wand versus conventional treatment: the evidence was uncertain regarding the effect of the wand on pain-related behaviour during delivery of LA. Four studies reported a benefit in using the wand while the remaining studies results suggested no difference between the two methods of delivering LA (six trials, 704 participants; very low-certainty evidence). Counter-stimulation/distraction versus conventional treatment: the evidence was uncertain for the outcome pain experience during delivery of LA with children experiencing less pain when counter-stimulation was used (RR 0.12, 95% CI 0.04 to 0.34; 1 trial, 134 participants; very low-certainty evidence). Hypnosis versus conventional treatment: the evidence was uncertain for the outcome pain experience during delivery of LA with participants in the hypnosis group experiencing less pain (mean difference (MD) -1.79, 95% CI -3.01 to -0.57; 1 trial, 29 participants; very low-certainty evidence). Other comparisons considered included pre-cooling of the injection site, the wand versus Sleeper One, the use of a camouflage syringe, use of an electrical counter-stimulation device, and video modelling acclimatisation, and had a single study each. The findings from these other comparisons were insufficient to draw any affirmative conclusions about their effectiveness, and were considered to be very low-certainty evidence. We did not find sufficient evidence to draw firm conclusions as to the best interventions to increase acceptance of LA in children due to variation in methodology and nature/timing of outcome measures. We recommend further parallel RCTs, reported in line with the CONSORT Statement. Care should be taken when choosing outcome measures.
We identified 14 studies (16 reports) that met inclusion criteria for this review and involved 3077 randomised participants in total. Most of these studies included a mixed sample of participants; we obtained data for the subset of interest for this review (diagnosis of incurable cancer and receiving cancer treatment) from the study investigators of 12 studies, for which we included 535 participants in the subset meta-analysis for fatigue post intervention. Researchers investigated a broad range of psychosocial interventions with different intervention aims and durations. We identified sources of potential bias, including lack of description of methods of blinding and allocation concealment and inclusion of small study populations. Findings from our meta-analysis do not support the effectiveness of psychosocial interventions for reducing fatigue post intervention (standardised mean difference (SMD) -0.25, 95% confidence interval (CI) -0.50 to 0.00; not significant; 535 participants, 12 studies; very low-quality evidence). First follow-up findings on fatigue suggested benefit for participants assigned to the psychosocial intervention compared with control (SMD -0.66, 95% CI -1.00 to -0.32; 147 participants, four studies; very low-quality evidence), which was not sustained at second follow-up (SMD -0.41, 95% CI -1.12 to 0.30; not significant; very low-quality evidence). Results for our secondary outcomes revealed very low-quality evidence for the efficacy of psychosocial interventions in improving physical functioning post intervention (SMD 0.32, 95% CI 0.01 to 0.63; 307 participants, seven studies). These findings were not sustained at first follow-up (SMD 0.37, 95% CI -0.20 to 0.94; not significant; 122 participants, two studies; very low-quality evidence). Findings do not support the effectiveness of psychosocial interventions for improving social functioning (mean difference (MD) 4.16, 95% CI -11.20 to 19.53; not significant; 141 participants, four studies), role functioning (MD 3.49, 95% CI -12.78 to 19.76; not significant; 143 participants, four studies), emotional functioning (SMD -0.11, 95% CI -0.56 to 0.35; not significant; 115 participants, three studies), or cognitive functioning (MD -2.23, 95% CI -12.52 to 8.06; not significant; 86 participants, two studies) post intervention. Only three studies evaluated adverse events. These studies found no difference between the number of adverse events among participants in the intervention versus control group. Using GRADE, we considered the overall quality of evidence for our primary and secondary outcomes to be very low. Therefore, we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect. Limitations in study quality and imprecision due to sparse data resulted in downgrading of the quality of data. Additionally, most studies were at high risk of bias owing to their small sample size for the subset of patients with incurable cancer (fewer than 50 participants per arm), leading to uncertainty about effect estimates. We found little evidence around the benefits of psychosocial interventions provided to reduce fatigue in adult patients with incurable cancer receiving cancer treatment with palliative intent. Additional studies with larger samples are required to assess whether psychosocial interventions are beneficial for addressing fatigue in patients with incurable cancer.
We included 22 studies (total of 2761 participants). Of those 22 studies, 12 were included in the original published review and 10 were newly identified. Eleven trials compared the use of fluconazole to placebo or no antifungal treatment. Three trials compared ketoconazole versus placebo. One trial compared anidulafungin with placebo. One trial compared caspofungin to placebo. Two trials compared micafungin to placebo. One trial compared amphotericin B to placebo. Two trials compared nystatin to placebo and one trial compared the effect of clotrimazole, ketoconazole, nystatin and no treatment. We found two new ongoing studies and four new studies awaiting classification. The RCTs included participants of both genders with wide age range, severity of critical illness and clinical characteristics. Funding sources from pharmaceutical companies were reported in 11 trials and one trial reported funding from a government agency. Most of the studies had an overall unclear risk of bias for key domains of this review (random sequence generation, allocation concealment, incomplete outcome data). Two studies had a high risk of bias for key domains. Regarding the other domains (blinding of participants and personnel, outcome assessment, selective reporting, other bias), most of the studies had a low or unclear risk but four studies had a high risk of bias. There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce or increase total (all-cause) mortality (RR 0.93, 95% CI 0.79 to 1.09, P value = 0.36; participants = 2374; studies = 19). With regard to the outcome of proven invasive fungal infection, there was low grade evidence that untargeted antifungal treatment significantly reduced the risk (RR 0.57, 95% CI 0.39 to 0.83, P value = 0.0001; participants = 2024; studies = 17). The risk of fungal colonization was significantly reduced (RR 0.71, 95% CI 0.52 to 0.97, P value = 0.03; participants = 1030; studies = 12) but the quality of evidence was low. There was no difference in the risk of developing superficial fungal infection (RR 0.69, 95% CI 0.37 to 1.29, P value = 0.24; participants = 662; studies = 5; low grade of evidence) or in adverse events requiring cessation of treatment between the untargeted treatment group and the other group (RR 0.89, 95% CI 0.62 to 1.27, P value = 0.51; participants = 1691; studies = 11; low quality of evidence). The quality of evidence for the outcome of total (all-cause) mortality was moderate due to limitations in study design. The quality of evidence for the outcome of invasive fungal infection, superficial fungal infection, fungal colonization and adverse events requiring cessation of therapy was low due to limitations in study design, non-optimal total population size, risk of publication bias, and heterogeneity across studies. There is moderate quality evidence that the use of untargeted antifungal treatment is not associated with a significant reduction in total (all-cause) mortality among critically ill, non-neutropenic adults and children compared to no antifungal treatment or placebo. The untargeted antifungal treatment may be associated with a reduction of invasive fungal infections but the quality of evidence is low, and both the heterogeneity and risk of publication bias is high. Further high-quality RCTs are needed to improve the strength of the evidence, especially for more recent and less studied drugs (e.g. echinocandins). Future trials should adopt standardized definitions for microbiological outcomes (e.g. invasive fungal infection, colonization) to reduce heterogeneity. Emergence of resistance to antifungal drugs should be considered as outcome in studies investigating the effects of untargeted antifungal treatment to balance risks and benefit.
Six RCTs with 1162 participants were included: three trials compared 2 g of preoperative amoxicillin versus placebo (927 participants), one compared 3 g of preoperative amoxicillin versus placebo (55 participants), one compared 1 g of preoperative amoxicillin plus 500 mg four times a day for two days versus no antibiotics (80 participants), and one compared four groups: (1) 2 g of preoperative amoxicillin; (2) 2 g of preoperative amoxicillin plus 1 g twice a day for seven days; (3) 1 g of postoperative amoxicillin twice a day for seven days, and (4) no antibiotics (100 participants). The overall body of evidence was considered to be of moderate quality. The meta-analyses of the six trials showed a statistically significant higher number of participants experiencing implant failures in the group not receiving antibiotics (RR 0.33; 95% CI 0.16 to 0.67, P value 0.002, heterogeneity: Tau2 0.00; Chi2 2.87, df = 5 (P value 0.57); I2 0%). The number needed to treat for one additional beneficial outcome (NNTB) to prevent one person having an implant failure is 25 (95% CI 14 to 100), based on an implant failure rate of 6% in participants not receiving antibiotics. There was borderline statistical significance for prosthesis failures (RR 0.44; 95% CI 0.19 to 1.00), with no statistically significant differences for infections (RR 0.69; 95% CI 0.36 to 1.35), or adverse events (RR 1; 95% CI 0.06 to 15.85) (only two minor adverse events were recorded, one in the placebo group). No conclusive information can be derived from the only trial that compared three different durations of antibiotic prophylaxis since no event (implant/prosthesis failures, infections or adverse events) occurred in any of the 25 participants included in each study group. There were no trials that evaluated different antibiotics or different antibiotic dosages. Scientific evidence suggests that, in general, antibiotics are beneficial for reducing failure of dental implants placed in ordinary conditions. Specifically 2 g or 3 g of amoxicillin given orally, as a single administration, one hour preoperatively significantly reduces failure of dental implants. No significant adverse events were reported. It might be sensible to suggest the use of a single dose of 2 g prophylactic amoxicillin prior to dental implant placement. It is still unknown whether postoperative antibiotics are beneficial, and which antibiotic is the most effective.
We included eight studies, with a total of 1308 women randomised. The pooled data from these studies show a statistically significant and clinically meaningful reduction in non-cephalic presentation at birth (average risk ratio (RR) 0.42, 95% confidence interval (CI) 0.29 to 0.61, eight trials, 1305 women); vaginal cephalic birth not achieved (average RR 0.46, 95% CI 0.33 to 0.62, seven trials, 1253 women, evidence graded very low); and caesarean section (average RR 0.57, 95% CI 0.40 to 0.82, eight trials, 1305 women, evidence graded very low) when ECV was attempted in comparison to no ECV attempted. There were no significant differences in the incidence of Apgar score ratings below seven at one minute (average RR 0.67, 95% CI 0.32 to 1.37, three trials, 168 infants) or five minutes (RR 0.63, 95% CI 0.29 to 1.36, five trials, 428 infants, evidence graded very low), low umbilical vein pH levels (RR 0.65, 95% CI 0.17 to 2.44, one trial, 52 infants, evidence graded very low), neonatal admission (RR 0.80, 95% CI 0.48 to 1.34, four trials, 368 infants, evidence graded very low), perinatal death (RR 0.39, 95% CI 0.09 to 1.64, eight trials, 1305 infants, evidence graded low), nor time from enrolment to delivery (mean difference -0.25 days, 95% CI -2.81 to 2.31, two trials, 256 women). All of the trials included in this review had design limitations, and the level of evidence was graded low or very low. No studies attempted to blind the intervention, and the process of random allocation was suboptimal in several studies. Three of the eight trials had serious design limitations, however excluding these studies in a sensitivity analysis for outcomes with substantial heterogeneity did not alter the results. Attempting cephalic version at term reduces the chance of non-cephalic presentation at birth, vaginal cephalic birth not achieved and caesarean section. There is not enough evidence from randomised trials to assess complications of ECV at term. Large observational studies suggest that complications are rare. A visual summary of some of the results from this review can be found here.
We included 11 trials with a total of 828 oncology patients (adults and children). We assessed most included studies to be at a low or unclear risk of bias. Five trials compared the use of antibiotics (vancomycin, teicoplanin or ceftazidime) given before the insertion of the long-term CVC with no antibiotics, and six trials compared antibiotics (vancomycin, amikacin or taurolidine) and heparin with a heparin-only solution for flushing or locking the long-term CVC after use. Administering an antibiotic prior to insertion of the CVC did not significantly reduce Gram positive catheter-related sepsis (CRS) (five trials, 360 adults; risk ratio (RR) 0.72, 95% confidence interval (CI) 0.33 to 1.58; I² = 5 2%; P = 0.41). Flushing and locking long-term CVCs with a combined antibiotic and heparin solution significantly reduced the risk of Gram positive catheter-related sepsis compared with a heparin-only solution (468 participants, mostly children; RR 0.47, 95% CI 0.28 to 0.80; I² = 0%; P = 0.005). For a baseline infection rate of 15%, this reduction translated into a number needed to treat (NNT) of 12 (95% CI 9 to 33) to prevent one catheter-related infection. We considered this evidence to be of a moderate quality. There was no benefit to administering antibiotics before the insertion of long-term CVCs to prevent Gram positive catheter-related infections. Flushing or locking long-term CVCs with a combined antibiotic and heparin solution appeared to reduce Gram positive catheter-related sepsis experienced in people at risk of neutropenia through chemotherapy or disease. Due to insufficient data it was not clear whether this applied equally to TCVCs and totally implanted devices (TIDs), or equally to adults and children. The use of a combined antibiotic and heparin solution may increase microbial antibiotic resistance, therefore it should be reserved for high risk people or where baseline CVC infection rates are high (> 15%). Further research is needed to identify high risk groups most likely to benefit.
We included six studies (375 participants) in this review; these compared alginate dressings with basic wound contact dressings, foam dressings and a silver-containing, fibrous-hydrocolloid dressing. Meta analysis of two studies found no statistically significant difference between alginate dressings and basic wound contact dressings: risk ratio (RR) 1.09 (95% CI 0.66 to 1.80). Pooled data from two studies comparing alginate dressings with foam dressings found no statistically significant difference in ulcer healing (RR 0.67, 95% CI 0.41 to 1.08). There was no statistically significant difference in the number of diabetic foot ulcers healed when an anti-microbial (silver) hydrocolloid dressing was compared with a standard alginate dressing (RR 1.40, 95% CI 0.79 to 2.47). All studies had short follow-up times (six to 12 weeks), and small sample sizes. Currently there is no research evidence to suggest that alginate wound dressings are more effective in healing foot ulcers in people with diabetes than other types of dressing however many trials in this field are very small. Decision makers may wish to consider aspects such as dressing cost and the wound management properties offered by each dressing type e.g. exudate management.
Twenty randomised controlled trials involving 1170 patients were included in this systematic review. The overall risk of bias in included trials was assessed as unclear, because concealment of allocation processes and blinding of outcome assessors were poorly described. Due to inconsistent outcome reporting, data from 17 included trials could be pooled for some endpoints only. Eight trials compared tramadol administration with placebo and five trials found that the need for rescue analgesia in the postoperative care unit (PACU) was reduced in children receiving tramadol (RR 0.40; 95% CI 0.20 to 0.78; low quality evidence). Only one trial investigated the number of patients with moderate to severe pain, but a non-validated pain scale was used (very low quality evidence). Four trials compared morphine with tramadol administration. There was no clear evidence of difference in the need for rescue analgesia in the PACU (RR 1.25; 95% CI 0.83 to 1.89; low quality evidence) with tramadol compared with morphine. No trials could be pooled for the outcome 'number of patients with moderate to severe pain'. Three trials were included for the comparison of tramadol with nalbuphine. There was no clear evidence for the need for rescue analgesia in the PACU (RR 0,63; 95% CI 0.16 to 2.45; low quality evidence). Only one trial reported the number of patients with moderate to severe pain, but used a non-validated pain scale (very low quality evidence). Two out of six included trials, which compared pethidine with tramadol, reported the number of children with a need for rescue analgesia within the PACU and showed no clear evidence (RR 0.93; 95% CI 0.43 to 2.02; very low quality evidence). Two trials reported the number of patients with moderate to severe pain and showed a lower RR in patients treated with tramadol (RR 0.64; 95% CI 0.36 to 1.16; low quality evidence). Only one trial was included, which compared tramadol with fentanyl, reporting the number of patients with the need for rescue analgesia (very low quality evidence). Generally, adverse events were poorly reported. Most data could be pooled for the comparison with placebo focusing on the RR for postoperative nausea and vomiting (PONV) in the postoperative care unit and 24 h postoperation. Children treated with tramadol, compared to placebo, did not show clear evidence of benefit for PONV in the postoperative care unit (RR 0.84; 95% CI 0.28 to 2.52; moderate quality evidence) and 24 h postoperation (RR 0.78; 95% CI 0.54 to 1.12; moderate quality evidence). The overall evidence regarding tramadol for postoperative pain in children is currently low or very low and should be interpreted with caution due to small studies and methodological problems (different validated and non-validated pain scales with different pain triggers, missing sample size calculations and missing intention-to-treat analysis). Nevertheless, we demonstrated that tramadol administration might provide appropriate analgesia when compared to placebo; this is based on results showing reduced rescue analgesia in children treated with tramadol compared to placebo. In contrast, the evidence regarding the comparison with other opioids (for example morphine) was uncertain. Adverse events were only poorly reported, so an accurate risk-benefit analysis was not possible.
We included 11 randomised trials, involving 638 women. The overall risk of bias was judged to be unclear due to lack of methodological detail in the included studies. For the mother, there was no clear evidence of a difference between women in the exercise group and those in the control group for the risk of pre-eclampsia as the measure of hypertensive disorders of pregnancy (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.01 to 7.09; two RCTs, 48 women; low-quality evidence), birth by caesarean section (RR 0.86, 95% CI 0.63 to 1.16; five RCTs, 316 women; I2 = 0%; moderate-quality evidence), the risk of induction of labour (RR 1.38, 95% CI 0.71 to 2.68; one RCT, 40 women; low-quality evidence) or maternal body mass index at follow-up (postnatal weight retention or return to pre-pregnancy weight) (mean difference (MD) 0.11 kg/m2, 95% CI -1.04 to 1.26; three RCTs, 254 women; I2 = 0%; high-quality evidence). Development of type 2 diabetes, perineal trauma/tearing and postnatal depression were not reported as outcomes in the included studies. For the infant/child/adult, a single small (n = 19) trial reported no perinatal mortality (stillbirth and neonatal mortality) events in either the exercise intervention or control group (low-quality evidence). There was no clear evidence of a difference between groups for a mortality and morbidity composite (variously defined by trials, e.g. perinatal or infant death, shoulder dystocia, bone fracture or nerve palsy) (RR 0.56, 95% CI 0.12 to 2.61; two RCTs, 169 infants; I2 = 0%; moderate-quality evidence) or neonatal hypoglycaemia (RR 2.00, 95% CI 0.20 to 20.04; one RCT, 34 infants; low-quality evidence). None of the included trials pre-specified large-for-gestational age, adiposity (neonatal/infant, childhood or adulthood), diabetes (childhood or adulthood) or neurosensory disability (neonatal/infant) as trial outcomes. Other maternal outcomes of interest: exercise interventions were associated with both reduced fasting blood glucose concentrations (average standardised mean difference (SMD) -0.59, 95% CI -1.07 to -0.11; four RCTs, 363 women; I2 = 73%; T2 = 0.19) and a reduced postprandial blood glucose concentration compared with control interventions (average SMD -0.85, 95% CI -1.15 to -0.55; three RCTs, 344 women; I2 = 34%; T2 = 0.03). Short- and long-term outcomes of interest for this review were poorly reported. Current evidence is confounded by the large variety of exercise interventions. There was insufficient high-quality evidence to be able to determine any differences between exercise and control groups for our outcomes of interest. For the woman, both fasting and postprandial blood glucose concentrations were reduced compared with the control groups. There are currently insufficient data for us to determine if there are also benefits for the infant. The quality of the evidence in this review ranged from high to low quality and the main reason for downgrading was for risk of bias and imprecision (wide CIs, low event rates and small sample size). Development of type 2 diabetes, perineal trauma/tearing, postnatal depression, large-for-gestational age, adiposity (neonate/infant, childhood or adulthood), diabetes (childhood or adulthood) or neurosensory disability (neonate/infant) were not reported as outcomes in the included studies. Further research is required comparing different types of exercise interventions with control groups or with another exercise intervention that reports on both the short- and long-term outcomes (for both the mother and infant/child) as listed in this review.
The review included 19 studies randomising 1190 participants with carpal tunnel syndrome. Two studies compared splinting with no treatment, five compared different splint designs, one compared different splint-wearing regimens, seven compared splint delivered as a single intervention with another non-surgical intervention, and five compared splint delivered alongside other non-surgical interventions with another non-surgical intervention. Only three studies reported concealing the allocation sequence, and only one reported blinding of participants. Three studies measured the primary outcome, short-term overall improvement at three months or less. One low quality study with 80 wrists found that compared to no treatment, splints worn at night more than tripled the likelihood of reporting overall improvement at the end of four weeks of treatment (RR 3.86, 95% CI 2.29 to 6.51). However, the lack of patient blinding and unclear allocation concealment suggests this result should be interpreted with caution. A very low quality quasi-randomised trial with 90 wrists found that wearing a neutral splint more than doubled the likelihood of reporting 'a lot or complete relief' at the end of two weeks of treatment compared with an extension splint (RR 2.43, 95% CI 1.12 to 5.28). The third study which measured short-term overall improvement did not report outcome data separately per group. Nine studies measured adverse effects of splinting and all found either no or few participants reporting discomfort or swelling due to splinting; however, the precision of all RRs was very low. Differences between groups in the secondary outcomes - symptoms, function, and neurophysiologic parameters - were most commonly small with 95% CIs incorporating effects in either direction. Overall, there is limited evidence that a splint worn at night is more effective than no treatment in the short term, but there is insufficient evidence regarding the effectiveness and safety of one splint design or wearing regimen over others, and of splint over other non-surgical interventions for CTS. More research is needed on the long-term effects of this intervention for CTS.
We included 51 trials (2920 participants, 18 trials of manipulation/mobilisation versus control; 34 trials of manipulation/mobilisation versus another treatment, 1 trial had two comparisons). Cervical manipulation versus inactive control:For subacute and chronic neck pain, a single manipulation (three trials, no meta-analysis, 154 participants, ranged from very low to low quality) relieved pain at immediate- but not short-term follow-up. Cervical manipulation versus another active treatment:For acute and chronic neck pain, multiple sessions of cervical manipulation (two trials, 446 participants, ranged from moderate to high quality) produced similar changes in pain, function, quality of life (QoL), global perceived effect (GPE) and patient satisfaction when compared with multiple sessions of cervical mobilisation at immediate-, short- and intermediate-term follow-up. For acute and subacute neck pain, multiple sessions of cervical manipulation were more effective than certain medications in improving pain and function at immediate- (one trial, 182 participants, moderate quality) and long-term follow-up (one trial, 181 participants, moderate quality). These findings are consistent for function at intermediate-term follow-up (one trial, 182 participants, moderate quality). For chronic CGH, multiple sessions of cervical manipulation (two trials, 125 participants, low quality) may be more effective than massage in improving pain and function at short/intermediate-term follow-up. Multiple sessions of cervical manipulation (one trial, 65 participants, very low quality) may be favoured over transcutaneous electrical nerve stimulation (TENS) for pain reduction at short-term follow-up. For acute neck pain, multiple sessions of cervical manipulation (one trial, 20 participants, very low quality) may be more effective than thoracic manipulation in improving pain and function at short/intermediate-term follow-up. Thoracic manipulation versus inactive control: Three trials (150 participants) using a single session were assessed at immediate-, short- and intermediate-term follow-up. At short-term follow-up, manipulation improved pain in participants with acute and subacute neck pain (five trials, 346 participants, moderate quality, pooled SMD -1.26, 95% confidence interval (CI) -1.86 to -0.66) and improved function (four trials, 258 participants, moderate quality, pooled SMD -1.40, 95% CI -2.24 to -0.55) in participants with acute and chronic neck pain. A funnel plot of these data suggests publication bias. These findings were consistent at intermediate follow-up for pain/function/quality of life (one trial, 111 participants, low quality). Thoracic manipulation versus another active treatment: No studies provided sufficient data for statistical analyses. A single session of thoracic manipulation (one trial, 100 participants, moderate quality) was comparable with thoracic mobilisation for pain relief at immediate-term follow-up for chronic neck pain. Mobilisation versus inactive control: Mobilisation as a stand-alone intervention (two trials, 57 participants, ranged from very low to low quality) may not reduce pain more than an inactive control. Mobilisation versus another active treatment:For acute and subacute neck pain, anterior-posterior mobilisation (one trial, 95 participants, very low quality) may favour pain reduction over rotatory or transverse mobilisations at immediate-term follow-up. For chronic CGH with temporomandibular joint (TMJ) dysfunction, multiple sessions of TMJ manual therapy (one trial, 38 participants, very low quality) may be more effective than cervical mobilisation in improving pain/function at immediate- and intermediate-term follow-up. For subacute and chronic neck pain, cervical mobilisation alone (four trials, 165 participants, ranged from low to very low quality) may not be different from ultrasound, TENS, acupuncture and massage in improving pain, function, QoL and participant satisfaction at immediate- and intermediate-term follow-up. Additionally, combining laser with manipulation may be superior to using manipulation or laser alone (one trial, 56 participants, very low quality). Although support can be found for use of thoracic manipulation versus control for neck pain, function and QoL, results for cervical manipulation and mobilisation versus control are few and diverse. Publication bias cannot be ruled out. Research designed to protect against various biases is needed. Findings suggest that manipulation and mobilisation present similar results for every outcome at immediate/short/intermediate-term follow-up. Multiple cervical manipulation sessions may provide better pain relief and functional improvement than certain medications at immediate/intermediate/long-term follow-up. Since the risk of rare but serious adverse events for manipulation exists, further high-quality research focusing on mobilisation and comparing mobilisation or manipulation versus other treatment options is needed to guide clinicians in their optimal treatment choices.
We included 27 trials, 18 of which were conducted in the USA. Nineteen studies employed randomised controlled trial (RCT) designs. Fifteen trials tested strategies to implement healthy eating policies, practice or programs; six trials tested strategies targeting physical activity policies or practices; and three trials targeted tobacco policies or practices. Three trials targeted a combination of risk factors. None of the included trials sought to increase the implementation of interventions to delay initiation or reduce the consumption of alcohol. All trials examined multi-strategic implementation strategies and no two trials examined the same combinations of implementation strategies. The most common implementation strategies included educational materials, educational outreach and educational meetings. For all outcomes, the overall quality of evidence was very low and the risk of bias was high for the majority of trials for detection and performance bias. Among 13 trials reporting dichotomous implementation outcomes—the proportion of schools or school staff (e.g. classes) implementing a targeted policy or practice—the median unadjusted (improvement) effect sizes ranged from 8.5% to 66.6%. Of seven trials reporting the percentage of a practice, program or policy that had been implemented, the median unadjusted effect (improvement), relative to the control ranged from -8% to 43%. The effect, relative to control, reported in two trials assessing the impact of implementation strategies on the time per week teachers spent delivering targeted policies or practices ranged from 26.6 to 54.9 minutes per week. Among trials reporting other continuous implementation outcomes, findings were mixed. Four trials were conducted of strategies that sought to achieve implementation 'at scale', that is, across samples of at least 50 schools, of which improvements in implementation were reported in three trials. The impact of interventions on student health behaviour or weight status were mixed. Three of the eight trials with physical activity outcomes reported no significant improvements. Two trials reported reductions in tobacco use among intervention relative to control. Seven of nine trials reported no between-group differences on student overweight, obesity or adiposity. Positive improvements in child dietary intake were generally reported among trials reporting these outcomes. Three trials assessed the impact of implementation strategies on the attitudes of school staff and found mixed effects. Two trials specified in the study methods an assessment of potential unintended adverse effects, of which, they reported none. One trial reported implementation support did not significantly increase school revenue or expenses and another, conducted a formal economic evaluation, reporting the intervention to be cost-effective. Trial heterogeneity, and the lack of consistent terminology describing implementation strategies, were important limitations of the review. Given the very low quality of the available evidence, it is uncertain whether the strategies tested improve implementation of the targeted school-based policies or practices, student health behaviours, or the knowledge or attitudes of school staff. It is also uncertain if strategies to improve implementation are cost-effective or if they result in unintended adverse consequences. Further research is required to guide efforts to facilitate the translation of evidence into practice in this setting.
One study was included in the review. This multi-centre trial was based in five Australian hospitals and recruited 272 children with chronic cough. Children were randomly assigned to early (two weeks) or delayed (six weeks) referral to respiratory specialists who used a cough management pathway. When an intention-to-treat analysis was performed, clinical failure at six weeks post randomisation (defined as < 75% improvement in cough score, or total resolution for fewer than three consecutive days) was significantly less in the early pathway arm compared with the control arm (odds ratio (OR) 0.35, 95% confidence interval (CI) 0.21 to 0.58). These results indicate that one additional child will be cured for every five children treated via the cough pathway (number needed to treat for an additional beneficial outcome (NNTB) = 5, 95% CI 3 to 9) at six weeks. Cough-specific parent-reported quality of life scores were significantly better in the early-pathway group; the mean difference (MD) between groups was 0.60 (95% CI 0.19 to 1.01). Duration of cough post randomisation was significantly shorter in the intervention group (early-pathway arm) compared with the control group (delayed-pathway arm) (MD -2.70 weeks, 95% CI -4.26 to -1.14). Current evidence suggests that using a clinical algorithm for the management of children with chronic cough in hospital outpatient settings is more effective than providing wait-list care. Futher high-quality randomised controlled trials are needed to perform ongoing evaluation of cough management pathways in general practitioner and other primary care settings.
We included 75 systematic reviews of varied methodological quality. Reviews assessed interventions with diverse aims including support for behaviour change, risk minimisation and skills acquisition. No reviews aimed to promote systems-level consumer participation in medicines-related activities. Medicines adherence was the most frequently-reported outcome, but others such as knowledge, clinical and service-use outcomes were also reported. Adverse events were less commonly identified, while those associated with the interventions themselves, or costs, were rarely reported. Looking across reviews, for most outcomes, medicines self-monitoring and self-management programmes appear generally effective to improve medicines use, adherence, adverse events and clinical outcomes; and to reduce mortality in people self-managing antithrombotic therapy. However, some participants were unable to complete these interventions, suggesting they may not be suitable for everyone. Other promising interventions to improve adherence and other key medicines-use outcomes, which require further investigation to be more certain of their effects, include: · simplified dosing regimens: with positive effects on adherence; · interventions involving pharmacists in medicines management, such as medicines reviews (with positive effects on adherence and use, medicines problems and clinical outcomes) and pharmaceutical care services (consultation between pharmacist and patient to resolve medicines problems, develop a care plan and provide follow-up; with positive effects on adherence and knowledge). Several other strategies showed some positive effects, particularly relating to adherence, and other outcomes, but their effects were less consistent overall and so need further study. These included: · delayed antibiotic prescriptions: effective to decrease antibiotic use but with mixed effects on clinical outcomes, adverse effects and satisfaction; · practical strategies like reminders, cues and/or organisers, reminder packaging and material incentives: with positive, although somewhat mixed effects on adherence; · education delivered with self-management skills training, counselling, support, training or enhanced follow-up; information and counselling delivered together; or education/information as part of pharmacist-delivered packages of care: with positive effects on adherence, medicines use, clinical outcomes and knowledge, but with mixed effects in some studies; · financial incentives: with positive, but mixed, effects on adherence. Several strategies also showed promise in promoting immunisation uptake, but require further study to be more certain of their effects. These included organisational interventions; reminders and recall; financial incentives; home visits; free vaccination; lay health worker interventions; and facilitators working with physicians to promote immunisation uptake. Education and/or information strategies also showed some positive but even less consistent effects on immunisation uptake, and need further assessment of effectiveness and investigation of heterogeneity. There are many different potential pathways through which consumers' use of medicines could be targeted to improve outcomes, and simple interventions may be as effective as complex strategies. However, no single intervention assessed was effective to improve all medicines-use outcomes across all diseases, medicines, populations or settings. Even where interventions showed promise, the assembled evidence often only provided part of the picture: for example, simplified dosing regimens seem effective for improving adherence, but there is not yet sufficient information to identify an optimal regimen. In some instances interventions appear ineffective: for example, the evidence suggests that directly observed therapy may be generally ineffective for improving treatment completion, adherence or clinical outcomes. In other cases, interventions may have variable effects across outcomes. As an example, strategies providing information or education as single interventions appear ineffective to improve medicines adherence or clinical outcomes, but may be effective to improve knowledge; an important outcome for promoting consumers' informed medicines choices. Despite a doubling in the number of reviews included in this updated overview, uncertainty still exists about the effectiveness of many interventions, and the evidence on what works remains sparse for several populations, including children and young people, carers, and people with multimorbidity. This overview presents evidence from 75 reviews that have synthesised trials and other studies evaluating the effects of interventions to improve consumers' medicines use. Systematically assembling the evidence across reviews allows identification of effective or promising interventions to improve consumers’ medicines use, as well as those for which the evidence indicates ineffectiveness or uncertainty. Decision makers faced with implementing interventions to improve consumers' medicines use can use this overview to inform decisions about which interventions may be most promising to improve particular outcomes. The intervention taxonomy may also assist people to consider the strategies available in relation to specific purposes, for example, gaining skills or being involved in decision making. Researchers and funders can use this overview to identify where more research is needed and assess its priority. The limitations of the available literature due to the lack of evidence for important outcomes and important populations, such as people with multimorbidity, should also be considered in practice and policy decisions.
Twenty-eight randomised controlled trials comprising 3940 participants were included. The most frequent reasons for exclusion were non-randomised trials and the inclusion of women with metastatic disease. A wide range of interventions were evaluated, with 24 trials investigating a cognitive behavioural therapy and four trials investigating psychotherapy compared to control. Pooled standardised mean differences (SMD) from baseline indicated less depression (SMD -1.01, 95% confidence interval (CI) -1.83 to -0.18; P = 0.02; 7 studies, 637 participants, I2 = 95%, low quality evidence), anxiety (SMD -0.48, 95% CI -0.76 to -0.21; P = 0.0006; 8 studies, 776 participants, I2 = 64%, low quality evidence) and mood disturbance (SMD -0.28, 95% CI -0.43 to -0.13; P = 0.0003; 8 studies, 1536 participants, I2 = 47%, moderate quality evidence) for the cognitive behavioural therapy group than the control group. For quality of life, only an individually-delivered cognitive behavioural intervention showed significantly better quality of life than the control with an SMD of 0.65 (95% CI 0.07 to 1.23; P = 0.03; 3 studies, 141 participants, I2 = 41%, very low quality evidence). Pooled data from two group-delivered studies showed a non-significant overall survival benefit favouring cognitive behavioural therapy compared to control (pooled hazard ratio (HR) 0.76, 95% CI 0.25 to 2.32; P = 0.63; 530 participants, I2 = 84%, low quality evidence). Four studies compared psychotherapy to control with one to two studies reporting on each outcome. The four studies were assessed as high risk of bias and provided limited evidence of the efficacy of psychotherapy. Adverse events were not reported in any of the included studies. A psychological intervention, namely cognitive behavioural therapy, produced favourable effects on some psychological outcomes, in particular anxiety, depression and mood disturbance. However, the evidence for survival improvement is still lacking. These findings are open to criticism because of the notable heterogeneity across the included studies and the shortcomings of the included studies.
We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma. Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease. Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin, bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants). Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated liposomal doxorubicin versus liposomal daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group. Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing liposomal daunorubicin to ABV, there was no significant difference with the use of liposomal daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants). An additional non-randomised study showed a non-statistically significant overall mortality benefit from liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events. The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between liposomal doxorubicin, liposomal daunorubicin and paclitaxel.
There are no included trials. We found no randomised controlled trials that assessed the effect of antenatal fetal surveillance regimens of a suspected LGA fetus on important health outcomes for the mother and baby. There has been a rise in the prevalence of LGA babies over the past few decades in many countries. Research is therefore required on regimens of antenatal surveillance of suspected LGA infants, in order to guide practice and improve the health outcomes for the mother and infant. In particular, randomised control trials to investigate whether serial antenatal clinic and ultrasound assessments of suspected LGA infants (including liquor volume and markers of fetal adiposity) would be useful, to assess whether surveillance methods improve health outcomes. In addition, as there are concerns that identifying suspected LGA fetuses may lead to unnecessary maternal anxiety, investigations and interventions, any such trial would need to assess the risks as well as benefits of regimens of fetal surveillance for suspected LGA fetuses.
Only one randomised trial met our inclusion criteria, despite our initial search yielding 141 citations. This was a small study, with 17 people completing a trial comparing CBT to an attention placebo (supportive psychotherapy) for people with delusional disorder. Most participants were already taking medication and this was continued during the trial. We were not able to include any randomised trials on medications of any type due to poor data reporting, which left us with no usable data for these trials. For the included study, usable data were limited, risk of bias varied and the numbers involved were small, making interpretation of data difficult. In particular there were no data on outcomes such as global state and behaviour, nor any information on possible adverse effects. A positive effect for CBT was found for social self esteem using the Social Self-Esteem Inventory (1 RCT, n = 17, MD 30.5, CI 7.51 to 53.49, very low quality evidence), however this is only a measure of self worth in social situations and may thus not be well correlated to social function. More people left the study early if they were in the supportive psychotherapy group with 6/12 leaving early compared to 1/6 from the CBT group, but the difference was not significant (1 RCT, n = 17, RR 0.17, CI 0.02 to 1.18, moderate quality evidence). For mental state outcomes the results were skewed making interpretation difficult, especially given the small sample. Despite international recognition of this disorder in psychiatric classification systems such as ICD-10 and DSM-5, there is a paucity of high quality randomised trials on delusional disorder. There is currently insufficient evidence to make evidence-based recommendations for treatments of any type for people with delusional disorder. The limited evidence that we found is not generalisable to the population of people with delusional disorder. Until further evidence is found, it seems reasonable to offer treatments which have efficacy in other psychotic disorders. Further research is needed in this area and could be enhanced in two ways: firstly, by conducting randomised trials specifically for people with delusional disorder and, secondly, by high quality reporting of results for people with delusional disorder who are often recruited into larger studies for people with a variety of psychoses.
We included four randomised controlled trials (RCTs). We found evidence of missing data and poor reporting. When bifeprunox 20 mg was compared with placebo for schizophrenia, the drug resulted in a reduction of the Positive and Negative Syndrome Scale (PANSS) positive subscale score regarding positive symptoms (n = 549, 2 RCTs, MD -1.89, 95% CI -2.85 to -0.92, low-quality evidence) and the PANSS negative subscale regarding negative symptoms (n = 549, 2 RCTs, MD -1.53, 95% CI -2.37 to -0.69, low-quality evidence). There was a clear improvement regarding deterioration in the bifeprunox 20 mg group (n = 231, 1 RCT, RR 0.71 95% CI, 0.54 to 0.93, very low-quality evidence). The total number of participants with equal to or greater than 7% weight increase was similar between bifeprunox and placebo (n = 483, 1 RCT, RR 1.02 95% CI 0.31 to 3.33 moderate-quality evidence). There were no useable data for quality of life, economic outcomes, and service use. Our results showed some positive effects and a favourable adverse effect profile for bifeprunox, although there were few data overall and none were of high quality. It would seem that these data alone would not have been enough for the FDA to decide to halt progress of the drug to market. We can only assume that we are missing important data. Both the FDA and the relevant pharmaceutical companies have not made all relevant data accessible. As some of these trials also involved an additional haloperidol, olanzapine, quetiapine, or risperidone arm, these data are not only relevant to evaluation of bifeprunox. In not making all data accessible, it is hard to see how the FDA and the drug companies have fulfilled their full obligations to people with schizophrenia or their clinicians.
Only one study enrolling 14 participants was eligible for inclusion in the review. The double-blind study compared a daily dose of 600 mg omalizumab or placebo along with twice daily itraconazole and oral corticosteroids, with a maximum daily dose of 400 mg. Treatment lasted six months but the study was terminated prematurely and complete data were not available. We contacted the study investigator and were told that the study was terminated due to the inability to recruit participants into the study despite all reasonable attempts. One or more serious side effects were encountered in six out of nine (66.67%) and one out of five (20%) participants in omalizumab group and placebo group respectively. There is lack of evidence for the efficacy and safety of anti-IgE (omalizumab) therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis. There is a need for large prospective randomized controlled studies of anti-IgE therapy in people with cystic fibrosis and allergic bronchopulmonary aspergillosis with both clinical and laboratory outcome measures such as steroid requirement, allergic bronchopulmonary aspergillosis exacerbations and lung function.
We found 8 RCTs with 11,164 participants but one study did not provide enough data. Studies compared VCT to no VCT and education to no intervention and to alternative education. VCT uptake increased to 51% when provided at the workplace compared to a voucher for VCT (RR=14.0 (95% CI 11.8 to16.7)). After VCT, self-reported STD decreased (RR = 0.10 (95% CI 0.01 to 0.73)) but HIV incidence (RR=1.4 (95% CI 0.7 to 2.7)) and unprotected sex (RR=0.71 (0.48 to 1.06)) did not decrease significantly. . Education reduced STDs (RR = 0.68 (95%CI 0.48 to 0.96)), unprotected sex (Standardised Mean Difference (SMD)= -0.17 (95% CI -0.29 to -0.05), sex with a commercial sex worker (RR = 0.88 (95% CI 0.81 to 0.96) but not multiple sexual partners (Mean Difference (MD) = -0.22 (95% CI -0.52 to 0.08) nor use of alcohol before sex (MD = -0.01 (95% CI of -0.11 to 0.08). Workplace interventions to prevent HIV are feasible. There is moderate quality evidence that VCT offered at the work site increases the uptake of testing. Even though this did no lower HIV-incidence, there was a decrease in self-reported sexual transmitted diseases and a decrease in risky sexual behaviour. There is low quality evidence that educational interventions decrease sexually transmitted diseases, unprotected sex and sex with commercial sex workers but not sex with multiple partners and the use of alcohol before sex. More and better randomised trials are needed directed at high risk groups such as truck drivers or workers in areas with a very high HIV prevalence such as Southern Africa. Risky sexual behaviour should be measured in a standardised way.
We included seven studies with a total of 138 participants, with data available for 123. Sample sizes ranged from 9 to 37. Judgements for categories of risk of bias varied: concerns were greatest regarding allocation concealment, blinding of outcome assessors, and incomplete outcome data (dropout rates in the five community-based studies ranged from 3% to 54% and results were usually analysed on a per protocol basis). Participant characteristics in the seven studies were heterogeneous, but the vast majority had convictions for sexual offences, ranging from exhibitionism to rape and child molestation. Six studies examined the effectiveness of three testosterone-suppressing drugs: cyproterone acetate (CPA), ethinyl oestradiol (EO), and medroxyprogesterone acetate (MPA); a seventh evaluated two antipsychotics (benperidol and chlorpromazine). Five studies were placebo-controlled; in two, MPA was administered as an adjunctive treatment to a psychological therapy (assertiveness training or imaginal desensitisation). Meta-analysis was not possible due to heterogeneity of interventions, comparators, study designs, and other issues. The quality of the evidence overall was poor. In addition to methodological issues, much evidence was indirect. Primary outcome: recividism. Two studies reported recidivism rates formally. One trial of intramuscular MPA plus imaginal desensitisation (ID) found no reports of recividism at two-year follow-up for the intervention group (n = 10 versus one relapse within the group treated by ID alone). A three-armed trial of oral MPA, alone or in combination with psychological treatment, reported a 20% rate of recidivism amongst those in the combined treatment arm (n = 15) and 50% of those in the psychological treatment only group (n = 12). Notably, all those in the 'oral MPA only' arm of this study (n = 5) dropped out immediately, despite treatment being court mandated. Two studies did not report recidivism rates as they both took place in one secure psychiatric facility from which no participant was discharged during the study, whilst another three studies did not appear directly to measure recividism but rather abnormal sexual activity alone. Secondary outcomes:The included studies report a variety of secondary outcomes. Results suggest that the frequency of self reported deviant sexual fantasies may be reduced by testosterone-suppressing drugs, but not the deviancy itself (three studies). Where measured, hormonal levels, particularly levels of testosterone, tended to correlate with measures of sexual activity and with anxiety (two studies). One study measured anxiety formally; one study measured anger or aggression. Adverse events: Six studies provided information on adverse events. No study tested the effects of testosterone-suppressing drugs beyond six to eight months and the cross-over design of some studies may obscure matters (given the 'rebound effect' of some hormonal treatments). Considerable weight gain was reported in two trials of oral MPA and CPA. Side effects of intramuscular MPA led to discontinuation in some participants after three to five injections (the nature of these side effects was not described). Notable increases in depression and excess salivation were reported in one trial of oral MPA. The most severe side effects (extra-pyramidal movement disorders and drowsiness) were reported in a trial of antipsychotic medication for the 12 participants in the study. No deaths or suicide attempts were reported in any study. The latter is important given the association between antilibidinal hormonal medication and mood changes. We found only seven small trials (all published more than 20 years ago) that examined the effects of a limited number of drugs. Investigators reported issues around acceptance and adherence to treatment. We found no studies of the newer drugs currently in use, particularly SSRIs or GnRH analogues. Although there were some encouraging findings in this review, their limitations do not allow firm conclusions to be drawn regarding pharmacological intervention as an effective intervention for reducing sexual offending. The tolerability, even of the testosterone-suppressing drugs, was uncertain given that all studies were small (and therefore underpowered to assess adverse effects) and of limited duration, which is not consistent with current routine clinical practice. Further research is required before it is demonstrated that their administration reduces sexual recidivism and that tolerability is maintained. It is a concern that, despite treatment being mandated in many jurisdictions, evidence for the effectiveness of pharmacological interventions is so sparse and that no RCTs appear to have been published in two decades. New studies are therefore needed and should include trials with larger sample sizes, of longer duration, evaluating newer medications, and with results stratified according to category of sexual offenders. It is important that data are collected on the characteristics of those who refuse and those who drop out, as well as those who complete treatment.
We screened 2686 citations and included two trials enrolling 95 participants and one cohort study enrolling 17 participants. We assessed one randomized controlled trial as being at unclear risk of bias, and the other at high risk of bias; we assessed the non-randomized study as being at high risk of bias. We were unable to pool data due to the small number of studies meeting our inclusion criteria and therefore present narrative results rather than meta-analyses. One trial of 75 participants reported that extubation success (defined as no need for reintubation within 48 hours) was higher in the mechanical insufflation-exsufflation (MI-E) group (82.9% versus 52.5%, P < 0.05) (risk ratio (RR) 1.58, 95% confidence interval (CI) 1.13 to 2.20, very low-quality evidence). No study reported weaning success or reintubation as distinct from extubation success. One trial reported a statistically significant reduction in mechanical ventilation duration favouring MI-E (mean difference -6.1 days, 95% CI -8.4 to -3.8, very low-quality evidence). One trial reported mortality, with no participant dying in either study group. Adverse events (reported by two trials) included one participant receiving the MI-E protocol experiencing haemodynamic compromise. Nine (22.5%) of the control group compared to two (6%) MI-E participants experienced secretion encumbrance with severe hypoxaemia requiring reintubation (RR 0.25, 95% CI 0.06 to 1.10). In the lung volume recruitment trial, one participant experienced an elevated blood pressure for more than 30 minutes. No participant experienced new-onset arrhythmias, heart rate increased by more than 25%, or a pneumothorax. For outcomes assessed using GRADE, we based our downgrading decisions on unclear risk of bias, inability to assess consistency or publication bias, and uncertainty about the estimate of effect due to the limited number of studies contributing outcome data. The overall quality of evidence on the efficacy of cough augmentation techniques for critically-ill people is very low. Cough augmentation techniques when used in mechanically-ventilated critically-ill people appear to result in few adverse events.
Our search strategy identified 60 studies for consideration, of which 27 randomised trials involving 17,808 women undergoing caesarean section were included in the review. Overall, the methodological quality of the trials was variable, with 12 of the 27 included trials adequately describing the randomisation sequence, with less than half describing adequately methods of allocation concealment, and only six trials indicating blinding of outcome assessors. Two trials compared auto-suture devices with traditional hysterotomy involving 300 women. No statistically significant difference in febrile morbidity between the stapler and conventional incision groups was apparent (risk ratio (RR) 0.92; 95% confidence interval (CI) 0.38 to 2.20). Five studies were included in the review that compared blunt versus sharp dissection when performing the uterine incision involving 2141 women. There were no statistically significant differences identified for the primary outcome febrile morbidity following blunt or sharp extension of the uterine incision (four studies; 1941 women; RR 0.86; 95% CI 0.70 to 1.05). Mean blood loss (two studies; 1145 women; average mean difference (MD) -55.00 mL; 95% CI -79.48 to -30.52), and the need for blood transfusion (two studies; 1345 women; RR 0.24; 95% CI 0.09 to 0.62) were significantly lower following blunt extension. A single trial compared transverse with cephalad-caudad blunt extension of the uterine incision, involving 811 women, and while mean blood loss was reported to be lower following transverse extension (one study; 811 women; MD 42.00 mL; 95% CI 1.31 to 82.69), the clinical significance of such a small volume difference is of uncertain clinical relevance. There were no other statistically significant differences identified for the limited outcomes reported. A single trial comparing chromic catgut with polygactin-910, involving 9544 women reported that catgut closure versus closure with polygactin was associated with a significant reduction in the need for blood transfusion (one study, 9544 women, RR 0.49, 95% CI 0.32 to 0.76) and a significant reduction in complications requiring re-laparotomy (one study, 9544 women, RR 0.58, 95% CI 0.37 to 0.89). Nineteen studies were identified comparing single layer with double layer closure of the uterus, with data contributed to the meta-analyses from 14 studies. There were no statistically significant differences identified for the primary outcome, febrile morbidity (nine studies; 13,890 women; RR 0.98; 95% CI 0.85 to 1.12). Although the meta-analysis suggested single layer closure was associated with a reduction in mean blood loss, heterogeneity is high and this limits the clinical applicability of the result. There were no differences identified in risk of blood transfusion (four studies; 13,571 women; average RR 0.86; 95% CI 0.63 to 1.17; Heterogeneity: Tau² = 0.15; I² = 49%), or other reported clinical outcomes. Caesarean section is a common procedure performed on women worldwide. There is increasing evidence that for many techniques, short-term maternal outcomes are equivalent. Until long-term health effects are known, surgeons should continue to use the techniques they prefer and currently use.
Two trial were identified. The European Atrial Fibrillation Trial (EAFT) involving 455 patients, who received either anticoagulants (International Normalised Ratio (INR) 2.5 to 4.0), or aspirin (300 mg/day). Patients joined the trial within three months of transient ischemic attack or minor stroke. The mean follow up was 2.3 years. In the Studio Italiano Fibrillazione Atriale (SIFA) trial, 916 patients with NRAF and a TIA or minor stroke within the previous 15 days were randomised to open label anticoagulants (INR 2.0 to 3.5) or indobufen (a reversible platelet cyclooxygenase inhibitor, 100 or 200 mg BID). The follow-up period was one year. The combined results show that anticoagulants were significantly more effective than antiplatelet therapy both for all vascular events (Peto odds ratio (Peto OR) 0.67, 95% confidence interval (CI) 0.50 to 0.91) and for recurrent stroke (Peto OR 0.49, 95% CI 0.33 to 0.72). Major extracranial bleeding complications occurred more often in patients on anticoagulants (Peto OR 5.16, 95% CI 2.08 to 12.83), but the absolute difference was small (2.8% per year versus 0.9% per year in EAFT and 0.9% per year versus 0% in SIFA). Warfarin did not cause a significant increase of intracranial bleeds. The evidence from two trials suggests that anticoagulant therapy is superior to antiplatelet therapy for the prevention of stroke in people with NRAF and recent non-disabling stroke or TIA. The risk of extracranial bleeding was higher with anticoagulant therapy than with antiplatelet therapy.
Of 2091 titles and abstracts identified, full text versions of only three  (Morgan 2007; Murdoch 1999; Netsell 2001) were obtained. 2088 were excluded, largely on the basis of not including dysarthria, being diagnostic or descriptive papers, and for concerning adults rather than children. Morgan 2007 and Murdoch 1999 were excluded for not employing RCT or quasi-randomised methodology; Netsell 2001 on the basis of being a theoretical review paper, rather than an intervention study. Five references were identified and obtained from the bibliography of the Murdoch 1999 paper. All were excluded due to including populations without ABI, adults with dysarthria, or inappropriate design. Thus, no studies met inclusion criteria. The review demonstrates a critical lack of studies, let alone RCTs, addressing treatment efficacy for dysarthria in children with ABI. Possible reasons to explain this lack of data include i) a lack of understanding of the characteristics or natural history of dysarthria associated with this population; ii) the lack of a diagnostic classification system for children precluding the development of well targeted intervention programs; and iii) the heterogeneity of both the aetiologies and resultant possible dysarthria types of paediatric ABI. Efforts should first be directed at modest well-controlled studies to identify likely efficacious treatments that may then be trialed in multi-centre collaborations using quasi-randomised or RCT methodology.
Three studies met the inclusion criteria for this review. Two studies used clomipramine and one used tianeptine. All three trials were small, with between 12 and 32 participants. One of the clomipramine trials involved children and young adults, while the other two trials enrolled only children. Due to heterogeneity in study participant characteristics, the TCA medications investigated and the outcome measures used, we were not able to perform any meta-analysis. In only one of the three studies was there any indication that giving children tianeptine could be effective in the short term. In this study, parents and teachers reported that it reduced irritability, hyperactivity, inadequate eye contact and inappropriate speech, but clinician ratings found no significant impact on these symptoms. There were also significant adverse effects, including increased drowsiness and reduced activity levels in these individuals while being treated with tianeptine. The evidence of the impact of clomipramine in the two studies is contradictory. There was evidence of improvement in autistic symptoms, irritability and obsessive-compulsive disorder type symptoms, but conflicting evidence in relation to hyperactivity across the two studies, and no significant changes found with inappropriate speech. There were also adverse effects reported with the use of clomipramine. Although side effect ratings were not significantly different to placebo, there were significant dropout rates in the clomipramine arm of one study. Clinicians considering the use of TCAs need to be aware of the limited and conflicting evidence of effect and the side effect profile when discussing this treatment option with people who have ASD and their carers. Further research is required before TCAs can be recommended for treatment of individuals with ASD.
Six trials involving 705 patients were included. Mortality was not significantly different between groups, which was low in both the primary repair (1.94%) and the diverted groups (1.74%). The Peto OR for mortality was 1.22 (95% CI 0.40 to 3.74). However, the primary repair group experienced a significantly lower rate of complications (Peto OR 0.54; 95% CI 0.39 to 0.76), total infectious complications (Peto OR 0.44; 95% CI 0.17 to 1.1), abdominal infections including dehiscence (Peto OR 0.67; 95% CI 0.35 to 1.3), abdominal infections excluding dehiscence (Peto OR 0.69; 95% CI 0.34 to 1.39), wound complications including dehiscence (Peto OR 0.73; 95% CI 0.38 to 1.39), and wound complications excluding dehiscence (Peto OR 0.67; 95% CI 0.32 to 1.39). Statistical significance favoring primary repair over fecal diversion was achieved for all outcomes related to abdominal infections and wound complications when one study was excluded for both clinical and statistical heterogeneity in the sensitivity analysis. Meta-analysis of currently published randomized controlled trials favors primary repair over fecal diversion for penetrating colon injuries.
Three studies (a total of 112 participants) were included. All studies randomised participants to a singing group or a control group. The comparison groups included a film workshop, handcraft work, and no intervention. The frequency of the singing intervention in the studies ranged from 1 to 2 times a week over a 6 to 24 week period. The duration of each singing session was 60 minutes. All studies included participants diagnosed with COPD with a mean age ranging from 67 to 72 years and a mean forced expiratory volume in one second (FEV1) ranging from 37% to 64% of predicted values. The sample size of included studies was small (33 to 43 participants) and overall study quality was low to very low. Blinding of personnel and participants was not possible due to the physical nature of the intervention, and selection and reporting bias was present in two studies. For the primary outcome of health-related quality of life, there was no statistically significant improvement in the St George's Respiratory Questionnaire total score (mean difference (MD) -0.82, 95% confidence interval (CI) -4.67 to 3.02, 2 studies, n = 58, low-quality evidence). However, there was a statistically significant improvement in the SF-36 Physical Component Summary (PCS) score favouring the singing group (MD 12.64, 95% CI 5.50 to 19.77, 2 studies, n = 52, low-quality evidence). Only one study reported results for the other primary outcome of dyspnoea, in which the mean improvement in Baseline Dyspnoea Index (BDI) score favouring the singing group was not statistically significant (MD 0.40, 95% CI -0.65 to 1.45, 1 study, n = 30, very low-quality evidence). No studies examined any long-term outcomes and no adverse events or side effects were reported. There is low to very low-quality evidence that singing is safe for people with COPD and improves physical health (as measured by the SF-36 physical component score), but not dyspnoea or respiratory-specific quality of life. The evidence is limited due to the low number of studies and the small sample size of each study. No evidence exists examining the long-term effect of singing for people with COPD. The absence of studies examining singing performed in conjunction with pulmonary rehabilitation precludes the formulation of conclusions about the effects of singing in this context. More randomised controlled trials with larger sample sizes and long-term follow-up, and trials examining the effect of singing in addition to pulmonary rehabilitation, are required to determine the effect of singing on health-related quality of life and dyspnoea in people with COPD.
Our searches identified 28 references to eight trials; five trials were excluded (three were cross-over and one was not randomised and one did not have relevant outcomes), one cross-over trial is awaiting classification pending provision of data and one trial is ongoing. The included parallel randomised controlled trial compared ataluren to placebo for a duration of 48 weeks in 238 participants (age range 6 to 53 years) with cystic fibrosis who had at least one nonsense mutation (a type of class I mutation). The quality of evidence and risk of bias assessments for the trial were moderate overall. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented; participant blinding was less clear. Some participant data were excluded from the analysis. The trial was assessed as high risk of bias for selective outcome reporting, especially when reporting on the trial's post hoc subgroup of participants by chronic inhaled antibiotic use. The trial was sponsored by PTC Therapeutics Incorporated with grant support by the Cystic Fibrosis Foundation, the Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health (NIH). The trial reported no significant difference between treatment groups in quality of life, assessed by the Cystic Fibrosis Questionnaire-Revised respiratory domain score and no improvement in respiratory function measures (mean difference of relative change in forced expiratory volume at one second 2.97% (95% confidence interval -0.58 to 6.52)). Ataluren was associated with a significantly higher rate of episodes of renal impairment, risk ratio 17.70 (99% confidence interval 1.28 to 244.40). The trial reported no significant treatment effect for ataluren for the review's secondary outcomes: pulmonary exacerbation; computerised tomography score; weight; body mass index; and sweat chloride. No deaths were reported in the trial. A post hoc subgroup analysis of participants not receiving chronic inhaled tobramycin (n = 146) demonstrated favourable results for ataluren (n = 72) for relative change in % predicted forced expiratory volume at one second and pulmonary exacerbation rate. Participants receiving chronic inhaled tobramycin appeared to have a reduced rate of pulmonary exacerbation compared to those not receiving chronic inhaled tobramycin. This drug interaction was not anticipated and may affect the interpretation of the trial results. There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with cystic fibrosis with class I mutations. Future trials should carefully assess for adverse events, notably renal impairment and consider the possibility of drug interactions. Cross-over trials should be avoided given the potential for the treatment to change the natural history of cystic fibrosis.
Ten studies met our inclusion criteria, all of which were conducted in Africa. Of these four were randomised controlled trials while the remaining six were cohort studies. From the trial data, when nurses initiated and provided follow-up HIV therapy, there was high quality evidence of no difference in death at one year, unadjusted risk ratio was 0.96 (95% CI 0.82 to 1.12), one trial, cluster adjusted n = 2770. There was moderate quality evidence of lower rates of losses to follow-up at one year, relative risk of 0.73 (95% CI 0.55 to 0.97). From the cohort data, there was low quality evidence that there may be an increased risk of death in the task shifting group, relative risk 1.23 (95% CI 1.14 to 1.33, two cohorts, n = 39 160) and very low quality data reporting no difference in patients lost to follow-up between groups, relative risk 0.30 (95% CI 0.05 to 1.94). From the trial data, when doctors initiated therapy and nurses provided follow-up, there was moderate quality evidence that there is probably no difference in death compared with doctor-led care at one year, relative risk of 0.89 (95% CI 0.59 to 1.32), two trials, cluster adjusted n = 4332. There was moderate quality evidence that there is probably no difference in the numbers of patients lost to follow-up at one year, relative risk 1.27 (95% CI 0.92 to 1.77), P = 0.15. From the cohort data, there is very low quality data that death at one year may be lower in the task shifting group, relative risk 0.19 (95% CI 0.05 to 0.78), one cohort, n = 2772, and very low quality evidence that loss to follow-up was reduced, relative risk 0.34 (95% CI 0.18 to 0.66). From the trial data, for maintenance therapy delivered in the community there was moderate quality evidence that there is probably no difference in mortality when doctors deliver care in the hospital or specially trained field workers provide home-based maintenance care and antiretroviral therapy at one year, relative risk 1.0 (95% CI 0.62 to 1.62), 1 trial, cluster adjusted n = 559. There is moderate quality evidence from this trial that losses to follow-up are probably no different at one year, relative risk 0.52 (0.12 to 2.3), P = 0.39. The cohort studies did not report on one year follow-up for these outcomes. Across the studies that reported on virological and immunological outcomes, there was no clear evidence of difference whether a doctor or nurse or clinical officer delivered therapy. Three studies report on costs to patients, indicating a reduction in travel costs to treatment facilities where task shifting was occurring closer to patients homes. There is conflicting evidence regarding the relative cost to the health system, as implementation of the strategy may increase costs. The two studies reporting the patient and staff perceptions of the quality of care, report good acceptability of the service by patients, and general acceptance by doctors of the shifting of roles. One trial reported on the time to initiation of antiretroviral therapy, finding no clear evidence of a difference between groups. The same trial reports on new diagnosis of tuberculosis which favours nurse initiation of HIV care for increasing the numbers of diagnoses of tuberculosis made. Our review found moderate quality evidence that shifting responsibility from doctors to adequately trained and supported nurses or community health workers for managing HIV patients probably does not decrease the quality of care and, in the case of nurse initiated care, may decrease the numbers of patients lost to follow-up.
Completed randomised trials were not found. There is one trial that is currently ongoing in Italy; the results have yet to be published. Two prospective observational studies had data on recurrence-free survival. One study reported an odds ratio for recurrence rate at one year (where > 1 favours the luteal phase) of 0.86 (95% confidence interval (CI) 0.69 to 1.08); 0.87 at two years (95% CI 0.69 to 1.09); 0.95 at three years (95% CI 0.75 to 1.21); 1.12 at four years (95% CI 0.87 to 1.43); and 1.12 at five years (95% CI 0.87 to 1.43). Another study reported a hazard ratio for overall survival of 1.02 (95% CI 0.995 to 1.04, P = 0.14) and for disease-free survival of 1.00 (95% CI 0.98 to 1.02, P = 0.92) at three years based on the last and first menstrual period. The results were not significant. There was no difference in the recurrence rate whether the surgery was done during the follicular or luteal phase of the menstrual cycle. In the absence of RCTs, this review provides evidence from large prospective observational studies that timing of surgery does not show a significant effect on survival.
As of July 2017, we identified four trials with 192 participants that met the review inclusion criteria. Participating parents were mostly mothers (seven fathers were included in two studies), and children's ages ranged from one month to six years and five months. One study was conducted in Australia, one in Canada, one in the Netherlands, and one in the USA. Each studied a different intervention and considered different outcomes. Three interventions were delivered at home, and one in a community venue (e.g. a church). Interventions varied in duration from seven weeks to 12 months. They included a range of practical childcare skills, home safety and developing parents' ability to respond sensitively to their children. Parents in the comparison groups included in the review received treatment as usual and most of these received the index intervention after the study was complete. One study was funded by the Ontario Mental Health Foundation and the Ontario Ministry of Community and Social Services Research Grants Program; one by the Alabama Development Disabilities Council; one by the Best Practice Parenting Education Initiative of the Commonwealth Department of Family and Community Services and the New South Wales Aging and Disability Department; and one by ZonMw, The Netherlands Organisation for Health Research and Development. It was not possible for us to conduct a meta-analysis. The GRADE quality assessment varied from very low to moderate across the studies. Primary outcomes No study reported on the 'attainment of specific parenting skill targets'. 'Safe home practices' and 'understanding of child health': one study (30 parents, very low-quality evidence) reported some improvements in parents' knowledge of life-threatening emergencies, ability to recognise dangers, and identify precautions, in favour of the intervention group. It also found limited, very low-quality evidence that parent training improved parents' ability to understand child health, implement precautions, use medicines safely, recognise child illness and symptoms, and seek medical advice (i.e. visit the doctor). Another study (22 mothers, very low-quality evidence) reported improved attainment of skills related to childcare and safety, in favour of the intervention group. Secondary outcomes 'Parent-child interaction': one study (40 mothers, very low-quality evidence) reported improved maternal-child interaction following parent training at 12 months follow-up. Another study (83 mothers, 2 fathers, moderate-quality evidence) reported that inclusion in the intervention group led to a steeper decline in parenting stress related to the child compared to the control group. 'Parents' retention of child': one study (22 participants; very low-quality evidence) reported that before joining the programme nine of 11 (82%) families with a previous child had had the child removed from their care by child protection authorities due to maternal maltreatment, compared with only four of 22 (19%) families after participating in the programme (only one of these four mothers had also had a previous child removed). No study reported data on: 'return to independent care of child' or 'lifting of child-related court order'. There is some very low-quality evidence that some parents, mainly mothers, with intellectual disabilities are able to provide adequate parenting if they are given appropriate training and support to learn the parenting skills they need. However, there are few studies exploring how interventions might work, for whom and in what circumstances. In particular, there have been few studies that include fathers with intellectual disabilities, or that explore the views of parents themselves. There is a need for larger RCTs of parenting interventions, with longer follow-up, before conclusions can be drawn about the effectiveness of parent training for this group of parents.
We included three RCTs in this review. It was unclear if the RCTs were three separate studies involving 1199 participants in total, or if they were reports from the same study involving fewer participants. We decided to treat the studies separately, as we were unable to make contact with the study authors to clarify. All three RCTs are of very low study quality because of issues with unclear randomization methods, allocation concealment and uncertainty of effect size. Some of the studies were reported as abstracts only and contained limited data, which prevented meaningful analysis and assessment of potential biases. The studies included participants who all received automated electronic monitoring during their hospital stay. Participants were randomized to an intervention group (automated alerts sent from the system) or to usual care (no automated alerts sent from the system). Evidence from all three studies reported 'Time to initiation of antimicrobial therapy'. We were unable to pool the data, but the largest study involving 680 participants reported median time to initiation of antimicrobial therapy in the intervention group of 5.6 hours (interquartile range (IQR) 2.3 to 19.7) in the intervention group (n = not stated) and 7.8 hours (IQR 2.5 to 33.1) in the control group (n = not stated). No studies reported 'Time to initiation of fluid resuscitation' or the adverse event 'Mortality at 30 days'. However very low-quality evidence was available where mortality was reported at other time points. One study involving 77 participants reported 14-day mortality of 20% in the intervention group and 21% in the control group (numerator and denominator not stated). One study involving 442 participants reported mortality at 28 days, or discharge was 14% in the intervention group and 10% in the control group (numerator and denominator not reported). Sample sizes were not reported adequately for these outcomes and so we could not estimate confidence intervals. Very low-quality evidence from one study involving 442 participants reported 'Length of stay in ICU'. Median length of stay was 3.0 days in the intervention group (IQR = 2.0 to 5.0), and 3.0 days (IQR 2.0 to 4.0 in the control). Very low-quality evidence from one study involving at least 442 participants reported the adverse effect 'Failed detection of sepsis'. Data were only reported for failed detection of sepsis in two participants and it wasn't clear which group(s) this outcome occurred in. No studies reported 'Quality of life'. It is unclear what effect automated systems for monitoring sepsis have on any of the outcomes included in this review. Very low-quality evidence is only available on automated alerts, which is only one component of automated monitoring systems. It is uncertain whether such systems can replace regular, careful review of the patient's condition by experienced healthcare staff.
Five studies treated 168 participants with painful diabetic neuropathy or polyneuropathy. The mean age in individual studies was between 47 and 56 years. Four studies used a cross-over, and one a parallel group design; 126 participants were randomised to receive imipramine 25 mg to 350 mg daily (most took 100 mg to 150 mg daily). Comparators were placebo (an active placebo in one study), paroxetine, mianserin, venlafaxine, and amitriptyline, and treatment was given for 2 to 12 weeks. All studies had one or more sources of potential major bias. No study provided first or second tier evidence for any outcome. No data were available on the proportion of people with at least 50% or 30% reduction in pain or equivalent, and data were available from only one study for our other primary outcome of Patient Global Impression of Change, reported as patient evaluation of pain relief of complete or good. No pooling of data was possible, but third tier evidence in individual studies indicated some improvement in pain relief with imipramine compared with placebo, although this is was very low quality evidence, derived mainly from group mean data and completer analyses, in small, short duration studies where major bias is possible. Four studies reported some information about adverse events, but reporting was inconsistent and fragmented, and the quality of evidence was very low. Participants taking imipramine generally experienced more adverse events, notably dry mouth, and a higher rate of withdrawal due to adverse events, than did participants taking placebo. This review found little evidence to support the use of imipramine to treat neuropathic pain. There was very low quality evidence of benefit but this came from studies that were methodologically flawed and potentially subject to major bias. Effective medicines with much greater supportive evidence are available.
We identified three studies as eligible for inclusion in the review. Two were in the previous review and one new study was included. We considered the older studies to be at high or unclear risk of bias whereas we judged the newly included study at low risk of bias. The studies varied in treatment duration (from 7 to 14 days) and the antibiotic used (two studies used amoxicillin/clavulanate acid and one used erythromycin). We included 190 children (171 completed), mean ages ranged from 21 months to six years, in the meta-analyses. Analysis of all three trials (190 children) found that treatment with antibiotics reduced the proportion of children not cured at follow-up (primary outcome measure) (odds ratio (OR) 0.15, 95% confidence interval (CI) 0.07 to 0.31, using intention-to -treat analysis), which translated to a number needed to treat for an additional beneficial outcome (NNTB) of 3 (95% CI 2 to 4). We identified no significant heterogeneity (for both fixed-effect and random-effects model the I² statistic was 0%). Two older trials assessed progression of illness, defined by requirement for further antibiotics (125 children), which was significantly lower in the antibiotic group (OR 0.10, 95% CI 0.03 to 0.34; NNTB 4, 95% CI 3 to 5). All three trials (190 children) reported adverse events, which were not significantly increased in the antibiotic group compared to the control group (OR 1.88, 95% CI 0.62 to 5.69). We assessed the quality of evidence GRADE rating as moderate for all outcome measures, except adverse events which we assessed as low quality. Evidence suggests antibiotics are efficacious for the treatment of children with chronic wet cough (greater than four weeks) with an NNTB of three. However, antibiotics have adverse effects and this review reported only uncertainty as to the risk of increased adverse effects when they were used in this setting. The inclusion of a more robust study strengthened the previous Cochrane review and its results.
We included 15 studies, involving over 2000 women. Antibiotic treatment compared with placebo or no treatment may reduce the incidence of pyelonephritis (average risk ratio (RR) 0.24, 95% confidence interval (CI) 0.13 to 0.41; 12 studies, 2017 women; low-certainty evidence). Antibiotic treatment may be associated with a reduction in the incidence of preterm birth (RR 0.34, 95% CI 0.13 to 0.88; 3 studies, 327 women; low-certainty evidence), and low birthweight babies (average RR 0.64, 95% CI 0.45 to 0.93; 6 studies, 1437 babies; low-certainty evidence). There may be a reduction in persistent bacteriuria at the time of delivery (average RR 0.30, 95% CI 0.18 to 0.53; 4 studies; 596 women), but the results were inconclusive for serious adverse neonatal outcomes (average RR 0.64, 95% CI 0.23 to 1.79, 3 studies; 549 babies). There were very limited data on which to estimate the effect of antibiotics on other infant outcomes, and maternal adverse effects were rarely described. Overall, we judged only one trial at low risk of bias across all domains; the other 14 studies were assessed as high or unclear risk of bias. Many studies lacked an adequate description of methods, and we could only judge the risk of bias as unclear, but in most studies, we assessed at least one domain at high risk of bias. We assessed the quality of the evidence for the three primary outcomes with GRADE software, and found low-certainty evidence for pyelonephritis, preterm birth, and birthweight less than 2500 g. Antibiotic treatment may be effective in reducing the risk of pyelonephritis in pregnancy, but our confidence in the effect estimate is limited given the low certainty of the evidence. There may be a reduction in preterm birth and low birthweight with antibiotic treatment, consistent with theories about the role of infection in adverse pregnancy outcomes, but again, the confidence in the effect is limited given the low certainty of the evidence. Research implications identified in this review include the need for an up-to-date cost-effectiveness evaluation of diagnostic algorithms, and more evidence to learn whether there is a low-risk group of women who are unlikely to benefit from treatment of asymptomatic bacteriuria.
We included 14 studies (7 case-control and 7 cohort studies). These examined oral contraceptives (OCs), depot medroxyprogesterone acetate (DMPA), and the hormonal intrauterine device (IUD). This section focuses on the sensitivity analysis with six studies that provided moderate or high quality evidence. All six studies examined oral contraceptive use. We noted few associations with fracture risk. One cohort study reported OC ever-users had increased risk for all fractures (RR 1.20, 95% CI 1.08 to 1.34). However, a case-control study with later data from a subset reported no association except for those with 10 years or more since use (OR 1.55, 95% CI 1.03 to 2.33). Another case-control study reported increased risk only for those who had 10 or more prescriptions (OR 1.09, 95% CI 1.03 to 1.16). A cohort study of postmenopausal women found no increased fracture risk for OC use after excluding women with prior fracture. Two other studies found little evidence of association between OC use and fracture risk. A cohort study noted increased risk for subgroups, such as those with longer use or specific intervals since use. A case-control study reported increased risk for any fracture only among young women with less than average use. Two case-control studies also examined progestin-only contraceptives. One reported increased fracture risk for DMPA ever-use (OR 1.44, 95% CI 1.01 to 2.06), more than four years of use (OR 2.16, 95% CI 1.32 to 3.53), and women over 50 years old. The other reported increased risk for any past use, including one or two prescriptions (OR 1.17, 95% CI 1.07 to 1.29) and for current use of 3 to 9 prescriptions (OR 1.36, 95% CI 1.15 to 1.60) or 10 or more (OR 1.54, 95% CI 1.33 to 1.78). For the levonorgestrel-releasing IUD, one study reported reduced fracture risk for ever-use (OR 0.75, 95% CI 0.64 to 0.87) and for longer use. Observational studies do not indicate an overall association between oral contraceptive use and fracture risk. Some reported increased risk for specific user subgroups. DMPA users may have an increased fracture risk. One study indicated hormonal IUD use may be associated with decreased risk. Observational studies need adjusted analysis because the comparison groups usually differ. Investigators should be clear about the variables examined in multivariate analysis.
We found six trials (542 participants) that met our inclusion criteria. These trials assessed the effectiveness of hormonal therapy in women with advanced or recurrent endometrial cancer as a single agent, as part of combination therapy and as low versus high dose. All comparisons were restricted to single-trial analyses, where we found no evidence that hormonal therapy as a single agent or as a combination treatment prolonged overall or five-year disease-free survival of women with advanced or recurrent endometrial cancer. However, low-dose hormonal therapy may have had a benefit in terms of overall and progression-free survival (PFS) compared to high-dose hormonal therapy (HR 1.31, 95% CI 1.04 to 1.66 and HR 1.35, 95% CI 1.07 to 1.71 for overall and PFS, respectively). We found insufficient evidence that hormonal treatment in any form, dose or as part of combination therapy improves the survival of patients with advanced or recurrent endometrial cancer. However, a large number of patients would be needed to demonstrate an effect on survival and none of the included RCTs had a sufficient number of patients to demonstrate a significant difference. In the absence of a proven survival advantage and the heterogeneity of patient populations, the decision to use any type of hormonal therapy should be individualised and with the intent to palliate the disease. It is debatable whether outcomes such as quality of life, treatment response or palliative measures such as relieving symptoms should take preference over overall and PFS as the major objectives of future trials.
A total of 32 trials provided data for inclusion in the review in terms of efficacy, withdrawal and side effect analysis. We were unable to find any differences in efficacy when comparing classes of antidepressants. Tricyclic antidepressants (TCAs) compared less favourably with selective serotonin reuptake inhibitors (SSRIs) in terms of numbers of patients withdrawn irrespective of reason (RR: 1.23, CI 1.05 to 1.43) and number withdrawn due to side effects (RR: 1.36, CI 1.09 to 1.70). Further analyses demonstrated that TCA related antidepressants had similar withdrawal rates to SSRIs irrespective of reason of withdrawal (RR: 1.49, CI 0.74 to 2.98) or withdrawal due to side effects (RR: 1.07, CI 0.43 to 2.70). The qualitative analysis of side effects showed a small increased profile of gastro-intestinal and neuropsychiatric side effects associated with classical TCAs. Our findings suggest that SSRIs and TCAs are of the same efficacy. However, we have found some evidence suggesting that TCA related antidepressants and classical TCAs have different side effect profiles and are associated with differing withdrawal rates when compared with SSRIs. The review suggests that classical TCAs are associated with a higher withdrawal rate due to side effect experience, although these results must be interpreted with caution due to the heterogeneity of the drugs and patient populations.
We included three quasi-randomised controlled trials, with a total of 149 women and their babies. All three trials were at a high risk of bias. When comparing women receiving relaxin with those who did not receive relaxin, there was a significant reduction in birth within seven days of treatment in one trial of 30 women (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.87), yet no significant difference was seen for perinatal mortality in this trial (RR 0.83, 95% CI 0.32 to 2.15). The second and third included trials did not report on any of the primary outcomes pre-specified in the review, including birth within 48 hours of treatment, birth within seven days of treatment, perinatal mortality, and serious neonatal adverse outcomes. One trial found a significant increase in pregnancy prolongation for women receiving relaxin (RR 8.00, 95% CI 1.14 to 56.33; 30 women). None of the three included trials found significant differences in the outcomes of fetal death, neonatal death, birthweight or preterm birth, and no trial reported on longer-term outcomes for the babies. There is limited randomised controlled trial evidence available on the effect of relaxin during pregnancy for preventing preterm birth for women in preterm labour. Evidence from one quasi-randomised trial suggested a reduction in birth within seven days of treatment for women receiving relaxin, compared with women in a control group, however this trial was at a high risk of bias and included only 30 women. There is thus insufficient evidence to support or refute the use of relaxin in women in preterm labour for preventing preterm birth.
We included 38 studies (3679 women). Nine studies included pregnancies after intrauterine deaths, five studies included termination of pregnancies because of fetal anomalies when the fetus was still alive and the rest (24) presented the pooled data for intrauterine deaths, fetal anomalies and social reasons. When compared with agents that have traditionally been used to induce labour in this setting (for example, gemeprost, prostaglandin E2 and prostaglandin F2alpha), vaginal misoprostol is as effective in ensuring vaginal birth within 24 hours, with a similar induction to birth interval. Vaginal misoprostol is associated with a reduction in the occurrence of maternal gastrointestinal side effects such as nausea, vomiting and diarrhoea when compared with other prostaglandin preparations. While the different treatments involving various prostaglandin preparations appear comparable for the reported outcomes, the information available regarding rare maternal complications, such as uterine rupture, is limited. The use of vaginal misoprostol in the termination of second and third trimester of pregnancy is as effective as other prostaglandin preparations (including cervagem, prostaglandin E2 and prostaglandin F2alpha), and more effective than oral administration of misoprostol. However, important information regarding maternal safety, and in particular the occurrence of rare outcomes such as uterine rupture, remains limited. Future research efforts should be directed towards determining the optimal dose and frequency of administration, with particular attention to standardised reporting of all relevant outcomes and assessment of rare adverse events. Further information is required about the use of sublingual misoprostol in this setting.
Our search strategy yielded 2696 references. Two review authors independently assessed all references for inclusion. Two randomized controlled trials, for a total of 110 infants, met the inclusion criteria of this review. Both trials compared supine midline head position with the bed at 0° versus supine head rotated 90° with the bed at 0°. We found no trials that compared supine versus prone midline head position, and no trials that compared effects of head tilting. We found no significant differences in rates of GM-IVH (typical risk ratio [RR] 1.14, 95% confidence interval [CI] 0.55 to 2.35; typical risk difference [RD] 0.03, 95% CI -0.13 to 0.18; two studies, 110 infants; I2 = 0% for RR and I2 = 0% for RD), severe IVH (typical RR 1.57, 95% CI 0.28 to 8.98; typical RD 0.02, 95% CI -0.06 to 0.10; two studies, 110 infants; I2 = 0% for RR and I2 = 0% for RD), and neonatal mortality (typical RR 0.52, 95% CI 0.16 to 1.65; typical RD -0.07, 95% CI -0.18 to 0.05; two studies, 110 infants; I2 = 28% for RR and I2 = 44% for RD). Among secondary outcomes, we found no significant differences in terms of cystic periventricular leukomalacia (one study; RR 3.25, 95% CI 0.14 to 76.01; RD 0.04, 95% CI -0.07 to 0.15), retinopathy of prematurity (one study; RR 2.27, 95% CI 0.85 to 6.11; RD 0.25, 95% CI -0.02 to 0.53), and severe retinopathy of prematurity (one study; RR 2.73, 95% CI 0.31 to 24.14; RD 0.09, 95% CI -0.09 to 0.26). None of the included trials reported on the other specified outcomes of this review (i.e., cerebellar hemorrhage, brain magnetic resonance imaging abnormalities, impairment in cerebral hemodynamics, long-term neurodevelopmental outcomes, and major neurodevelopmental disability). The quality of evidence supporting these findings is limited owing to the imprecision of the estimates. We identified no ongoing studies. Given the imprecision of the estimate, results of this systematic review are consistent with beneficial or detrimental effects of a supine head midline position versus a lateral position and do not provide a definitive answer to the review question.
Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo. Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.
Nine studies were included representing 425 participants. All studies compared omega-3 fatty acid supplementation with placebo lasting from four weeks to two years. Three studies with long treatment periods administered additional substances, making any observed effects impossible to attribute to omega-3 fatty acids and were excluded from the statistical analyses. One study did not express any mean values and, therefore, could not be included in statistical analyses. No significant differences between intervention and control groups were observed in pain-free walking distance (mean difference (MD) 11.62 m, 95% confidence interval (CI) -67.74 to 90.98), maximal walking distance (MD 16.99 m, 95% CI -72.14 to 106.11), ankle brachial pressure index (MD -0.02, 95% CI -0.09 to 0.05), total cholesterol levels (MD 0.27 mmol/L, 95% CI -0.48 to 1.01), high-density lipoprotein cholesterol levels (MD 0.00 mmol/L, 95% CI -0.16 to 0.15), low-density lipoprotein cholesterol levels (MD 0.44 mmol/L, 95% CI -0.31 to 1.19), triglyceride levels (MD -0.39 mmol/L, 95% CI -1.10 to 0.33), systolic blood pressure (MD 5.00 mmHg, 95% CI -11.59 to 21.59) or plasma viscosity (MD 0.03 mPa/s, 95% CI -0.02 to 0.08). There was some limited evidence that blood but not plasma viscosity levels decreased with treatment and gastrointestinal side effects such as nausea, diarrhoea and flatulence were observed in two studies. Omega-3 fatty acids appear to have little haematological benefit in people with intermittent claudication and there is no evidence of consistently improved clinical outcomes (quality of life, walking distance, ankle brachial pressure index or angiographic findings). Supplementation may also cause adverse effects such as nausea, diarrhoea and flatulence. Further research is needed to evaluate fully short- and long-term effects of omega-3 fatty acids on the most clinically relevant outcomes in people with intermittent claudication before they can be recommended for routine use.
We included two RCTs involving a total of 149 children between three months and 18 years of age who were receiving antibiotics for septic arthritis. The most commonly affected joints were hips and knees. These studies were performed in Costa Rica and Israel. In both studies, dexamethasone administered intravenously (ranging from 0.15 to 0.2 mg/kg/dose every six to eight hours) during four days was the corticosteroid, and the comparator was placebo. Trials excluded patients with any degree of immunodeficiency or immunosuppression. The longest follow-up was one year. Trials did not report activities of daily living nor length of hospital stay. Both studies used adequate processes for randomisation, allocation concealment, and blinding, and review authors judged them to have low risk of selection and performance bias. Losses to follow-up were substantive in both studies, and we judged them to have high risk of attrition bias and of selective outcome reporting. We graded all outcomes as low quality due to concerns about study limitations and imprecision. The risk ratio (RR) for absence of pain at 12 months of follow-up was 1.33, favouring corticosteroids (95% confidence interval (CI) 1.03 to 1.72; P = 0.03; number needed to treat for an additional beneficial outcome (NNTB) = 13, 95% CI 6 to 139; absolute risk difference 24%, 95% CI 5% to 43%). The RR for normal function of the affected joint at 12 months of follow-up was 1.32, favouring corticosteroids (95% CI 1.12 to 1.57; P = 0.001; NNTB = 13, 95% CI 7 to 33; absolute risk difference 24%, 95% CI 11% to 37%). We found a reduction in the number of days of intravenous antibiotic treatment favouring corticosteroids (mean difference (MD) -2.77, 95% CI -4.16 to -1.39) based on two trials with 149 participants. Researchers did not report length of hospital stay. One trial (49 participants) reported that treatment with dexamethasone was associated with a shorter duration of IV antibiotic treatment, leading to a shorter hospital stay, and although duration of hospitalisation was a primary outcome of the study, study authors did not provide data on the duration of hospitalisation. We downgraded the quality by one level for concerns about study limitations (high risk of attrition bias and selective reporting), and by another level for imprecision. In one trial of 49 participants, researchers followed 29 children for 12 months, and parents reported that no children demonstrated adverse effects of the intervention. Evidence for corticosteroids as adjunctive therapy in children with a diagnosis of septic arthritis is of low quality and is derived from the findings of two trials (N = 149). Corticosteroids may increase the proportion of patients without pain and the proportion of patients with normal function of the affected joint at 12 months, and may also reduce the number of days of antibiotic treatment. However, we cannot draw strong conclusions based upon these trial results. Additional randomised clinical trials in children with relevant outcomes are needed.
Fourteen studies with data from 672 participants met the inclusion criteria. Five different antiepileptic drugs were examined. Sodium valproate/divalproex was superior to placebo for outpatient men with recurrent impulsive aggression, for impulsively aggressive adults with cluster B personality disorders, and for youths with conduct disorder, but not for children and adolescents with pervasive developmental disorder. Carbamazepine was superior to placebo in reducing acts of self-directed aggression in women with borderline personality disorder, but not in children with conduct disorder. Oxcarbazepine was superior to placebo for verbal aggression and aggression against objects in adult outpatients. Phenytoin was superior to placebo on the frequency of aggressive acts in male prisoners and in outpatient men including those with personality disorder, but not on the frequency of 'behavioral incidents' in delinquent boys. The authors consider that the body of evidence summarised in this review is insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity. Four antiepileptics (valproate/divalproex, carbamazepine, oxcarbazepine and phenytoin) were effective, compared to placebo, in reducing aggression in at least one study, although for three drugs (valproate, carbamazepine and phenytoin) at least one other study showed no statistically significant difference between treatment and control conditions. Side effects were more commonly noted for the intervention group although adverse effects were not well reported. Absence of information does not necessarily mean that the treatment is safe, nor that the potential gains from the medication necessarily balance the risk of an adverse event occurring. Further research is needed.
We identified four studies meeting our inclusion criteria. Overall, trials were of poor to moderate methodological quality. Few trial authors responded to our written inquiries seeking to resolve controversial issues and to obtain individual patient data. Strong heterogeneity amongst the trials prompted discussion between the review authors as to whether the data should or should not be pooled; we decided in favour of a quantitative synthesis to provide a rough impression about the effect sizes achievable with US-based triage algorithms. We pooled mortality data from three trials involving 1254 patients; the RR in favour of the FAST arm was 1.00 (95% CI 0.50 to 2.00). FAST-based pathways reduced the number of CT scans (random-effects model RD -0.52, 95% CI -0.83 to -0.21), but the meaning of this result was unclear. The experimental evidence justifying FAST-based clinical pathways in diagnosing patients with suspected abdominal or multiple blunt trauma remains poor. Because of strong heterogeneity between the trial results, the quantitative information provided by this review may only be used in an exploratory fashion. It is unlikely that FAST will ever be investigated by means of a confirmatory, large-scale RCT in the future. Thus, this Cochrane Review may be regarded as a review which provides the best available evidence for clinical practice guidelines and management recommendations. It can only be concluded from the few head-to-head studies that negative US scans are likely to reduce the incidence of MDCT scans which, given the low sensitivity of FAST (or reliability of negative results), may adversely affect the diagnostic yield of the trauma survey. At best, US has no negative impact on mortality or morbidity. Assuming that major blunt abdominal or multiple trauma is associated with 15% mortality and a CT-based diagnostic work-up is considered the current standard of care, 874, 3495, or 21,838 patients are needed per intervention group to demonstrate non-inferiority of FAST to CT-based algorithms with non-inferiority margins of 5%, 2.5%, and 1%, power of 90%, and a type-I error alpha of 5%.
Twenty studies involving 1898 subjects were evaluated, including 4 studies with multiple comparisons. We found eight comparisons of TURP with contact lasers, eight with non-contact lasers, four with hybrid techniques, and one with interstitial laser coagulation (ILC). Two studies compared transurethral electrovaporization (TUVP) with contact lasers, one study compared interstitial laser coagulation with transurethral microwave thermotherapy (TUMT), and one study compared holmium contact lasers (HoLRP) with open prostatectomy. Among the studies comparing laser prostatectomy with TURP, follow-up duration ranged from 6 to 36 months. Mean age (67.2 yrs), mean baseline symptom score (20.2), and mean baseline peak urinary flow (9.2 mL/s) did not differ by treatment group. The pooled percentage improvements for mean urinary symptoms ranged from 59% to 68% with lasers and 63% to 77% with TURP. The improvements for mean peak urinary flow ranged from 56% to 119% with lasers and 96% to 127% with TURP. Overall, laser subjects were less likely to receive transfusions or develop strictures and their hospitalizations were shorter. Non-contact laser subjects were more likely to have dysuria, urinary tract infection, and retention. Re-operation occurred more often following laser procedures. Laser techniques are a useful alternative to TURP for treating BPO. Small sample sizes and differences in study design limit any definitive conclusions regarding the preferred type of laser technique. Data were insufficient to compare laser techniques with other minimally invasive procedures.
The findings of this review are based on a single trial involving 425 women with gestational diabetes. The trial compared induction of labour with expectant management (waiting for the spontaneous onset of labour in the absence of any maternal or fetal issues that may necessitate birth) in pregnant women with gestational diabetes at term. We assessed the overall risk of bias as being low for most domains, apart from performance, detection and attrition bias (for outcome perineum intact), which we assessed as being at high risk. It was an open-label trial, and women and healthcare professionals were not blinded. There were no clear differences between women randomised to induction of labour and women randomised to expectant management for maternal mortality or serious maternal morbidity (risk ratio (RR) 1.48, 95% confidence interval (CI) 0.25 to 8.76, one trial, 425 women); caesarean section (RR 1.06, 95% CI 0.64 to 1.77, one trial, 425 women); or instrumental vaginal birth (RR 0.81, 95% CI 0.45 to 1.46, one trial, 425 women). For the primary outcome of maternal mortality or serious maternal morbidity, there were no deaths in either group and serious maternal morbidity related to admissions to intensive care unit. The quality of the evidence contributing to these outcomes was assessed as very low, mainly due to the study having high risk of bias for some domains and because of the imprecision of effect estimates. In relation to primary neonatal outcomes, there were no perinatal deaths in either group. The quality of evidence for this outcome was judged as very low, mainly due to high risk of bias and imprecision of effect estimates. There were no clear differences in infant outcomes between women randomised to induction of labour and women randomised to expectant management: shoulder dystocia (RR 2.96, 95% CI 0.31 to 28.21, one trial, 425 infants, very low-quality evidence); large-for-gestational age (RR 0.53, 95% CI 0.28 to 1.02, one trial, 425 infants, low-quality evidence). There were no clear differences between women randomised to induction of labour and women randomised to expectant management for postpartum haemorrhage (RR 1.17, 95% CI 0.53 to 2.54, one trial, 425 women); admission to intensive care unit (RR 1.48, 95% CI 0.25 to 8.76, one trial, 425 women); and intact perineum (RR 1.02, 95% CI 0.73 to 1.43, one trial, 425 women). No infant experienced a birth trauma, therefore, we could not draw conclusions about the effect of the intervention on the outcomes of brachial plexus injury and bone fracture at birth. Infants of women in the induction-of-labour group had higher incidences of neonatal hyperbilirubinaemia (jaundice) when compared to infants of women in the expectant-management group (RR 2.46, 95% CI 1.11 to 5.46, one trial, 425 women). We found no data on the following prespecified outcomes of this review: postnatal depression, maternal satisfaction, length of postnatal stay (mother), acidaemia, intracranial haemorrhage, hypoxia ischaemic encephalopathy, small-for-gestational age, length of postnatal stay (baby) and cost. The authors of this trial acknowledge that it is underpowered for their primary outcome of caesarean section. The authors of the trial and of this review note that the CIs demonstrate a wide range, therefore making it inappropriate to draw definite conclusions. There is limited evidence to inform implications for practice. The available data are not of high quality and lack power to detect possible important differences in either benefit or harm. There is an urgent need for high-quality trials evaluating the effectiveness of planned birth at or near term gestation for women with gestational diabetes compared with an expectant approach.
We included 19 trials in this review (2286 participants: 1103 allocated to HBOT and 1153 to control). For head and neck cancer, there was an overall reduction in the risk of dying at both one year and five years after therapy (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70 to 0.98, number needed to treat for an additional beneficial outcome (NNTB) = 11 and RR 0.82, 95% CI 0.69 to 0.98, high-quality evidence), and some evidence of improved local tumour control immediately following irradiation (RR with HBOT 0.58, 95% CI 0.39 to 0.85, moderate-quality evidence due to imprecision). There was a lower incidence of local recurrence of tumour when using HBOT at both one and five years (RR at one year 0.66, 95% CI 0.56 to 0.78, high-quality evidence; RR at five years 0.77, 95% CI 0.62 to 0.95, moderate-quality evidence due to inconsistency between trials). There was also some evidence with regard to the chance of metastasis at five years (RR with HBOT 0.45 95% CI 0.09 to 2.30, single trial moderate quality evidence imprecision). No trials reported a quality of life assessment. Any benefits come at the cost of an increased risk of severe local radiation reactions with HBOT (severe radiation reaction RR 2.64, 95% CI 1.65 to 4.23, high-quality evidence). However, the available evidence failed to clearly demonstrate an increased risk of seizures from acute oxygen toxicity (RR 4.3, 95% CI 0.47 to 39.6, moderate-quality evidence). For carcinoma of the uterine cervix, there was no clear benefit in terms of mortality at either one year or five years (RR with HBOT at one year 0.88, 95% CI 0.69 to 1.11, high-quality evidence; RR at five years 0.95, 95% CI 0.80 to 1.14, moderate-quality evidence due to inconsistency between trials). Similarly, there was no clear evidence of a benefit of HBOT in the reported rate of local recurrence (RR with HBOT at one year 0.82, 95% CI 0.63 to 1.06, high-quality evidence; RR at five years 0.85, 95% CI 0.65 to 1.13, moderate-quality evidence due to inconsistency between trials). We also found no clear evidence for any effect of HBOT on the rate of development of metastases at both two years and five years (two years RR with HBOT 1.05, 95% CI 0.84 to 1.31, high quality evidence; five years RR 0.79, 95% CI 0.50 to 1.26, moderate-quality evidence due to inconsistency). There were, however, increased adverse effects with HBOT. The risk of a severe radiation injury at the time of treatment with HBOT was 2.05, 95% CI 1.22 to 3.46, high-quality evidence. No trials reported any failure of local tumour control, quality of life assessments, or the risk of seizures during treatment. With regard to the treatment of urinary bladder cancer, there was no clear evidence of a benefit in terms of mortality from HBOT at one year (RR 0.97, 95% CI 0.74 to 1.27, high-quality evidence), nor any benefit in the risk of developing metastases at two years (RR 2.0, 95% CI 0.58 to 6.91, moderate-quality evidence due to imprecision). No trial reported on failure of local control, local recurrence, quality of life, or adverse effects. When all cancer types were combined, there was evidence for an increased risk of severe radiation tissue injury during the course of radiotherapy with HBOT (RR 2.35, 95% CI 1.66 to 3.33, high-quality evidence) and of oxygen toxic seizures during treatment (RR with HBOT 6.76, 96% CI 1.16 to 39.31, moderate-quality evidence due to imprecision). We found evidence that HBOT improves local tumour control, mortality, and local tumour recurrence for cancers of the head and neck. These benefits may only occur with unusual fractionation schemes. Hyperbaric oxygenation therapy is associated with severe tissue radiation injury. Given the methodological and reporting inadequacies of the included studies, our results demand a cautious interpretation. More research is needed for head and neck cancer, but is probably not justified for uterine cervical or bladder cancer. There is little evidence available concerning malignancies at other anatomical sites.
We identified four new trials for this update. In total, the evidence for this review rests on 26 trials (1369 participants). Listening to music was the main intervention used, and 23 of the studies did not include a trained music therapist. Results indicate that music interventions have a small beneficial effect on psychological distress in people with CHD and this effect is consistent across studies (MD = -1.26, 95% CI -2.30 to -0.22, P = 0.02, I² = 0%). Listening to music has a moderate effect on anxiety in people with CHD; however results were inconsistent across studies (SMD = -0.70, 95% CI -1.17 to -0.22, P = 0.004, I² = 77%). Studies that used music interventions in people with myocardial infarction found more consistent anxiety-reducing effects of music, with an average anxiety reduction of 5.87 units on a 20 to 80 point score range (95% CI -7.99 to -3.75, P < 0.00001, I² = 53%). Furthermore, studies that used patient-selected music resulted in greater anxiety-reducing effects that were consistent across studies (SMD = -0.89, 95% CI -1.42 to -0.36, P = 0.001, I² = 48%). Findings indicate that listening to music reduces heart rate (MD = -3.40, 95% CI -6.12 to -0.69, P = 0.01), respiratory rate (MD = -2.50, 95% CI -3.61 to -1.39, P < 0.00001) and systolic blood pressure (MD = -5.52 mmHg, 95% CI - 7.43 to -3.60, P < 0.00001). Studies that included two or more music sessions led to a small and consistent pain-reducing effect (SMD = -0.27, 95% CI -0.55 to -0.00, P = 0.05). The results also suggest that listening to music may improve patients' quality of sleep following a cardiac procedure or surgery (SMD = 0.91, 95% CI 0.03 to 1.79, P = 0.04). We found no strong evidence for heart rate variability and depression. Only one study considered hormone levels and quality of life as an outcome variable. A small number of studies pointed to a possible beneficial effect of music on opioid intake after cardiac procedures or surgery, but more research is needed to strengthen this evidence. This systematic review indicates that listening to music may have a beneficial effect on anxiety in persons with CHD, especially those with a myocardial infarction. Anxiety-reducing effects appear to be greatest when people are given a choice of which music to listen to. Furthermore, listening to music may have a beneficial effect on systolic blood pressure, heart rate, respiratory rate, quality of sleep and pain in persons with CHD. However, the clinical significance of these findings is unclear. Since many of the studies are at high risk of bias, these findings need to be interpreted with caution. More research is needed into the effects of music interventions offered by a trained music therapist.
Five trials, with a total of 336 randomised participants, were included. A total of 105 participants (31%) died. Of the five included trials, four (80%) had a high risk of bias. Meta-analysis using all five trials showed that pentoxifylline reduced mortality compared with control (RR 0.64; 95% CI 0.46 to 0.89). However, this result was not supported by trial sequential analysis, which adjusts for multiple testing on accumulating data. Furthermore, four of the five trials were judged to have a high risk of bias, thus risking an overestimated intervention effect. Meta-analysis showed that pentoxifylline reduced the hepatic-related mortality due to hepatorenal syndrome (RR 0.40; 95% CI 0.22 to 0.71), but trial sequential analysis did not support this result. Data from one trial suggests that pentoxifylline may increase the occurrence of serious and non-serious adverse events compared to control. The current available data may indicate a possible positive intervention effect of pentoxifylline on all-cause mortality and mortality due to hepatorenal syndrome, and conversely, an increase in serious and non-serious adverse events. However, the evidence is not firm; no conclusions can be drawn regarding whether pentoxifylline has a positive, negative, or neutral effect on participants with alcoholic hepatitis.
Twelve studies, with a total of 343 participants, met our inclusion criteria (four RCTs and eight before and after non-controlled studies). Of the four RCTs, one examined patients with non-epileptic seizures and three had a mixed diagnosis (pseudoseizures, conversion disorder and somatisation disorder). Most of the non-randomised studies used non-epileptic seizure patients exclusively. Overall, five studies examined the effectiveness of psychotherapy, three examined CBT, two investigated hypnosis, one assessed paradoxical intention and one had a mixed intervention design. We classified two included studies as low risk of bias, one as unclear and nine as high risk of bias. Meta-analysis could not be undertaken due to the heterogeneity of design and interventions. Most included studies reported improved outcomes for the intervention under investigation. One RCT investigating the effectiveness of CBT in this patient group found a significant reduction in seizure frequency compared to controls (P < 0.001). There is little reliable evidence to support the use of any treatment, including CBT, in the treatment of non-epileptic seizures. Further randomised controlled trials of CBT and other interventions are needed.
Sixteen studies met the inclusion criteria, all but one were from Africa, comprising two cluster randomised trials and 14 cohort studies. Antiretroviral therapy started at a hospital and maintained at a health centre (partial decentralisation) probably reduces attrition (RR 0.46, 95% CI 0.29 to 0.71, 4 studies, 39 090 patients, moderate quality evidence). There may be fewer patients lost to care with this model (RR 0.55, 95% CI 0.45 to 0.69, low quality evidence). We are uncertain whether there is a difference in attrition for antiretroviral therapy started and maintained at a health centre (full decentralisation) compared to a hospital at 12 months (RR 0.70, 95% CI 0.47 to 1.02; four studies, 56 360 patients, very low quality evidence), but there are probably fewer patients lost to care with this model (RR 0.3, 95% CI 0.17 to 0.54, moderate quality evidence). When antiretroviral maintenance therapy is delivered at home by trained volunteers, there is probably no difference in attrition at 12 months (RR 0.95, 95% CI 0.62 to 1.46, two trials, 1453 patients, moderate quality evidence). Decentralisation of HIV care aims to improve patient access and retention in care. Most data were from good quality cohort studies but confounding between site of treatment and outcomes cannot be excluded. Nevertheless, this review found that attrition appears to be lower in partial decentralisation models of treatment, where antiretrovirals were started at hospital and continued in the health centre; with antiretroviral drugs started and continued at health centres, no difference in attrition was detected, but there were fewer patients lost to care. For antiretroviral therapy provided at home by trained volunteers, no difference in outcomes were detected when compared to facility-based care.
We included 21 trials, involving 1746 participants, in this update; six trials were new. The included trials did not report the numbers of dead and dependent participants at the end of at least three months' follow-up. Of the 12 trials that reported adverse events, five events occurred in two trials. There was no significant difference between the treatment group and the control group. We assessed 20 trials to be of a poor quality: When analysing these trials together, mailuoning was associated with a significant increase in the number of participants with an improved neurological deficit (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.23 to 0.42) and showed a significant improvement of neurological deficit with the European Stroke Scale (ESS) (mean difference (MD) (fixed) 8.29, 95% CI 3.44 to 13.15). One placebo-controlled trial, assessed to be of a better methodological quality, failed to show a significant improvement of neurological deficit at the end of three months' follow-up (MD (fixed) 2.49, 95% CI -1.45 to 6.43) or in quality of life. One trial, which reported cognitive function using the Montreal Cognitive Assessment as a continuous scale, showed a significant improvement of cognitive function (MD (fixed) 2.68, 95% CI 1.82 to 3.54). Two trials assessed activities of daily life: One trial showed a significant improvement, but the other did not. This review did not provide sufficient evidence to support the routine use of mailuoning for the treatment of people with acute ischaemic stroke. High-quality large-scale randomised controlled trials are needed to confirm the efficacy of mailuoning.
Thirty-four trials were identified which included approximately 19,676 incontinent women of whom 9599 received oestrogen therapy (1464 involved in trials of local vaginal oestrogen administration). Sample sizes of the studies ranged from 16 to 16,117 women. The trials used varying combinations of type of oestrogen, dose, duration of treatment and length of follow up. Outcome data were not reported consistently and were available for only a minority of outcomes. The combined result of six trials of systemic administration (of oral systemic oestrogens) resulted in worse incontinence than on placebo (risk ratio (RR) 1.32, 95% CI 1.17 to 1.48). This result was heavily weighted by a subgroup of women from the Hendrix trial, which had large numbers of participants and a longer follow up of one year. All of the women had had a hysterectomy and the treatment used was conjugated equine oestrogen. The result for women with an intact uterus where oestrogen and progestogen were combined also showed a statistically significant worsening of incontinence (RR 1.11, 95% CI 1.04 to 1.18). There was some evidence that oestrogens used locally (for example vaginal creams or pessaries) may improve incontinence (RR 0.74, 95% CI 0.64 to 0.86). Overall, there were around one to two fewer voids in 24 hours amongst women treated with local oestrogen, and there was less frequency and urgency. No serious adverse events were reported although some women experienced vaginal spotting, breast tenderness or nausea. Women who were continent and received systemic oestrogen replacement, with or without progestogens, for reasons other than urinary incontinence were more likely to report the development of new urinary incontinence in one large study. One small trial showed that women were more likely to have an improvement in incontinence after pelvic floor muscle training (PFMT) than with local oestrogen therapy (RR 2.30, 95% CI 1.50 to 3.52). The data were too few to address questions about oestrogens compared with or in combination with other treatments, different types of oestrogen or different modes of delivery. Urinary incontinence may be improved with the use of local oestrogen treatment. However, there was little evidence from the trials on the period after oestrogen treatment had finished and no information about the long-term effects of this therapy was given. Conversely, systemic hormone replacement therapy using conjugated equine oestrogen may worsen incontinence. There were too few data to reliably address other aspects of oestrogen therapy, such as oestrogen type and dose, and no direct evidence comparing routes of administration. The risk of endometrial and breast cancer after long-term use of systemic oestrogen suggests that treatment should be for limited periods, especially in those women with an intact uterus.
We identified and included one trial (147 women from a pre-planned sample size of 310 women) that compared the effect of prophylactic antibiotic (single-dose, second-generation cephalosporin - cefotetan or cefoxitin, 1 g intravenously) on postpartum perineal wound complications in third- or fourth-degree perineal tears compared with placebo. Perineal wound complications (wound disruption and purulent discharge) at the two-week postpartum check up were 8.20% and 24.10% in the treatment and the control groups respectively (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.12 to 0.96). However, the high failed-appointment rate may limit the generalisability of the results. The overall risk of bias was low except for incomplete outcome data. The quality of the evidence using GRADE was moderate for infection rate at two weeks' postpartum, and low for infection rate at six weeks' postpartum. Although the data suggest that prophylactic antibiotics help to prevent perineal wound complications following third- or fourth-degree perineal tear, loss to follow-up was very high. The results should be interpreted with caution as they are based on one small trial.
We identified six trials eligible for inclusion, of which two are ongoing, and one awaiting classification study. The three included trials were conducted at many different sites in Europe, America, and Asia. All of the three studies recruited adult and elder participants (no children were included) with solid tumours, and compared TPO-RAs with placebo. No studies compared TPO-RAs alone, or in combination with other drugs, to no treatment, or other drugs, or another TPO-RAs. We judged the overall risk of bias as high as we found a high risk for detection bias. We assessed the risk of bias arising from inadequate blinding of outcome assessors as high for number and severity of bleeding episodes (one of the primary outcomes). To prevent CIT: We included two trials (206 participants) comparing TPO-RAs (eltrombopag, multiple-dose oral administration with chemotherapy) with placebo. The use of TPO-RAs may make little or no difference to the all-cause mortality at 33 weeks of follow-up (RR 1.35, 95% CI 0.53 to 3.45; one trial, 26 participants; low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 0.62, 95% CI 0.22 to 1.78; two trials, 206 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (RR 0.36, 95% CI 0.06 to 2.06; two trials, 206 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. To prevent recurrence of CIT: We included one trial (62 participants) comparing TPO-RAs (romiplostim, single-dose subcutaneous administration with chemotherapy) with placebo. There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one bleeding episode of any severity (RR 2.80, 95% CI 0.17 to 47.53; one trial, 62 participants; very low quality of evidence). There is not enough evidence to determine whether TPO-RAs reduce the number of patients with at least one severe/life-threatening bleeding episode (no severe/life-threatening bleeding episodes; one trial, 62 participants; very low quality of evidence). No studies were found that looked at overall survival (one of the primary outcomes), the number of treatment cycles with at least one bleeding episode, the number of days on which bleeding occurred, the amount of bleeding, or quality of life. We found one ongoing study (expected recruitment 74 participants), it is planned to give TPO-RAs (romiplostim, subcutaneous administration with chemotherapy) to participants, but to date this trial has not reported any outcomes. To treat CIT: We found one ongoing study (expected recruitment 83 participants), which is planned to give TPO-RAs (eltrombopag, seven days orally) to participants when their platelet counts are less than 75×109/L during chemotherapy. This trial was originally planned to complete in March 2017, however, the completion date has passed and no results are reported. The one awaiting classification study included patients without thrombocytopenia before chemotherapy (to prevent CIT), patients with thrombocytopenia during chemotherapy (to prevent recurrence of CIT), and other patients during chemotherapy (uncertain whether CIT had happened). There was no evidence for a difference in the number of patients with at least one bleeding episode of any severity (RR 0.27, 95% CI 0.07 to 1.02; one trial, 75 participants). There was no evidence for a difference in the number of patients with at least one severe/life-threatening bleeding episode (RR 0.44, 95% CI 0.03 to 6.77; one trial, 75 participants). This study did not address overall survival or quality of life. No certain conclusions can be drawn due to the lack of strong evidence in the review. The available weak evidence did not support the use of TPO-RAs for preventing CIT or preventing recurrence of CIT in patients with solid tumours. There was no evidence to support the use of TPO-RAs for treating CIT in patients with solid tumours.
We included four trials (3956 women and 3893 neonates) at a moderate risk of bias, comparing prophylactic administration of betamethasone or dexamethasone versus placebo or usual treatment without steroids in term elective caesarean section. Women randomised to treatment group received either two intramuscular doses of betamethasone in the 48 hours before delivery, or intramuscular dexamethasone (two or four doses) prior to delivery (at 37 weeks' gestation or 48 hours before delivery), and were compared to the control group who received a saline placebo or treatment as usual. Prophylactic antenatal corticosteroid administration appeared to decrease the risk of respiratory distress syndrome (RDS) (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.87; 4 studies; 3817 participants; low-quality evidence), transient tachypnoea of the neonate (TTN) (RR 0.43; 95% CI 0.29 to 0.65; 4 studies; 3821 participants; low-quality evidence), admission to the neonatal intensive care unit (NICU) for respiratory morbidity (RR 0.42; 95% CI 0.22 to 0.79; 3 studies; 3441 participants), and admission to neonatal special care (all levels) for respiratory complications (RR 0.45; 95% CI 0.22 to 0.90; 1 study; 942 participants; low-quality evidence). Administration of antenatal corticosteroids also appeared to reduce admission to neonatal special care (RR 0.62; 95% CI 0.43 to 0.89; 2 studies; 2169 participants) and neonatal intensive care (RR 0.14; 95% CI 0.03 to 0.61; 1 study; 452 participants) for any indication, compared to placebo or usual care. Finally, prophylactic antenatal corticosteroids also appeared to reduce the length of stay in NICU by 2.70 days (mean difference (MD) -2.70; 95% CI -2.76 to -2.64; 2 studies; 32 participants). No reduction was found in the need for mechanical ventilation (RR 0.67; 95% CI 0.27 to 1.68; 3 studies; 3441 participants; very-low quality), perinatal death (RR 0.67; 95% CI 0.11 to 4.10; 4 studies; 3893 participants) or neonatal sepsis (RR 1.00; 95% CI 0.06 to 15.95; 2 studies; 2214 participants) . There were no reported events of neonatal respiratory complications (other than RDS and tachypnoea of the newborn (TTN)), chronic lung disease, duration of mechanical ventilation or maternal postpartum infection, therefore results on these outcomes are non-estimable. The studies did not provide data on other pre-defined outcomes. The quality of evidence, as assessed using GRADE was low for the outcomes of RDS, TTN and admission to NICU for respiratory morbidity, indicating that the true effect could potentially be substantially different from our estimate of effect. The results from the four trials are promising, but more high-quality studies with larger sample sizes that are adequately powered to detect the effect of prophylactic antenatal corticosteroids on outcomes of respiratory morbidity are needed, given the potential of the current studies for bias. Consideration should be given to the balance between statistical significance and clinical significance, particularly in view of the low event rates of significant respiratory morbidity (RDS or admission to NICU for respiratory complications) in this population. In addition, further trials on the long-term outcomes of these infants are needed to identify any potential harms and complications of antenatal corticosteroid administration at term.
Sixteen studies with a combined total of 34,369 participants with an acute medical illness were included in this review. We identified 10 studies comparing heparin with placebo or no treatment and six studies comparing LMWH to UFH. Just under half of the studies had an open-label design, putting them at a risk of performance bias. Descriptions of random sequence generation and allocation concealment were missing in most of the studies. Heparin reduced the odds of deep vein thrombosis (DVT) (OR 0.41, 95% CI 0.25 to 0.67; P = 0.0004) . The estimated reductions in symptomatic non-fatal pulmonary embolism (PE) (OR 0.46; 95% CI 0.20 to 1.07; P = 0.07), fatal PE (OR 0.71; 95% CI 0.43 to 1.15; P = 0.16) and in combined non-fatal PE and fatal PE (OR 0.66, 95% CI 0.43 to 1.02; P = 0.06) associated with heparin were imprecise. Heparin resulted in an increase in major haemorrhage (OR 1.65, 95% CI 1.01 to 2.71; P = 0.05). There was no clear evidence that heparin had an effect on all-cause mortality and thrombocytopaenia. Compared with UFH, LMWH reduced the risk of DVT (OR 0.77; 95% CI 0.62 to 0.96; P = 0.02) and major bleeding (OR 0.43; 95% CI 0.22 to 0.83; P = 0.01). There was no clear evidence that the effects of LMWH and UFH differed for the PE outcomes, all-cause mortality and thrombocytopaenia. The data from this review describe a reduction in the risk of DVT in patients presenting with an acute medical illness who receive heparin thromboprophylaxis. This needs to be balanced against an increase in the risk of bleeding associated with thromboprophylaxis. The analysis favoured LMWH compared with UFH, with a reduced risk of both DVT and bleeding.
We screened 926 individual references and identified three studies that satisfied the inclusion criteria. Fifty-nine participants (37 men and 22 women) aged between 54 and 78 years were randomised initially, 47 participants completed the treatment. One study had a parallel design and two had a cross-over design. The studies included people with a variety of cancers and also differed in the dosage, route of administration, frequency and duration of treatment. One trial, which compared ghrelin with placebo, found that ghrelin improved food intake (very low-quality evidence) and had no adverse events (very low-quality evidence). Due to unavailability of data we were unable to report on comparisons for ghrelin versus no treatment or alternative experimental treatment modalities, or ghrelin in combination with other treatments or ghrelin analogues/ghrelin mimetics/ghrelin potentiators. Two studies compared a higher dose of ghrelin with a lower dose of ghrelin, however due to differences in study designs and great diversity in the treatment provided we did not pool the results. In both trials, food intake did not differ between participants on higher-dose and lower-dose ghrelin. None of the included studies assessed data on body weight. One study reported higher adverse events with a higher dose as compared to a lower dose of ghrelin. All studies were at high risk of attrition bias and bias for size of the study. Risk of bias in other domains was unclear or low. We rated the overall quality of the evidence for primary outcomes (food intake, body weight, adverse events) as very low. We downgraded the quality of the evidence due to lack of data, high or unclear risk of bias of the studies and small study size. There is insufficient evidence to be able to support or refute the use of ghrelin in people with cancer cachexia. Adequately powered randomised controlled trials focusing on evaluation of safety and efficacy of ghrelin in people with cancer cachexia is warranted.
The search identified eight trials including 500 participants. Six trials were conducted in the USA and two in Europe. 1. Parenteral nutrition (PN) versus oral nutrition: based on one study with 157 participants, PN may increase postoperative complications within 30 days (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.07 to 1.82; low-quality evidence). We downgraded the quality of evidence for serious study limitations (unclear risk of selection, performance and selective reporting bias) and serious imprecision. This corresponds to 198 more complications per 1000 participants (95% CI 35 more to 405 more). Length of hospital stay may be similar (mean difference (MD) 0.5 days higher, CI not reported; low-quality evidence). 2. Immuno-enhancing nutrition versus standard nutrition: based on one study including 29 participants, immuno-enhancing nutrition may reduce 90-day postoperative complications (RR 0.31, 95% CI 0.08 to 1.23; low-quality evidence). These findings correspond to 322 fewer complications per 1000 participants (95% CI 429 fewer to 107 more). Length of hospital stay may be similar (MD 0.20 days, 95% CI 1.69 lower to 2.09 higher; low-quality evidence). We downgraded the quality of evidence of both outcomes for very serious imprecision. 3. Preoperative oral nutritional support versus normal diet: based on one study including 28 participants, we are very uncertain if preoperative oral supplements reduces postoperative complications. We downgraded quality for serious study limitations (unclear risk of selection, performance, attrition and selective reporting bias) and very serious imprecision. The study did not report on length of hospital stay. 4. Early postoperative feeding versus standard postoperative management: based on one study with 102 participants, early postoperative feeding may increase postoperative complications (very low-quality evidence) but we are very uncertain of this finding. We downgraded the quality of evidence for serious study limitations (unclear risk of selection and performance bias) and very serious imprecision. Length of hospital stay may be similar (MD 0.95 days less, CI not reported; low-quality evidence). We downgraded the quality of evidence for serious study limitations (unclear risk of selection and performance bias) and serious imprecision. 5. Amino acid with dextrose versus dextrose: based on two studies with 104 participants, we are very uncertain whether amino acids reduce postoperative complications (very low-quality evidence). We are also very uncertain whether length of hospital stay is similar (very low-quality evidence). We downgraded the quality of evidence for both outcomes for serious study limitations (unclear and high risk of selection bias; unclear risk of performance, detection and selective reporting bias), serious indirectness related to the patient population and very serious imprecision. 6. Branch chain amino acids versus dextrose only: based on one study including 19 participants, we are very uncertain whether complication rates are similar (very low-quality evidence). We downgraded the quality of evidence for serious study limitations (unclear risk of selection, performance, detection, attrition and selective reporting bias), serious indirectness related to the patient population and very serious imprecision. The study did not report on length of hospital stay. 7. Perioperative oral nutritional supplements versus oral multivitamin and mineral supplement: based on one study with 61 participants, oral supplements compared to a multivitamin and mineral supplement may slightly decrease postoperative complications (low-quality evidence). These findings correspond to 135 fewer occurrences per 1000 participants (95% CI 256 fewer to 65 more). Length of hospital stay may be similar (low-quality evidence). We downgraded the quality of evidence of both outcomes for study limitations and imprecision. Based on few, small and dated studies, with serious methodological limitations, we found limited evidence for a benefit of perioperative nutrition interventions. We rated the quality of evidence as low or very low, which underscores the urgent need for high-quality research studies to better inform nutritional support interventions for people undergoing surgery for bladder cancer.
Fourteen trials with 2647 participants met the inclusion criteria. The interventions included in this review report on agonistic pharmacological interventions (buprenorphine, methadone and naltrexone) compared to no intervention, other non-pharmacological treatments (e.g. counselling) and other pharmacological drugs. The methodological trial quality was poorly described, and most studies were rated as 'unclear' by the reviewers. The biggest threats to risk of bias were generated through blinding (performance and detection bias) and incomplete outcome data (attrition bias). Studies could not be combined all together because the comparisons were too different. Only subgroup analysis for type of pharmacological treatment were done. When compared to non-pharmacological, we found low quality evidence that agonist treatments are not effective in reducing drug use or criminal activity, objective results (biological) (two studies, 237 participants (RR 0.72 (95% CI 0.51 to 1.00); subjective (self-report), (three studies, 317 participants (RR 0.61 95% CI 0.31 to 1.18); self-report drug use (three studies, 510 participants (SMD: -0.62 (95% CI -0.85 to -0.39). We found low quality of evidence that antagonist treatment was not effective in reducing drug use (one study, 63 participants (RR 0.69, 95% CI 0.28 to 1.70) but we found moderate quality of evidence that they significantly reduced criminal activity (two studies, 114 participants, (RR 0.40, 95% CI 0.21 to 0.74). Findings on the effects of individual pharmacological interventions on drug use and criminal activity showed mixed results. In the comparison of methadone to buprenorphine, diamorphine and naltrexone, no significant differences were displayed for either treatment for self report dichotomous drug use (two studies, 370 participants (RR 1.04, 95% CI 0.69 to 1.55), continuous measures of drug use (one study, 81 participants, (mean difference (MD) 0.70, 95% CI -5.33 to 6.73); or criminal activity (one study, 116 participants, (RR 1.25, 95% CI 0.83 to 1.88) between methadone and buprenorphine. Similar results were found for comparisons with diamorphine with no significant differences between the drugs for self report dichotomous drug use for arrest (one study, 825 participants, (RR 1.25, 95% CI 1.03 to 1.51) or naltrexone for dichotomous measures of reincarceration (one study, 44 participants, (RR 1.10, 95% CI 0.37 to 3.26), and continuous outcome measure of crime, (MD -0.50, 95% CI -8.04 to 7.04) or self report drug use (MD 4.60, 95% CI -3.54 to 12.74). When compared to non-pharmacological treatment, agonist treatments did not seem effective in reducing drug use or criminal activity. Antagonist treatments were not effective in reducing drug use but significantly reduced criminal activity. When comparing the drugs to one another we found no significant differences between the drug comparisons (methadone versus buprenorphine, diamorphine and naltrexone) on any of the outcome measures. Caution should be taken when interpreting these findings, as the conclusions are based on a small number of trials, and generalisation of these study findings should be limited mainly to male adult offenders. Additionally, many studies were rated at high risk of bias.
Of 23 eligible trials identified, 22 had been completed and 17 provided results for relevant outcomes. Completed trials comparing interventions for problem drinking to no intervention reported reduced motor-vehicle crashes and related injuries, falls, suicide attempts, domestic violence, assaults and child abuse, alcohol-related injuries and injury emergency visits, hospitalizations and deaths. Reductions ranged from 27% to 65%. Because few trials were sufficiently large to assess effects on injuries, individual effect estimates were generally imprecise. We did not combine the results quantitatively because the interventions, patient populations, and outcomes were so diverse. The most commonly evaluated intervention was brief counseling in the clinical setting. This was studied in seven trials, in which injury-related deaths were reduced: relative risk (RR) 0.65; 95% confidence interval (CI) 0.21 to 2.00. However, this reduction may have been due to chance. The majority of trials of brief counseling also showed beneficial effects on diverse non-fatal injury outcomes. Interventions for problem drinking appear to reduce injuries and their antecedents (e.g. falls, motor vehicle crashes, suicide attempts). Because injuries account for much of the morbidity and mortality from problem drinking, larger studies are warranted to evaluate the effect of treating problem drinking on injuries.
Twelve papers reporting on 10 studies met the inclusion criteria. These studies dealt with the following: working wrist splints (5), resting hand and wrist splints (2), special shoes and insoles (3). There is evidence that wearing wrist splints during work statistically significantly decreases grip strength and does not affect pain, morning stiffness, pinch grip, or quality of life after up to six months of regular wear. We found no evidence that resting wrist and hand splints change pain, grip strength, Ritchie Index, or number of swollen joints. However, participants who wore these splints for two months reported that they preferred use to non-use, and padded resting splints to unpadded ones. The one study of special shoes provided evidence of significant benefits of wearing extra-depth shoes for two months, including less pain on walking and stair climbing, and more minutes of pain free walking time. Extra-depth shoes with semi-rigid insoles provided better pain relief than extra-depth shoes alone when worn over 12 weeks. Supporting insoles prevented progression of hallux valgus angle but did not affect pain or function. There is insufficient evidence to make firm conclusions about the effectiveness of working wrist splints in decreasing pain or increasing function for people with RA. Potential adverse effects, such as decreased range of motion, do not seem to be an issue although some of these splints decrease grip strength and dexterity. Similarly, preliminary evidence suggests that resting hand and wrist splints do not seem to affect range of motion (ROM) or pain, although participants preferred wearing a resting splint to not wearing one. There is evidence that extra-depth shoes and molded insoles decrease pain during weight-bearing activities such as standing, walking, and stair-climbing. Supported insoles may be effective in preventing progression of hallux abductus angle but do not appear to have any impact on pain.
We included 31 trials (8019 participants) in the analysis. In short-term (≤ 6 weeks) trials, pimecrolimus cream was significantly more effective and well-tolerated than vehicle (cream base, but not containing pimecrolimus). In long-term trials (≥ 6 months), pimecrolimus was significantly better than vehicle in preventing flares (9 trials, 3091 participants, RR 1.47, 95% CI 1.32 to 1.64 at six months) and in improving quality of life.   Pimecrolimus was significantly less effective than two topical corticosteroids, i.e. 0.1% triamcinolone acetonide for investigators' global assessment (1 trial, 658 participants, RR 0.75, 95% CI 0.67 to 0.83) and 0.1% betamethasone valerate for participants' global assessment (1 trial, 87 participants, RR 0.61, 95% CI 0.45 to 0.81) at three weeks. Pimecrolimus was also associated with significantly more overall withdrawals and skin burning. None of the trials reported on key adverse effects such as thinning of skin. Pimecrolimus was significantly less effective than 0.1% tacrolimus for investigators' global assessment at 6 weeks (RR 0.58, 95% CI 0.46 to 0.74) and led to more withdrawals due to lack of efficacy (RR 2.37, 95% CI 1.10 to 5.08) based on 2 trials involving 639 participants, but there was no significant difference in proportions of participants experiencing any adverse events. Topical pimecrolimus is less effective than moderate and potent corticosteroids and 0.1% tacrolimus. The therapeutic role of topical pimecrolimus is uncertain due to the absence of key comparisons with mild corticosteroids.
This review included 28 studies. The updated analysis included 6871 randomised women, while the original review had 3643 women. Of the 28 included studies, we considered 19 studies to be at low risk of bias overall; however, some studies failed to report details on allocation concealment and methods of outcome assessment for those outcomes that are more likely to be influenced by a lack of blinding (for example tumour response rate). Studies varied in the taxane-containing chemotherapy backbone, and the comparator arms and were categorised into three groups: Regimen A plus taxane versus Regimen A (2 studies); Regimen A plus taxane versus Regimen B (14 studies); and single-agent taxane versus Regimen C (13 studies). Thirteen studies used paclitaxel, 14 studies used docetaxel, and 1 study allowed the investigator to decide on the type of taxane; the majority of studies delivered a taxane every 3 weeks. Twenty studies administered taxanes as first-line treatment, and 21 studies involved anthracycline naïve women in the metastatic setting. The combined HR for overall survival and time to progression favoured the taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.88 to 0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 5122 events, respectively) with moderate to substantial heterogeneity across trials. If the analyses were restricted to studies of first-line chemotherapy, this effect persisted for overall survival (HR 0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for time to progression (HR 0.96, 95% CI 0.90 to 1.02, P = 0.22). Tumour response rates appeared to be better with taxane-containing chemotherapy in assessable women (RR 1.20, 95% CI 1.14 to 1.27, P < 0.00001) with substantial heterogeneity across studies. Taxanes were associated with an increased risk of neurotoxicity (RR 4.84, 95% CI 3.18 to 7.35, P < 0.00001, 24 studies) and hair loss (RR 2.37, 95% CI 1.45 to 3.87, P = 0.0006, 11 studies) but less nausea/vomiting compared to non-taxane-containing regimens (RR 0.62, 95% CI 0.46 to 0.83, P = 0.001, 26 studies). Leukopaenia and treatment-related death did not differ between the two groups (RR 1.07, 95% CI 0.97 to 1.17, P = 0.16, 28 studies; and RR 1.00, 95% CI 0.63 to 1.57, P = 0.99, 23 studies, respectively). For quality of life measures, none of the individual studies reported a difference in overall or any of quality of life subscales between taxane-containing and non-taxane chemotherapy regimens. Taxane-containing regimens appear to improve overall survival, time to progression, and tumour response rate in women with metastatic breast cancer. Taxanes are also associated with an increased risk of neurotoxicity but less nausea and vomiting compared to non-taxane-containing regimens. The considerable heterogeneity encountered across studies probably reflects the varying efficacy of the comparator regimens used in these studies and indicates that taxane-containing regimens are more effective than some, but not all, non-taxane-containing regimens.
We included 32 studies (21 RCTs and 11 CBAs); 26 of these (16 RCTs and 10 CBAs) were in meta-analyses. More than 50% of the RCTs were judged to have low risk of bias for random selection and incomplete outcome assessment. We judged most RCTS to be unclear for allocation concealment, blinding of outcome assessment, and selective outcome reporting. Because children and parents knew that they were given food, we judged blinding of participants and personnel to be at high risk for all studies. Growth. Supplementary feeding had positive effects on growth in low- and middle-income countries. Meta-analysis of the RCTs showed that supplemented children gained an average of 0.12 kg more than controls over six months (95% confidence interval (CI) 0.05 to 0.18, 9 trials, 1057 participants, moderate quality evidence). In the CBAs, the effect was similar; 0.24 kg over a year (95% CI 0.09 to 0.39, 1784 participants, very low quality evidence). In high-income countries, one RCT found no difference in weight, but in a CBA with 116 Aboriginal children in Australia, the effect on weight was 0.95 kg (95% CI 0.58 to 1.33). For height, meta-analysis of nine RCTs revealed that supplemented children grew an average of 0.27 cm more over six months than those who were not supplemented (95% CI 0.07 to 0.48, 1463 participants, moderate quality evidence). Meta-analysis of seven CBAs showed no evidence of an effect (mean difference (MD) 0.52 cm, 95% CI -0.07 to 1.10, 7 trials, 1782 participants, very low quality evidence). Meta-analyses of the RCTs demonstrated benefits for weight-for-age z-scores (WAZ) (MD 0.15, 95% CI 0.05 to 0.24, 8 trials, 1565 participants, moderate quality evidence), and height-for-age z-scores (HAZ) (MD 0.15, 95% CI 0.06 to 0.24, 9 trials, 4638 participants, moderate quality evidence), but not for weight-for-height z-scores MD 0.10 (95% CI -0.02 to 0.22, 7 trials, 4176 participants, moderate quality evidence). Meta-analyses of the CBAs showed no effects on WAZ, HAZ, or WHZ (very low quality evidence). We found moderate positive effects for haemoglobin (SMD 0.49, 95% CI 0.07 to 0.91, 5 trials, 300 participants) in a meta-analysis of the RCTs. Psychosocial outcomes. Eight RCTs in low- and middle-income countries assessed psychosocial outcomes. Our meta-analysis of two studies showed moderate positive effects of feeding on psychomotor development (SMD 0.41, 95% CI 0.10 to 0.72, 178 participants). The evidence of effects on cognitive development was sparse and mixed. We found evidence of substantial leakage. When feeding was given at home, children benefited from only 36% of the energy in the supplement. However, when the supplementary food was given in day cares or feeding centres, there was less leakage; children took in 85% of the energy provided in the supplement. Supplementary food was generally more effective for younger children (less than two years of age) and for those who were poorer/ less well-nourished. Results for sex were equivocal. Our results also suggested that feeding programmes which were given in day-care/feeding centres and those which provided a moderate-to-high proportion of the recommended daily intake (% RDI) for energy were more effective. Feeding programmes for young children in low- and middle-income countries can work, but good implementation is key.
Thirty-two trials (2281 participants) met our inclusion criteria. Most trials (25) included participants with rotator cuff disease and calcific deposits, five trials included participants with rotator cuff disease and no calcific deposits, and two trials included a mixed population of participants with and without calcific deposits. Twelve trials compared shock wave therapy to placebo, 11 trials compared high-dose shock wave therapy (0.2 mJ/mm² to 0.4 mJ/mm² and above) to low-dose shock wave therapy. Single trials compared shock wave therapy to ultrasound-guided glucocorticoid needling, ultrasound-guided hyaluronic acid injection, transcutaneous electric nerve stimulation (TENS), no treatment or exercise; dual session shock wave therapy to single session therapy; and different delivery methods of shock wave therapy. Our main comparison was shock wave therapy versus placebo and results are reported for the 3 month follow up. All trials were susceptible to bias; including selection (74%), performance (62%), detection (62%), and selective reporting (45%) biases. No trial measured participant-reported pain relief of 30%. However, in one trial (74 participants), at 3 months follow up, 14/34 participants reported pain relief of 50% or greater with shock wave therapy compared with 15/40 with placebo (risk ratio (RR) 1.10, 95% confidence interval (CI) 0.62 to 1.94); low-quality evidence (downgraded for bias and imprecision). Mean pain (0 to 10 scale, higher scores indicate more pain) was 3.02 points in the placebo group and 0.78 points better (0.17 better to 1.4 better; clinically important change was 1.5 points) with shock wave therapy (9 trials, 608 participants), moderate-quality evidence (downgraded for bias). Mean function (scale 0 to 100, higher scores indicate better function) was 66 points with placebo and 7.9 points better (1.6 better to 14 better, clinically important difference 10 points) with shock wave therapy (9 trials, 612 participants), moderate-quality evidence (downgraded for bias). Participant-reported success was reported by 58/150 people in shock wave therapy group compared with 35/137 people in placebo group (RR 1.59, 95% CI 0.87 to 2.91; 6 trials, 287 participants), low-quality evidence (downgraded for bias and imprecision). None of the trials measured quality of life. Withdrawal rate or adverse event rates may not differ between extracorporeal shock wave therapy and placebo, but we are uncertain due to the small number of events. There were 11/34 withdrawals in the extracorporeal shock wave therapy group compared with 13/40 withdrawals in the placebo group (RR 0.75, 95% CI 0.43 to 1.31; 7 trials, 581 participants) low-quality evidence (downgraded for bias and imprecision); and 41/156 adverse events with extracorporeal shock wave therapy compared with 10/139 adverse events in the placebo group (RR 3.61, 95% CI 2.00 to 6.52; 5 trials, 295 participants) low-quality evidence (downgraded for bias and imprecision). Subgroup analyses indicated that there were no between-group differences in pain and function outcomes in participants who did or did not have calcific deposits in the rotator cuff. Based upon the currently available low- to moderate-certainty evidence, there were very few clinically important benefits of shock wave therapy, and uncertainty regarding its safety. Wide clinical diversity and varying treatment protocols means that we do not know whether or not some trials tested subtherapeutic doses, possibly underestimating any potential benefits. Further trials of extracorporeal shock wave therapy for rotator cuff disease should be based upon a strong rationale and consideration of whether or not they would alter the conclusions of this review. A standard dose and treatment protocol should be decided upon before further research is conducted. Development of a core set of outcomes for trials of rotator cuff disease and other shoulder disorders would also facilitate our ability to synthesise the evidence.
One study was included involving 39 participants who received either enzyme replacement therapy with galsulfase (recombinant human arylsulphatase B) or placebo. This small study was considered to be of overall unclear quality, since the authors did not report how both the allocation generation and concealment were performed. The key finding at 24 weeks in the 12-minute walk test was a statistically significant mean difference of 92.00 meters between the two groups in favour of the galsulfase group (95% confidence interval 11.00 to 172.00). While week 24 results for the three-minute stair climb demonstrated some improvement in the treatment group as compared to the placebo group, this was not significant, mean difference 5.70 (95% confidence interval -0.10 to 11.50). A significant decrease in the urinary glycosaminoglycan levels was observed in favour of the galsulfase group at 24 weeks, mean difference -227.00 (95% confidence interval -264.00 to -190.00). In general, the dose of galsulfase was well tolerated and there were no significant differences in relation to adverse events. These events include drug-related adverse events, serious and severe adverse events, those during infusion, drug-related adverse events during infusion, and deaths. More infusion-related reactions were observed in the galsulfase group and were managed with interruption or slowing of infusion rate or administration of antihistamines or corticosteroids drugs. No deaths occurred during the study. The results of one small study (based on 24-week randomised phase of the study and prior to the open-label extension) demonstrated that galsulfase is more effective than placebo in people with MPS VI, with significant improvements in the 12-minute walk test and a reduction in urinary glycosaminoglycans. There were no significant changes in cardiac or pulmonary functions, liver or spleen volume, overnight apnea-hypopnea, height and weight, quality of life and adverse effects. Further studies are needed to obtain more information on the long-term effectiveness and safety of enzyme replacement therapy with galsulfase.
Five retrospective cohort studies (535 women with a diagnosis of GCT) that used appropriate statistical methods for adjustment were included in the review. Two studies, which carried out multivariate analyses that attempted to identify factors associated with better outcomes (in terms of overall survival), reported no apparent evidence of a difference in overall survival between surgical approaches, whether a participant underwent lymphadenectomy or received adjuvant chemotherapy or radiotherapy. Only percentage of survival for all participants combined was reported in two trials and was not reported at all in one study. One study showed that women who received postoperative radiotherapy had lower risk of disease recurrence compared with those who underwent surgery alone (adjusted hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.1 to 0.6, P value 0.04). Three studies reportedthat there was no evidence of differences in disease recurrence based on execution and type of adjuvant chemotherapy or on type of surgery or surgical approach, other than that surgical staging may be important. One study described no apparent evidence of a difference in disease recurrence between fertility-sparing surgery and conventional surgery. Recurrence-free survival was not reported in one study. Toxicity and adverse event data were incompletely reported in the five studies. None of the five studies reported on quality of life (QoL). All studies were at very high risk of bias. One study showed a lower recurrence rate with the use of adjuvant radiotherapy, although this study was at high risk of bias and the results should be interpreted with caution. After evaluating the five small retrospective studies, we are unable to reach any firm conclusions as to the effectiveness and safety of different types and approaches of surgery, including conservative surgery, as well as adjuvant chemotherapy or radiotherapy, for management of GCTs of the ovary. The available evidence is very limited, and the review provides only low-quality evidence. Further research is very likely to have an important impact on our confidence in the estimate of effect and may alter our findings. Ideally, multinational RCTs are needed to answer these questions. The disease is relatively rare and generally has a good prognosis. RCTs are challenging to conduct, but three ongoing trials have been identified, demonstrating that they are feasible, although two of these studies are single-arm trials. The study that may be able to provide answers to the question of which chemotherapeutic regimen should be selected for management of sex cord stromal tumours is an ongoing, randomised, phase 2 study, led by the Gynaecological Oncology Group to compare the efficacy of carboplatin and paclitaxel versus standard BEP. These investigators are also looking into the value of inhibin A and inhibin B as predictive biomarkers. Additional trials are required to assess toxicity and QoL associated with different treatment regimens as well as the safety of conservative surgical options.
We included seven randomised trials with 296 participants. Four trials examined nifedipine and the remainder nicardipine. Comparisons were with placebo in six trials and with both dazoxiben and placebo in one trial (only the nifedipine versus placebo data were used within this review). Treatment with oral calcium channel blockers was minimally effective in primary Raynaud's phenomenon at decreasing the frequency of attacks (standardised mean difference of 0.23; 95% confidence interval (CI) 0.08 to 0.38, P = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on calcium channel blockers compared to placebo. One trial provided details on duration of attacks reporting no statistically significant difference between the nicardipine and placebo groups (no P value reported). Only two trials provided any detail of statistical comparisons of (unvalidated) severity scores between treatment groups: one of these trials (60 participants) reported a mean severity score of 1.55 on placebo and 1.36 on nicardipine, difference 0.2 (95% CI of difference 0 to 0.4, no P value reported) and the other trial (three participants only with primary Raynaud's phenomenon) reported a median severity score of 2 on both nicardipine and placebo treatment (P > 0.999) suggesting little effect on severity. Participant-preference scores were included in four trials, but in only two were results specific to participants with primary Raynaud's phenomenon, and scoring systems differed between trials: scores differed between treatments in only one trial, in which 33% of participants on placebo and 73% on nifedipine reported improvement in symptoms (P < 0.001). Physiological measurements were included as outcome measures in five trials (different methodologies were used in each): none of these trials found any statistically significant between-treatment group differences. Treatment with calcium channel blockers appeared to be associated with a number of adverse reactions, including headaches, flushing and oedema (swelling). Overall, the trials were classed as being at low or unclear risk of bias; and the quality of the evidence presented was moderate for number of attacks, very low for duration of attacks, high for severity scores and low for patient preference scores. The randomised controlled trials included in this review provide moderate quality evidence that oral calcium channel blockers are minimally effective in the treatment of primary Raynaud's phenomenon as measured by the frequency of attacks and high-quality evidence that they have little effect on severity. We are unable to comment on duration of attacks or on patient preference due to the very low and low quality of evidence as a result of small sample sizes in the included studies and the variable data quality of outcome measures.
Six studies met the inclusion criteria, with a total of 334 adult participants. We identified no studies that included children as participants. All studies were affected by high risk of bias due to a lack of blinding of participants and personnel; five studies were affected by high risk of bias for lack of blinding of outcome assessors. There was high or unclear risk of biases affecting some studies across all the Cochrane risk of bias measures. Three studies compared a psychological intervention (either cognitive behaviour therapy or mindfulness-based cognitive therapy) with a control intervention. Data regarding depression symptom outcome measures were combined in a meta-analysis, but did not find an effect in favour of treatment (SMD -0.14; 95% CI -0.47 to 0.19; Z = 0.83; P = 0.41). The other comparisons comprised of single studies of depression symptoms and compared; cognitive behaviour therapy versus supportive psychotherapy (SMD -0.09; 95% CI -0.65 to 0.48; Z = 0.30; P = 0.77); repetitive transcranial magnetic stimulation plus tricyclic antidepressant (rTMS + TCA) versus tricyclic antidepressant alone (SMD -0.84; 95% CI -1.36 to -0.32; Z = 3;19, P = 0.001); and a supervised exercise program versus exercise as usual (SMD -0.43; 95% CI -0.88 to 0.03; Z = 1.84; P = 0.07). There was very-low quality evidence, small effect sizes and wide variability of results, suggesting that no comparisons showed a reliable effect for any intervention. Only one study mentioned minor, transient adverse events from repetitive transcranial magnetic stimulation. The review did not find compelling evidence in favour of any intervention. Future studies should focus on participants with a diagnosed TBI and include only participants who have a diagnosis of depression, or who record scores above a clinical cutoff on a depression measure. There is a need for additional RCTs that include a comparison between an intervention and a control that replicates the effect of the attention given to participants during an active treatment.
Two trials were included this review. One (involving 213 women and 213 neonates) evaluated the impact of Hib vaccination during pregnancy and the other study (involving 2116 women and 2049 neonates) evaluated the impact of viral influenza vaccination during pregnancy. Overall, the HiB vaccination trial was judged to be at 'high risk of bias' due to inadequate randomisation while the other trial was judged to be at 'low risk of bias'. Hib vaccination during pregnancy versus placebo One trial involving 213 women and 213 neonates evaluating the impact of Hib vaccination during pregnancy was included under this comparison. The study did not report on any of this review's prespecified primary outcomes (including mortality, respiratory tract infection and sepsis) or secondary outcomes (including adverse events) except preterm delivery. There was no clear difference between the Hib vaccination and placebo control groups in terms of preterm delivery (risk ratio (RR) 1.28, 95% confidence interval (CI) 0.12 to 13.86, one study, 213 participants), fetal distress (RR 1.23, 95% CI 0.67 to 2.26, one study, 213 infants), intubation (RR 1.03, 95% CI 0.55 to 1.95, one study, 213 infants) and neonatal jaundice (RR 1.01, 95% CI 0.52 to 1.97, one study, 213 infants). We could not grade the evidence for quality due to lack of outcome data. Viral influenza vaccination during pregnancy versus placebo One trial involving 2116 women and 2049 infants evaluating the impact of trivalent inactivated influenza vaccine (IIV3) during pregnancy was included under this comparison. There was no clear difference between the viral influenza and placebo control group in terms of most of this review's primary outcomes: maternal death (RR 4.96, 95% CI 0.24 to 103.24, moderate quality evidence), infant death up to 175 days after birth (RR 0.71, 95% CI 0.37 to 1.37, moderate quality evidence), perinatal death (stillbirth and death in the first week of life) (RR 1.32, 95% CI 0.73 to 2.38, moderate quality evidence), influenza-like illness in women (RR 0.96, 95% CI 0.79 to 1.16) or their babies (RR 1.02, 95% CI 0.94 to 1.09), any respiratory illness in women (RR 0.97, 95% CI 0.91 to 1.04, high quality evidence) or their babies (RR 1.01, 95% CI 0.95 to 1.07, high quality evidence). There were also no clear differences between vaccination and placebo control groups in terms of maternal hospitalisation for any infection (RR 2.27, 95% CI 0.94 to 5.49; 2116 women, moderate quality evidence), and neonatal hospitalisation for sepsis (RR 1.60, 95% CI 0.73 to 3.50; 2049 infants, moderate quality evidence). However, viral influenza vaccination during pregnancy was associated with a reduction in reverse-transcriptase–polymerase-chain-reaction (RT-PCR) confirmed influenza among infants (RR 0.51, 95% CI 0.30 to 0.88, one study, 2049 infants) and women (RR 0.50, 95% CI 0.29 to 0.86, one study, 2116 women). In terms of this review's secondary outcomes, there were no clear differences in terms of the impact on pregnancy outcomes (miscarriage, preterm labour and stillbirth), hospitalisation for respiratory infection among women and infants. Similarly, there was no difference between the viral influenza vaccine and placebo control groups in terms of any adverse systemic reactions. There is limited evidence (from one small trial at a high risk of bias) on the effectiveness on Hib during pregnancy for improving maternal, neonatal and infant health outcomes. Evidence from one large high quality trial on the effectiveness of viral influenza vaccine during pregnancy suggests reduced RT-PCR confirmed influenza among women and their babies, suggesting the potential of this strategy for scale up but further evidence from varying contexts is required. Further trials for both Hib and viral influenza vaccines with appropriate study designs and suitable comparison groups are required. There are currently two 'ongoing' studies - these will be incorporated into the review in future updates.
Only one study was eligible. Chowdhry (1984) enrolled 23 infants < 1250 g and 25 - 28 weeks gestation with transient hypothyroxinaemia (serum total T4 ≤ 4 μg/dl and TSH ≤ 20 IU/L). Infants were randomised to thyroxine 10 μg/kg/day or placebo beginning on day 15 and continuing daily for seven weeks. Chowdhry (1984) reported no neonatal mortality and one infant death in each group prior to discharge. No significant difference was reported in CLD at 28 days or 36 weeks, patent ductus arteriosus, necrotising enterocolitis, retinopathy or prematurity, weight gain, growth in head circumference or length. No significant difference was reported for mean T4 levels between thyroxine and placebo treated infants on day 21, 35, 49, 63 and 77 after birth. Free T4 was not measured. Neurodevelopmental follow up was inadequate to draw any conclusions from. There is insufficient evidence to determine whether use of thyroid hormones for treatment of preterm infants with transient hypothyroxinaemia results in changes in neonatal morbidity and mortality, or reductions in neurodevelopmental impairments. Further research is required.
A total of 1299 references were identified by the searches. After removal of duplicates, 794 references were left. Out of these, two abstract reports of one ongoing randomised trial fulfilled the inclusion criteria of the review. This ongoing trial studies total withdrawal of immunosuppression in patients who receive a calcineurin inhibitor (cyclosporine or tacrolimus) or mycophenolate mofetil as the only immunosuppressive agent. The trial compares withdrawal of calcineurin inhibitor or mycophenolate mofetil with continuation of calcineurin inhibitor or mycophenolate mofetil. However, no trial results on the outcomes of interest to this review were available. This review shows that strategies regarding calcineurin inhibitor minimisation, that is, reduction or withdrawal, without substitution versus continuation of calcineurin inhibitor treatment lack evidence from randomised trials. More research with calcineurin inhibitor reduction and withdrawal regimens is needed to optimise dosing and timing of calcineurin inhibitor treatment in order to achieve optimal patient and graft survival with a minimum of adverse events. Specifically regarding calcineurin inhibitor reduction versus no reduction, we recommend that randomised trials evaluating calcineurin inhibitor reduction versus continuation of calcineurin inhibitor treatment are conducted. Regarding calcineurin inhibitor withdrawal, we recommend that mechanisms for tolerance and 'graft acceptance' are clarified, and patient groups likely to tolerate calcineurin inhibitor withdrawal are identified in order to select the right patients for total withdrawal of calcineurin inhibitors without substitution with another immunosuppressive drug. The randomised trials should only be performed in highly selected patients.
We included18 RCTs (n = 1321 patients). Seven trials were published as full-text papers, and 11 trials only as meeting abstracts. All the included trials had adequate methods of randomization and allocation concealment. The results suggest that, compared with placebo or neostigmine, sugammadex can more rapidly reverse rocuronium-induced neuromuscular blockade regardless of the depth of the block. We identified 2, 4, and 16 mg/kg of sugammadex for reversal of rocuronium-induced neuromuscular blockade at T2 reappearance , 1 to 2 post-tetanic counts, and 3 to 5 minutes after rocuronium, respectively. The number of trials are very limited regarding vecuronium and pancuronium. Serious adverse events occurred in < 1% of all patients who received the medication. There was no significant difference between sugammadex and placebo in terms of the prevalence of drug-related adverse events (RR 1.20, 95% CI 0.61 to 2.37; P = 0.59, I2 = 0%, 5 RCTs). Also, no significant difference was found between sugammadex and neostigmine for adverse events (RR 0.98, 95% CI 0.48 to1.98; P = 0.95, I2 = 43%, 3 RCTs). Sugammadex was shown to be effective in reversing rocuronium-induced neuromuscular blockade. This review has found no evidence of a difference in the instance of unwanted effects between sugammadex, placebo or neostigmine. These results need to be confirmed by future trials on larger patient populations and with more focus on patient-related outcomes.
We included 21 RCTs involving 1755 participants: 18 studies recruited adults (mean age 22 to 41 years); three studies targeted young people (mean age 20 years). Most (75%) participants were male. The studies were at low risk of performance, detection and selective outcome reporting bias. One study was at risk of selection bias, and three studies were at risk of attrition bias. All studies involved comparison of active medication and placebo. The medications were diverse, as were the outcomes reported, which limited the extent of analysis. Abstinence at end of treatment was no more likely with Δ9-tetrahydrocannabinol (THC) preparations than with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.64 to 1.52; 305 participants; 3 studies; moderate-quality evidence). For selective serotonin reuptake inhibitor (SSRI) antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine, there was no difference in the likelihood of abstinence at end of treatment compared to placebo (low- to very low-quality evidence). There was qualitative evidence of reduced intensity of withdrawal symptoms with THC preparations compared to placebo. For other pharmacotherapies, this outcome was either not examined, or no significant differences was reported. Adverse effects were no more likely with THC preparations (RR 1.02, 95% CI 0.89 to 1.17; 318 participants; 3 studies) or N-acetylcysteine (RR 0.94, 95% CI 0.71 to 1.23; 418 participants; 2 studies) compared to placebo (moderate-quality evidence). For SSRI antidepressants, mixed action antidepressants, buspirone and N-acetylcysteine, there was no difference in adverse effects compared to placebo (low- to very low-quality evidence). There was no difference in the likelihood of withdrawal from treatment due to adverse effects with THC preparations, SSRIs antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo (low- to very low-quality evidence). There was no difference in the likelihood of treatment completion with THC preparations, SSRI antidepressants, mixed action antidepressants and buspirone compared to placebo (low- to very low-quality evidence) or with N-acetylcysteine compared to placebo (RR 1.06, 95% CI 0.93 to 1.21; 418 participants; 2 studies; moderate-quality evidence). Anticonvulsants and mood stabilisers appeared to reduce the likelihood of treatment completion (RR 0.66, 95% CI 0.47 to 0.92; 141 participants; 3 studies; low-quality evidence). Available evidence on gabapentin (anticonvulsant), oxytocin (neuropeptide) and atomoxetine was insufficient for estimates of effectiveness. There is incomplete evidence for all of the pharmacotherapies investigated, and for many outcomes the quality of the evidence was low or very low. Findings indicate that SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine are probably of little value in the treatment of cannabis dependence. Given the limited evidence of efficacy, THC preparations should be considered still experimental, with some positive effects on withdrawal symptoms and craving. The evidence base for the anticonvulsant gabapentin, oxytocin, and N-acetylcysteine is weak, but these medications are also worth further investigation.
We identified 11 studies (1172 participants). We assessed seven out of 11 studies as having high overall risk of bias. There was low-quality evidence that MID was associated with worse leg pain than MD/OD at follow-up ranging from six months to two years (e.g. at one year: MD 0.13, 95% CI 0.09 to 0.16), but differences were small (less than 0.5 points on a 0 to 10 scale) and did not meet standard thresholds for clinically meaningful differences. There was low-quality evidence that MID was associated with worse LBP than MD/OD at six-month follow-up (MD 0.35, 95% CI 0.19 to 0.51) and at two years (MD 0.54, 95% CI 0.29 to 0.79). There was no significant difference at one year (0 to 10 scale: MD 0.19, 95% CI -0.22 to 0.59). Statistical heterogeneity was small to high (I2 statistic = 35% at six months, 90% at one year and 65% at two years). There were no clear differences between MID techniques and MD/OD on other primary outcomes related to functional disability (Oswestry Disability Index greater than six months postoperatively) and persistence of motor and sensory neurological deficits, though evidence on neurological deficits was limited by the small numbers of participants in the trials with neurological deficits at baseline. There was just one study for each of the sciatica-specific outcomes including the Sciatica Bothersomeness Index and the Sciatica Frequency Index, which did not need further analysis. For secondary outcomes, MID was associated with lower risk of surgical site and other infections, but higher risk of re-hospitalisation due to recurrent disc herniation. In addition, MID was associated with slightly lower quality of life (less than 5 points on a 100-point scale) on some measures of quality of life, such as some physical subclasses of the 36-item Short Form. Some trials found MID to be associated with shorter duration of hospitalisation than MD/OD, but results were inconsistent. MID may be inferior in terms of relief of leg pain, LBP and re-hospitalisation; however, differences in pain relief appeared to be small and may not be clinically important. Potential advantages of MID are lower risk of surgical site and other infections. MID may be associated with shorter hospital stay but the evidence was inconsistent. Given these potential advantages, more research is needed to define appropriate indications for MID as an alternative to standard MD/OD.
Fifteen studies (2,223,592 participants - 25,008 treated and 2,198,584 untreated) that fulfilled the inclusion criteria for this review were identified from the literature search. The meta-analysis demonstrated that treatment for CIN did not adversely affect the chances of conception. The overall pregnancy rate was higher for treated (43%) versus untreated women (38%; RR 1.29, 95% CI 1.02 to 1.64; 4 studies, 38,050 participants, very low quality), although the inter-study heterogeneity was considerable (P < 0.01). The pregnancy rates in treated and untreated women with an intention to conceive (88% versus 95%, RR 0.93, 95% CI 0.80 to 1.08; 2 studies, 70 participants, very low quality) and the number of women requiring more than 12 months to conceive (14% versus 9%, RR 1.45, 95% CI 0.89 to 2.37; 3 studies, 1348 participants, very low quality) were no different. Although the total miscarriage rate (4.6% versus 2.8%, RR 1.04, 95% CI 0.90 to 1.21; 10 studies, 39,504 participants, low quality) and first trimester miscarriage rate (9.8% versus 8.4%, RR 1.16, 95% CI 0.80 to 1.69, 4 studies, 1103 participants, low quality) was similar for treated and untreated women, CIN treatment was associated with an increased risk of second trimester miscarriage, (1.6% versus 0.4%, RR 2.60, 95% CI 1.45 to 4.67; 8 studies, 2,182,268 participants, low quality). The number of ectopic pregnancies (1.6% versus 0.8%, RR 1.89, 95% CI 1.50 to 2.39; 6 studies, 38,193 participants, low quality) and terminations (12.2% versus 7.4%, RR 1.71, 95% CI 1.31 to 2.22; 7 studies, 38,208 participants, low quality) were also higher in treated women. The results should be interpreted with caution. The included studies were often small with heterogenous design. Most of these studies were retrospective and of low or very low quality (GRADE assessment) and were therefore prone to bias. Subgroup analyses for the individual treatment methods and comparison groups and analysis to stratify for the cone length was not possible. This meta-analysis suggests that treatment for CIN does not adversely affect fertility, although treatment was associated with an increased risk of miscarriage in the second trimester. These results should be interpreted with caution as the included studies were non-randomised and many were of low or very low quality and therefore at high risk of bias. Research should explore mechanisms that may explain the increase in mid-trimester miscarriage risk and stratify this impact of treatment by the length of the cone and the treatment method used.
We included 25 studies involving 10,996 women. Study methods were not well described in many of the included studies and thus assessing risk of bias was difficult. The main limitations of the studies were lack of blinding and high attrition. Studies were mainly funded by international organisations, universities, and ministries of health within the countries. Approximately one third of the included studies did not provide a funding source. Although quality across studies was variable, the results consistently showed that intermittent iron supplementation (alone or with any other vitamins and minerals) compared with no intervention or a placebo, reduced the risk of having anaemia (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.49 to 0.87; 11 studies, 3135 participants; low-quality evidence), and improved the concentration of haemoglobin (mean difference (MD) 5.19 g/L, 95% CI 3.07 to 7.32; 15 studies, 2886 participants; moderate-quality evidence), and ferritin (MD 7.46 μg/L, 95% CI 5.02 to 9.90; 7 studies, 1067 participants; low-quality evidence). Intermittent regimens may also reduce the risk of having iron deficiency (RR 0.50, 95% CI 0.24 to 1.04; 3 studies, 624 participants; low-quality evidence), but evidence was inconclusive regarding iron deficiency anaemia (RR 0.07, 95% CI 0.00 to 1.16; 1 study, 97 participants; very low-quality evidence) and all-cause morbidity (RR 1.12, 95% CI 0.82 to 1.52; 1 study, 119 participants; very low-quality evidence). Women in the control group were less likely to have any adverse side effects than those receiving intermittent iron supplements (RR 1.98, 95% CI 0.31 to 12.72; 3 studies, 630 participants; moderate-quality evidence). In comparison with daily supplementation, results showed that intermittent supplementation (alone or with any other vitamins and minerals) produced similar effects to daily supplementation (alone or with any other vitamins and minerals) on anaemia (RR 1.09, 95% CI 0.93 to 1.29; 8 studies, 1749 participants; moderate-quality evidence). Intermittent supplementation may produce similar haemoglobin concentrations (MD 0.43 g/L, 95% CI −1.44 to 2.31; 10 studies, 2127 participants; low-quality evidence) but lower ferritin concentrations on average (MD −6.07 μg/L, 95% CI −10.66 to −1.48; 4 studies, 988 participants; low-quality evidence) compared to daily supplementation. Compared to daily regimens, intermittent regimens may also reduce the risk of having iron deficiency (RR 4.30, 95% CI 0.56 to 33.20; 1 study, 198 participants; very low-quality evidence). Women receiving iron supplements intermittently were less likely to have any adverse side effects than those receiving iron supplements daily (RR 0.41, 95% CI 0.21 to 0.82; 6 studies, 1166 participants; moderate-quality evidence). No studies reported on the effect of intermittent regimens versus daily regimens on iron deficiency anaemia and all-cause morbidity. Information on disease outcomes, adherence, economic productivity, and work performance was scarce, and evidence about the effects of intermittent supplementation on these outcomes unclear. Overall, whether the supplements were given once or twice weekly, for less or more than three months, contained less or more than 60 mg of elemental iron per week, or given to populations with different degrees of anaemia at baseline did not seem to affect the findings. Furthermore, the response did not differ in areas where malaria was frequent, although very few trials were conducted in these settings. Intermittent iron supplementation may reduce anaemia and may improve iron stores among menstruating women in populations with different anaemia and malaria backgrounds. In comparison with daily supplementation, the provision of iron supplements intermittently is probably as effective in preventing or controlling anaemia. More information is needed on morbidity (including malaria outcomes), side effects, work performance, economic productivity, depression, and adherence to the intervention. The quality of this evidence base ranged from very low to moderate quality, suggesting that we are uncertain about these effects.
Fifteen trials (twelve parallel group studies; three crossover trials recruiting 1422 children (837 males and 585 females)) were included. The studies were generally of good methodological quality. Two large long term studies used nedocromil for six months and four to six years and showed conflicting results in symptom free days. Short term studies (duration between 4 weeks to 12 weeks) showed that nedocromil sodium produced some improvement in a number of efficacy measures compared to placebo including FEV1, FVC, FEV1 % predicted, PC20 FEV1, evening PEF and symptom scores. The parent's assessment of efficacy was in favour of nedocromil (odds ratio (OR) 0.5 (95% CI 0.3 to 0.8). Nedocromil sodium has a good safety profile. The only significant side effect observed was unpleasant taste. There was little evidence for a clinically dose response effect and only a few studies recruited participants with severe asthma. A limited number of small studies have shown that nedocromil is of benefit in improving lung function and some measures of symptoms, but the evidence with regard to the primary outcome of the review was conflicting. Two long-term trials did not show consistent effects on lung function outcomes, whereas several small short-term trials have shown benefit in these outcomes. Differing severities at baseline may explain this difference with milder participants experiencing less benefit, although the discrepancy between study findings may also reflect publication bias. Nedocromil sodium is associated with a very good safety profile with no significant short term or long- term adverse side effects. Although nedocromil may have advantages over inhaled corticosteroids in terms of side effects, there is a need for head to head trials of nedocromil and inhaled corticosteroids to establish whether asthma control is similar, especially in mild asthma. It is not yet clear where nedocromil should sit in relation to other therapies in the treatment of asthma in children.
Two studies (enrolling 118 participants) examined the association between intense hydration and ureteric colic outcomes. There was no significant difference in pain at six hours (1 study, 60 participants: RR 1.06, 95% CI 0.71 to 1.57), surgical stone removal (1 study, 60 participants: RR 1.20, 95% CI 0.41 to 3.51) or manipulation by cystoscopy (1 study, 60 participants: RR 0.67, 95% CI 0.21 to 2.13) when no fluids over six hours was compared to three litres IV fluids administered over a six hour period. There was no difference in stone clearance (1 study 43 participants: RR 1.38, 95% CI 0.50 to 3.84), hourly pain score or patients' narcotic requirements (P > 0.05 for all comparisons) when forced IV hydration of two litres over four hours was compared with minimal IV hydration at 20 mL/hour. One study did not provide any details which would have allowed us to assess any of the risk of bias items (selection, detection, performance, attrition or reporting bias). The second study did not report the method of randomisation or allocation (selection bias - unclear), they reported that the patients were blinded to therapy (low risk of bias), analgesics were administered according to predetermined pain score criteria (low risk), and assessment of stone passage was unlikely to have been biased by knowledge of group assignment (low risk). However the second study also reported a high percentage of participants excluded post randomisation (26%; high risk of bias). We were unable to assess or ascertain any of the other risk of bias items. We found no reliable evidence in the literature to support the use of diuretics and high volume fluid therapy for people with acute ureteric colic. However, given the potential positive therapeutic impact of fluids and diuretics to facilitate stone passage, the capacity of these interventions warrants further investigation to determine safety and efficacy profiles.
Two ITS studies, conducted between 1972 and 1984, met our inclusion criteria for the primary objective, and one study contributed to the quantitative analysis. This study was conducted in India, reported the incidence of malaria in four separate sites, and covered a total population of 18,460 people. In the pooled analysis across sites, there was no step effect for the incidence of uncomplicated malaria (step rate ratio 1.00, 95% confidence interval (CI) 0.51 to 1.92). There was an effect on the slope: the number of cases was reduced by 15% per month (slope rate ratio 0.85, 95% CI 0.79 to 0.91). Using these ratios, we estimated the effect of 12 months of space spraying on malaria incidence to be a reduction from 6 cases to 1 case per month per 1000 population (95% CI 0 to 2 cases, very low-certainty evidence). The second study reported the impact of space spraying on malaria incidence and adult mosquito density in a population of 15,106 in Haiti, but it did not provide data from previous years. Thus, we could not estimate an effect of space spraying that was independent from temporal trends. For the review's secondary objective, we identified a further two studies in addition to the two ITS studies; both used a CBA design and were conducted between 1973 and 2000. The four studies used a range of delivery methods including handheld, vehicle-mounted, and aircraft-mounted spraying equipment. A variety of insecticides, doses, and spraying times were also used, with methods typically determined based on environmental factors and vector profiles. Evidence from one state in India conducted over 30 years ago suggests an effect of space spraying on the incidence of malaria, but the certainty of the evidence is very low. Reliable research in a variety of settings will help establish whether and when this intervention may be worthwhile.
165 trials were reviewed and eight were included; a total of 461 patients have been studied (229 with CBA; 232 with intermittent beta-agonists). Overall, admission to hospital was reduced with CBA compared to intermittent beta-agonists (RR: 0.68; 95% CI: 0.5 to 0.9); patients with severe airway obstruction at presentation appeared to benefit most from this intervention (RR: 0.64; 95% CI: 0.5 to 0.9). Patients receiving CBA demonstrated small but statistically significant improvements in pulmonary function tests when all studies were pooled. Patients receiving CBA had greater improvements in % predicted FEV-1 (SMD: 0.3; 95% CI: 0.03 to 0.5) and PEFR (SMD: 0.33; 95% CI: 0.1 to 0.5); this effect was observed by 2-3 hours. Continuous treatment was generally well tolerated, with no clinically important differences observed in pulse rate (WMD: -2.87; 95% CI: -6.0 to 0.3) or blood pressure (WMD: -1.75; 95% CI: -5.6 to 2.1) between the treatment groups. Tremor was equally common in both groups (OR: 0.81; 95% CI: 0.5 to 1.3) and potassium concentration was unchanged (WMD: 0.02; 95% CI: -0.2 to 0.2). Current evidence supports the use of CBA in patients with severe acute asthma who present to the emergency department to increase their pulmonary functions and reduce hospitalisation. Moreover, CBA treatment appears to be safe and well tolerated in patients who receive it.
We included 17 trials, recruiting 2422 participants, for which outcome data are currently available. Participants tended to be a selected elderly group of stroke survivors with moderate disability. The ESD group showed reductions in the length of hospital stay equivalent to approximately six days (mean difference (MD) -5.5; 95% confidence interval (CI) -3 to -8 days; P < 0.0001; moderate-grade evidence). The primary outcome was available for 16 trials (2359 participants). Overall, the odds ratios (OR) for the outcome of death or dependency at the end of scheduled follow-up (median 6 months; range 3 to 12) was OR 0.80 (95% CI 0.67 to 0.95, P = 0.01, moderate-grade evidence) which equates to five fewer adverse outcomes per 100 patients receiving ESD. The results for death (16 trials; 2116 participants) and death or requiring institutional care (12 trials; 1664 participants) were OR 1.04 (95% CI 0.77 to 1.40, P = 0.81, moderate-grade evidence) and OR 0.75 (95% CI 0.59 to 0.96, P = 0.02, moderate-grade evidence), respectively. Small improvements were also seen in participants' extended activities of daily living scores (standardised mean difference (SMD) 0.14, 95% CI 0.03 to 0.25, P = 0.01, low-grade evidence) and satisfaction with services (OR 1.60, 95% CI 1.08 to 2.38, P = 0.02, low-grade evidence). We saw no clear differences in participants' activities of daily living scores, patients subjective health status or mood, or the subjective health status, mood or satisfaction with services of carers. We found low-quality evidence that the risk of readmission to hospital was similar in the ESD and conventional care group (OR 1.09, 95% CI 0.79 to 1.51, P = 0.59, low-grade evidence). The evidence for the apparent benefits were weaker at one- and five-year follow-up. Estimated costs from six individual trials ranged from 23% lower to 15% greater for the ESD group in comparison to usual care. In a series of pre-planned analyses, the greatest reductions in death or dependency were seen in the trials evaluating a co-ordinated ESD team with a suggestion of poorer results in those services without a co-ordinated team (subgroup interaction at P = 0.06). Stroke patients with mild to moderate disability at baseline showed greater reductions in death or dependency than those with more severe stroke (subgroup interaction at P = 0.04). Appropriately resourced ESD services with co-ordinated multidisciplinary team input provided for a selected group of stroke patients can reduce long-term dependency and admission to institutional care as well as reducing the length of hospital stay. Results are inconclusive for services without co-ordinated multidisciplinary team input. We observed no adverse impact on the mood or subjective health status of patients or carers, nor on readmission to hospital.
We identified 83 publications and 29 were included, representing 15 data sets (475 participants). There was insufficient evidence to confirm or exclude any differences, between CCPT and other airway clearance techniques in terms of respiratory function measured by standard lung function tests. Studies undertaken during acute exacerbations demonstrated relatively large gains in respiratory function irrespective of airway clearance technique. Longer-term studies demonstrated smaller improvements or deterioration over time. Ten studies reported individual preferences for technique, with participants tending to favour self-administered techniques. Heterogeneity in the measurement of preference precluded these data from meta-analysis. This review was unable to demonstrate any advantage of CCPT over other airway clearance techniques in terms of respiratory function, but this may have reflected insufficient evidence rather than real equivalence between methods. There was a trend for participants to prefer self-administered airway clearance techniques. Limitations of this review included a paucity of well-designed, adequately-powered, long-term trials.
Five studies with a total of 105 participants were found to be eligible for inclusion in this review. All included trials were short-term studies (two days or less), measuring immediate effects of the interventions. There was insufficient detail in the reports to assess methods of randomisation and allocation concealment. All five studies were at a high risk of bias from lack of blinding. The studies did not report on mortality, morbidity, quality of life, serious adverse events or any of the other prespecified outcomes. One study was a randomised cross-over trial conducted over two days, in which investigators applied two interventions twice daily in randomly assigned order, with a reverse cross-over the following day. Four studies applied multiple interventions for cough augmentation to each participant, in random order. One study reported fatigue as an adverse effect of MI-E, using a visual analogue scale. Peak cough expiratory flow (PCEF) was the most common outcome measure and was reported in four studies. Based on three studies, MI-E may improve PCEF compared to an unassisted cough. All interventions increased PCEF to the critical level necessary for mucus clearance. The included studies did not clearly show that MI-E improves cough expiratory flow more than other cough augmentation techniques. Based on one study, which was at risk of assessor bias, the addition of MI-E may reduce treatment time when added to a standard airway clearance regimen with manually assisted cough. MI-E appeared to be as well tolerated as other cough augmentation techniques, based on three studies which reported comfort visual analogue scores. The results of this review do not provide sufficient evidence on which to base clinical practice as we were unable to address important short- and long-term outcomes, including adverse effects of MI-E. There is currently insufficient evidence for or against the use of MI-E in people with NMDs. Further randomised controlled clinical trials are needed to test the safety and efficacy of MI-E.
Twenty-one trials, involving 22,129 women were eligible for this review. Four trials did not contribute data. All of the remaining 17 trials assessed vitamin E in combination with vitamin C and/or other agents. Overall the risk of bias ranged from low to unclear to high; 10 trials were judged to be at low risk of bias, six trials to be at unclear risk of bias and five trials to be at high risk of bias. No clear difference was found between women supplemented with vitamin E in combination with other supplements during pregnancy compared with placebo for the risk of stillbirth (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.88 to 1.56, nine studies, 19,023 participants, I² = 0%; moderate quality evidence), neonatal death (RR 0.81, 95% CI 0.58 to 1.13, nine trials, 18,617 participants, I² = 0%), pre-eclampsia (average RR 0.91, 95% CI 0.79 to 1.06; 14 trials, 20,878 participants; I² = 48%; moderate quality evidence), preterm birth (average RR 0.98, 95% CI 0.88 to 1.09, 11 trials, 20,565 participants, I² = 52%; high quality evidence) or intrauterine growth restriction (RR 0.98, 95% CI 0.91 to 1.06, 11 trials, 20,202 participants, I² = 17%; high quality evidence). Women supplemented with vitamin E in combination with other supplements compared with placebo were at decreased risk of having a placental abruption (RR 0.64, 95% CI 0.44 to 0.93, seven trials, 14,922 participants, I² = 0%; high quality evidence). Conversely, supplementation with vitamin E was associated with an increased risk of self-reported abdominal pain (RR 1.66, 95% CI 1.16 to 2.37, one trial, 1877 participants) and term prelabour rupture of membranes (PROM) (average RR 1.77, 95% CI 1.37 to 2.28, two trials, 2504 participants, I² = 0%); however, there was no corresponding increased risk for preterm PROM (average RR 1.27, 95% CI 0.93 to 1.75, five trials, 1999 participants, I² = 66%; low quality evidence). There were no clear differences between the vitamin E and placebo or control groups for any other maternal or infant outcomes. There were no clear differing patterns in subgroups of women based on the timing of commencement of supplementation or baseline risk of adverse pregnancy outcomes. The GRADE quality of the evidence was high for preterm birth, intrauterine growth restriction and placental abruption, moderate for stillbirth and clinical pre-eclampsia, and low for preterm PROM. The data do not support routine vitamin E supplementation in combination with other supplements for the prevention of stillbirth, neonatal death, preterm birth, pre-eclampsia, preterm or term PROM or poor fetal growth. Further research is required to elucidate the possible role of vitamin E in the prevention of placental abruption. There was no convincing evidence that vitamin E supplementation in combination with other supplements results in other important benefits or harms.
Four studies met all of the inclusion criteria (with a total of 40 participants). Three subclasses of anxiety medications were used including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and azapirones. Although two studies used SSRIs as the intervention (total of 21 participants), we were unable to meta-analyse the anxiety outcomes as one study had a standard deviation of zero for the control group. Included studies had relatively poor quality including small sample sizes and short follow-up periods. Due to the small number of included studies, we were unable to meta-analyse all the subclasses of medications. Due to the sub-optimal quality of the trials and statistically non-significant results, it is not possible to draw any conclusions for treatment. This review highlights the paucity of data in this area. As such, there is a need for scientifically rigorous research trials to evaluate the role of pharmacological interventions for anxiety disorders in patients with COPD, using a sample size large enough to demonstrate meaningful clinical significance.
We included 17 studies, with a total of 1025 participants; 12 studies were published (567 patients) and five were unpublished (458 patients). Sixteen studies including 953 people compared betahistine with placebo. All studies with analysable data lasted three months or less. The majority were at high risk of bias, but in some the risk of bias was unclear. One study, at high risk of bias, included 72 people with benign paroxysmal positional vertigo (BPPV) and compared betahistine with placebo; all patients also had particle repositioning manoeuvres. The studies varied considerably in terms of types of participants, their diagnoses, the dose of betahistine and the length of time it was taken for, the study methods and the way any improvement in vertigo symptoms was measured. Using the GRADE system, we judged the quality of evidence overall to be low for two outcomes (proportion of patients with improvement and proportion with adverse events). Pooled data showed that the proportion of patients reporting an overall reduction in their vertigo symptoms was higher in the group treated with betahistine than the placebo group: risk ratio (RR) 1.30, 95% confidence interval (CI) 1.05 to 1.60; 606 participants; 11 studies). This result should be interpreted with caution as the test for statistical heterogeneity as measured by the I2 value was high. Adverse effects (mostly gastrointestinal symptoms and headache) were common but medically serious events in the study were rare and isolated: there was no difference in the frequency of adverse effects between the betahistine and placebo groups, where the rates were 16% and 15% respectively (weighted values, RR 1.03, 95% CI 0.76 to 1.40; 819 participants; 12 studies). Sixteen per cent of patients from both the betahistine and the placebo groups withdrew (dropped out) from the studies (RR 0.96, 95% CI 0.65 to 1.42; 481 participants; eight studies). Three studies looked at objective vestibular function tests as an outcome; the numbers of participants were small, techniques of measurement very diverse and reporting details sparse, so analysis of this outcome was inconclusive. We looked for information on generic quality of life and falls, but none of the studies reported on these outcomes. Low quality evidence suggests that in patients suffering from vertigo from different causes there may be a positive effect of betahistine in terms of reduction in vertigo symptoms. Betahistine is generally well tolerated with a low risk of adverse events. Future research into the management of vertigo symptoms needs to use more rigorous methodology and include outcomes that matter to patients and their families.
Twenty-two studies were included in the review: 16 RCTs, two non-RCTs, one partially randomised trial that contained two randomised intervention arms and one non-randomised control arm, two CBA studies, and one quasi-randomised controlled trial. Seventeen studies provided interventions comprising parenting education and other support services, 15 of which were home visiting programmes and two of which were paediatric practice-based interventions. Two provided solely educational interventions. Nineteen studies recruited families who were from socio-economically disadvantaged populations who were at risk of adverse child outcomes or people who may benefit from extra support, such as single mothers, teenage mothers, first-time mothers, and mothers with learning difficulties. Ten RCTs involving 5074 participants were included in the meta-analysis, which indicated that intervention families had a statistically significant lower risk of injury than control families (RR 0.83, 95% confidence interval (CI) 0.73 to 0.94). Sensitivity analyses undertaken that included only RCTs at low risk of various sources of bias found the findings to be robust to including only those studies at low risk of detection bias in terms of blinded outcome assessment and attrition bias in terms of follow-up of fewer than 80% of participants in each arm. When analyses were restricted to studies at low risk of selection bias in terms of inadequate allocation concealment, the effect size was no longer statistically significant. Several studies found statistically significantly fewer home hazards or a greater number of safety practices in intervention families. Of ten studies reporting scores on the HOME scale, data from three RCTs were included in a meta-analysis, which found no evidence of a difference in quality of the home environment between treatment arms (mean difference 0.57, 95% CI -0.59 to 1.72). Most of the studies reporting home safety practices, home hazards, or composite home safety scores found statistically significant effects favouring intervention arm families. Overall, when Grading of Recommendations Assessment, Development, and Evaluation guidelines (GRADE) were used, the quality of the evidence was rated as moderate. Parenting interventions, most commonly provided within the home using multi-faceted interventions, are effective in reducing child injury. Fairly consistent evidence suggests that they also improve home safety. This evidence relates mainly to interventions provided to families from disadvantaged populations, who are at risk of adverse child health outcomes, or whose families may benefit from extra support. Further research is required to explore mechanisms by which these interventions may reduce injury, to identify the features of parenting interventions that are necessary or sufficient to reduce injury, and to assess the generalisability of these findings to different population groups.
We identified three randomised controlled trials (RCTs) of rhIGF-I, involving 779 participants, for inclusion in the analysis. In a European trial (183 participants) the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08). In a North American trial (266 participants), the MD after nine months was -6.00 (95% CI -10.99 to -1.01). The combined analysis from both RCTs showed a MD after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. There was an increased risk of injection site reactions with rhIGF-I (risk ratio 1.26, 95% CI 1.04 to 1.54). . A second North American trial (330 participants) used a novel primary end point involving manual muscle strength testing. No differences were demonstrated between the treated and placebo groups in this study. All three trials were at high risk of bias. Meta-analysis revealed a significant difference in favour of rhIGF-I treatment; however, the quality of the evidence from the two included trials was low. A third study showed no difference between treatment and placebo. There is no evidence for increase in survival with IGF1. All three included trials were at high risk of bias.
Eighteen trials were included, involving a total of 10,049 participants. Trials differed considerably in their inclusion criteria, outcomes measured, and type of lipid-lowering therapy used. Only one trial (PQRST) reported a detrimental effect of active treatment on blood lipid/lipoprotein levels. The pooled results from all eligible trials indicated that lipid-lowering therapy had no statistically significant effect on overall mortality (Odds Ratio (OR) 0.86; 95% Confidence Interval (CI) 0.49 to 1.50) or on total cardiovascular events (OR 0.8; 95% CI 0.59 to 1.09). However, subgroup analysis which excluded PQRST showed that lipid-lowering therapy significantly reduced the risk of total cardiovascular events (OR 0.74; CI 0.55 to 0.98). This was primarily due to a positive effect on total coronary events (OR 0.76; 95% CI 0.67 to 0.87). Greatest evidence of effectiveness came from the use of simvastatin in people with a blood cholesterol ≥ 3.5 mmol/litre (HPS). Pooling of the results from several small trials on a range of different lipid-lowering agents indicated an improvement in total walking distance (Mean Difference (MD) 152 m; 95% CI 32.11 to 271.88) and pain-free walking distance (WMD 89.76 m; 95% CI 30.05 to 149.47) but no significant impact on ankle brachial index (WMD 0.04; 95% CI -0.01 to 0.09). Lipid-lowering therapy is effective in reducing cardiovascular mortality and morbidity in people with PAD. It may also improve local symptoms. Until further evidence on the relative effectiveness of different lipid-lowering agents is available, use of a statin in people with PAD and a blood cholesterol level ≥ 3.5 mmol/litre is most indicated.
Five trials (612 women) met the inclusion criteria. Only three trials (404 women) provided data that were suitable for analysis. Combined oral contraceptive pill versus placebo Two trials compared COCP with a placebo. These studies were at high risk of bias. For GRADE outcomes (self-reported pain (dysmenorrhoea) at the end of treatment), the quality of the evidence very low. Evidence was downgraded for imprecision as it was based on a single, small trial and for the visual analogue scale data there were wide confidence intervals (CIs). There appeared to have been substantial involvement of the pharmaceutical company funding the trials. Treatment with the COCP was associated with an improvement in self-reported pain at the end of treatment as evidenced by a lower score on the Dysmenorrhoea verbal rating scale (scale 0 to 3) compared with placebo (mean difference (MD) -1.30 points, 95% CI -1.84 to -0.76; 1 RCT, 96 women; very low quality evidence), a lower score on the Dysmenorrhoea visual analogue scale (no details of scale) compared with placebo (MD -23.68 points, 95% CI -28.75 to -18.62, 2 RCTs, 327 women; very low quality evidence) and a reduction in menstrual pain from baseline to the end of treatment (MD 2.10 points, 95% CI 1.38 to 2.82; 1 RCT, 169 women; very low quality evidence). Combined oral contraceptive pill versus medical therapies One underpowered trial compared the COCP with another medical treatment (goserelin). The study was at high risk of bias; the trial was unblinded and there was insufficient detail to judge allocation concealment and randomisation. For GRADE outcomes (self-reported pain (dysmenorrhoea) at the end of treatment), the quality of the evidence ranged from low to very low. At the end of treatment, the women in the goserelin group were amenorrhoeic and therefore no comparisons could be made between the groups for the primary outcome. At six months' follow-up, there was no clear evidence of a difference between women treated with the COCP and women treated with goserelin for measures of dysmenorrhoea on a visual analogue scale (scale 1 to 10) (MD -0.10, 95% CI -1.28 to 1.08; 1 RCT, 50 women; very low quality evidence) or a verbal rating scale (scale 0 to 3) (MD -0.10, 95% CI -0.99 to 0.79; 1 RCT, 50 women; very low quality evidence). At six months' follow-up, there was no clear evidence of a difference between the COCP and goserelin groups for reporting complete absence of pain as measured by the visual analogue scale (risk ratio (RR) 0.36, 95% CI 0.02 to 8.43; 1 RCT, 50 women; very low quality evidence) or the verbal rating scale (RR 1.00, 95% CI 0.93 to 1.08; 1 RCT, 49 women; low quality evidence). Based on the limited evidence from two trials at high risk of bias and limited data for the prespecified outcomes for this review, there is insufficient evidence to make a judgement on the effectiveness of the COCP compared with placebo and the findings cannot be generalised. Based on the limited evidence from one small trial that was at high risk of bias, there is insufficient evidence to make a judgement on the effectiveness of the COCP compared with other medical treatments. Only one comparison was possible, with the medical intervention being goserelin, and the findings cannot be generalised. Further research is needed to fully evaluate the role of COCPs in managing pain-related symptoms associated with endometriosis. There are other formulations of the combined hormonal contraception such as the transdermal patch, vaginal ring or combined injectable contraceptives which this review did not cover but should be considered in future updates.
A total of 2306 references were found from our searches, 61 of which were identified as potential trials comparing surgery and sclerotherapy. However, only nine randomised trials, described in a total of 14 separate papers, fulfilled the inclusion criteria. Fifty trials were excluded and one trial is ongoing and is due for completion in 2004. The trials used a variety of outcome measures and classification systems which made direct comparison between trials difficult. However, the trend was for sclerotherapy to be evaluated as significantly better than surgery at one year; after one year (sclerotherapy resulted in worse outcomes) the benefits with sclerotherapy were less, and by three to five years surgery had better outcomes. The data on cost-effectiveness was not adequately reported. There was insufficient evidence to preferentially recommend the use of sclerotherapy or surgery. There needs to be more research that specifically examines both costs and outcomes for surgery and sclerotherapy.
We identified two small trials (Alexander 1991and Nishikawa 1996 which fulfilled the inclusion criteria, (total n=17, duration 3-6 weeks). Few data were reported and, because of inappropriate use of crossover methodology, we could not include all of the data in this review. For the few chronically ill people in these trials, neither the 'active' tetracycline bacteriostatic agent, oral demeclocycline, nor the opiate antagonist naloxone, nor placebo, gave any suggestion of serious adverse effects for a period of up to six weeks. The studies did not report any useful data on measures of polydipsia, physical symptoms secondary to increased fluid intake, mental state, general functioning or economic outcomes. The trials offer little useful data to the clinician hoping to treat psychosis-related polydipsia with drugs, except that further evaluative studies need to be conducted in this area. Treatment of any sort for psychosis related polydipsia might only be informative within a well designed, conducted and reported randomised study. The two pioneering studies suggest that larger trials, though difficult, would not be impossible with adequate support and co-ordination.
We found 55 trials (163,471 participants) with a median duration of 12 month follow up. Fourteen trials (139,256 participants) with reported clinical event endpoints, the pooled ORs for total and CHD mortality were 1.00 (95% CI 0.96 to 1.05) and 0.99 (95% CI 0.92 to 1.07), respectively. Total mortality and combined fatal and non-fatal cardiovascular events showed benefits from intervention when confined to trials involving people with hypertension (16 trials) and diabetes (5 trials): OR 0.78 (95% CI 0.68 to 0.89) and OR 0.71 (95% CI 0.61 to 0.83), respectively. Net changes (weighted mean differences) in systolic and diastolic blood pressure (53 trials) and blood cholesterol (50 trials) were -2.71 mmHg (95% CI -3.49 to -1.93), -2.13 mmHg (95% CI -2.67 to -1.58 ) and -0.24 mmol/l (95% CI -0.32 to -0.16), respectively. The OR for reduction in smoking prevalence (20 trials) was 0.87 (95% CI 0.75 to 1.00). Marked heterogeneity (I2 > 85%) for all risk factor analyses was not explained by co-morbidities, allocation concealment, use of antihypertensive or cholesterol-lowering drugs, or by age of trial. Interventions using counselling and education aimed at behaviour change do not reduce total or CHD mortality or clinical events in general populations but may be effective in reducing mortality in high-risk hypertensive and diabetic populations. Risk factor declines were modest but owing to marked unexplained heterogeneity between trials, the pooled estimates are of dubious validity. Evidence suggests that health promotion interventions have limited use in general populations.
Six trials involving 159 patients satisfied the inclusion criteria. Data could not be analysed from one trial due to changes in patient numbers and from a second because the data provided were not in a usable format. All trials reported intelligibility measures but a statistically significant result was only reported for the diagnostic rhyme test used in the study of Lee Silverman Voice Treatment -LOUD (LSVT-LOUD) versus a modified version of this therapy (LSVT-ARTIC). In this case a difference of 12.5 points (95% confidence interval (CI) -22.2 to -2.8; P = 0.01) between the mean changes in favour of the LSVT-LOUD group was reported for a speech sample overlaid with Babble noise; this difference was not reproduced for the two additional noise conditions under which the speech samples were assessed. LSVT-LOUD also outperformed LSVT-ARTIC and Respiration therapy (RT) in improving loudness, with a difference in reading a sample text of 5.0 dB (95%CI -8.3 to -1.7; P = 0.003) and 5.5 dB (95% CI 3.4 to 7.7; P < 0.00001) respectively, and a difference in monologue speech of 2.9 dB (95% CI 0.6 to 5.2; P = 0.01) versus RT. Considering the small patient numbers in these trials, there is insufficient evidence to support or refute the efficacy of any form of SLT over another to treat speech problems in patients with Parkinson's disease.
Thirty-four trials (1314 participants) were included: fifteen in the empirical treatment group, fifteen in the ENRD group and four in both. In empirical treatment of GORD the risk ratio (RR) for heartburn remission (the primary efficacy variable) in placebo-controlled trials for PPI was 0.37 (two trials, 95% confidence interval (CI) 0.32 to 0.44), for H2RAs 0.77 (two trials, 95% CI 0.60 to 0.99) and for prokinetics 0.86 (one trial, 95% CI 0.73 to 1.01). In a direct comparison PPIs were more effective than H2RAs (seven trials, RR 0.66, 95% CI 0.60 to 0.73) and prokinetics (two trials, RR 0.53, 95% CI 0.32 to 0.87). In treatment of ENRD, the RR for heartburn remission for PPI versus placebo was 0.71 (ten trials, 95% CI 0.65 to 0.78) and for H2RA versus placebo was 0.84 (two trials, 95% CI 0.74 to 0.95). The RR for PPI versus H2RA was 0.78 (three trials, 95% CI 0.62 to 0.97) and for PPI versus prokinetic 0.72 (one trial, 95% CI 0.56 to 0.92). PPIs are more effective than H2RAs in relieving heartburn in patients with GORD who are treated empirically and in those with ENRD, although the magnitude of benefit is greater for those treated empirically.
Five paediatric (parallel group or cross-over) trials met the inclusion criteria. We considered two (40%) trials to be at a low risk of bias. Four published trials, representing 559 children (aged ≥ six years) and adolescents with mild to moderate asthma, contributed data to the review. No trial enrolled preschoolers. All trials used montelukast as the anti-leukotriene agent administered for between four and 16 weeks. Three trials evaluated the combination of anti-leukotrienes and ICS compared to the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (N = 268 participants; risk ratio (RR) 0.80, 95% confidence interval (CI) 0.34 to 1.91). There was also no statistically significant difference in percentage change in FEV₁ (forced expiratory volume in 1 second) with mean difference (MD) 1.3 (95% CI -0.09 to 2.69) in this trial, but a significant group difference was observed in the morning (AM) and evening (PM) peak expiratory flow rates (PEFR): N = 218 participants; MD 9.70 L/min (95% CI 1.27 to 18.13) and MD 10.70 (95% CI 2.41 to 18.99), respectively. One trial compared the combination of anti-leukotrienes and ICS to a higher-dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over 16 weeks (N = 182 participants; RR 0.82, 95% CI 0.54 to 1.25), nor was there any significant difference in exacerbations requiring hospitalisation. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding anti-leukotrienes as a means to taper the dose of ICS. The addition of anti-leukotrienes to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although anti-leukotrienes have been licensed for use in children for over 10 years, the paucity of paediatric trials, the absence of data on preschoolers, and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of anti-leukotrienes as add-on therapy to ICS as a step-3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS.
We included 26 studies with 526 participants. We assessed the studies as being at high or unclear risk of bias overall. We only included randomised controlled trials (RCTs), although the description of randomisation was incomplete in some included studies. We aimed to include double blind RCTs, but two studies were only single blinded. There was inconsistency in the reporting of outcome measures. We analysed the data using a fixed-effect model, and for some outcomes heterogeneity was high. There was a risk of imprecise results due to the low numbers of participants in the included studies. For these reasons we downgraded the quality of the evidence from high to either low or very low. For the primary outcome of breathlessness, the standardised mean post-treatment dyspnoea score was 0.32 points better in the opioid group compared to the placebo group (ranging from a 0.53 point reduction to a 0.10 point reduction) (12 RCTs, 338 participants, low quality evidence). The standardised mean change from baseline dyspnoea score was 0.11 points better in the opioids group compared to the placebo group (ranging from a 0.40 point reduction to a 0.19 increase) (six RCTs, 194 participants, very low quality evidence). A lower score indicates an improvement in breathlessness. The evidence for the six-minute walk test (6MWT) was conflicting. The total distance in 6MWT was 28 metres (m) better in the opioids group compared to placebo (ranging from 113 m to 58 m) (one RCT, 11 participants, very low quality evidence). However, the change in baseline was 48 m worse in the opioids group (ranging from 36 m to 60 m) (two RCTs, 26 participants, very low quality evidence). The adverse effects reported included drowsiness, nausea and vomiting, and constipation. In those studies, participants were 4.73 times more likely to experience nausea and vomiting compared to placebo, three times more likely to experience constipation, and 2.86 times more likely to experience drowsiness (nine studies, 162 participants, very low quality evidence). Only four studies assessed quality of life, and none demonstrated any significant change. There is some low quality evidence that shows benefit for the use of oral or parenteral opioids to palliate breathlessness, although the number of included participants was small. We found no evidence to support the use of nebulised opioids. Further research with larger numbers of participants, using standardised protocols and with quality of life measures included, is needed.
We identified two RCTs that fulfilled our inclusion criteria. The two trials tested different comparisons. One multi-institutional RCT included 130 participants and compared hyperfractionated radiotherapy (six-week course with twice a day treatment of 117 cGy per fraction to a total dose of 7020 cGy) with conventional radiotherapy (six-week course with once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy). The median time overall survival (OS) was 8.5 months in the conventional group and 8.0 months in the hyperfractionated group. We detected no clear evidence of effect on OS or event-free survival (EFS) in participants receiving hyperfractionated radiotherapy compared with conventional radiotherapy (OS: hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.75 to 1.53; EFS: HR 1.26, 95% CI 0.83 to 1.90). Radiological response (risk ratio (RR) 0.94, 95% CI 0.54 to 1.63) and various types of toxicities were similar in the two groups. There was no information on other outcomes. According to the GRADE approach, we judged the quality of evidence to be low (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate) for OS and EFS, and very low (i.e. we are very uncertain about the estimate) for radiological response and toxicities. The second RCT included 71 participants and compared hypofractionated radiotherapy (39 Gy in 13 fractions over 2.6 weeks, 3 Gy per fraction) with conventional radiotherapy (54 Gy in 30 fractions over six weeks, 1.8 Gy per fraction). This trial reported a median OS of 7.8 months for the hypofractionated group and 9.5 months for the conventional group. It reported a progression-free survival (PFS) of 6.3 months for the hypofractionated group and 7.3 months for the conventional group. We found no clear evidence of effect on OS (HR 1.03, 95% CI 0.53 to 2.01) or PFS (HR 1.19, 95% CI 0.63 to 2.22) in participants receiving hypofractionated radiotherapy when compared with participants receiving conventional radiotherapy. The mainly observed adverse effect was local erythema and dry desquamation especially behind the auricles. There were some other toxicities, but there was no statistically significant difference between treatment groups. There was no information on other outcomes. We judged the quality of evidence to be moderate (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) for OS, and low for PFS and toxicities. It should be mentioned that the sample size in this RCT was small, which could lead to insufficient statistical power for a clinically relevant outcome. We could make no definitive conclusions from this review based on the currently available evidence. Further research is needed to establish the role of radiotherapy in the management of newly diagnosed diffuse brainstem glioma in children and young adults. Future RCTs should be conducted with adequate power and all relevant outcomes should be taken into consideration. Moreover, international multicentre collaboration is encouraged. Considering the potential advantage of hypofractionated radiotherapy to decrease the treatment burden and increase the quality of remaining life, we suggest that more attention should be paid to hypofractionated radiotherapy.
The four included studies involved 163 participants, mainly active young adult males. All had had a primary (first time) traumatic anterior shoulder dislocation. Methodological quality was variable. All participants of one trial returned to active military duty. Two trials respectively reported similar numbers with reduced sports participation or non return to previous activities. The other, an inadequately reported, trial found significantly fewer people in the surgical group failed to attain previous levels of sports activity. Pooled results from all four trials showed that subsequent instability, either redislocation or subluxation, was statistically significantly less frequent in the surgical group (risk ratio 0.25, 95% confidence interval 0.14 to 0.44). This result remained statistically significant (risk ratio 0.32, 95% confidence interval 0.17 to 0.59) for the three trials reported in full. Half (17/33) of the conservatively treated patients with shoulder instability in these three trials opted for subsequent surgery. Different, mainly patient rated, functional assessment measures for the shoulder were recorded in these trials. The results were more favourable, usually statistically significantly so, in those treated surgically. The only complication reported was a septic joint in a surgically treated patient. There was no information on shoulder pain, long-term complications or resource use. Limited evidence supports primary surgery for young adults, usually male, engaged in highly demanding physical activities who have sustained their first acute traumatic shoulder dislocation. There is no evidence available to determine which treatment is better for other patient groups. Sufficiently powered, good quality, well reported randomised trials are required that compare surgical treatment with conservative treatment for these injuries, including in people at lower risk of recurrence. Long-term surveillance of outcome, looking at shoulder disorders including osteoarthritis is also required.
Three studies qualified for inclusion in this review (Khilnani 1991; Loisel 1996; Soupre 1998). There was a decrease in the ML-UVCs group in the number of additional PIVs used in the first week of life [WMD -1.42, (95% CI -1.74, -1.10), p<0.00001, number of infants (n) = 99]. There was no significant effect on the number of additional PIVs used in the first four weeks of life [MD -2.30, (95% CI -6.65, 2.05), n=36]. There was an increase in catheter malfunction in the ML-UVCs group [typical RR 3.69 (95% CI 0.99, 13.81), p=0.05; RD 0.15 (95% CI 0.03, 0.27), p=0.01; NNH was 7, 95% CI 4, 33; n=99]. The following outcomes were not significantly different in the two groups: clinical sepsis, catheter related blood stream infection, catheter-associated thrombosis, complications related to catheter malposition in heart and great vessels, NEC and early neonatal mortality. The use of ML-UVCs in comparison to SL-UVCs in neonates is associated with decrease in the usage of PIVs in first week of life, but an increase in catheter malfunctions. As the quality of included randomized studies is poor and the estimates of clinically important complications are imprecise, no firm recommendations can be made regarding the choice of UVC. Adequately powered, properly randomized and properly blinded controlled trials are needed that address the effectiveness and safety of ML-UVCs (double and triple lumen) in comparison to SL-UVCs. These studies should also address the impact of type of catheter material.
Thirteen trials involving 2914 women were included, of whom 2494 were included in the analysis. Oil-soluble contrast media (OSCM) versus no intervention The OSCM group had a higher rate of live birth (odds ratio (OR) 3.09, 95% CI 1.39 to 6.91, 1 RCT, 158 women, low quality evidence) and ongoing pregnancy (OR 3.59, 95% CI 2.06 to 6.26, 3 RCTs, 382 women, I2 = 0%, low quality evidence) than women who had no intervention. Our findings suggest that among subfertile women with a 17% chance of an ongoing pregnancy if they have no intervention, the rate will increase to between 29% and 55% if they have tubal flushing with OSCM. Water-soluble contrast media (WSCM) versus no intervention There was no evidence of a difference between the groups in rates of live birth (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, very low quality evidence) or ongoing pregnancy (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, very low quality evidence). OSCM versus WSCM Two RCTs reported live birth: one found a higher live birth rate in the oil-soluble group and the other found no evidence of a difference between the groups. These studies were not pooled due to very high heterogeneity (I2 = 93%). There was no evidence of a difference between the groups in rates of ongoing pregnancy, however there was high heterogeneity (OR 1.44, 95% CI 0.84 to 2.47, 5 RCTs, 1454 women, I2 = 76%, random-effects model, very low quality evidence). OSCM plus WSCM versus WSCM alone There was no evidence of a difference between the groups in rates of live birth (OR 1.06, 95% CI 0.64 to 1.77, 1 RCT, 393 women, very low quality evidence) or ongoing pregnancy (OR 1.23, 95% CI 0.87 to 1.72, 4 RCTs, 633 women, I2 = 0%, low quality evidence). There was no evidence of a difference between any of the interventions in rates of adverse events, but such events were poorly reported in most studies. The evidence suggests that tubal flushing with oil-soluble contrast media may increase the chance of pregnancy and live birth compared to no intervention. Findings for other comparisons were inconclusive due to inconsistency and lack of statistical power. There was insufficient evidence on adverse events to reach firm conclusions. Further robust randomised controlled trials are needed.
Nine trials (1752 women) were included. Analyses of all included trials showed a significant reduction in the rates of all grades of PVH (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.50 to 0.83; nine trials; 1591 women) and severe grades PVH (3 and 4) (RR 0.41, 95% CI 0.20 to 0.85; eight trials; 1527 women) in infants whose mothers had been given prenatal phenobarbital. These results were influenced by trials of poor quality which contributed excessive weight in the analysis due to their higher rates of severe PVH. When only the two higher quality trials were included, these beneficial effects disappeared for all grades of PVH (RR 0.90, 95% CI 0.75 to 1.08; two trials; 945 women), and severe grades of PVH (RR 1.05, 95% CI 0.60 to 1.83; two trials; 945 women). No difference was found in the incidence of neurodevelopmental abnormalities at paediatric follow up at 18 to 24 months or seven years of age between children born to mothers given prenatal phenobarbital and children not so exposed.   Maternal sedation was more likely in women receiving phenobarbital (RR 2.06, 95% CI 1.79 to 2.37; one trial; 576 women). The evidence in this review does not support the use of prophylactic maternal phenobarbital administration to prevent PVH in preterm infants or to protect them from neurological disability in childhood. Phenobarbital administration may lead to maternal sedation. If any future trials are carried out, they should measure neurodevelopmental status at follow up.
The one included trial, in which 258 participants were randomized, was stopped early for futility. At the time of the 24-month report the follow-up rate was 95.3% for six months and 67.4% for 24 months (174 participants; 89 careful follow-up and 85 surgery). There was no evidence of a benefit of surgery on visual acuity. Measurements of visual acuity and visual fields were performed by a technician masked to the treatment received. At six months 32.0% of the surgery group had improved visual acuity by 3 or more lines compared with 42.6% of the careful follow-up group (unadjusted risk ratio (RR) 0.75, 95% confidence interval (CI) 0.54 to 1.04). At 24 months 29.4% of the surgery group had improved compared with 31.0% of the careful follow-up group (unadjusted RR 0.95, 95% CI 0.60 to 1.49). Participants who underwent surgery more often lost 3 or more lines of visual acuity in the study eye, although the increased risk was not statistically significant. At six months 18.9% in the surgery group had worsened visual acuity in the study eye compared with 14.8% in the careful follow-up group (RR 1.28; 95% CI 0.73 to 2.24). At 24 months 20.0% in the surgery group had worsened visual acuity in the study eye compared with 21.8% in the careful follow-up group (RR 0.92; 95% CI 0.51 to 1.64). Participants who received surgery experienced both intraoperative and postoperative adverse events, including central retinal artery occlusion during surgery and light perception vision at six months (one participant); and immediate loss of light perception following surgery and loss of vision that persisted to the 12-month visit (two participants). In the careful follow-up group, two participants had no light perception at the six-month follow-up visit; one of these had improved to light perception at 12 months. Pain was the most common adverse event in the surgery group (17% in surgery group versus 3% in the careful follow-up group at one week). Diplopia (double vision) was the next most common complication (8% in the surgery group versus 1% in the careful follow-up group at one week); at three months there was no statistically significant difference in proportion of participants with diplopia between the two groups. The only eligible trial provided no evidence of a beneficial effect of optic nerve decompression surgery for NAION. Future research should focus on increasing our understanding of the etiology and prognosis of NAION. New treatment options should be examined in the context of randomized clinical trials.
We included seven studies that involved a total of 444 adults with distal femur fractures. Each of the included studies was small and assessed to be at substantial risk of bias, with four studies being quasi-randomised and none of the studies using blinding in outcome assessment. All studies provided an incomplete picture of outcome. Based on GRADE criteria, we assessed the quality of the evidence as very low for all reported outcomes, which means we are very uncertain of the reliability of these results. One study compared surgical (dynamic condylar screw (DCS) fixation) and non-surgical (skeletal traction) treatment in 42 older adults (mean age 79 years) with displaced fractures of the distal femur. This study, which did not report on PROMs, provided very low quality evidence of little between-group differences in adverse events such as death (2/20 surgical versus 1/20 non-surgical), re-operation or repeat procedures (1/20 versus 3/20) and other adverse effects including delayed union. However, while none of the findings were statistically significant, there were more complications such as pressure sores (0/20 versus 4/20) associated with prolonged immobilisation in the non-surgical group, who stayed on average one month longer in hospital. The other six studies compared different surgical interventions. Three studies, including 159 participants, compared retrograde intramedullary nail (RIMN) fixation versus DCS or blade-plate fixation (fixed-angle devices). None of these studies reported PROMS relating to function. None of the results for the reported adverse events showed a difference between the two implants. Thus, although there was very low quality evidence of a higher risk of re-operation in the RIMN group, the 95% confidence interval (CI) also included the possibility of a higher risk of re-operation for the fixed-angle device (9/83 RIMN versus 4/96 fixed-angle device; 3 studies: RR 1.85, 95% CI 0.62 to 5.57). There was no clinically important difference between the two groups found in quality of life assessed using the 36-item Short Form in one study (23 fractures). One study (18 participants) provided very low quality evidence of there being little difference in adverse events between RIMN and non-locking plate fixation. One study (53 participants) provided very low quality evidence of a higher risk of re-operation after locking plate fixation compared with a single fixed-angle device (6/28 locking plate versus 1/25 fixed-angle device; RR 5.36, 95% CI 0.69 to 41.50); however, the 95% CI also included the possibility of a higher risk of re-operation for the fixed-angle device. Neither of these trials reported on PROMs. The largest included study, which reported outcomes in 126 participants at one-year follow-up, compared RIMN versus locking plate fixation; both implants are commonly used in current practice. None of the between-group differences in the reported outcomes were statistically significant; thus the CIs crossed the line of no effect. There was very low quality evidence of better patient-reported musculoskeletal function in the RIMN group based on Short Musculoskeletal Function Assessment (0 to 100: best function) scores (e.g. dysfunction index: MD -5.90 favouring RIMN, 95% CI -15.13 to 3.33) as well as quality of life using the EuroQoL-5D Index (0 to 1: best quality of life) (MD 0.10 favouring RIMN, 95% CI -0.01 to 0.21). The CIs for both results included a clinically important effect favouring RIMN but also a clinically insignificant effect in favour of locking plate fixation. This review highlights the major limitations of the available evidence concerning current treatment interventions for fractures of the distal femur. The currently available evidence is incomplete and insufficient to inform current clinical practice. Priority should be given to a definitive, pragmatic, multicentre randomised controlled clinical trial comparing contemporary treatments such as locked plates and intramedullary nails. At minimum, these should report validated patient-reported functional and quality-of-life outcomes at one and two years. All trials should be reported in full using the CONSORT guidelines.
We included 48 studies that involved 4937 participants and covered three types of programme: behavioural, cognitive-behavioural and multimodal. Overall, we found that group-based parenting programmes led to statistically significant short-term improvements in depression (standardised mean difference (SMD) -0.17, 95% confidence interval (CI) -0.28 to -0.07), anxiety (SMD -0.22, 95% CI -0.43 to -0.01), stress (SMD -0.29, 95% CI -0.42 to -0.15), anger (SMD -0.60, 95% CI -1.00 to -0.20), guilt (SMD -0.79, 95% CI -1.18 to -0.41), confidence (SMD -0.34, 95% CI -0.51 to -0.17) and satisfaction with the partner relationship (SMD -0.28, 95% CI -0.47 to -0.09). However, only stress and confidence continued to be statistically significant at six month follow-up, and none were significant at one year. There was no evidence of any effect on self-esteem (SMD -0.01, 95% CI -0.45 to 0.42). None of the trials reported on aggression or adverse effects. The limited data that explicitly focused on outcomes for fathers showed a statistically significant short-term improvement in paternal stress (SMD -0.43, 95% CI -0.79 to -0.06). We were unable to combine data for other outcomes and individual study results were inconclusive in terms of any effect on depressive symptoms, confidence or partner satisfaction. The findings of this review support the use of parenting programmes to improve the short-term psychosocial wellbeing of parents. Further input may be required to ensure that these results are maintained. More research is needed that explicitly addresses the benefits for fathers, and that examines the comparative effectiveness of different types of programme along with the mechanisms by which such programmes bring about improvements in parental psychosocial functioning.
We identified three short-term trials (total of 156 participants, duration five to 12 weeks). Outcomes were prone to at least a moderate risk of overestimating positive effects. We found that virtual reality had little effects regarding compliance (3 RCTs, n = 156, RD loss to follow-up 0.02 CI -0.08 to 0.12, low quality evidence), cognitive functioning (1 RCT, n = 27, MD average score on Cognistat 4.67 CI -1.76 to 11.10, low quality evidence), social skills (1 RCT, n = 64, MD average score on social problem solving SPSI-R (Social Problem Solving Inventory - Revised) -2.30 CI -8.13 to 3.53, low quality evidence), or acceptability of intervention (2 RCTs, n = 92, RD 0.05 CI -0.09 to 0.19, low quality evidence). There were no data reported on mental state, insight, behaviour, quality of life, costs, service utilisation, or adverse effects. Satisfaction with treatment - measured using an un-referenced scale - and reported as "interest in training" was better for the virtual reality group (1 RCT, n = 64, MD 6.00 CI 1.39 to 10.61,low quality evidence). There is no clear good quality evidence for or against using virtual reality for treatment compliance among people with serious mental illness. If virtual reality is used, the experimental nature of the intervention should be clearly explained. High-quality studies should be undertaken in this area to explore any effects of this novel intervention and variations of approach.
The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants. The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue. The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published.
We identified 10 randomised placebo-controlled trials involving 3541 participants with hip or knee osteoarthritis. The paracetamol dose varied from 1.95 g/day to 4 g/day, and the majority of trials followed participants for three months only. Most trials did not clearly report randomisation and concealment methods and were at unclear risk of selection bias. Trials were at low risk of performance, detection, and reporting bias. At 3 weeks' to 3 months' follow-up, there was high-quality evidence that paracetamol provided no clinically important improvements in pain and physical function. Mean reduction in pain was 23 points (0 to 100 scale, lower scores indicated less pain) with placebo and 3.23 points better (5.43 better to 1.02 better) with paracetamol, an absolute reduction of 3% (1% better to 5% better, minimal clinical important difference 9%) and relative reduction of 5% (2% better to 8% better) (seven trials, 2355 participants). Physical function improved by 12 points on a 0 to 100 scale (lower scores indicated better function) with placebo and was 2.9 points better (0.95 better to 4.89 better) with paracetamol, an absolute improvement of 3% (1% better to 5% better, minimal clinical important difference 10%) and relative improvement of 5% (2% better to 9% better) (7 trials, 2354 participants). High-quality evidence from eight trials indicated that the incidence of adverse events was similar between groups: 515/1586 (325 per 1000) in the placebo group versus 537/1666 (328 per 1000, range 299 to 360) in the paracetamol group (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.92 to 1.11). There was less certainty (moderate-quality evidence) around the risk of serious adverse events, withdrawals due to adverse events, and the rate of abnormal liver function tests, due to wide CIs or small event rates, indicating imprecision. Seventeen of 1480 (11 per 1000) people treated with placebo and 28/1729 (16 per 1000, range 8 to 29) people treated with paracetamol experienced serious adverse events (RR 1.36, 95% CI 0.73 to 2.53; 6 trials). The incidence of withdrawals due to adverse events was 65/1000 participants in with placebo and 77/1000 (range 59 to 100) participants with paracetamol (RR 1.19, 95% CI 0.91 to 1.55; 7 trials). Abnormal liver function occurred in 18/1000 participants treated with placebo and 70/1000 participants treated with paracetamol (RR 3.79, 95% CI 1.94 to 7.39), but the clinical importance of this effect was uncertain. None of the trials reported quality of life. Subgroup analyses indicated that the effects of paracetamol on pain and function did not differ according to the dose of paracetamol (3.0 g/day or less versus 3.9 g/day or greater). Based on high-quality evidence this review confirms that paracetamol provides only minimal improvements in pain and function for people with hip or knee osteoarthritis, with no increased risk of adverse events overall. Subgroup analysis indicates that the effects on pain and function do not differ according to the dose of paracetamol. Due to the small number of events, we are less certain if paracetamol use increases the risk of serious adverse events, withdrawals due to adverse events, and rate of abnormal liver function tests. Current clinical guidelines consistently recommend paracetamol as the first-line analgesic medication for hip or knee osteoarthritis, given its low absolute frequency of substantive harm. However, our results call for reconsideration of these recommendations.
We included 25 studies with a total of 2488 participants. Our primary outcome 'symptoms rated by participant or medical practitioner or proportion symptom-free' was commonly reported. No two trials examined the same drugs, therefore we grouped similar types of drugs together. Macrolides/streptogramins were found to be more effective than penicillin antibiotics (Risk ratio (RR) 0.84, 95% CI 0.73 to 0.97). In 3 trials involving 419 people, 2 of these studies used oral macrolide against intravenous (iv) penicillin demonstrating that oral therapies can be more effective than iv therapies (RR 0.85, 95% CI 0.73 to 0.98). Three studies with a total of 88 people comparing a penicillin with a cephalosporin showed no difference in treatment effect (RR 0.99, 95% CI 0.68 to 1.43). Six trials which included 538 people that compared different generations of cephalosporin, showed no difference in treatment effect (RR 1.00, 95% CI 0.94 to1.06). We found only small single studies for duration of antibiotic treatment, intramuscular versus intravenous route, the addition of corticosteroid to antibiotic treatment compared with antibiotic alone, and vibration therapy, so there was insufficient evidence to form conclusions. Only two studies investigated treatments for severe cellulitis and these selected different antibiotics for their comparisons, so we cannot make firm conclusions. We cannot define the best treatment for cellulitis and most recommendations are made on single trials. There is a need for trials to evaluate the efficacy of oral antibiotics against intravenous antibiotics in the community setting as there are service implications for cost and comfort.
We included 128 trials with 8754 participants in the review, and 94 trials with 5846 participants in the analysis. Trials included in the review were funded as follows: charity (n = 19), departmental resources (n = 8), governmental sources (n = 15) and industry (in part or in total) (n = 15). The source of funding was not specified for the other studies. Results of 22 trials including 1138 participants show that an epidural containing a local anaesthetic will decrease the time required for return of gastrointestinal transit as measured by time to first flatus after an abdominal surgery (standardized mean difference (SMD) -1.28, 95% confidence interval (CI) -1.71 to -0.86; high quality of evidence; equivalent to 17.5 hours). The effect is proportionate to the concentration of local anaesthetic used. A total of 28 trials including 1559 participants reported a decrease in time to first faeces (stool) (SMD -0.67, 95% CI -0.86 to -0.47; low quality of evidence; equivalent to 22 hours). Thirty-five trials including 2731 participants found that pain on movement at 24 hours after surgery was also reduced (SMD -0.89, 95% CI -1.08 to -0.70; moderate quality of evidence; equivalent to 2.5 on scale from 0 to 10). From findings of 22 trials including 1154 participants we did not find a difference in the incidence of vomiting within 24 hours (risk ratio (RR) 0.84, 95% CI 0.57 to 1.23; low quality of evidence). From investigators in 17 trials including 848 participants we did not find a difference in the incidence of gastrointestinal anastomotic leak (RR 0.74, 95% CI 0.41 to 1.32; low quality of evidence). Researchers in 30 trials including 2598 participants noted that epidural analgesia reduced length of hospital stay for an open surgery (SMD -0.20, 95% CI -0.35 to -0.04; very low quality of evidence; equivalent to one day). Data on costs were very limited. An epidural containing a local anaesthetic, with or without the addition of an opioid, accelerates the return of gastrointestinal transit (high quality of evidence). An epidural containing a local anaesthetic with an opioid decreases pain after abdominal surgery (moderate quality of evidence). We did not find a difference in the incidence of vomiting or anastomotic leak (low quality of evidence). For open surgery, an epidural containing a local anaesthetic would reduce the length of hospital stay (very low quality of evidence).
Ten trials enrolling 1467 infants met our inclusion criteria. Investigators in nine trials (1458 infants) administered sustained inflation with no chest compressions. Use of sustained inflation had no impact on the primary outcomes of this review: mortality in the delivery room (typical RR 2.66, 95% confidence interval (CI) 0.11 to 63.40 (I² not applicable); typical RD 0.00, 95% CI −0.02 to 0.02; I² = 0%; 5 studies, 479 participants); and mortality during hospitalisation (typical RR 1.09, 95% CI 0.83 to 1.43; I² = 42%; typical RD 0.01, 95% CI −0.02 to 0.04; I² = 24%; 9 studies, 1458 participants). The quality of the evidence was low for death in the delivery room because of limitations in study design and imprecision of estimates (only one death was recorded across studies). For death before discharge the quality was moderate: with longer follow-up there were more deaths (n = 143) but limitations in study design remained. Among secondary outcomes, duration of mechanical ventilation was shorter in the SLI group (mean difference (MD) −5.37 days, 95% CI −6.31 to −4.43; I² = 95%; 5 studies, 524 participants; low-quality evidence). Heterogeneity, statistical significance, and magnitude of effects of this outcome are largely influenced by a single study at high risk of bias: when this study was removed from the analysis, the size of the effect was reduced (MD −1.71 days, 95% CI −3.04 to −0.39; I² = 0%). Results revealed no differences in any of the other secondary outcomes (e.g. risk of endotracheal intubation outside the delivery room by 72 hours of age (typical RR 0.91, 95% CI 0.79 to 1.04; I² = 65%; 5 studies, 811 participants); risk of surfactant administration during hospital admission (typical RR 0.99, 95% CI 0.91 to 1.08; I² = 0%; 9 studies, 1458 participants); risk of chronic lung disease (typical RR 0.99, 95% CI 0.83 to 1.18; I² = 0%; 4 studies, 735 participants); pneumothorax (typical RR 0.89, 95% CI 0.57 to 1.40; I² = 34%; 8 studies, 1377 infants); or risk of patent ductus arteriosus requiring pharmacological treatment (typical RR 0.99, 95% CI 0.87 to 1.12; I² = 48%; 7 studies, 1127 infants). The quality of evidence for these secondary outcomes was moderate (limitations in study design ‒ GRADE) except for pneumothorax (low quality: limitations in study design and imprecision of estimates ‒ GRADE). We could not perform any meta-analysis in the comparison of the use of initial sustained inflation versus standard inflations in newborns receiving resuscitation with chest compressions because we identified only one trial for inclusion (a pilot study of nine preterm infants). Our meta-analysis of nine studies shows that sustained lung inflation without chest compression was not better than intermittent ventilation for reducing mortality in the delivery room (low-quality evidence ‒ GRADE) or during hospitalisation (moderate-quality evidence ‒ GRADE), which were the primary outcomes of this review. However, the single largest study, which was well conducted and had the greatest number of enrolled infants, was stopped early for higher mortality rate in the sustained inflation group. When considering secondary outcomes, such as rate of intubation, rate or duration of respiratory support, or bronchopulmonary dysplasia, we found no benefit of sustained inflation over intermittent ventilation (moderate-quality evidence ‒ GRADE). Duration of mechanical ventilation was shortened in the SLI group (low-quality evidence ‒ GRADE); this result should be interpreted cautiously, however, as it might have been influenced by study characteristics other than the intervention. There is no evidence to support the use of sustained inflation based on evidence from our review.
We included 77 randomised clinical trials, which included 6753 participants with fatty liver disease. The risks of bias (overestimation of benefits and underestimation of harms) was high in all trials. The mean sample size was 88 participants (ranging from 40 to 200 participants) per trial. Seventy-five different herbal medicine products were tested. Herbal medicines tested in the randomised trials included single-herb products (Gynostemma pentaphyllum, Panax notoginseng, andPrunus armeniaca), proprietary herbal medicines commercially available, and combination formulas prescribed by practitioners. The most commonly used herbs wereCrataegus pinnatifida,Salvia miltiorrhiza,Alisma orientalis,Bupleurum chinense,Cassia obtusifolia, Astragalus membranaceous, and Rheum palmatum. None of the trials reported death, hepatic-related morbidity, quality of life, or costs. A large number of trials reported positive effects on putative surrogate outcomes such as serum aspartate aminotransferase, alanine aminotransferase, glutamyltransferase, alkaline phosphatases, ultrasound, and computed tomography scan. Twenty-seven trials reported adverse effects and found no significant difference between herbal medicines versus control. However, the risk of bias of the included trials was high. The outcomes were ultrasound findings in 22 trials, liver computed tomography findings in eight trials, aspartate aminotransferase levels in 64 trials, alanine aminotransferase activity in 77 trials, and glutamyltransferase activities in 44 trials. Six herbal medicines showed statistically significant beneficial effects on ultrasound, four on liver computed tomography, 42 on aspartate aminotransferase activity, 49 on alanine aminotransferase activity, three on alkaline phosphatases activity, and 32 on glutamyltransferase activity compared with control interventions. Some herbal medicines seemed to have positive effects on aspartate aminotransferase, alanine aminotransferase, ultrasound, and computed tomography. We found no significant difference on adverse effects between herbal medicine and control groups. The findings are not conclusive due to the high risk of bias of the included trials and the limited number of trials testing individual herbal medicines. Accordingly, there is also high risk of random errors.
We included two trials involving a total of 66 patients in this review. Pooling analyses of data was not possible due to considerable heterogeneity between the trials and a lack of data in both trials. One study found a significant increase in respiratory muscle strength favouring inspiratory muscle training over sham inspiratory muscle training, but there was no significant difference between groups on quality of life. The other study showed that patients receiving inspiratory muscle training were more likely to improve their activities of daily living, quality of life and cardiorespiratory fitness than those patients who received no intervention. However, the main results were not compared directly with breathing retraining. Furthermore, neither of the trials assessed the safety and tolerance of inspiratory muscle training. There is insufficient evidence to support inspiratory muscle training as an effective treatment to improve function after stroke, and no evidence relating to the safety of inspiratory muscle training. Further well-designed RCTs are required.
We identified no new studies for this updated review, which includes six studies with 1214 participants in comparisons of etoricoxib with placebo. All six studies reported on the 120 mg dose (798 participants in a comparison with placebo). Sixty-six per cent of participants with etoricoxib 120 mg and 12% with placebo reported at least 50% pain relief (NNT 1.8 (1.7 to 2.0); high-quality evidence). For dental studies only, the NNT was 1.6 (1.5 to 1.8). A single dose of 90 mg produced similar results in one large trial. Other doses (60, 180, and 240 mg) were each studied in only one treatment arm. Significantly fewer participants used rescue medication over 24 hours when taking etoricoxib 120 mg than placebo (NNT to prevent remedication 2.2 (1.9 to 2.8)), and the median time to use of rescue medication was 20 hours for etoricoxib and two hours for placebo. Adverse events were reported at a similar rate to placebo (moderate-quality evidence), with no serious events. Single-dose oral etoricoxib produces high levels of good quality pain relief after surgery, and adverse events did not differ from placebo in these studies. The 120 mg dose is as effective as, or better than, other commonly used analgesics.
: With regards to the effect of adjuvant therapy on stage II colon cancer, the pooled relative risk ratio for overall survival was 0.96 (95% confidence interval 0.88, 1.05). With regards to disease-free survival, the pooled relative risk ratio was 0.83 (95% confidence interval 0.75, 0.92). : Although there was no improvement in overall survival in the pooled analysis, we did find that disease-free survival in patients with stage II colon cancer was signficantly better with the use of adjuvant therapy. It seems reasonable to discuss the benefits of adjuvant systemic chemotherapy with those stage II patients who have high risk features, including obstruction, perforation, inadequate lymph node sampling or T4 disease. The co-morbidities and likelihood of tolerating adjuvant systemic chemotherapy should be considered as well. There exists a need to further define which high-risk features in stage II colon cancer patients should be used to select patients for adjuvant therapy. Also, researchers must continue to search for other therapies which might be more effective, shorter in duration and less toxic than those available today.
In the current update, we have added six new relevant studies, resulting in a total of 17 studies included in this review involving financial interventions directed at smokers or healthcare providers, or both. Full financial interventions directed at smokers had a favourable effect on abstinence at six months or longer when compared to no intervention (RR 1.77, 95% CI 1.37 to 2.28, I² = 33%, 9333 participants). There was no evidence that full coverage interventions increased smoking abstinence compared to partial coverage interventions (RR 1.02, 95% CI 0.71 to 1.48, I² = 64%, 5914 participants), but partial coverage interventions were more effective in increasing abstinence than no intervention (RR 1.27 95% CI 1.02 to 1.59, I² = 21%, 7108 participants). The economic evaluation showed costs per additional quitter ranging from USD 97 to USD 7646 for the comparison of full coverage with partial or no coverage. There was no clear evidence of an effect on smoking cessation when we pooled two trials of financial incentives directed at healthcare providers (RR 1.16, CI 0.98 to 1.37, I² = 0%, 2311 participants). Full financial interventions increased the number of participants making a quit attempt when compared to no interventions (RR 1.11, 95% CI 1.04 to 1.17, I² = 15%, 9065 participants). There was insufficient evidence to show whether partial financial interventions increased quit attempts compared to no interventions (RR 1.13, 95% CI 0.98 to 1.31, I² = 88%, 6944 participants). Full financial interventions increased the use of smoking cessation treatment compared to no interventions with regard to various pharmacological and behavioural treatments: nicotine replacement therapy (NRT): RR 1.79, 95% CI 1.54 to 2.09, I² = 35%, 9455 participants; bupropion: RR 3.22, 95% CI 1.41 to 7.34, I² = 71%, 6321 participants; behavioural therapy: RR 1.77, 95% CI 1.19 to 2.65, I² = 75%, 9215 participants. There was evidence that partial coverage compared to no coverage reported a small positive effect on the use of bupropion (RR 1.15, 95% CI 1.03 to 1.29, I² = 0%, 6765 participants). Interventions directed at healthcare providers increased the use of behavioural therapy (RR 1.69, 95% CI 1.01 to 2.86, I² = 85%, 25820 participants), but not the use of NRT and/or bupropion (RR 0.94, 95% CI 0.76 to 1.18, I² = 6%, 2311 participants). We assessed the quality of the evidence for the main outcome, abstinence from smoking, as moderate. In most studies participants were not blinded to the different study arms and researchers were not blinded to the allocated interventions. Furthermore, there was not always sufficient information on attrition rates. We detected some imprecision but we judged this to be of minor consequence on the outcomes of this study. Full financial interventions directed at smokers when compared to no financial interventions increase the proportion of smokers who attempt to quit, use smoking cessation treatments, and succeed in quitting. There was no clear and consistent evidence of an effect on smoking cessation from financial incentives directed at healthcare providers. We are only moderately confident in the effect estimate because there was some risk of bias due to a lack of blinding in participants and researchers, and insufficient information on attrition rates.
We included 29 RCTs, involving a total of 4458 participants. We deemed 23 trials to be at high risk of bias in at least one domain. We are uncertain of the effect of a long course of antibiotic prophylaxis (> 24 hours) compared to a short course (≤ 24 hours) on abdominal surgical site infection (RR 1.00, 95% CI 0.81 to 1.23; I² = 0%; 7 studies, 1261 participants; very low-quality evidence), mortality (Peto OR 1.67, 95% CI 0.73 to 3.82; I² = 8%; 7 studies, 1261 participants; very low-quality evidence), or intra-abdominal infection (RR 1.23, 95% CI 0.84 to 1.80; I² = 0%; 6 studies, 111 participants; very-low quality evidence). Based on very low-quality evidence from fifteen studies, involving 2020 participants, which compared different drug regimens with activity against three classes of gastrointestinal flora (gram positive, gram negative, anaerobic), we are uncertain whether there is a benefit of one regimen over another. TSA showed the majority of comparisons did not cross the alpha adjusted boundary for benefit or harm, or reached the required information size, indicating that further studies are required for these analyses. However, in the three analyses which crossed the boundary for futility, further studies are unlikely to show benefit or harm. Very low-quality evidence means that we are uncertain about the effect of either the duration of antibiotic prophylaxis, or the superiority of one drug regimen over another for penetrating abdominal trauma on abdominal surgical site infection rates, mortality, or intra-abdominal infections. Future RCTs should be adequately powered, test currently used antibiotics, known to be effective against gut flora, use methodology to minimise the risk of bias, and adequately report the level of peritoneal contamination encountered at laparotomy.
Nine studies were included, six of which were published as abstracts. Five studies were included in the meta-analysis (86 participants who undertook pulmonary rehabilitation and 82 control participants). One study used a blinded assessor and intention-to-treat analysis. No adverse effects of pulmonary rehabilitation were reported. Pulmonary rehabilitation improved the six-minute walk distance with weighted mean difference (WMD) of 44.34 metres (95% confidence interval (CI) 26.04 to 62.64 metres) and improved oxygen consumption (VO2) peak with WMD of 1.24 mL/kg/min-1 (95% CI 0.46 to 2.03 mL/kg/min-1). Improvements in six-minute walk distance and VO2 peak were also seen in the subgroup of participants with idiopathic pulmonary fibrosis (IPF) (WMD 35.63 metres, 95% CI 16.02 to 55.23 metres; WMD 1.46 mL/kg/min-1, 95% CI 0.54 to 2.39 mL/kg/min-1, respectively). Reduced dyspnoea (standardised mean difference (SMD) -0.66, 95% CI -1.05 to -0.28) following pulmonary rehabilitation was also seen in the IPF subgroup (SMD -0.68, 95% CI -1.12 to -0.25). Quality of life improved following pulmonary rehabilitation for all participants on a variety of measures (SMD 0.59, 95% CI 0.20 to 0.98) and for the subgroup of people with IPF (SMD 0.59, 95% CI 0.14 to 1.03). Two studies reported longer-term outcomes, with no significant effects of pulmonary rehabilitation on clinical variables or survival at three or six months. Available data were insufficient to allow examination of the impact of disease severity or exercise training modality. Pulmonary rehabilitation seems to be safe for people with ILD. Improvements in functional exercise capacity, dyspnoea and quality of life are seen immediately following pulmonary rehabilitation, with benefits also evident in IPF. Because of inadequate reporting of methods and small numbers of included participants, the quality of evidence was low to moderate. Little evidence was available regarding longer-term effects of pulmonary rehabilitation.
We included 67 studies (representing 3632 women with epithelial ovarian cancer). The most striking observations of this review address the lack of uniformity in conduct and reporting of early-phase immunotherapy studies. Response definitions show substantial variation between trials, which makes comparison of trial results unreliable. Information on adverse events is frequently limited. Furthermore, reports of both RCTs and NRSs frequently lack the relevant information necessary for risk of bias assessment. Therefore, we cannot rule out serious biases in most of the included trials. However, selection, attrition, and selective reporting biases are likely to have affected the studies included in this review. GRADE ratings were high only for survival; for other primary outcomes, GRADE ratings were very low. The largest body of evidence is currently available for CA-125-targeted antibody therapy (17 studies, 2347 participants; very low-certainty evidence). Non-randomised studies of CA-125-targeted antibody therapy suggest improved survival among humoral and/or cellular responders, with only moderate adverse events. However, four large randomised placebo-controlled trials did not show any clinical benefit, despite induction of immune responses in approximately 60% of participants. Time to relapse with CA-125 monoclonal antibody versus placebo, respectively, ranged from 10.3 to 18.9 months versus 10.3 to 13 months (six RCTs, 1882 participants; high-certainty evidence). Only one RCT provided data on overall survival, reporting rates of 80% in both treatment and placebo groups (three RCTs, 1062 participants; high-certainty evidence). Other small studies targeting many different tumour antigens have presented promising immunological results. As these strategies have not yet been tested in RCTs, no reliable inferences about clinical efficacy can be made. Given the promising immunological results and the limited side effects and toxicity reported, exploration of clinical efficacy in large well-designed RCTs may be worthwhile. We conclude that despite promising immunological responses, no clinically effective antigen-specific active immunotherapy is yet available for ovarian cancer. Results should be interpreted cautiously, as review authors found a significant dearth of relevant information for assessment of risk of bias in both RCTs and NRSs.
Eight randomised controlled trials were identified. A total 976 men were allocated to receive a PDE-5 inhibitor and 741 were randomised to the control groups. Overall, 80% of the participants suffered from type 2 diabetes mellitus. The weighted mean difference (WMD) for the International Index of Erectile Function (IIEF) questions 3 and 4 (frequency of penetration during and maintaining erection to completion of intercourse) was 0.9 (95% CI 0.8 to 1.1) and 1.1 (95% CI 1.0 to 1.2) at the end of the study period, in favour of the intervention group. The WMD for the IIEF erectile dysfunction domain at the end of the study period was 6.6 (95% CI 5.2 to 7.9) in favour of the PDE-5 inhibitors arm. The relative risk (RR) for answering "yes" to a global efficacy question ( "did the treatment improve your erections?") was 3.8 (CI 95% 3.1 to 4.5) in the PDE-5 inhibitors compared with the control arm. The WMD between the percentage of successful attempts in the PDE-5 inhibitors and in the control arm was 26.7 (95% CI 23.1 to 30.3). Mortality was not reported in any of the included trials. Adverse cardiovascular effects were reported in one study. Headache was the most frequent adverse event reported, flushing was the second most common event, with upper respiratory tract complaints and flu like syndromes, dyspepsia, myalgia, abnormal vision and back pain also reported in a descending order of frequency. The overall risk ratio for developing any adverse reaction was 4.8 (CI 95% 3.74 to 6.16) in the PDE-5 inhibitors arm as compared to the control. Sufficient evidence exists that PDE-5 inhibitors form a care that improves erectile dysfunction in diabetic men.
Six multicentre, well designed studies including 5640 participants were eligible for this review. Pooling analysis did not performed due to the data not similar enough. Two studies included primary EOC participants, remain four included recurrent EOC participants. In primary EOC participants, topotecan did not show benefit on overall survival (OS) (HR 1.051, 95%CI 0.925 to 1.194, and HR 1.051, 95% CI 0.93 to 1.19, respectively) and progression-free survival (PFS)(HR 1.066, 95%CI 0.958 to 1.186, and HR 1.18, 95%CI 0.86- 1.63, respectively). The median overall survival of participants treated by topotecan were 39.6 to 63 weeks, no significant difference was found in comparing with no further cytotoxic or noncytotoxic treatment (P = 0.30), pegylated liposomal doxorubicin (PLD)(P=0.341), paclitaxel (P=0.44), topotecan plus thalidomide (P=0.67), respectively; but significantly superior than treosulfan (P = 0.0023). in the platinum-sensitive participants group, overall survival (OS) favoured PLD over Topotecan (HR = 1.23, 95% CI 1.01 to 1.05). The greatest effect was seen in the partially platinum sensitive subgroup where HR was 1.58 (1.071-2.335). To comparable effectiveness to prolong progression-free survival (PFS), topotecan was 16 to 23 weeks, no statistical significant difference existed in the comparing with PLD (P= 0.095), and no further cytotoxic or noncytotoxic treatment (P=0.31, HR 1.07; 95% CI 0.94 to 1.23); Topotecan showed significantly delayed the progression campared with treosulfan (23.1 weeks versus 12.7 weeks, P = 0.0020), but no significant difference with paclitaxel (18.9 weeks versus 14.7 weeks, P=0.076); on the PFS, topotecan significantly shorter than topotecan plus thalidomide (4 months versus 6 months, P = 0.02). Topotecan was more hematologically toxic compared with paclitaxel, PLD, treosulfan, relative risks (RRs) of hematological events ranged from 1.03 to 14.46 and 1.73 to 27.12, or incidence were 50% versus 12.2%, respectively. Small tumour diameter, sensitivity to platinum-based chemotherapy was associated with better prognosis. Three studies with lower risk of bias, remain four studies unclear due to poor reporting of the methodology. The evidence quality ranged from low to high, Topotecan appears to have a similar level of effectiveness as paclitaxel, topotecan plus thalidomide, but shorter overall survival than PLD in the platinum-sensitive participants; adelays progression of disease than paclitaxel, treosulfan; topotecan plus thalidomide superior than topotecan alone on PFS. After received carboplatin and paclitaxel, further treatment by topotecan not appeared benefit than no further treatment for ovarian cancer on overall survival and progression-free survival. Topotecan may has different patterns of side effects. The quality of evidence from these studies ranged from low to moderate. More large, well-designed and good conducted and good reported, particularly post-market studies are still required in the future in order to conform the effect and safety, and to have better representativeness.
We included two studies in this review, both of which were double-blind, randomised controlled trials comparing perioperative beta-adrenergic blockade (metoprolol) with placebo, on cardiovascular outcomes in people undergoing major non-cardiac vascular surgery. We included 599 participants receiving beta-adrenergic blockers (301 participants) or placebo (298 participants). The overall quality of studies was good. However, one study did not report random sequence generation or allocation concealment techniques, indicating possible selection bias, and the other study did not report outcome assessor blinding and was possibly underpowered. It should be noted that several of the outcomes were only reported in a single study and neither of the studies reported on vascular patency/graft occlusion, which reduces the quality of evidence to moderate. There was no evidence that perioperative beta-adrenergic blockade reduced all-cause mortality (OR 0.62, 95% CI 0.03 to 15.02), cardiovascular mortality (OR 0.34, 95% CI 0.01 to 8.32), non-fatal myocardial infarction (OR 0.83, 95% CI 0.46 to 1.49; P value = 0.53), arrhythmia (OR 0.70, 95% CI 0.26 to 1.88), heart failure (OR 1.71, 95% CI 0.40 to 7.23), stroke (OR 2.67, 95% CI 0.11 to 67.08), composite cardiovascular events (OR 0.87, 95% CI 0.55 to 1.39; P value = 0.57) or re-hospitalisation at 30 days (OR 0.86, 95% CI 0.48 to 1.52). However, there was strong evidence that beta-adrenergic blockers increased the odds of intra-operative bradycardia (OR 4.97, 95% CI 3.22 to 7.65; P value < 0.00001) and intra-operative hypotension (OR 1.84, 95% CI 1.31 to 2.59; P value = 0.0005). This meta-analysis currently offers no clear evidence that perioperative beta-adrenergic blockade reduces postoperative cardiac morbidity and mortality in people undergoing major non-cardiac vascular surgery. There is evidence that intra-operative bradycardia and hypotension are more likely in people taking perioperative beta-adrenergic blockers, which should be weighed with any benefit.
Five trials were included with 787 participants in total. All were randomised, double-blind, placebo-controlled parallel-group studies. We conducted a meta-analysis of two trials (114 participants) and the results gave moderate quality evidence that oral corticosteroids did not prevent postherpetic neuralgia six months after the onset of herpes (RR 0.95, 95% CI 0.45 to 1.99). One of these trials was at high risk of bias because of incomplete outcome data, the other was at low risk of bias overall. The three other trials that fulfilled our inclusion criteria were not included in the meta-analysis because the outcomes were reported at less than one month or not in sufficient detail to add to the meta-analysis. These three trials were generally at low risk of bias. Adverse events during or within two weeks after stopping treatment were reported in all five included trials. There were no significant differences in serious or non-serious adverse events between the corticosteroid and placebo groups. There was also no significant difference between the treatment groups and placebo groups in other secondary outcome analyses and subgroup analyses. The review was first published in 2008 and no new RCTs were identified for inclusion in subsequent updates in 2010 and 2012. There is moderate quality evidence that corticosteroids given acutely during zoster infection are ineffective in preventing postherpetic neuralgia. In people with acute herpes zoster the risks of administration of corticosteroids do not appear to be greater than with placebo, based on moderate quality evidence. Corticosteroids have been recommended to relieve the zoster-associated pain in the acute phase of disease. If further research is designed to evaluate the efficacy of corticosteroids for herpes zoster, long-term follow-up should be included to observe their effect on the transition from acute pain to postherpetic neuralgia. Future trials should include measurements of function and quality of life.
Twenty studies were identified for all the comparison groups, involving 1609 patients. There were seven studies (with 443 patients) comparing terlipressin to placebo, five of which were considered to be high quality studies based on the Jadad scale. The meta-analysis indicates that terlipressin was associated with a statistically significant reduction in all cause mortality compared to placebo (relative risk 0.66, 95% confidence interval 0.49 to 0.88). Three studies (with 302 patients) were identified comparing terlipressin to somatostatin, two of which were high quality studies; only one high quality study (219 patients) comparing terlipressin to endoscopic treatment was identified. Within the limited power provided by these small numbers of patients, no statistically significant difference was demonstrated between terlipressin and either somatostatin or endoscopic treatment in any of the outcomes. For the remaining comparison groups (terlipressin versus balloon tamponade, terlipressin versus octreotide, and terlipressin versus vasopressin) only small, low quality studies were identified and no difference was demonstrated in any of the major outcomes. There was no significant difference between the terlipressin group and any of the comparison groups in the number of adverse events that caused death or withdrawal of medication. On the basis of a 34% relative risk reduction in mortality, terlipressin should be considered to be effective in the treatment of acute variceal hemorrhage. Further, since no other vasoactive agent has been shown to reduce mortality in single studies or meta-analyses, terlipressin might be the vasoactive agent of choice in acute variceal bleeding.
We included 13 RCTs (n=485), with between eight and 15 weeks follow-up. The results of the individual trials were heterogeneous. Combining all trials, participants receiving calcium supplementation as compared to control had a statistically significant reduction in SBP (mean difference: -2.5 mmHg, 95% CI: -4.5 to -0.6, I2 = 42%), but not DBP (mean difference: -0.8 mmHg, 95% CI: -2.1 to 0.4, I2 = 48%). Sub-group analyses indicated that heterogeneity between trials could not be explained by dose of calcium or baseline blood pressure. Heterogeneity was reduced when poor quality trials were excluded. The one trial reporting adequate concealment of allocation and the one trial reporting adequate blinding yielded results consistent with the primary meta-analysis. Due to poor quality of included trials and heterogeneity between trials, the evidence in favour of causal association between calcium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treatment. Larger, longer duration and better quality double-blind placebo controlled trials are needed to assess the effect of calcium supplementation on blood pressure and cardiovascular outcomes.
Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI −0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD −0.13, 95% CI −0.19 to −0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD −0.22, 95% CI −0.29 to −0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD −0.57, 95% CI −0.69 to −0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups (typical RR 1.69, 95% CI 0.18 to 16.25; typical RD 0.01, 95% CI −0.04 to 0.05; 5 trials; N = 214). Nephrotoxicity was not noted with either of the treatment regimens. Overall, the quality of evidence was considered to be moderate on GRADE analysis, given the small sample size and unclear/high risk of bias in some of the domains in a few of the included studies. There is insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, data suggest that pharmacokinetic properties of a 'once a day' gentamicin regimen are superior to a 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There was no change in nephrotoxicity or auditory toxicity. Based on the assessment of pharmacokinetics, a 'once a day regimen' may be superior in treating sepsis in neonates of more than 32 weeks' gestation.
We included three RCTs, all new to this update, of very low to low methodological quality, with a total of 270 participants. Two studies exclusively enrolled participants with a known positive response to BtA treatment. This raises concerns of population enrichment, with a higher probability of benefit from BtA treatment. None of the trials were free of for-profit bias, nor did they provide information regarding registered study protocols. All trials evaluated the effect of a single Bt treatment session, and not repeated treatment sessions, using doses from 100 U to 250 U of BtA (all onabotulinumtoxinA, or Botox, formulations) and 5000 U to 10,000 U of BtB (rimabotulinumtoxinB, or Myobloc/Neurobloc). We found no difference between the two types of botulinum toxin in terms of overall efficacy, with a mean difference of -1.44 (95% CI -3.58 to 0.70) points lower on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for BtB-treated participants, measured at two to four weeks after injection. The proportion of participants with adverse events was also not different between BtA and BtB (BtB versus BtA risk ratio (RR) 1.40; 95% CI 1.00 to 1.96). However, when compared to BtA, treatment with BtB was associated with an increased risk of one adverse events of special interest, namely treatment-related sore throat/dry mouth (BtB versus BtA RR of 4.39; 95% CI 2.43 to 7.91). Treatment-related dysphagia (swallowing difficulties) was not different between BtA and BtB (RR 2.89; 95% CI 0.80 to 10.41). The two types of botulinum toxin were otherwise clinically non-distinguishable in all the remaining outcomes. The previous version of this review did not include any trials, since these were still ongoing at the time. Therefore, with this update we are able to change the conclusions of this review. There is low quality evidence that a single treatment session of BtA (specifically onabotulinumtoxinA) and a single treatment session of BtB (rimabotulinumtoxinB) are equally effective and safe in the treatment of adults with certain types of cervical dystonia. Treatment with BtB appears to present an increased risk of sore throat/dry mouth, compared to BtA. Overall, there is no clinical evidence from these single-treatment trials to support or contest the preferential use of one form of botulinum toxin over the other.
We included five new studies in this update. In total, we included 11 trials in the review, including data from 12,944 adult participants, who suffered either out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA). We excluded studies explicitly including patients with cardiac arrest caused by trauma, drowning, hypothermia and toxic substances. These conditions are routinely excluded from cardiac arrest intervention studies because they have a different underlying pathophysiology, require a variety of interventions specific to the underlying condition and are known to have a prognosis different from that of cardiac arrest with no obvious cause. The exclusions were meant to reduce heterogeneity in the population while maintaining generalisability to most patients with sudden cardiac death. The overall quality of evidence for the outcomes of included studies was moderate to low due to considerable risk of bias. Three studies (N = 7587) reported on the designated primary outcome of survival to hospital discharge with good neurologic function (defined as a Cerebral Performance Category (CPC) score of one or two), which had moderate quality evidence. One study showed no difference with mechanical chest compressions (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.82 to 1.39), one study demonstrated equivalence (RR 0.79, 95% CI 0.60 to 1.04), and one study demonstrated reduced survival (RR 0.41, CI 0.21 to 0.79). Two other secondary outcomes, survival to hospital admission (N = 7224) and survival to hospital discharge (N = 8067), also had moderate quality level of evidence. No studies reported a difference in survival to hospital admission. For survival to hospital discharge, two studies showed benefit, four studies showed no difference, and one study showed harm associated with mechanical compressions. No studies demonstrated a difference in adverse events or injury patterns between comparison groups but the quality of data was low. Marked clinical and statistical heterogeneity between studies precluded any pooled estimates of effect. The evidence does not suggest that CPR protocols involving mechanical chest compression devices are superior to conventional therapy involving manual chest compressions only. We conclude on the balance of evidence that mechanical chest compression devices used by trained individuals are a reasonable alternative to manual chest compressions in settings where consistent, high-quality manual chest compressions are not possible or dangerous for the provider (eg, limited rescuers available, prolonged CPR, during hypothermic cardiac arrest, in a moving ambulance, in the angiography suite, during preparation for extracorporeal CPR [ECPR], etc.). Systems choosing to incorporate mechanical chest compression devices should be closely monitored because some data identified in this review suggested harm. Special attention should be paid to minimising time without compressions and delays to defibrillation during device deployment.
We identified 11 randomised controlled trials (RCTs) that generated 15 publications. All trials applied an intention-to-treat analysis with varied randomisation methods. The 11 studies recruited 778 patients; 712 children and adolescents and 66 adults. We assessed all 11 studies to be at low to unclear risk of bias for the following domains: random sequence generation, allocation concealment and selective reporting. For the other domains (blinding, incomplete outcome data, other bias) assessments were varied (low, unclear and high risk of bias). We could not conduct a meta-analysis due to the heterogeneity of the studies and the quality of the evidence was low to very low (GRADE ratings). Reported rates of seizure freedom reached as high as 55% in a classical 4:1 KD group after three months and reported rates of seizure reduction reached as high as 85% in a classical 4:1 KD group after three months (GRADE rating low). One trial found no significant difference between the fasting-onset and gradual-onset KD for rates of seizure freedom, and reported a greater rate of seizure reduction in the gradual-onset KD group. Studies assessing the efficacy of the MAD reported seizure freedom rates of up to 25% and seizure reduction rates of up to 60% in children. One study used a simplified MAD (sMAD) and reported seizure freedom rates of 15% and seizure reduction rates of 56% in children. One study utilised a MAD in adults and reported seizure reduction rates of 35%, but no patients became seizure free (GRADE rating low). Adverse effects of the dietary interventions were experienced in all studies. The most commonly reported adverse effects were gastrointestinal syndromes. It was common that adverse effects were the reason for participants dropping out of trials (GRADE rating low). Other reasons for dropout included lack of efficacy and non-acceptance of the diet (GRADE rating low). Although there was some evidence for greater antiepileptic efficacy for a classical 4:1 KD over lower ratios, the classical 4:1 KD was consistently associated with more adverse effects. One study assessed the effect of dietary interventions on quality of life, cognition and behavioural functioning, reporting participants in the KD group to be more active, more productive and less anxious after four months, compared to the control group. However, no significant difference was found in quality-adjusted life years (QALYs) between the KD group and control group at four or 16 months (GRADE rating very low). The RCTs discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and the limited studies in adults, resulted in a low to very low overall quality of evidence. There were adverse effects within all of the studies and for all KD variations, such as short-term gastrointestinal-related disturbances and increased cholesterol. However, study periods were short, therefore the long-term risks associated with these adverse effects is unknown. Attrition rates remained a problem with all KDs and across all studies; reasons for this being lack of observed efficacy and dietary tolerance. Only one study reported the use of KDs in adults with epilepsy; therefore further research would be of benefit. Other more palatable but related diets, such as the MAD, may have a similar effect on seizure control as the classical KD, but this assumption requires more investigation. For people who have medically intractable epilepsy or people who are not suitable for surgical intervention, KDs remain a valid option; however, further research is required.
The included study was a single-institution, randomised, double-blind, placebo-controlled trial of intralesional cidofovir administered at the time of surgical debulking. Adults (n = 15) and children (n = 4) were included. We judged the study to have a reasonably low risk of bias. After a 12-month trial period, no difference was found between the cidofovir and placebo groups. Both groups showed a significant reduction in disease extent (as assessed at the time of surgery using the Derkay Scoring System), but no significant change in health-related quality of life. There is insufficient evidence to support the efficacy of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children or adults. The included randomised controlled trial showed no advantage of intralesional cidofovir over placebo at 12 months. The study was limited by a small sample size and a change in the cidofovir concentration midway through the trial, from 0.3 mg/ml in children and 0.75 mg/ml in adults, to 5 mg/ml in both adults and children. An adequately powered randomised controlled trial of intra-lesional cidofovir, consistently using higher concentrations of cidofovir in comparison with injected placebo, would be required to determine effectiveness convincingly. Future studies must include health-related quality of life and symptom-based outcome measures.
We included two studies involving 252 children with AOM aged from three months to six years receiving hospital ambulatory care who were treated with intramuscular ceftriaxone, and who were then randomised to the corticosteroid group (corticosteroid and corticosteroid plus antihistamine) or the placebo group (antihistamine and double placebo). In one study, children also had a needle aspiration of middle ear fluid. Both studies were at unclear risk of bias for allocation concealment, and unclear to high risk of bias for selective reporting. One study (N = 179) included pain as an outcome, but we were unable to derive the proportion of children with persistent pain at Day 5 and Day 14. Reduction of overall or specific symptoms was presented as improvement in clinical symptoms and resolution of inflamed tympanic membranes without the need for additional antibiotic treatment: at Day 5 (94% of children in the treatment group (N = 89) versus 89% in the placebo group (N = 90); risk ratio (RR) 1.06, 95% confidence interval (CI) 0.97 to 1.16) and Day 14 (91% versus 87%; RR 1.05, 95% CI 0.95 to 1.17). Low-quality evidence meant that we are uncertain of the effectiveness of corticosteroids for this outcome. The second study (N = 73) reported a reduction of overall or specific symptoms without additional antibiotic treatment during the first two weeks as a favourable outcome. Children in the treatment group had more favourable outcomes (adjusted odds ratio 65.9, 95% CI 1.28 to 1000; P = 0.037), although the numbers were small. We were unable to pool the results with the other study because it did not report the proportion of children with this outcome by treatment group. Only one study reported adverse effects of corticosteroids (e.g. drowsiness, nappy rash), but did not quantify incidence, so we were unable to draw conclusions about adverse effects. Neither study reported a reduction in overall or specific symptom duration. The evidence for the effect of systemic corticosteroids on AOM is of low to very low quality, meaning the effect of systemic corticosteroids on important clinical outcomes in AOM remains uncertain. Large, high-quality studies are required to resolve the question.
One completed randomised trial was found. In one subgroup of this trial, 16 patients with symptomatic severe vertebral artery stenosis were randomised to endovascular treatment (eight patients) or medical treatment alone (eight patients). There were no strokes in any arterial territory or deaths from any cause in either group within 30 days of treatment (endovascular group) or 30 days of randomisation (medical group). In the endovascular group, two patients had a posterior circulation transient ischaemic attack at the time of the procedure. In the endovascular group, the mean vessel stenosis at follow up was 47% (range 0% to 80%). Patients were followed up for a mean of 4.5 years in the endovascular group and 4.9 years in the medical group. There were no further vertebrobasilar territory strokes in either group for the duration of follow up. Morbidity and mortality was related to carotid and coronary artery disease in this study. There is currently insufficient evidence to assess the effects of percutaneous transluminal angioplasty with or without stenting or primary stenting for vertebral artery stenosis.
The review includes 31 trials with 12,579 participants. Of 24 comparisons made, 6 compared a COC to placebo, 17 different COCs, and 1 compared a COC to an antibiotic. Of nine placebo-controlled trials with data for analysis, all showed COCs reduced acne lesion counts, severity grades and self-assessed acne compared to placebo. A levonorgestrel-COC group had fewer total lesion counts (MD -9.98; 95% CI -16.51 to -3.45), inflammatory and non-inflammatory lesion counts, and were more likely to have a clinician assessment of clear or almost clear lesions and participant self-assessment of improved acne lesions. A norethindrone acetate COC had better results for clinician global assessment of no acne to mild acne (OR 1.86; 95% CI 1.32 to 2.62). In two combined trials, a norgestimate COC showed reduced total lesion counts (MD-9.32; 95% CI -14.19 to -4.45), reduced inflammatory lesion and comedones counts, and more with clinician assessment of improved acne. For two combined trials of a drospirenone COC, the investigators' assessment of clear or almost clear skin favored the drospirenone group (OR 3.02; 95% CI 1.99 to 4.59). In one trial, the drospirenone-COC group showed greater (more positive) percent changes for total lesion count (MD 29.08; 95% CI 3.13 to 55.03), inflammatory and non-inflammatory lesion counts, and papule and closed comedone counts. A dienogest-COC group had greater percentage decreases in total lesion count (MD -15.30; 95% CI -19.98 to -10.62) and inflammatory lesion count, and more women assessed with overall improvement of facial acne. A CMA-COC group had more 'responders,' those with 50% or greater decrease in facial papules and pustules (OR 2.31; 95% CI 1.50 to 3.55) Differences in the comparative effectiveness of COCs containing varying progestin types and dosages were less clear, and data were limited for any particular comparison. COCs that contained chlormadinone acetate or cyproterone acetate improved acne better than levonorgestrel. A COC with cyproterone acetate showed better acne outcomes than one with desogestrel, but the studies produced conflicting results. Likewise, levonorgestrel showed a slight improvement over desogestrel in acne outcomes, but results were not consistent. A drospirenone COC appeared to be more effective than norgestimate or nomegestrol acetate plus 17β-estradiol but less effective than cyproterone acetate. This update yielded six new trials but no change in conclusions. The six COCs evaluated in placebo-controlled trials are effective in reducing inflammatory and non-inflammatory facial acne lesions. Few important and consistent differences were found between COC types in their effectiveness for treating acne. How COCs compare to alternative acne treatments is unknown since only one trial addressed this issue. The use of standardized methods for assessing acne severity would help in synthesizing results across trials as well as aid in interpretation.
We included three RCTs (124 participants), two of which we assessed as at high risk of bias and one at unclear risk of bias. All studies were hospital-based and recruited participants undergoing superficial parotidectomy. Most participants were diagnosed with benign lesions of the parotid gland. Participants were followed up for more than six months. The studies evaluated the two comparisons shown below: Sternocleidomastoid muscle flap versus no flap Two studies assessed this comparison. Both assessed the effects of the sternocleidomastoid muscle flap procedure on the incidence rate of Frey's syndrome assessed clinically but neither showed a significant difference between groups (risk ratio (RR) 0.08, 95% confidence interval (CI) 0.00 to 1.23; 24 participants and RR 1.23, 95% CI 0.88 to 1.73; 36 participants; very low-certainty evidence). We did not pool the data due to the high heterogeneity (I² = 87%). One study found that the sternocleidomastoid muscle flap may result in little or no difference in other complications including haematoma (RR 2.18, 95% CI 0.09 to 50.16; 36 participants; low-certainty evidence), subjective painful or restricted cervical movement (RR 0.54, 95% CI 0.14 to 2.05; 36 participants; low-certainty evidence) and scar spread in the cervical region (RR 0.71, 95% CI 0.05 to 10.54; 36 participants; low-certainty evidence). Both studies reported the incidence rate of Frey's syndrome assessed by participants, with one reporting no events in either group and the other finding no evidence of a difference (RR 0.63, 95% CI 0.32 to 1.26; 36 participants; low-certainty evidence). Acellular dermal matrix versus no graft Only one study assessed this comparison. Use of an acellular dermal matrix graft may result in little or no difference to the incidence rate of Frey's syndrome (assessed clinically) in comparison with the no graft group, but the evidence is very uncertain (RR 0.08, 95% CI 0.00 to 1.25; 30 participants; very low-certainty evidence). Acellular dermal matrix may slightly increase the wound infection rate compared with control (RR 17.00, 95% CI 1.02 to 282.67; 64 participants; low-certainty evidence). Acellular dermal matrix may result in little or no difference to the incidence of seromas or sialoceles (RR 2.33, 95% CI 0.66 to 8.23; 64 participants; low-certainty evidence). Acellular dermal matrix may result in little or no difference to the incidence rate of Frey's syndrome (assessed by participants) in comparison with the no graft group (RR 0.33, 95% CI 0.04 to 3.04; 64 participants; low-certainty evidence). The evidence for the effectiveness of graft interposition in preventing Frey's syndrome is of low or very low certainty. The use of acellular dermal matrix may be associated with an increase in the wound infection rate, and little or no difference in the incidence of seromas or sialoceles. Further studies are needed to draw reliable conclusions.
We included 59 trials involving 7667 participants. We rated two trials at low risk of bias in all domains (selection, attrition, reporting, blinding and other). We rated 25 trials at high risk in one or more risk-of-bias domains. Compared with sham treatment, PC6 acupoint stimulation significantly reduced the incidence of nausea (RR 0.68, 95% CI 0.60 to 0.77; 40 trials, 4742 participants), vomiting (RR 0.60, 95% CI 0.51 to 0.71; 45 trials, 5147 participants) and the need for rescue antiemetics (RR 0.64, 95% CI 0.55 to 0.73; 39 trials, 4622 participants). As heterogeneity among trials was substantial and there were study limitations, we rated the quality of evidence as low. Using trial sequential analysis, the required information size and boundary for benefit were reached for both primary outcomes. PC6 acupoint stimulation was compared with six different types of antiemetic drugs (metoclopramide, cyclizine, prochlorperazine, droperidol. ondansetron and dexamethasone). There was no difference between PC6 acupoint stimulation and antiemetic drugs in the incidence of nausea (RR 0.91, 95% CI 0.75 to 1.10; 14 trials, 1332 participants), vomiting (RR 0.93, 95% CI 0.74 to 1.17; 19 trials, 1708 participants), or the need for rescue antiemetics (RR 0.87, 95% CI 0.65 to 1.16; 9 trials, 895 participants). We rated the quality of evidence as moderate, due to the study limitations. Using trial sequential analyses, the futility boundary was crossed before the required information size was surpassed for both primary outcomes. Compared to antiemetic drugs, the combination of PC6 acupoint stimulation and antiemetic therapy reduced the incidence of vomiting (RR 0.56, 95% CI 0.35 to 0.91; 9 trials, 687 participants) but not nausea (RR 0.79, 95% CI 0.55 to 1.13; 8 trials, 642 participants). We rated the quality of evidence as very low, due to substantial heterogeneity among trials, study limitations and imprecision. Using trial sequential analysis, none of the boundaries for benefit, harm or futility were crossed for PONV. The need for rescue antiemetic was lower in the combination PC6 acupoint stimulation and antiemetic group than the antiemetic group (RR 0.61, 95% CI 0.44 to 0.86; 5 trials, 419 participants). The side effects associated with PC6 acupoint stimulation were minor, transient and self-limiting (e.g. skin irritation, blistering, redness and pain) in 14 trials. Publication bias was not apparent in the contour-enhanced funnel plots. There is low-quality evidence supporting the use of PC6 acupoint stimulation over sham. Compared to the last update in 2009, no further sham comparison trials are needed. We found that there is moderate-quality evidence showing no difference between PC6 acupoint stimulation and antiemetic drugs to prevent PONV. Further PC6 acupoint stimulation versus antiemetic trials are futile in showing a significant difference, which is a new finding in this update. There is inconclusive evidence supporting the use of a combined strategy of PC6 acupoint stimulation and antiemetic drug over drug prophylaxis, and further high-quality trials are needed.
We identified 14 eligible studies which randomised a total of 5,500 women. Median follow-up ranged from 18 to 124 months. Eight studies described a satisfactory method of randomisation. Data, based on 1139 estimated deaths in 4620 women available for analysis, show equivalent overall survival rates with a HR of 0.98 (95% CI, 0.87 to 1.09; p, 0.67; no heterogeneity). Preoperative chemotherapy increases breast conservation rates, yet at the associated cost of increased loco regional recurrence rates. However, this rate was not increased as long as surgery remains part of the treatment even after complete tumour regression (HR, 1.12; 95% CI, 0.92 to 1.37; p, 0.25; no heterogeneity. Preoperative chemotherapy was associated with fewer adverse effects. Pathological complete response is associated with better survival than residual disease (HR, 0.48; 95% CI, 0.33 to 0.69; p, < 10-4). This review suggests safe application of preoperative chemotherapy in the treatment of women with early stage breast cancer in order to down-stage surgical requirement, to evaluate chemosensitivity and to facilitate translational research.
Twelve RCTs (comprising 1669 participants) met the eligibility criteria. We judged five studies to have a moderate risk of bias and assessed the remaining seven as having a high risk of bias. It was possible to include SF-36 physical health component scores from five studies in a meta-analysis. Participating in a MDRP was associated with an increase in SF-36 physical health component scores (mean difference (MD) 2.22, 95% confidence interval (CI) 0.12 to 4.31, P = 0.04). The findings from the narrative analysis suggested that MDRPs with a single domain or outcome focus appeared to be more successful than programmes with multiple aims. In addition, programmes that comprised participants with different types of cancer compared to cancer site-specific programmes were more likely to show positive improvements in physical outcomes. The most effective mode of service delivery appeared to be face-to-face contact supplemented with at least one follow-up telephone call. There was no evidence to indicate that MDRPs which lasted longer than six months improved outcomes beyond the level attained at six months. In addition, there was no evidence to suggest that services were more effective if they were delivered by a particular type of health professional. There is some evidence to support the effectiveness of brief, focused MDRPs for cancer survivors. Rigorous and methodologically sound clinical trials that include an economic analysis are required.
IRS versus no IRS Stable malaria (entomological inoculation rate (EIR) > 1): In one RCT in Tanzania IRS reduced re-infection with malaria parasites detected by active surveillance in children following treatment; protective efficacy (PE) 54%. In the same setting, malaria case incidence assessed by passive surveillance was marginally reduced in children aged one to five years; PE 14%, but not in children older than five years (PE -2%). In the IRS group, malaria prevalence was slightly lower but this was not significant (PE 6%), but mean haemoglobin was higher (mean difference 0.85 g/dL). In one CBA trial in Nigeria, IRS showed protection against malaria prevalence during the wet season (PE 26%; 95% CI 20 to 32%) but not in the dry season (PE 6%; 95% CI -4 to 15%). In one ITS in Mozambique, the prevalence was reduced substantially over a period of 7 years (from 60 to 65% prevalence to 4 to 8% prevalence; the weighted PE before-after was 74% (95% CI 72 to 76%). Unstable malaria (EIR < 1): In two RCTs, IRS reduced the incidence rate of all malaria infections;PE 31% in India, and 88% (95% CI 69 to 96%) in Pakistan. By malaria species, IRS also reduced the incidence of P. falciparum (PE 93%, 95% CI 61 to 98% in Pakistan) and P. vivax (PE 79%, 95% CI 45 to 90% in Pakistan); There were similar impacts on malaria prevalence for any infection: PE 76% in Pakistan; PE 28% in India. When looking separately by parasite species, for P. falciparum there was a PE of 92% in Pakistan and 34% in India; forP. vivax there was a PE of 68% in Pakistan and no impact demonstrated in India (PE of -2%). IRS versus Insecticide Treated Nets (ITNs) Stable malaria (EIR > 1): Only one RCT was done in an area of stable transmission (in Tanzania). When comparing parasitological re-infection by active surveillance after treatment in short-term cohorts, ITNs appeared better, but it was likely not to be significant as the unadjusted CIs approached 1 (risk ratio IRS:ITN = 1.22). When the incidence of malaria episodes was measured by passive case detection, no difference was found in children aged one to five years (risk ratio = 0.88, direction in favour of IRS). No difference was found for malaria prevalence or haemoglobin. Unstable malaria (EIR < 1): Two studies; for incidence and prevalence, the malaria rates were higher in the IRS group compared to the ITN group in one study. Malaria incidence was higher in the IRS arm in India (risk ratio IRS:ITN = 1.48) and in South Africa (risk ratio 1.34 but the cluster unadjusted CIs included 1). For malaria prevalence, ITNs appeared to give better protection against any infection compared to IRS in India (risk ratio IRS:ITN = 1.70) and also for both P. falciparum (risk ratio IRS:ITN = 1.78) and P. vivax (risk ratio IRS:ITN = 1.37). Historical and programme documentation has clearly established the impact of IRS. However, the number of high-quality trials are too few to quantify the size of effect in different transmission settings. The evidence from randomized comparisons of IRS versus no IRS confirms that IRS reduces malaria incidence in unstable malaria settings, but randomized trial data from stable malaria settings is very limited. Some limited data suggest that ITN give better protection than IRS in unstable areas, but more trials are needed to compare the effects of ITNs with IRS, as well as to quantify their combined effects. Ideally future trials should try and evaluate the effect of IRS in areas with no previous history of malaria control activities.
Combined data from two eating disorder prevention programs based on a media literacy and advocacy approach indicate a reduction in the internalisation or acceptance of societal ideals relating to appearance at a 3- to 6-month follow-up (Kusel 1999; Neumark* 2000) [SMD -0.28, -0.51 to -0.05, 95% CI]. There is insufficient evidence to support the effect of five programs designed to address eating attitudes and behaviours and other adolescent issues in the general community or those classified as being at high risk for eating disorder (Buddeberg* 1998; Dalle Grave 2001; Killen 1993; Santonastaso 1999; Zanetti 1999) and insufficient evidence to support the effect of two programs designed to improve self-esteem (O'Dea 2000; Wade 2003). Data from two didactic eating disorder awareness programs could not be pooled for analysis. There is not sufficient evidence to suggest that harm resulted from any of the prevention programs included in the review. The one significant pooled effect in the current review does not allow for any firm conclusions to be made about the impact of prevention programs for eating disorders in children and adolescents, although none of the pooled comparisons indicated evidence of harm. The meta-analysis is in the process of being revised to account for the impact of cluster randomised trials.
We included one study, with 60 randomized participants, in the review. The study population had a range of ulcer types that were venous arteriolosclerotic and venous/arterial in origin. Study participants had recalcitrant ulcers that had not healed after treatment over a six-month period. Participants allocated to NPWT received continuous negative pressure until they achieved 100% granulation (wound preparation stage). A punch skin-graft transplantation was conducted and the wound then exposed to further NPWT for four days followed by standard care. Participants allocated to the control arm received standard care with dressings and compression until 100% granulation was achieved. These participants also received a punch skin-graft transplant and then further treatment with standard care. All participants were treated as in-patients until healing occurred. There was low quality evidence of a difference in time to healing that favoured the NPWT group: the study reported an adjusted hazard ratio of 3.2, with 95% confidence intervals (CI) 1.7 to 6.2. The follow-up period of the study was a minimum of 12 months. There was no evidence of a difference in the total number of ulcers healed (29/30 in each group) over the follow-up period; this finding was also low quality evidence. There was low quality evidence of a difference in time to wound preparation for surgery that favoured NPWT (hazard ratio 2.4, 95% CI 1.2 to 4.7). Limited data on adverse events were collected: these provided low quality evidence of no difference in pain scores and Euroqol (EQ-5D) scores at eight weeks after surgery. There is limited rigorous RCT evidence available concerning the clinical effectiveness of NPWT in the treatment of leg ulcers. There is some evidence that the treatment may reduce time to healing as part of a treatment that includes a punch skin graft transplant, however, the applicability of this finding may be limited by the very specific context in which NPWT was evaluated. There is no RCT evidence on the effectiveness of NPWT as a primary treatment for leg ulcers.
We included seven studies from the literature search, but only six provided sufficient data for analyses. Included studies were European, cluster RCTs with adult participants seeing their usual doctor (in total 233 general practitioners and 1787 participants). Methodological quality was only moderate as studies had no blinding of healthcare professionals and several studies had a risk of recruitment and attrition bias. Studies were heterogeneous with regard to selection of patient populations and intensity of interventions. Outcomes relating to physical or general health (physical symptoms, quality of life) showed substantial heterogeneity between studies (I2 > 70%) and post hoc analysis suggested that benefit was confined to more intensive interventions; thus we did not calculate a pooled effect. Outcomes relating to mental health showed less heterogeneity and we conducted meta-analyses, which found non-significant overall effect sizes with SMDs for changes at 6 to 24 months follow-up: mental health (3 studies) SMD -0.04 (95% CI -0.18 to 0.10), illness worry (3 studies) SMD 0.09 (95% CI -0.04 to 0.22), depression (4 studies) SMD 0.07 (95% CI -0.05 to 0.20) and anxiety (2 studies) SMD -0.07 (95% CI -0.38 to 0.25). Effects on sick leave could not be estimated. Three studies of patient satisfaction with care all showed positive but non-significant effects, and measures were too heterogeneous to allow meta-analysis. Results on healthcare utilisation were inconclusive. We analysed study discontinuation and found that both short term and long term discontinuation occurred more often in patients allocated to the intervention group, RR of 1.25 (95% CI 1.08 to 1.46) at 12 to 24 months. Current evidence does not answer the question whether enhanced care delivered by front line primary care professionals has an effect or not on the outcome of patients with functional somatic symptoms. Enhanced care may have an effect when delivered per protocol to well-defined groups of patients with functional disorders, but this needs further investigation. Attention should be paid to difficulties including limited consultation time, lack of skills, the need for a degree of diagnostic openness, and patient resistance towards psychosomatic attributions. There is some indication from this and other reviews that more intensive interventions are more successful in changing patient outcomes.
Our searches found no randomised controlled trials or quasi-randomised controlled trials that met the eligibility criteria for this review. There is very low quality evidence from one randomised trial involving 79 participants with acute Bell's palsy, but this study was excluded as the outcome assessor was not blinded to treatment allocation and thus did not meet pre-defined eligibility criteria. The trial compared 42 people who received hyperbaric oxygen therapy (2.8 atmospheres for 60 minutes twice daily, five days per week until the facial palsy resolved; maximum 30 'dives') and placebo tablets with 37 people who received placebo hyperbaric oxygen therapy (achieving only a normal partial pressure of oxygen) and prednisone (40 mg twice daily, reducing over eight days). Facial function recovered in more participants treated with hyperbaric oxygen therapy than with prednisone (hyperbaric oxygen therapy, 40/42 (95%); prednisone, 28/37 (76%); risk ratio 1.26, 95% CI 1.04 to 1.53). There were no reported major complications and all participants completed the trial. Very low quality evidence from one trial suggests that hyperbaric oxygen therapy may be an effective treatment for moderate to severe Bell's palsy, but this study was excluded as the outcome assessor was not blinded to treatment allocation. Further randomised controlled trials are needed.
We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life. Acarbose had a clear effect on glycemic control compared to placebo: glycated haemoglobin -0.8% (95% confidence interval -0.9 to -0.7), fasting blood glucose -1.1 mmol/L (95% confidence interval -1.4 to -0.9), post-load blood glucose -2.3 mmol/L (95% confidence interval -2.7 to -1.9). The effect on glycated haemoglobin by acarbose was not dose-dependent. We found a decreasing effect on post-load insulin and no clinically relevant effects on lipids or body weight. Adverse effects were mostly of gastro-intestinal origin and dose dependent. Compared to sulphonylurea, acarbose decreased fasting and post-load insulin levels by -24.8 pmol/L (95% confidence interval -43.3 to -6.3) and -133.2 pmol/L (95% confidence interval -184.5 to -81.8) respectively and acarbose caused more adverse effects. It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated hemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.
The previous version of this review included no trials. We identified two trials that could be included from the 2015 and 2017 searches. They randomised 30 in- and outpatients with schizophrenia in the USA and Germany. Overall, the risk of bias was unclear, mainly due to poor reporting: allocation concealment was not described; generation of the sequence was not explicit; studies were not clearly blinded; and outcome data were not fully reported. Findings were sparse. One study reported on the primary outcomes and found that significantly more participants allocated to procyclidine (anticholinergic) had not improved to a clinically important extent compared with those allocated to isocarboxazid (MAO-inhibitor) after 40 weeks' treatment (1 RCT, n = 20; RR 4.20, 95% CI 1.40 to 12.58; very low quality evidence); that there was no evidence of a difference in the incidence of any adverse effects (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence); or acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence). The other trial compared anticholinergic withdrawal with anticholinergic continuation and found no evidence of a difference in the incidence of acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 10; RR 2.14, 95% CI 0.11 to 42.52; very low quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life — outcomes designated important to patients. No studies comparing either i. anticholinergics with placebo or no treatment, or ii. studies of anticholinergic withdrawal, were found that reported on the primary outcome 'no clinically important improvement in TD symptoms and adverse events'. Based on currently available evidence, no confident statement can be made about the effectiveness of anticholinergics to treat people with antipsychotic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with antipsychotic-induced TD should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow-up.
We identified five trials. There were 1633 participants in the narrow excision margin group and 1664 in the wide excision margin group. Narrow margin definition ranged from 1 to 2 cm; wide margins ranged from 3 to 5 cm. Median follow-up ranged from 5 to 16 years. This systematic review summarises the evidence regarding width of excision margins for primary cutaneous melanoma. None of the five published trials, nor our meta-analysis, showed a statistically significant difference in overall survival between narrow or wide excision. The summary estimate for overall survival favoured wide excision by a small degree [Hazard Ratio 1.04; 95% confidence interval 0.95 to 1.15; P = 0.40], but the result was not significantly different. This result is compatible with both a 5% relative reduction in overall mortality favouring narrower excision and a 15% relative reduction in overall mortality favouring wider excision. Therefore, a small (but potentially important) difference in overall survival between wide and narrow excision margins cannot be confidently ruled out. The summary estimate for recurrence free survival favoured wide excision [Hazard Ratio 1.13; P = 0.06; 95% confidence interval 0.99 to 1.28] but again the result did not reach statistical significance (P < 0.05 level). Current randomised trial evidence is insufficient to address optimal excision margins for primary cutaneous melanoma.
We included nine RCTs involving 407 adults with asthma in this review; no studies included adolescents under 18. Study size ranged from 10 to 94 (median 40), and mean age ranged from 39 to 53. Study populations generally had persistent asthma, but severity and diagnostic measures varied. Three studies recruited participants with psychological symptomatology, although with different criteria. Interventions ranged from 4 to 15 sessions, and primary measurements were taken at a mean of 3 months (range 1.2 to 12 months). Participants given CBT had improved scores on the Asthma Quality of Life Questionnaire (AQLQ) (MD 0.55, 95% confidence interval (CI) 0.17 to 0.93; participants = 214; studies = 6; I2 = 53%) and on measures of asthma control (SMD -0.98, 95% CI -1.76 to -0.20; participants = 95; studies = 3; I2 = 68%) compared to people getting usual care. The AQLQ effect appeared to be sustained up to a year after treatment, but due to its low quality this evidence must be interpreted with caution. As asthma exacerbations requiring at least a course of oral steroids were not consistently reported, we could not perform a meta-analysis. Anxiety scores were difficult to pool but showed a benefit of CBT compared with usual care (SMD -0.38, 95% CI -0.73 to -0.03), although this depended on the analysis used. The confidence intervals for the effect on depression scales included no difference between CBT and usual care when measured as change from baseline (SMD -0.33, 95% CI -0.70 to 0.05) or endpoint scores (SMD -0.41, 95% CI -0.87 to 0.05); the same was true for medication adherence (MD -1.40, 95% CI -2.94 to 0.14; participants = 23; studies = 1; I2 = 0%). Subgroup analyses conducted on the AQLQ outcome did not suggest a clear difference between individual and group CBT, baseline psychological status, or CBT model. The small number of studies and the variation between their designs, populations, and other intervention characteristics limited the conclusions that could be drawn about these possibly moderating factors. The inability to blind participants and investigators to group allocation introduced significant potential bias, and overall we had low confidence in the evidence. For adults with persistent asthma, CBT may improve quality of life, asthma control, and anxiety levels compared with usual care. Risks of bias, imprecision of effects, and inconsistency between results reduced our confidence in the results to low, and evidence was lacking regarding the effect of CBT on asthma exacerbations, unscheduled contacts, depression, and medication adherence. There was much variation between studies in how CBT was delivered and what constituted usual care, meaning the most optimal method of CBT delivery, format, and target population requires further investigation. There is currently no evidence for the use of CBT in adolescents with asthma.
Six trials with 3847 participants met our inclusion criteria. Trials were conducted in areas of low malaria endemicity (three trials), and moderate to high endemicity (three trials). Four trials were in areas of seasonal malaria transmission. Iron was given to all children in two trials, and evaluated in a factorial design in a further two trials. IPT for children with anaemia probably has little or no effect on the proportion anaemic at 12 weeks follow-up (four trials, 2237 participants, (moderate quality evidence). IPT in anaemic children probably increases the mean change in haemoglobin levels from baseline to follow-up at 12 weeks on average by 0.32 g/dL (MD 0.32, 95% CI 0.19 to 0.45; four trials, 1672 participants, moderate quality evidence); and may improve haemoglobin levels at 12 weeks (MD 0.35, 95% CI 0.06 to 0.64; four trials, 1672 participants, low quality evidence). For both of these outcomes, subgroup analysis did not demonstrate a difference between children receiving iron and those that did not. IPT for children with anaemia probably has little or no effect on mortality or hospital admissions at six months (three trials, 3160 participants moderate quality evidence). Subgroup analysis did not show a difference between those children receiving iron supplements and those that did not. Trials did show a small effect on average haemoglobin levels but this did not appear to translate into an effect on mortality and hospital admissions. Three of the six trials were conducted in low endemicity areas where transmission is low and thus any protective effect is likely to be modest.
We included 28 trials, encompassing 5939 randomized patients. The atypical antibiotic was administered as monotherapy in all but three studies. Only one study assessed a beta-lactam combined with a macrolide compared to the same beta-lactam. There was no difference in mortality between the atypical arm and the non-atypical arm (RR 1.14; 95% CI 0.84 to 1.55), RR < 1 favors the atypical arm. The atypical arm showed an insignificant trend toward clinical success and a significant advantage to bacteriological eradication, which disappeared when evaluating methodologically high quality studies alone. Clinical success for the atypical arm was significantly higher for Legionella pneumophilae (L. pneumophilae) and non-significantly lower for pneumococcal pneumonia. There was no significant difference between the groups in the frequency of (total) adverse events, or those requiring discontinuation of treatment. However, gastrointestinal events were less common in the atypical arm (RR 0.70; 95% CI 0.53 to 0.92). Although the trials assessed different antibiotics, no significant heterogeneity was detected in the analyses. No benefit of survival or clinical efficacy was shown with empirical atypical coverage in hospitalized patients with CAP. This conclusion relates mostly to the comparison of quinolone monotherapy to beta-lactams. Further trials, comparing beta-lactam monotherapy to the same combined with a macrolide, should be performed.
Nine small trials involving 219 participants were included. Two trials compared HBOT versus sham therapy on acute closed soft tissue injuries (ankle sprain and medial collateral knee ligament injury respectively). The other seven trials examined the effect of HBOT on DOMS following eccentric exercise in unconditioned volunteers. All 32 participants of the ankle sprain trial returned to their normal activities. There were no significant differences between the two groups in time to recovery, functional outcomes, pain, or swelling. There was no difference between the two groups in knee function scores in the second acute injury trial; however, intention-to-treat analysis was not possible for this trial. Pooling of data from the seven DOMS trials showed significantly and consistently higher pain at 48 and 72 hours in the HBOT group (mean difference in pain score at 48 hours [0 to 10 worst pain] 0.88, 95% CI 0.09 to 1.67, P = 0.03) in trials where HBOT was started immediately. There were no differences between the two groups in longer-term pain scores or in any measures of swelling or muscle strength. No trial reported complications of HBOT but careful selection of participants was evident in most trials. There was insufficient evidence from comparisons tested within randomised controlled trials to establish the effects of HBOT on ankle sprain or acute knee ligament injury, or on experimentally induced DOMS. There was some evidence that HBOT may increase interim pain in DOMS. Any future use of HBOT for these injuries would need to have been preceded by carefully conducted randomised controlled trials which have demonstrated effectiveness.
Nine trials were included in the first published version of this review, and nine further trials have been included in four updates. The included studies cover a wide diversity of people, settings and types of influenza vaccination, and we pooled data from the studies that employed similar vaccines. Protective effects of inactivated influenza vaccine during the influenza season A single parallel-group trial, involving 696 children, was able to assess the protective effects of influenza vaccination. There was no significant reduction in the number, duration or severity of influenza-related asthma exacerbations. There was no difference in the forced expiratory volume in one second (FEV1) although children who had been vaccinated had better symptom scores during influenza-positive weeks. Two parallel-group trials in adults did not contribute data to these outcomes due to very low levels of confirmed influenza infection. Adverse effects of inactivated influenza vaccine in the first two weeks following vaccination Two cross-over trials involving 1526 adults and 712 children (over three years old) with asthma compared inactivated trivalent split-virus influenza vaccine with a placebo injection. These trials excluded any clinically important increase in asthma exacerbations in the two weeks following influenza vaccination (risk difference 0.014; 95% confidence interval -0.010 to 0.037). However, there was significant heterogeneity between the findings of two trials involving 1104 adults in terms of asthma exacerbations in the first three days after vaccination with split-virus or surface-antigen inactivated vaccines. There was no significant difference in measures of healthcare utilisation, days off school/symptom-free days, mean lung function or medication usage. Effects of live attenuated (intranasal) influenza vaccination There were no significant differences found in exacerbations or measures of lung function following live attenuated cold recombinant vaccine versus placebo in two small studies on 17 adults and 48 children. There were no significant differences in asthma exacerbations found for the comparison live attenuated vaccine (intranasal) versus trivalent inactivated vaccine (intramuscular) in one study on 2229 children (over six years of age). Uncertainty remains about the degree of protection that vaccination affords against asthma exacerbations that are related to influenza infection. Evidence from more recently published randomised trials of inactivated split-virus influenza vaccination indicates that there is no significant increase in asthma exacerbations immediately after vaccination in adults or children over three years of age. We were unable to address concerns regarding possible increased wheezing and hospital admissions in infants given live intranasal vaccination.
After initially screening 920 titles, 15 full-text articles were closely examined by two authors. We identified four cohort studies that met our inclusion criteria for data extraction, coding, and potential meta-analysis. Using the Newcastle-Ottawa Scale and Cochrane risk of bias assessments, all observational studies had cohorts that were representative of average (treated and untreated) HIV-infected children with Kaposi sarcoma. For all outcomes of interest, no study adjusted for any other potential confounders. Two of four observational studies either explicitly described complete follow up of the study participants and/or described the characteristics of the participants lost to follow up. The use of ART together with a chemotherapeutic regimen versus ART alone appears to increase the likelihood of KS remission in HIV-infected children diagnosed with KS, although data are sparse and not adequately adjusted for staging of disease and comorbidities. Additionally, though data are sparse, the use of ART together with a chemotherapeutic regimen versus chemotherapy alone in some analyses appears to increase the likelihood of KS remission and reduce the risk of death in HIV-infected children diagnosed with KS. In this analysis, we found that the quality of evidence was very low due to small sample sizes and a paucity of paediatric literature. Data describing the efficacy of different treatment options for pediatric KS, to include chemotherapy and ART, are sparse. However, the use of ART together with a chemotherapy regimen may be superior to the use of ART alone or of chemotherapy alone.
The search identified 61 reports but only two studies (total n=137) met the inclusion criteria. Both compared art therapy plus standard care with standard care alone. More people completed the therapy if allocated to the art therapy group compared with standard care in the short (n=90, 1 RCT, RR 0.97 CI 0.41 to 2.29), medium (n=47, 1 RCT, RR 0.34 CI 0.15 to 0.80) and long term (n=47, 1 RCT, RR 0.96 CI 0.57 to 1.60). Data from one mental state measure (SANS) showed a small but significant difference favouring the art-therapy group (n=73, 1 RCT, WMD -2.3 CI -4.10 to -0.5). In the short term, a measure of social functioning (SFS) showed no clear difference between groups in endpoint scores (n=70, 1 RCT, WMD 7.20 CI -2.53 to 16.93) and quality of life, as measured by the PerQoL, did not indicate effects of art therapy (n=74, 1 RCT, WMD 0.1 CI -2.7 to 0.47). Randomised studies are possible in this field. Further evaluation of the use of art therapy for serious mental illnesses is needed as its benefits or harms remain unclear.
For this second updated version we identified only one small trial reporting grade 4 toxicity results, without disease-free or overall survival data with a median follow-up of 16 months. From the first updated version, we identified three trials that were ongoing, and remain so in 2016. Four trials including 401 women with evaluable results with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Three trials compared chemotherapy combined with radiotherapy versus radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy versus radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size. Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (three trials, 321 women; risk ratio (RR) 6.26, 95% CI 2.50 to 15.67). We considered the evidence for all three outcomes to be of a moderate quality, using the GRADE approach due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease. In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no difference in disease recurrence between the groups (one trial, 71 women; HR = 1.34; 95% CI 0.24 to 7.66) and overall survival was not reported. We considered this evidence to be of a low quality. No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence. The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long term due to a lack of long-term data. This evidence is limited by the small numbers and low to moderate methodological quality of the included studies. We await the results of three ongoing trials, which are likely to have an important impact on our confidence in this evidence.
Seventeen trials (1811 participants), of poor to moderate quality, were included. There were more treatment failures with ORT (RD 4%, 95% confidence interval (CI) 1 to 7, random-effects model; 1811 participants, 18 trials; NNT = 25). Six deaths occurred in the IVT group and two in the ORT groups (4 trials). There were no significant differences in weight gain (369 participants, 6 trials), hyponatremia (248 participants, 2 trials) or hypernatremia (1062 participants, 10 trials), duration of diarrhea (960 participants, 8 trials), or total fluid intake at six hours (985 participants, 8 trials) and 24 hours (835 participants, 7 trials). Shorter hospital stays were reported for the ORT group (WMD -1.20 days, 95% CI -2.38 to -0.02 days; 526 participants, 6 trials). Phlebitis occurred more often in the IVT group (NNT 50, 95% CI 25 to 100) and paralytic ileus more often in the ORT group (NNT 33, 95% CI 20 to 100, fixed-effect model), but there was no significant difference between ORT using the low osmolarity solutions recommended by the World Health Organization and IVT (729 participants, 6 trials). Although no clinically important differences between ORT and IVT, the ORT group did have a higher risk of paralytic ileus, and the IVT group was exposed to risks of intravenous therapy. For every 25 children (95% CI 14 to 100) treated with ORT one would fail and require IVT.
In this 2013 update, we updated the searches, but identified only two new ongoing studies. The review includes four trials involving 139 participants. The primary outcome measure in each was pain relief. Three trials compared one of the oral non-antiepileptic drugs tizanidine, tocainide or pimozide with carbamazepine. The quality of evidence for all outcomes for which data were available was low. In a trial of tizanidine involving 12 participants (one dropped out due to unrelated disease), one of five participants treated with tizanidine and four of six treated with carbamazepine improved (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.05 to 1.89). Few side effects were noted with tizanidine. For pimozide, there was evidence of greater efficacy than carbamazepine at six weeks. Up to 83% of participants reported adverse effects but these did not lead to withdrawal; the report did not provide comparable data for carbamazepine. Limited data meant that we could not assess the effects of tocainide; however, data from non-randomised studies (not included in this review) indicate that serious haematological adverse events can occur. A trial involving 47 participants compared 0.5% proparacaine hydrochloride eyedrops with placebo but did not show any significant benefits, again according to low-quality evidence. The report did not mention adverse events. The proparacaine trial was at low risk of bias; the other trials were at unclear risk of bias overall. There is low-quality evidence that the effect of tizanidine is not significantly different than that of carbamazepine in treating trigeminal neuralgia. Pimozide is more effective than carbamazepine, although the evidence is of low quality and the data did not allow comparison of adverse event rates. There is also low-quality evidence that 0.5% proparacaine hydrochloride eye drops have no benefit over placebo. Limitations in the data for tocainide prevent any conclusions being drawn. There is insufficient evidence from randomised controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.
We found 13 eligible systematic reviews relevant to this overview that contained a total of 17 relevant RCTs. One review reported the results of a network meta-analysis and so presented information on indirect, as well as direct, treatment effects. Collectively the reviews reported findings for 11 different comparisons supported by direct data and 26 comparisons supported by indirect data only. Only four comparisons informed by direct data found evidence of a difference in wound healing between dressing types, but the evidence was assessed as being of low or very low quality (in one case data could not be located and checked). There was also no robust evidence of a difference between dressing types for any secondary outcomes assessed. There is currently no robust evidence for differences between wound dressings for any outcome in foot ulcers in people with diabetes (treated in any setting). Practitioners may want to consider the unit cost of dressings, their management properties and patient preference when choosing dressings.
Twenty-nine studies met the criteria for detailed scrutiny. However, none of these met the pre-determined criteria for comparative groups and none included comparisons between randomly allocated groups of pregnant women. While there is no doubt that penicillin is effective in the treatment of syphilis in pregnancy and the prevention of congenital syphilis, uncertainty remains about what are the optimal treatment regimens. Further studies are needed to evaluate treatment failure cases with currently recommended regimens and this should include an assessment of the role of HIV infection in cases of prenatal syphilis treatment failure. The effectiveness of various antibiotic regimens for the treatment of primary and secondary syphilis in pregnant women need to be assessed using randomised controlled trials which compare them with existing recommendations. This should include treatment with oral antibiotics which could be particularly relevant in resource-poor countries where the availability of safe needles and syringes cannot be guaranteed.
We included in the review two studies with a total of 30 randomly assigned participants. We rated the quality of the evidence as very low as the result of study limitations, small numbers of events, and small sample sizes, with imprecision in the confidence interval (CI). We were not able to perform meta-analysis because of heterogeneity related to the different interventions evaluated between included studies. Very low-quality evidence from one trial (20 participants) comparing effects of rivastigmine plus rehabilitation versus rehabilitation on overall USN at discharge showed the following: Barrage (mean difference (MD) 0.30, 95% confidence interval (CI) -0.18 to 0.78); Letter Cancellation (MD 10.60, 95% CI 2.07 to 19.13); Sentence Reading (MD 0.20, 95% CI -0.69 to 1.09), and the Wundt-Jastrow Area Illusion Test (MD -4.40, 95% CI -8.28 to -0.52); no statistical significance was observed for the same outcomes at 30 days' follow-up. In another trial (10 participants), study authors showed statistically significant reduction in omissions in the three cancellation tasks under transdermal nicotine treatment (mean number of omissions 2.93 ± 0.5) compared with both baseline (4.95 ± 0.8) and placebo (5.14 ± 0.9) (main effect of treatment condition: F (2.23) = 11.06; P value < 0.0001). One major adverse event occurred in the transdermal nicotine treatment group, and treatment was discontinued in the affected participant. None of the included trials reported data on several of the prespecified outcomes (falls, balance, depression or anxiety, poststroke fatigue, and quality of life). The quality of the evidence from available RCTs was very low. The effectiveness and safety of pharmacological interventions for USN after stroke are therefore uncertain. Additional large RCTs are needed to evaluate these treatments.
Thirty five studies have been analyzed on the treatment of tubal ectopic pregnancy, describing 25 different comparisons.   Surgery  Laparoscopic salpingostomy is significantly less successful than the open surgical approach in the elimination of tubal ectopic pregnancy (2 RCTs, n = 165, OR 0.28, 95% confidence interval (CI) 0.09 to 0.86) due to a significant higher persistent trophoblast rate in laparoscopic surgery (OR 3.5, 95% CI 1.1 to 11). However, the laparoscopic approach is significantly less costly than open surgery (P = 0.03). Long term follow up (n = 127) shows no evidence of a difference in intra uterine pregnancy rate (OR 1.2, 95% CI 0.59 to 2.5) but there is a non significant tendency to a lower repeat ectopic pregnancy rate (OR 0.47, 95% 0.15 to 1.5). Medical treatment  Systemic methotrexate in a fixed multiple dose intramuscular regimen has a non significant tendency to a higher treatment success than laparoscopic salpingostomy (1 RCT, n = 100, OR 1.8, 95% CI 0.73 to 4.6). No significant differences are found in long term follow up (n=74): intra uterine pregnancy (OR 0.82, 95% CI 0.32 to 2.1) and repeat ectopic pregnancy (OR 0.87, 95% CI 0.19 to 4.1). Expectant management  Expectant management is significantly less successful than prostaglandin therapy (1 RCT, n = 23, OR 0.08, 95% CI 0.02 to 0.39). In the surgical treatment of tubal ectopic pregnancy laparoscopic surgery is a cost effective treatment. An alternative non surgical treatment option in selected patients is medical treatment with systemic methotrexate. Expectant management can not be adequately evaluated yet.
Five studies compared low versus high protein intake. Improved weight gain and higher nitrogen accretion were demonstrated in infants receiving formula with higher protein content while other nutrients were kept constant. No significant differences were seen in rates of necrotizing enterocolitis, sepsis, or diarrhea. One study compared high versus very high protein intake during and after an initial hospital stay. Very high protein intake promoted improved gain in length at term, but differences did not remain significant at 12 weeks corrected age. Three of the 24 infants receiving very high protein intake developed uremia. A post-facto analysis revealed further improvement in all growth parameters in infants receiving formula with higher protein content. No significant difference in the concentration of plasma phenylalanine was noted between high and low protein intake groups. However, one study (Goldman 1969) documented a significantly increased incidence of low intelligence quotient (IQ) scores among infants of birth weight less than 1300 grams who received a very high protein intake (6 to 7.2 g/kg). Higher protein intake (≥ 3.0 g/kg/d but < 4.0 g/kg/d) from formula accelerates weight gain. However, limited information is available regarding the impact of higher formula protein intake on long-term outcomes such as neurodevelopmental abnormalities. Available evidence is not adequate to permit specific recommendations regarding the provision of very high protein intake (> 4.0 g/kg/d) from formula during the initial hospital stay or after discharge.
One RCT involving 36 patients with generalised anxiety disorder was eligible for inclusion. This was a 4 week pilot study of valerian, diazepam and placebo. There were no significant differences between the valerian and placebo groups in HAM-A total scores, or in somatic and psychic factor scores. Similarly, there were no significant differences in HAM-A scores between the valerian and diazepam groups, although based on STAI-Trait scores, significantly greater symptom improvement was indicated in the diazepam group. There were no significant differences between the three groups in the number of patients reporting side effects or in dropout rates. Since only one small study is currently available, there is insufficient evidence to draw any conclusions about the efficacy or safety of valerian compared with placebo or diazepam for anxiety disorders. RCTs involving larger samples and comparing valerian with placebo or other interventions used to treat of anxiety disorders, such as antidepressants, are needed.
We included 15 studies that involved 1101 children in this updated review. One study was added as a result of our 2012 search, another previously included study was removed due to lack of randomization. Fourteen included studies compared NSAIDs with other analgesics or placebo and reported on bleeding requiring surgical intervention. The use of NSAIDs was associated with a non-significant increase in the risk of bleeding requiring surgical intervention: Peto odds ratio (OR) 1.69 (95% confidence interval (CI) 0.71 to 4.01). Ten studies involving 365 children reported perioperative bleeding requiring non-surgical intervention. NSAIDs did not significantly alter the number of perioperative bleeding events requiring non-surgical intervention: Peto OR 0.99 (95% CI 0.41 to 2.40) but the confidence intervals did not exclude an increased risk. Thirteen studies involving 1021 children reported postoperative vomiting. There was less vomiting when NSAIDs were used as part of the analgesic regime than when NSAIDs were not used: Mantel Haenszel (M-H) risk ratio (RR) 0.72 (95% CI 0.61 to 0.85). There is insufficient evidence to exclude an increased risk of bleeding when NSAIDs are used in paediatric tonsillectomy. They do however confer the benefit of a reduction in vomiting.
Five studies (combined total n=998) met inclusion criteria. Four studies (n=724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs n=353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT n=240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT n=236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT n=94, RR 0.96 CI 0.3 to 3.6). Two studies contributed data to assessment of adverse effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. One trial suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (n=80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison. One study contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (n=92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One other study contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (n=89, MD 0.01 CI -0.6 to 0.6) and global improvement (n=89, MD -0.03 CI -0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria. With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia.
We included eight trials of influenza vaccination compared with placebo or no vaccination, with 12,029 participants receiving at least one vaccination or control treatment. We included six new studies (n = 11,251), in addition to the two included in the previous version of the review. Four of these trials (n = 10,347) focused on prevention of influenza in the general or elderly population and reported cardiovascular outcomes among their safety analyses; four trials (n = 1682) focused on prevention of cardiovascular events in patients with established coronary heart disease. These populations were analysed separately. Follow-up continued between 42 days and one year. Five RCTs showed deficits in at least three of the risk of bias criteria assessed. When reported (seven studies), vaccination provided adequate immunogenicity or protection against influenza. Cardiovascular mortality was reported by four secondary prevention trials and was significantly reduced by influenza vaccination overall (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.26 to 0.76; P value 0.003) with no significant heterogeneity between studies, and by three trials reporting cardiovascular mortality as part of their safety analyses when the numbers of events were too small to permit conclusions. In studies of patients with coronary heart disease, composite outcomes of cardiovascular events tended to be decreased with influenza vaccination compared with placebo. Generally no significant difference was found between comparison groups regarding individual outcomes such as myocardial infarction. In patients with cardiovascular disease, influenza vaccination may reduce cardiovascular mortality and combined cardiovascular events. However, studies had some risk of bias, and results were not always consistent, so additional higher-quality evidence is necessary to confirm these findings. Not enough evidence was available to establish whether influenza vaccination has a role to play in the primary prevention of cardiovascular disease.
For viable lesions in children, there were no trials. For viable lesions in adults, no difference was detected for albendazole compared with no treatment for recurrence of seizures (116 participants, one trial); but fewer participants with albendazole had lesions at follow up (RR 0.56, 95% CI 0.45 to 0.70; 192 participants, two trials). For non-viable lesions in children, seizures recurrence was less common with albendazole compared with no treatment (RR 0.49, 95% CI 0.32 to 0.75; 329 participants, four trials). There was no difference detected in the persistence of lesions at follow up (570 participants, six trials). For non-viable lesions in adults, there were no trials. In trials including viable, non-viable or mixed lesions (in both children and adults), headaches were more common with albendazole alone (RR 9.49, 95% CI 1.40 to 64.45; 106 participants, two trials), but no difference was detected in one trial giving albendazole with corticosteroids (116 participants, one trial). In patients with viable lesions, evidence from trials of adults suggests albendazole may reduce the number of lesions. In trials of non-viable lesions, seizure recurrence was substantially lower with albendazole, which is counter-intuitive. It may be that steroids influence headache during treatment, but further research is needed to test this.
We found two randomised controlled trials fulfilling the inclusion criteria of our review. The trials provided data for meta-analysis. We judged the two trials as trials at low risk of bias. The two trials randomised a total of 213 infants to glucocorticosteroids versus placebo. In our Trial Sequential Analysis, the required information size (that is, the meta-analytic sample size) was not reached for any outcome. Trials were funded by charities, public organisations, and received support from private sector companies, none of which seemed to have an interest in the outcome of the respective trials. The effect of glucocorticosteroids after Kasai portoenterostomy on all-cause mortality is uncertain; the confidence interval is consistent with appreciable benefit and harm (RR 1.00; 95% CI 0.14 to 6.90; low-certainty evidence). The results showed little or no difference in adverse effects between the use of glucocorticosteroids or placebo after Kasai portoenterostomy, however this analysis was based on a single trial and we have low certainty in the result (RR 1.02; 95% CI 0.87 to 1.20;). Available data suggest that the proportions of infants who do not clear their jaundice at six months is similar between the two groups (RR 0.89; 95% CI 0.67 to 1.17; low-certainty evidence). All-cause mortality or liver transplantation did not differ at two years between the two groups (RR 1.00; 95% CI 0.72 to 1.39; low-certainty evidence). There were no data regarding health-related quality of life. Our searches also yielded 19 observational studies, some of them containing limited information on harmful effects of glucocorticosteroid treatment. We presented the extracted information narratively. We identified one further ongoing trial with no currently available results. The two meta-analysed randomised clinical trials present insufficient evidence to determine the effects of using glucocorticosteroids versus placebo after Kasai portoenterostomy in infants with biliary atresia on any of the primary or secondary review outcomes. There is insufficient evidence to support glucocorticosteroid use in the postoperative management of infants with biliary atresia for long-term outcomes of all-cause mortality or liver transplantation. It is also unclear if glucocorticosteroids are able to reduce the numbers of infants who did not clear their jaundice by six months. Further randomised, placebo-controlled trials are required to be able to determine if glucocorticosteroids may be of benefit in the postoperative management of infants with biliary atresia treated with Kasai portoenterostomy. Such trials need to be conducted as multicentre trials.
Six studies (four RCTs and two prospective observational cohort studies), involving 7999 participants comparing supervised OST treatment with unsupervised treatment, met the inclusion criteria. The risk of bias was generally moderate across trials, but the results reported on outcomes that we planned to consider were limited. Overall, we judged the quality of the evidence from very low to low for all the outcomes. We found no difference in retention at any duration with supervised compared to unsupervised dosing (RR 0.99, 95% CI 0.88 to 1.12, 716 participants, four trials, low-quality evidence) or in retention in the shortest follow-up period, three months (RR 0.94; 95% CI 0.84 to 1.05; 472 participants, three trials, low-quality evidence). Additional data at 12 months from one observational study found no difference in retention between groups (RR 0.94, 95% CI 0.77 to 1.14; n = 300).There was no difference in abstinence at the end of treatment (self-reported drug use) (67% versus 60%, P = 0.33, 293 participants, one trial, very low-quality evidence); and in diversion of medication (5% versus 2%, 293 participants, one trial, very low-quality evidence). Regarding our secondary outcomes, we did not found a difference in the incidence of adverse effects in the supervised compared to unsupervised control group (RR 0.63; 96% CI 0.10 to 3.86; 363 participants, two trials, very low-quality evidence). Data on severity of dependence were very limited (244 participants, one trial) and showed no difference between the two approaches. Data on deaths were reported in two studies. One trial reported two deaths in the supervised group (low-quality evidence), while in the cohort study all-cause mortality was found lower in regular supervision group (crude mortality rate 0.60 versus 0.81 per 100 person-years), although after adjustment insufficient evidence existed to suggest that regular supervision was protective (mortality rate ratio = 1.23, 95% CI = 0.67 to 2.27). No studies reported pain symptoms, drug craving, aberrant opioid-related behaviours, days of unsanctioned opioid use and overdose. Take-home medication strategies are attractive to treatment services due to lower costs, and place less restrictions on clients, but it is unknown whether they may be associated with increased risk of diversion and unsanctioned use of medication. There is uncertainty about the effects of supervised dosing compared with unsupervised medication due to the low and very low quality of the evidence for the primary outcomes of interest for this review. Data on defined secondary outcomes were similarly limited. More research comparing supervised and take-home medication strategies is needed to support decisions on the relative effectiveness of these strategies. The trials should be designed and conducted with high quality and over a longer follow-up period to support comparison of strategies at different stages of treatment. In particular, there is a need for studies assessing in more detail the risk of diversion and safety outcomes of using supervised OST to manage opioid dependence.
Eight studies, recruiting over 700 participants, compared the use of dental cavity liners to no liners for Class I and Class II resin-based composite restorations. Seven studies evaluated postoperative hypersensitivity measured by various methods. All studies were at unclear or high risk of bias. There was inconsistent evidence regarding postoperative hypersensitivity (either measured using cold response or patient-reported), with a benefit shown at some, but not all, time points (low-quality evidence). Four trials measured restoration longevity. Two of the studies were judged to be at high risk and two at unclear risk of bias. No difference in restoration failure rates were shown at 1 year follow-up, with no failures reported in either group for three of the four studies; the fourth study had a risk ratio (RR) 1.00 (95% confidence interval (CI) 0.07 to 15.00) (low-quality evidence). Three studies evaluated restoration longevity at 2 years follow-up and, again, no failures were shown in either group. No adverse events were reported in any of the included studies. There is inconsistent, low-quality evidence regarding the difference in postoperative hypersensitivity subsequent to placing a dental cavity liner under Class I and Class II posterior resin-based composite restorations in permanent posterior teeth in adults or children 15 years or older. Furthermore, no evidence was found to demonstrate a difference in the longevity of restorations placed with or without dental cavity liners.
Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta-analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low certainty evidence), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate certainty evidence) and minor bleeding (RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate certainty evidence). The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence). The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for bleeding. Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
A total of 14 RCTs, with 4732 participants, were included in this review covering short-term (≤ 4 weeks; 6 studies), medium-term (> 4 weeks ≤ 6 months; 6 studies) and long-term treatment (> 6 months; 2 studies) with eszopiclone. Most RCTs included in the review included participants aged between 18 and 64 years, three RCTs only included elderly participants (64 to 85 years) and one RCT included participants with a broader age range (35 to 85 years). Seven studies considered primary insomnia; the remaining studies considered secondary insomnia comorbid with depression (2), generalised anxiety (1), back pain (1), Parkinson's disease (1), rheumatoid arthritis (1) and menopausal transition (1). Meta-analytic integrations of participant-reported data on sleep efficacy outcomes demonstrated better results for eszopiclone compared to placebo: a 12-minute decrease of sleep onset latency (mean difference (MD) -11.94 min, 95% confidence interval (CI) -16.03 to -7.86; 9 studies, 2890 participants, moderate quality evidence), a 17-minute decrease of wake time after sleep onset (MD -17.02 min, 95% CI -24.89 to -9.15; 8 studies, 2295 participants, moderate quality evidence) and a 28-minute increase of total sleep time (MD 27.70 min, 95% CI 20.30 to 35.09; 10 studies, 2965 participants, moderate quality evidence). There were no significant changes from baseline to the first three nights after drug discontinuation for sleep onset latency (MD 17.00 min, 95% CI -4.29 to 38.29; 1 study, 291 participants, low quality evidence) and wake time after sleep onset (MD -6.71 min, 95% CI -21.25 to 7.83; 1 study, 291 participants, low quality evidence). Adverse events during treatment that were documented more frequently under eszopiclone compared to placebo included unpleasant taste (risk difference (RD) 0.18, 95% CI 0.14 to 0.21; 9 studies, 3787 participants), dry mouth (RD 0.04, 95% CI 0.02 to 0.06; 6 studies, 2802 participants), somnolence (RD 0.04, 95% CI 0.02 to 0.06; 8 studies, 3532 participants) and dizziness (RD 0.03, 95% CI 0.01 to 0.05; 7 studies, 2933 participants). According to the GRADE criteria, evidence was rated as being of moderate quality for sleep efficacy outcomes and adverse events and of low quality for rebound effects and next-day functioning. Eszopiclone appears to be an efficient drug with moderate effects on sleep onset and maintenance. There was no or little evidence of harm if taken as recommended. However, as certain patient subgroups were underrepresented in RCTs included in the review, findings might not have displayed the entire spectrum of possible adverse events. Further, increased caution is required in elderly individuals with cognitive and motor impairments and individuals who are at increased risk of using eszopiclone in a non-recommended way.
We included seven RCTs conducted in low-income countries that involved 1529 children (780 with pneumonia and 749 with severe or very severe pneumonia). Four studies used a single 100,000 IU dose of vitamin D₃ at the onset of illness or within 24 hours of hospital admission; two used a daily dose of oral vitamin D₃ (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used a daily dose of oral vitamin D₃ (50,000 IU) for two days. One study reported microbiological and radiological diagnosis of pneumonia. The effects of vitamin D on outcomes were inconclusive when compared with control: time to resolution of acute illness (hours) (mean difference (MD) -0.95, 95% confidence interval (CI) -6.14 to 4.24; 3 studies; 935 children; low-quality evidence) mortality rate (risk ratio (RR) 0.97, 95% CI 0.06 to 15.28; 1 study; 193 children; very low-quality evidence); duration of hospitalisation (MD 0.49, 95% CI -8.41 to 9.4; 4 studies; 835 children; very low-quality evidence) and time to resolution of fever (MD 1.66, 95% CI -2.44 to 5.76; 4 studies; 584 children; very low-quality evidence). No major adverse events were reported. The GRADE assessment found very low-quality evidence (due to serious study limitations, inconsistencies, indirectness, and imprecision) for all outcomes except time to resolution of acute illness. One study was funded by the New Zealand Aid Corporation; one study was funded by an institutional grant; and five studies were unfunded. We are uncertain as to whether vitamin D has an important effect on outcomes because the results were imprecise. No major adverse events were reported. We assessed the quality of the evidence as very low to low. Several trials are ongoing and may provide additional information.
We included two trials that involved 294 infants. No new studies were included for the 2017 update. The incidence of death or BPD at 36 weeks' postmenstrual age was not statistically significantly different between infants who received inhaled or systemic steroids (RR 1.09, 95% CI 0.88 to 1.35; RD 0.05, 95% CI -0.07 to 0.16; 1 trial, N = 278). The incidence of BPD at 36 weeks' postmenstrual age among survivors was not statistically significant between groups (RR 1.34, 95% CI 0.94 to 1.90; RD 0.11, 95% CI -0.02 to 0.24; 1 trial, N = 206). There was no statistically significant difference in the outcomes of BPD at 28 days, death at 28 days or 36 weeks' postmenstrual age and the combined outcome of death or BPD by 28 days between groups (2 trials, N = 294). The duration of mechanical ventilation was significantly longer in the inhaled steroid group compared with the systemic steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%) as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%). The incidence of hyperglycaemia was significantly lower with inhaled steroids (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14; 1 trial, N = 278; NNTB 4, 95% CI 3 to 7 to avoid 1 infant experiencing hyperglycaemia). The rate of patent ductus arteriosus increased in the group receiving inhaled steroids (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33; 1 trial, N = 278; NNTH 5, 95% CI 3 to 10). In a subset of surviving infants in the United Kingdom and Ireland there were no significant differences in developmental outcomes at 7 years of age. However, there was a reduced risk of having ever been diagnosed as asthmatic by 7 years of age in the inhaled steroid group compared with the systemic steroid group (N = 48) (RR 0.42, 95% CI 0.19 to 0.94; RD -0.31, 95% CI -0.58 to -0.05; NNTB 3, 95% CI 2 to 20). According to GRADE the quality of the evidence was moderate to low. Evidence was downgraded on the basis of design (risk of bias), consistency (heterogeneity) and precision of the estimates. Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified. We found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.
We included eight studies meeting the inclusion criteria, but four double-blind, double-dummy studies of around 2000 people dominated the analyses. These four trials were between 14 and 24 weeks long, all comparing tiotropium (usually Respimat) with salmeterol on top of medium doses of ICS. Studies reporting exacerbations requiring OCS showed no difference between the two add-ons, but our confidence in the effect was low due to inconsistency between studies and because the confidence intervals (CI) included significant benefit of either treatment (odds ratio (OR) 1.05, 95% CI 0.50 to 2.18; 1753 participants; 3 studies); three more people per 1000 might have an exacerbation on LAMA, but the CIs ranged from 29 fewer to 61 more. Imprecision was also an issue for serious adverse events and exacerbations requiring hospital admission, rated low (serious adverse events) and very low quality (exacerbations requiring hospital admission), because there were so few events in the analyses. People taking LAMA scored slightly worse on two scales measuring quality of life (Asthma Quality of Life Questionnaire; AQLQ) and asthma control (Asthma Control Questionnaire; ACQ); the evidence was rated high quality but the effects were small and unlikely to be clinically significant (AQLQ: mean difference (MD) -0.12, 95% CI -0.18 to -0.05; 1745 participants; 1745; 4 studies; ACQ: MD 0.06, 95% CI 0.00 to 0.13; 1483 participants; 3 studies). There was some evidence to support small benefits of LAMA over LABA on lung function, including on our pre-specified preferred measure trough forced expiratory volume in one second (FEV1) (MD 0.05 L, 95% CI 0.01 to 0.09; 1745 participants, 4 studies). However, the effects on other measures varied, and it is not clear whether the magnitude of the differences were clinically significant. More people had adverse events on LAMA but the difference with LABA was not statistically significant. Direct evidence of LAMA versus LABA as add-on therapy is currently limited to studies of less than six months comparing tiotropium (Respimat) to salmeterol, and we do not know how they compare in terms of exacerbations and serious adverse events. There was moderate quality evidence that LAMAs show small benefits over LABA on some measures of lung function, and high quality evidence that LABAs are slightly better for quality of life, but the differences were all small. Given the much larger evidence base for LABA versus placebo for people whose asthma is not well controlled on ICS, the current evidence is not strong enough to say that LAMA can be substituted for LABA as add-on therapy. The results of this review, alongside pending results from related reviews assessing the use of LAMA in other clinical scenarios, will help to define the role of these drugs in asthma and it is important that they be updated as results from ongoing and planned trials emerge.
A total of 14 trials, including 364 randomised participants, met the selection criteria. The risk of bias was low in most studies. Only one trial had a high risk of selection, performance and detection bias. No new studies were identified at this update. Meta-analysis of six trials in muscular dystrophies including 192 participants revealed a significant increase in muscle strength in the creatine group compared to placebo, with a mean difference of 8.47%; (95% confidence intervals (CI) 3.55 to 13.38). Pooled data of four trials including 115 participants showed that a significantly higher number of participants felt better during creatine treatment compared to placebo with a risk ratio of 4.51 (95% CI 2.33 to 8.74). One trial in 37 participants with idiopathic inflammatory myopathies also showed a significant improvement in functional performance. No trial reported any clinically relevant adverse event. In metabolic myopathies, meta-analyses of three cross-over trials including 33 participants revealed no significant difference in muscle strength. One trial reported a significant deterioration of activities of daily living (mean difference 0.54 on a 1 to 10 scale; 95% CI 0.14 to 0.93) and an increase in muscle pain during high-dose creatine treatment in McArdle disease. High quality evidence from RCTs shows that short- and medium-term creatine treatment increases muscle strength in muscular dystrophies. There is also evidence that creatine improves functional performance in muscular dystrophy and idiopathic inflammatory myopathy. Creatine is well tolerated in these people. High quality but limited evidence from RCTs does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine treatment impaired activities of daily living and increased muscle pain in McArdle disease.
We identified 26 completed trials, of which 17 were randomised. Overall, counselling and educational interventions, with or without provision of free or discounted smoke alarms, modestly increased the likelihood of owning an alarm (OR = 1.21; 95% CI 0.89 to 1.64) and having an installed, functional alarm (OR = 1.33; 95% CI 0.98 to 1.80). Whether or not the intervention programme provided free or discounted smoke alarms in addition to education did not influence these results. The results were sensitive to trial quality, however. Counselling as part of primary care child health surveillance had somewhat greater effects on alarm ownership (OR = 1.96; 95% CI 1.03 to 3.72) and function (OR = 1.46; 95% CI 1.15 to 1.85), results that were generally supported by non-randomised trials evaluating similar interventions. Injury outcomes were reported in only one randomised controlled trial, which found no effect of a smoke alarm give-away programme on total injuries (rate ratio 1.3; 95% CI 0.9 to 1.9) or on hospitalizations and deaths (rate ratio 1.3; 95% CI 0.7 to 2.3), in contrast to the substantial reduction in serious injuries reported in a non-randomised trial that evaluated a similar give-away programme. Neither trial showed a beneficial effect on fires. Mass media and community education showed little benefit in multiple non-randomised trials. Two trials, one of which was randomised, showed that smoke alarm installation programmes increase the likelihood of having a working smoke alarm, and the non-randomised trial reported reductions in fire-related injuries. This review found that programmes to promote smoke alarms have at most modest beneficial effects on smoke alarm ownership and function, and no demonstrated beneficial effect on fires or fire-related injuries. Counselling as part of child health surveillance has a somewhat greater effect on smoke alarm ownership and function, but its effects on injuries are unevaluated. Community smoke alarm give-away programmes have not been demonstrated to increase smoke alarm prevalence or to reduce fires or fire-related injuries. Community-based education programmes have not been shown to reduce burns or fire-related injuries. Community smoke alarm installation programmes may increase the prevalence of working alarms and reduce fire-related injuries, but these results require confirmation, and the cost-effectiveness of such programmes has not been evaluated. Efforts to promote smoke alarms through installation programmes should be evaluated by adequately designed randomised controlled trials measuring injury outcomes and cost-effectiveness.
We included six RCTs (521 participants), comparing abdominal drainage and no drainage in patients undergoing emergency open appendectomy for complicated appendicitis. The studies were conducted in North America, Asia and Africa. The majority of the participants had perforated appendicitis with local or general peritonitis. All participants received antibiotic regimens after open appendectomy. None of the trials was at low risk of bias. There was insufficient evidence to determine the effects of abdominal drainage and no drainage on intra-peritoneal abscess at 14 days (RR 1.23, 95% CI 0.47 to 3.21; 5 RCTs; 453 participants; very low-quality evidence) or for wound infection at 14 days (RR 2.01, 95% CI 0.88 to 4.56; 5 RCTs; 478 participants; very low-quality evidence). The increased risk of 30-day overall complication rate (morbidity) in the drainage group was rated as very low-quality evidence (RR 6.67, 95% CI 2.13 to 20.87; 1 RCT; 90 participants). There were seven deaths in the drainage group (N = 183) compared to one in the no drainage group (N = 180), equating to an increase in the risk of 30-day mortality from 0.6% to 2.7% (Peto odds ratio (OR) 4.88, 95% CI 1.18 to 20.09; 4 RCTs; 363 participants; moderate-quality evidence). There is 'very low-quality' evidence that drainage increases hospital stay compared to the no drainage group by 2.17 days (95% CI 1.76 to 2.58; 3 RCTs; 298 participants).  Other outlined outcomes, hospital costs, pain, and quality of life, were not reported in any of the included studies. The quality of the current evidence is very low. The effect of abdominal drainage on the prevention of intra-peritoneal abscess or wound infection after open appendectomy is uncertain for patients with complicated appendicitis. The increased rates for overall complication rate and hospital stay for the drainage group compared to no drainage group is also subject to great uncertainty. Thus, there is no evidence for any clinical improvement by using abdominal drainage in patients undergoing open appendectomy for complicated appendicitis. The increased risk of mortality with drainage comes from eight deaths observed in just under 400 people recruited to the studies. Larger studies are needed to determine the effects of drainage on morbidity and mortality outcomes more reliably.
Six studies (484 participants) met our inclusion criteria. Five studies compared high volume PD with daily haemodialysis, extended daily haemodialysis, or continuous renal replacement therapy. One study focused on the intensity of PD. The overall risk of bias was low to unclear. Compared to extracorporeal therapy, PD probably made little or no difference to all-cause mortality (4 studies, 383 participants: RR 1.12, 95% CI 0.81 to 1.55; I2 = 69%; moderate certainty evidence), or kidney function recovery (3 studies, 333 participants: RR 0.95, 95% CI 0.68 to 1.35; I2 = 0%; moderate certainty evidence). PD probably slightly reduces the amount of fluid removal compared to extracorporeal therapy (3 studies, 313 participants: MD -0.59 L/d, 95% CI -1.19 to 0.01; I2 = 89%; low certainty evidence), and probably made little or no difference to infectious complications (2 studies, 263 participants: RR 1.03, 95% CI 0.60 to 1.78; I2 = 0%; low certainty evidence). It is uncertain whether PD compared to extracorporeal therapy has any effects on weekly delivered Kt/V (2 studies, 263 participants: MD -2.47, 95% CI -5.17 to 0.22; I2 = 99%; very low certainty evidence), correction of acidosis (2 studies, 89 participants: RR 1.32, 95% CI 0.13 to 13.60; I2 = 96%; very low certainty evidence), or duration of dialysis (2 studies, 170 participants: MD -1.01 hours, 95% CI -91.49 to 89.47; I2 = 98%; very low certainty evidence). Heterogeneity was high and this may be due to the different extracorporeal therapies used. One study (61 participants) reported little or no difference to all-cause mortality, kidney function recovery, or infection between low and high and intensity PD. Weekly delivered Kt/V and fluid removal was lower with low compared to high intensity PD. Based on moderate (mortality, recovery of kidney function), low (infectious complications), or very low certainty evidence (correction of acidosis) there is probably little or no difference between PD and extracorporeal therapy for treating AKI. Fluid removal (low certainty) and weekly delivered Kt/V (very low certainty) may be higher with extracorporeal therapy.
There were no randomised controlled trials (RCTs) that reported results in terms of the review's primary outcome of interest, weight gain or maintenance. However, we identified one RCT that assessed the effect of intravenous immunoglobulin on swallowing function in people with IBM. The trial authors did not specify the number of study participants who had dysphagia. There was also incomplete reporting of findings from videofluoroscopic investigations, which was one of the review's secondary outcome measures. The study did report reductions in the time taken to swallow, as measured using ultrasound. No serious adverse events occurred during the study, although data for the follow-up period were lacking. It was also unclear whether the non-serious adverse events reported occurred in the treatment group or the placebo group. We assessed this study as having a high risk of bias and uncertain confidence intervals for the review outcomes, which limited the overall quality of the evidence. Using GRADE criteria, we downgraded the quality of the evidence from this RCT to 'low' for efficacy in treating dysphagia, due to limitations in study design and implementation, and indirectness in terms of the population and outcome measures. Similarly, we assessed the quality of the evidence for adverse events as 'low'. From our search for RCTs, we identified two other non-randomised studies, which reported the effects of long-term intravenous immunoglobulin therapy in adults with IBM and lip-strengthening exercises in children with myotonic dystrophy type 1. Headaches affected two participants treated with long-term intravenous immunoglobulin therapy, who received a tailored dose reduction; there were no adverse events associated with lip-strengthening exercises. Both non-randomised studies identified improved outcomes for some participants following the intervention, but neither study specified the number of participants with dysphagia or demonstrated any group-level treatment effect for swallowing function using the outcomes prespecified in this review. There is insufficient and low-quality RCT evidence to determine the effect of interventions for dysphagia in long-term, progressive muscle disease. Clinically relevant effects of intravenous immunoglobulin for dysphagia in inclusion body myositis can neither be confirmed or excluded using the evidence presented in this review. Standardised, validated, and reliable outcome measures are needed to assess dysphagia and any possible treatment effect. Clinically meaningful outcomes for dysphagia may require a shift in focus from measures of impairment to disability associated with oral feeding difficulties.
We included three trials involving 1671 participants; oxytocin was the only uterotonic drug that was used. The dose and route of administration of oxytocin varied among the included studies. Administration of oxytocin before and after the expulsion of placenta does not significantly influence the incidence of postpartum haemorrhage (blood loss greater than 500 ml) (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.62 to 1.04; n = 1667, three trials); retained placenta (RR 1.54, 95% CI 0.76 to 3.11; n = 1667, three trials); length of third stage of labour (minutes) (mean difference (MD) -0.30, 95% CI -0.95 to 0.36; n = 1667, three trials); postpartum blood loss (ml) (MD 22.32, 95% CI -58.21 to 102.86; n = 181, two trials); changes in haemoglobin (g/dL) (MD 0.06, 95% CI -0.60 to 0.72; n = 51, one trial); blood transfusion (RR 0.79, 95% CI 0.23 to 2.73; n = 1667, three trials); the use of additional uterotonics (RR 1.10, 95% CI 0.80 to 1.52; n = 1667, three trials); the incidence of maternal hypotension (RR 2.48, 95% CI 0.23 to 26.70; n = 130, one trial) and the incidence of severe postpartum haemorrhage (blood loss 1000 ml or more) (RR 0.98, 95% CI 0.48 to 1.98; n = 130, one trial). No data on other maternal or neonatal outcome measures were available. Administration of oxytocin before and after the expulsion of placenta did not have any significant influence on many clinically important outcomes such as the incidence of postpartum haemorrhage, rate of placental retention and the length of the third stage of labour. However, the number of available studies were limited. The only uterotonic drug used was oxytocin, mainly through intravenous infusion, therefore its extrapolation to other routes of administration should be interpreted cautiously. More studies are required to examine other maternal and neonatal outcomes using consistent approaches.
The meta-analysis included 894 men. No studies reported live birth. The combined fixed-effect odds ratio (OR) of the 10 studies for the outcome of pregnancy was 1.47 (95% confidence interval (CI) 1.05 to 2.05, very low quality evidence), favouring the intervention. The number needed to treat for an additional beneficial outcome was 17, suggesting benefit of varicocele treatment over expectant management for pregnancy rate in subfertile couples in whom varicocele in the man was the only abnormal finding. Omission of the studies including men with normal semen analysis and subclinical varicocele, some of which had semen analysis improvement as the primary outcome rather than live birth or pregnancy rate, was the subject of a planned subgroup analysis. The outcome of the subgroup analysis (five studies) also favoured treatment, with a combined OR 2.39 (95% CI 1.56 to 3.66). The number needed to treat for an additional beneficial outcome was 7. The evidence was suggestive rather than conclusive, as the main analysis was subject to fairly high statistical heterogeneity (I2 = 67%) and findings were no longer significant when a random-effects model was used or when analysis was restricted to higher quality studies. There is evidence suggesting that treatment of a varicocele in men from couples with otherwise unexplained subfertility may improve a couple's chance of pregnancy. However, findings are inconclusive as the quality of the available evidence is very low and more research is needed with live birth or pregnancy rate as the primary outcome.
Eight trials recruiting a total of 637 infants met the inclusion criteria for the systematic review. The infants included in the review were mainly formula-fed term infants. The trials were of variable methodological quality. Formula-fed term infants with GOR on feed thickeners had nearly two fewer episodes of regurgitation per day (mean difference -1.97 episodes per day, 95% confidence interval (CI) -2.32 to -1.61; 6 studies, 442 infants, moderate-certainty evidence) and were 2.5 times more likely to be asymptomatic from regurgitation at the end of the intervention period (risk ratio 2.50, 95% CI 1.38 to 4.51; number needed to treat for an additional beneficial outcome 5, 95% CI 4 to 13; 2 studies, 186 infants, low-certainty evidence) when compared to infants with GOR on unthickened feeds. No studies reported failure to thrive as an outcome. We found low-certainty evidence based on 2 studies recruiting 116 infants that use of feed thickeners improved the oesophageal pH probe parameters of reflux index (i.e. percentage of time pH < 4), number of reflux episodes lasting longer than 5 minutes, and duration of longest reflux episode. No major side effects were reported with the use of feed thickeners. Information was insufficient to conclude which type of feed thickener is superior. Gastro-oesophageal reflux is a physiological self resolving phenomenon in infants that does not necessarily require any treatment. However, we found moderate-certainty evidence that feed thickeners should be considered if regurgitation symptoms persist in term bottle-fed infants. The reduction of two episodes of regurgitation per day is likely to be of clinical significance to caregivers. Due to the limited information available, we were unable to assess the use of feed thickeners in infants who are breastfeeding or preterm nor could we conclude which type of feed thickener is superior.
Four trials were included (602 participants). Three trials were small single-centre trials, and the fourth a large multi-centre trial including 424 participants. All trials had methodological flaws, usually failure to conceal allocation and incomplete follow-up data, which put them at high risk of bias. Follow-up ranged from 1 to 15 years after treatment. Data for functional outcomes, including walking ability, from three trials could not be pooled. The strongest evidence was from the multi-centre trial. This showed no statistically or clinically significant differences between the surgical and conservatively treated groups at three years follow-up in the ''validated disease-specific" score (0 to 100: perfect result; 424 participants; mean difference (MD) 4.30, 95% confidence interval (CI) -1.11 to 9.71; P = 0.12). There was no significant difference between the two groups in the risk of chronic pain at follow-up (19/40 versus 24/42; risk ratio (RR) 0.79, 95% CI 0.53 to 1.18; 2 trials). The multi-centre trial found no statistically or clinically significant difference between the two groups in health-related quality of life at three years follow-up (SF-36 (0 to 100: best outcome): MD 4.00, 95% CI -1.16 to 9.16; P = 0.13). Two small trials provided some limited evidence of a tendency for a higher return to previous employment after surgery (27/34 versus 15/27; RR 1.45, 95% CI 0.75 to 2.81; I² = 55%; 2 trials). One small trial found no difference between the two groups in the ability to wear normal shoes, whereas another small trial found that surgery resulted in more people who were able to wear all shoes comfortably. There was a higher rate of major complications, such as surgical site infection, after surgery compared with conservative treatment (57/206 versus 42/218; RR 1.44, 95% CI 1.01 to 2.04; 1 trial). Conversely, significantly fewer surgical participants had subtalar arthrodeses due to the development of subtalar arthritis (7/206 versus 37/218; RR 0.20, 95% CI 0.09 to 0.44; 1 trial). There were no significant differences between the two groups in range of movement outcomes or radiological measurements (e.g. Bohler's angle). The bulk of the evidence in this review derives from one large multi-centre but inadequately reported trial conducted over 15 years ago. This found no significant differences between surgical or conservative treatment in functional ability and health related quality of life at three years after displaced intra-articular calcaneal fracture. Though it reported a greater risk of major complications after surgery, subtalar arthrodeses for the development of subtalar arthritis was significantly greater after conservative treatment. Overall, there is insufficient high quality evidence relating to current practice to establish whether surgical or conservative treatment is better for adults with displaced intra-articular calcaneal fracture. Evidence from adequately powered randomised, multi-centre controlled trials, assessing patient-centred and clinically relevant outcomes is required. However, it would be prudent to reassess this need after an update of the review that incorporates new evidence from a currently ongoing multi-centre trial.
Six trials with 658 participants met the inclusion criteria. At the time of this review, five trials were published in full text, and one study was available in abstract form only. No significant differences were demonstrated between the two delivery methods in terms of the need for hospital admission (RR 1.00, 95% CI 0.63 to 1.59), change in oxygen saturation (SMD -0.03, 95% CI -0.39 to 0.33), PEFR (SMD 0.04, 95% CI -0.72 to 0.80), clinical score (WMD 0.00, 95% CI -0.37 to 0.37), in terms of need for additional treatment (RR 1.18, 95% CI 0.84 to 1.65), or regarding change in heart rate per minute (SMD 0.09, 95% CI -0.24 to 0.42). Overall, this review did not identify a statistically significant difference between these two methods for delivering bronchodilator therapy to children with acute asthma or lower airways obstruction attacks. Care should be taken in the interpretation and applicability of our results because of the small number of RCTs along with few events available meeting the criteria for inclusion in the review, absence of the primary outcome of interest and other clinically important outcomes in the majority of included studies. The possible need for a face-mask in younger children using home-made spacers should also be considered in practice.
This is an update of a previous review. We included 27 studies with 3963 participants. The meta-analysis included 21 studies of 2721 participants. Seventeen studies compared multiple session early psychological intervention versus treatment as usual and four studies compared a multiple session early psychological intervention with active control condition. Low-certainty evidence indicated that multiple session early psychological interventions may be more effective than usual care in reducing PTSD diagnosis at three to six months' follow-up (RR 0.62, 95% CI 0.41 to 0.93; I2 = 34%; studies = 5; participants = 758). However, there was no statistically significant difference post-treatment (RR 1.06, 95% CI 0.85 to 1.32; I2 = 0%; studies = 5; participants = 556; very low-certainty evidence) or at seven to 12 months (RR 0.94, 95% CI 0.20 to 4.49; studies = 1; participants = 132; very low-certainty evidence). Meta-analysis indicated that there was no statistical difference in dropouts compared with usual care (RR 1.34, 95% CI 0.91 to 1.95; I2 = 34%; studies = 11; participants = 1154; low-certainty evidence) .At the primary endpoint of three to six months, low-certainty evidence indicated no statistical difference between groups in reducing severity of PTSD (SMD –0.10, 95% CI –0.22 to 0.02; I2 = 34%; studies = 15; participants = 1921), depression (SMD –0.04, 95% CI –0.19 to 0.10; I2 = 6%; studies = 7; participants = 1009) or anxiety symptoms (SMD –0.05, 95% CI –0.19 to 0.10; I2 = 2%; studies = 6; participants = 945). No studies comparing an intervention and active control reported outcomes for PTSD diagnosis. Low-certainty evidence showed that interventions may be associated with a higher dropout rate than active control condition (RR 1.61, 95% CI 1.11 to 2.34; studies = 2; participants = 425). At three to six months, low-certainty evidence indicated no statistical difference between interventions in terms of severity of PTSD symptoms (SMD –0.02, 95% CI –0.31 to 0.26; I2 = 43%; studies = 4; participants = 465), depression (SMD 0.04, 95% CI –0.16 to 0.23; I2 = 0%; studies = 2; participants = 409), anxiety (SMD 0.00, 95% CI –0.19 to 0.19; I2 = 0%; studies = 2; participants = 414) or quality of life (MD –0.03, 95% CI –0.06 to 0.00; studies = 1; participants = 239). None of the included studies reported on adverse events or use of health-related resources. While the review found some beneficial effects of multiple session early psychological interventions in the prevention of PTSD, the certainty of the evidence was low due to the high risk of bias in the included trials. The clear practice implication of this is that, at present, multiple session interventions aimed at everyone exposed to traumatic events cannot be recommended. There are a number of ongoing studies, demonstrating that this is a fast moving field of research. Future updates of this review will integrate the results of these new studies.
This updated review includes nine new studies, in total 26 studies with 28 comparisons and involving 2790 participants. No study of local paracervical versus general anaesthesia met our criteria. Ten studies compared local anaesthetic versus placebo. Paracervical local anaesthetic (PLA) reduced pain on cervical dilatation with a standardized mean difference (SMD) of 0.37 (95% CI 0.17 to 0.58) and a relative risk (RR) of severe pain of 0.16 (95% CI 0.06 to 0.74). PLA also reduced abdominal pain during, but not after, uterine intervention (SMD 0.74, 95% CI 0.28 to 1.19); there was no evidence of any effect on postoperative back or shoulder pain. Comparisons against no treatment did not demonstrate any effect of PLA. Five studies compared paracervical block with uterosacral block, intracervical block, or intrauterine topical anaesthesia. Two of these studies showed no significant difference in pain during the procedure. Compared to intrauterine instillation, PLA slightly reduced severe pain (from 8.3 to 7.6 on a 10-point scale), which may be negligible. Six studies compared PLA with sedation. There were no statistically significant differences in pain during or after the procedure, postoperative analgesia requirement, adverse effects, patient satisfaction, and the operator's perception of analgesia. We performed risk of bias assessment using six domains and found that more than half of the included studies had low risk of bias. We found that no technique provided reliable pain control in the 26 included studies. Some studies reported that women experienced severe pain (mean scores of 7 to 9 out of 10) during uterine intervention, irrespective of the analgesic technique used. We concluded that the available evidence fails to show whether paracervical block is inferior, equivalent, or superior to alternative analgesic techniques in terms of efficacy and safety for women undergoing cervical dilatation and uterine interventions. We suggest that woman are likely to consider the rates and severity of pain during uterine interventions when performed awake to be unacceptable in the absence of neuraxial blockade, which are unaltered by paracervical block.
We included 54 studies involving 2729 participants, most of which were of poor methodological quality. The studies evaluated endometrial biomarkers either in specific phases of the menstrual cycle or outside of it, and the studies tested the biomarkers either in menstrual fluid, in whole endometrial tissue or in separate endometrial components. Twenty-seven studies evaluated the diagnostic performance of 22 endometrial biomarkers for endometriosis. These were angiogenesis and growth factors (PROK-1), cell-adhesion molecules (integrins α3β1, α4β1, β1 and α6), DNA-repair molecules (hTERT), endometrial and mitochondrial proteome, hormonal markers (CYP19, 17βHSD2, ER-α, ER-β), inflammatory markers (IL-1R2), myogenic markers (caldesmon, CALD-1), neural markers (PGP 9.5, VIP, CGRP, SP, NPY, NF) and tumour markers (CA-125). Most of these biomarkers were assessed in single studies, whilst only data for PGP 9.5 and CYP19 were available for meta-analysis. These two biomarkers demonstrated significant diversity for the diagnostic estimates between the studies; however, the data were too limited to reliably determine the sources of heterogeneity. The mean sensitivities and specificities of PGP 9.5 (7 studies, 361 women) were 0.96 (95% confidence interval (CI) 0.91 to 1.00) and 0.86 (95% CI 0.70 to 1.00), after excluding one outlier study, and for CYP19 (8 studies, 444 women), they were were 0.77 (95% CI 0.70 to 0.85) and 0.74 (95% CI 0.65 to 84), respectively. We could not statistically evaluate other biomarkers in a meaningful way. An additional 31 studies evaluated 77 biomarkers that showed no evidence of differences in expression levels between the groups of women with and without endometriosis. We could not statistically evaluate most of the biomarkers assessed in this review in a meaningful way. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Although PGP 9.5 met the criteria for a replacement test, it demonstrated considerable inter study heterogeneity in diagnostic estimates, the source of which could not be determined. Several endometrial biomarkers, such as endometrial proteome, 17βHSD2, IL-1R2, caldesmon and other neural markers (VIP, CGRP, SP, NPY and combination of VIP, PGP 9.5 and SP) showed promising evidence of diagnostic accuracy, but there was insufficient or poor quality evidence for any clinical recommendations. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and using any non-invasive tests should only be undertaken in a research setting. We have also identified a number of biomarkers that demonstrated no diagnostic value for endometriosis. We recommend that researchers direct future studies towards biomarkers with high diagnostic potential in good quality diagnostic studies.
Thirteen randomized controlled trials were included in the analysis. The studies demonstrated an initial improvement in respiratory status (improved oxygenation and decreased need for ventilator support). The meta-analysis supports a significant decrease in the risk of any air leak (typical relative risk 0.47, 95% CI 0.39, 0.58; typical risk difference -0.16, 95% CI -0.21, -0.12), pneumothorax (typical relative risk 0.42, 95% CI 0.34, 0.52; typical risk difference -0.17, 95% CI -0.21, -0.13), and a significant decrease in the risk of pulmonary interstitial emphysema (typical relative risk 0.45, 95% CI 0.37, 0.55; typical risk difference -0.20, 95% CI -0.25, -0.15). There is a significant decrease in the risk of neonatal mortality (typical relative risk 0.68, 95% CI 0.57, 0.82; typical risk difference -0.09, 95% CI -0.13, -0.05), a significant decrease in the risk of mortality prior to hospital discharge (typical relative risk 0.63, 95% CI 0.44, 0.90; typical risk difference -0.10, 95% CI -0.18, -0.03) and a significant decrease in the risk of bronchopulmonary dysplasia (BPD) or death at 28 days of age (typical relative risk 0.83, 95% CI 0.77, 0.90; typical risk difference -0.11, 95 CI -0.16, -0.06). No differences are reported in the risk of patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, BPD or retinopathy of prematurity. Infants with established respiratory distress syndrome who receive animal derived surfactant extract treatment have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, a decreased risk of mortality, and a decreased risk of bronchopulmonary dysplasia or death.
Four studies enrolling a total of 179 participants with cystic fibrosis (143 (80%) were children aged 1 to 16 years) were included in this review. There was no study comparing a vaccine to a placebo or a whole virus vaccine to a subunit or split virus vaccine. Two studies compared an intranasal applied live vaccine to an intramuscular inactivated vaccine and the other two studies compared a split virus to a subunit vaccine and a virosome to a subunit vaccine (all intramuscular). The incidence of all reported adverse events was high depending on the type of influenza vaccine. The total adverse event rate ranged from 48 out of 201 participants (24%) for the intranasal live vaccine to 13 out of 30 participants (43%) for the split virus vaccine. With the limitation of a statistical low power there was no significant difference between the study vaccinations. None of the events were severe. All study influenza vaccinations generated a satisfactory serological antibody response. No study reported other clinically important benefits. There is currently no evidence from randomised studies that influenza vaccine given to people with cystic fibrosis is of benefit to them. There remains a need for a well-constructed clinical study, that assesses the effectiveness of influenza vaccination on important clinical outcome measures.
We identified 24 studies that enrolled a total of 8112 participants. However, there was significant heterogeneity in the comparators used and the outcomes measured, which limited the ability to pool data. Many of the studies did not report sufficient information in their methods to allow judgment of their risk of bias. From the information that was reported, three of the studies had a high risk of selection bias and one was at high risk of bias due to lack of blinding of the outcome assessors. None of the included studies reported the minimum clinically important difference for the outcomes that were measured. We have therefore reported results from the studies but have been unable to interpret whether differences were of clinical importance. The main findings of the review are as follows. Knowledge: There is low quality evidence that multimedia education was more effective than usual care (non-standardised education provided as part of usual clinical care) or no education (standardised mean difference (SMD) 1.04, 95% confidence interval (CI) 0.49 to1.58, six studies with 817 participants). There was considerable statistical heterogeneity (I2 = 89%), however, all but one of the studies favoured the multimedia group. There is moderate quality evidence that multimedia education was not more effective at improving knowledge than control multimedia interventions (i.e. multimedia programs that do not provide information about the medication) (mean difference (MD) of knowledge scores 2.78%, 95% CI -1.48 to 7.0, two studies with 568 participants). There is moderate quality evidence that multimedia education was more effective when added to a co-intervention (written information or brief standardised instructions provided by a health professional) compared with the co-intervention alone (MD of knowledge scores 24.59%, 95% CI 22.34 to 26.83, two studies with 381 participants). Skill acquisition: There is moderate quality evidence that multimedia education was more effective than usual care or no education (MD of inhaler technique score 18.32%, 95% CI 11.92 to 24.73, two studies with 94 participants) and written education (risk ratio (RR) of improved inhaler technique 2.14, 95% CI 1.33 to 3.44, two studies with 164 participants). There is very low quality evidence that multimedia education was equally effective as education by a health professional (MD of inhaler technique score -1.01%, 95% CI -15.75 to 13.72, three studies with 130 participants). Compliance with medications: There is moderate quality evidence that there was no difference between multimedia education and usual care or no education (RR of complying 1.02, 95% CI 0.96 to 1.08, two studies with 4552 participants). We could not determine the effect of multimedia education on other outcomes, including patient satisfaction, self-efficacy and health outcomes, due to an inadequate number of studies from which to draw conclusions. This review provides evidence that multimedia education about medications is more effective than usual care (non-standardised education provided by health professionals as part of usual clinical care) or no education, in improving both knowledge and skill acquisition. It also suggests that multimedia education is at least equivalent to other forms of education, including written education and education provided by a health professional. However, this finding is based on often low quality evidence from a small number of trials. Multimedia education about medications could therefore be considered as an adjunct to usual care but there is inadequate evidence to recommend it as a replacement for written education or education by a health professional. Multimedia education may be considered as an alternative to education provided by a health professional, particularly in settings where provision of detailed education by a health professional is not feasible. More studies evaluating multimedia educational interventions are required in order to increase confidence in the estimate of effect of the intervention. Conclusions regarding the effect of multimedia education were limited by the lack of information provided by study authors about the educational interventions, and variability in their content and quality. Studies testing educational interventions should provide detailed information about the interventions and comparators. Research is required to establish a framework that is specific for the evaluation of the quality of multimedia educational programs. Conclusions were also limited by the heterogeneity in the outcomes reported and the instruments used to measure them. Research is required to identify a core set of outcomes which should be measured when evaluating patient educational interventions. Future research should use consistent, reliable and validated outcome measures so that comparisons can be made between studies.
We identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% CI 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. We did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment. This review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias. Therefore, prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, we urge the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations.
Three trials, all classified at high risk of bias, contributed to this review (Miller 1961; BPSM 1995; Zivadinov 2001) resulting in a total of 183 participants (91 treated). Corticosteroid therapy did not reduce the risk of being worse at the end of follow-up (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.26 to 1.02) but there was a substantial heterogeneity between studies (I2: 78.4%). I. v. periodic high dose methylprednisolone (MP) was associated with a significant reduction in the risk of disability progression at 5 years in relapsing-remitting (RR) MS (OR 0.26, 95% CI 0.10 to 0.66), while oral continuous low dose prednisolone was not associated with any risk reduction in disability progression at 18 months (OR 1.23, 95% CI 0.43 to 3.56). Risk of experiencing at least one exacerbation at end of follow-up was not significantly reduced with corticosteroid treatment (OR 0.36; 95% CI 0.10 to 1.25).  Only one study recorded adverse events: in one patient i. v. MP was discontinued after the fourth pulse when he developed acute glomerulonephritis; a second patient was removed from the study after the fifth i. v. MP pulse because of severe osteoporosis. There is no enough evidence that long-term corticosteroid treatment delays progression of long term disability in patients with MS. Since one study at high risk of bias showed that the administration of pulsed high dose i. v. MP is associated with a significant reduction in the risk of long term disability progression in patients with RR MS, an adequately powered, high quality RCT is needed to investigate this finding.
Two trials met criteria for an RCT of antenatal psychosocial assessment. One trial examined the impact of an antenatal tool (ALPHA) on clinician awareness of psychosocial risk, and the capacity of the antenatal ALPHA to predict women with elevated postnatal Edinburgh Depression Scale (EDS) scores, finding a trend towards increased clinician awareness of 'high level' psychosocial risk where the ALPHA intervention had been used (relative risk (RR) 4.61 95% confidence interval (CI) 0.99 to 21.39). No differences between groups were seen for numbers of women with antenatal EDS scores, a score of greater than 9 being identified by ALPHA as of concern for depression (RR 0.69 95% CI 0.35 to 1.38); 139 providers. The other trial reported no differences in EPS scores greater than 12 at 16 weeks postpartum between the intervention (communication about the EDS scores with the woman and her healthcare providers plus a patient information booklet) and the standard care groups (RR 0.86 95% CI 0.61 to 1.21; 371 women). While the use of an antenatal psychosocial assessment may increase the clinician's awareness of psychosocial risk, neither of these small studies provides sufficient evidence that routine antenatal psychosocial assessment by itself leads to improved perinatal mental health outcomes. Further studies with better sample size and statistical power are required to further explore this important public health issue. It will also be important to examine outcomes up to one year postpartum not only for mother, but also infant and family.
We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare. There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy. Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare. Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.
We included 11 randomised controlled trials (RCTs) with a total of 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for HGG participants receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 (95% confidence interval (CI) 1.58 to 2.55, P < 0.00001), moderate GRADE quality evidence favouring postoperative radiotherapy. Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated versus conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17, P = 0.63), very low GRADE quality evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one patient in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was also similar between hypofractionated versus conventional radiotherapy in the subset of two trials (293 participants) which included 60 years and older participants with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46, P = 0.21), high GRADE quality evidence. There were two trials which compared hyperfractionated radiation therapy versus conventional radiation and one trial which compared accelerated radiation therapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiation therapy regimens were 4500 to 6000 cGy given in 180 to 200 cGy daily fractions, over 5 to 6 weeks. All these trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these randomized trials. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life. Postoperative conventional daily radiotherapy improves survival for adults with good performance status and HGG as compared to no postoperative radiotherapy. Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma. There is insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These poor prognosis HGG individuals have generally been excluded from the randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these poor prognosis patients.
We considered eight RCTs, including 332 participants, to be eligible for inclusion in the review. These trials were homogeneous and the overall risk of bias low. Five studies, in a total of 235 participants compared IVIg against placebo. One trial with 20 participants compared IVIg with plasma exchange, one trial compared IVIg with prednisolone in 32 participants, and one trial, newly included at this update, compared IVIg with intravenous methylprednisolone in 46 participants. A significantly higher proportion of participants improved in disability within one month after IVIg treatment as compared with placebo (risk ratio (RR) 2.40, 95% confidence interval (CI) 1.72 to 3.36; number needed to treat for an additional beneficial outcome 3.03 (95% CI 2.33 to 4.55), high quality evidence). Whether all these improvements are equally clinically relevant cannot be deduced from this analysis because each trial used different disability scales and definitions of significant improvement. In three trials, including 84 participants, the disability score could be transformed to the modified Rankin score, on which improvement of one point after IVIg treatment compared to placebo was barely significant (RR 2.40, 95% CI 0.98 to 5.83) (moderate quality evidence). Only one placebo-controlled study included in this review had a long-term follow-up. The results of this study suggest that IVIg improves disability more than placebo over 24 and 48 weeks. The mean disability score revealed no significant difference between IVIg and plasma exchange at six weeks (moderate quality evidence). There was no significant difference in improvement in disability on prednisolone compared with IVIg after two or six weeks, or on methylprednisolone compared to IVIg after two weeks or six months (moderate quality evidence). There were no statistically significant differences in frequencies of side effects between the three types of treatment for which data were available (IVg versus placebo or steroids). (moderate or high quality evidence) Mild and transient adverse events were found in 49% of participants treated with IVIg, while serious adverse events were found in six per cent. The evidence from RCTs shows that IVIg improves disability for at least two to six weeks compared with placebo, with an NNTB of three. During this period it has similar efficacy to plasma exchange, oral prednisolone and intravenous methylprednisolone. In one large trial, the benefit of IVIg persisted for 24 and possibly 48 weeks. Further research is needed to compare the long-term benefits as well as side effects of IVIg with other treatments.
We included two RCTs, seven CBA studies and two ITS studies. Nine studies with 7820 participants evaluated the screening process of pre-employment examinations as a whole, and two studies with 2164 participants evaluated the measures to mitigate the risks found following the screening process. The studies were too heterogeneous for statistical pooling of results. We rated the quality of the evidence for all outcomes as very low quality. The two new CBA studies both used historical controls and both had a high risk of bias. Of those studies that evaluated the screening process, there is very low quality evidence based on one RCT that a general examination for light duty work may not reduce the risk for sick leave (mean difference (MD) -0.09, 95% confidence interval (CI) -0.47 to 0.29). For army recruits, there is very low quality evidence based on one CBA study that there is a positive effect on fitness for duty after 12 months follow-up (odds ratio (OR) 0.40, 95% CI 0.19 to 0.85). We found inconsistent evidence of an effect of job-focused pre-employment examinations on the risk of musculoskeletal injuries in comparison with general or no pre-employment examination based on one RCT with high risk of bias, and four CBA studies. There is very low quality evidence based on one ITS study that incorporation of a bronchial challenge test may decrease occupational asthma (trend change -2.6, 95% CI -3.6 to -1.5) compared to a general pre-employment examination with lung function tests. Pre-employment examinations may also result in a rejection of the applicant for the new job. In six studies, the rates of rejecting job applicants increased because of the studied examinations , on average, from 2% to 35%, but not in one study. There is very low quality evidence based on two CBA studies that risk mitigation among applicants considered not fit for work at the pre-employment examination may result in a similar risk of work-related musculoskeletal injury during follow-up compared to workers considered fit for work at the health examination. There is very low quality evidence that a general examination for light duty work may not reduce the risk for sick leave, but may have a positive effect on fitness for duty for army recruits after 12 months follow-up. There is inconsistent evidence of an effect of job-focused pre-employment examinations on the risk of musculoskeletal injuries in comparison with general or no pre-employment examination. There is very low quality evidence that incorporation of a bronchial challenge test may decrease occupational asthma compared to a general pre-employment examination with lung function tests. Pre-employment examinations may result in an increase of rejecting job applicants in six out of seven studies. Risk mitigation based on the result of pre-employment examinations may be effective in reducing an increased risk for occupational injuries based on very low quality evidence. This evidence supports the current policy to restrict pre-employment examinations to only job-specific examinations. Better quality evaluation studies on pre-employment examinations are necessary, including the evaluation of the benefits of risk mitigation, given the effect on health and on the financial situation for those employees who do not pass the pre-employment examination.
Only one eligible study, involving 21 participants, was included. The study compared platelet-rich therapy and allogenic bone graft with allogenic bone graft alone in patients undergoing corrective osteotomy for medial compartment osteoarthrosis of the knee. The risk of bias associated with this study was substantial. There was no significant difference in patient-reported or clinician-assessed functional outcome scores between groups at one year. There was a statistically significant benefit from platelet-rich therapy in the proportion of bones that were united at one year (8/9 versus 3/9; RR 2.67; 95% CI 1.03 to 6.91). This benefit, however, was not maintained when assuming poor outcomes for participants who were lost to follow-up (8/11 versus 3/10; RR 2.42; 95% CI 0.88 to 6.68). One adverse event was reported in a participant receiving platelet-rich therapy. One other eligible study involving hip fracture patients is currently underway. While a potential benefit of platelet-rich therapies to augment long bone healing in adults cannot be ruled out, the currently available evidence from a single trial is insufficient to support the routine use of this intervention in clinical practice. Future trials should focus on reporting patient-reported functional outcomes from all trial participants for a minimum follow-up of one year.
We included 7 RCTs with a total of 923 participants: 529 randomised to an intervention and 394 to a comparator. The number of participants per trial ranged from 18 to 475. Six trials were parallel RCTs, and one was a cluster RCT. Two trials were three-arm trials, each comparing two interventions with a control group. The interventions and comparators in the trials varied. We categorised the comparisons into two groups: multicomponent interventions and dietary interventions. The overall quality of the evidence was low or very low, and six trials had a high risk of bias on individual 'Risk of bias' criteria. The children in the included trials were followed up for between six months and three years. In trials comparing a multicomponent intervention with usual care, enhanced usual care, or information control, we found a greater reduction in body mass index (BMI) z score in the intervention groups at the end of the intervention (6 to 12 months): mean difference (MD) -0.3 units (95% confidence interval (CI) -0.4 to -0.2); P < 0.00001; 210 participants; 4 trials; low-quality evidence, at 12 to 18 months' follow-up: MD -0.4 units (95% CI -0.6 to -0.2); P = 0.0001; 202 participants; 4 trials; low-quality evidence, and at 2 years' follow-up: MD -0.3 units (95% CI -0.4 to -0.1); 96 participants; 1 trial; low-quality evidence. One trial stated that no adverse events were reported; the other trials did not report on adverse events. Three trials reported health-related quality of life and found improvements in some, but not all, aspects. Other outcomes, such as behaviour change and parent-child relationship, were inconsistently measured. One three-arm trial of very low-quality evidence comparing two types of diet with control found that both the dairy-rich diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 59 participants) and energy-restricted diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 57 participants) resulted in greater reduction in BMI than the comparator at the end of the intervention period, but only the dairy-rich diet maintained this at 36 months' follow-up (BMI z score change in MD -0.7 units (95% CI -0.71 to -0.69); P < 0.0001; 52 participants). The energy-restricted diet had a worse BMI outcome than control at this follow-up (BMI z score change MD 0.1 units (95% CI 0.09 to 0.11); P < 0.0001; 47 participants). There was no substantial difference in mean daily energy expenditure between groups. Health-related quality of life, adverse effects, participant views, and parenting were not measured. No trial reported on all-cause mortality, morbidity, or socioeconomic effects. All results should be interpreted cautiously due to their low quality and heterogeneous interventions and comparators. Muticomponent interventions appear to be an effective treatment option for overweight or obese preschool children up to the age of 6 years. However, the current evidence is limited, and most trials had a high risk of bias. Most trials did not measure adverse events. We have identified four ongoing trials that we will include in future updates of this review. The role of dietary interventions is more equivocal, with one trial suggesting that dairy interventions may be effective in the longer term, but not energy-restricted diets. This trial also had a high risk of bias.
We included three RCTs in this review. The studies reported mean logMAR visual acuity achieved. Mean difference in visual acuity was calculated. When comparing conventional part-time occlusion (with any necessary glasses), PEDIG 2006 reported that this treatment was more beneficial than glasses alone for strabismic amblyopia; the mean difference between groups was -0.18 LogMAR (statistically significant 95% confidence interval (CI) -0.32 to -0.04). Supplementing occlusion therapy with near activities may produce a better visual outcome compared to non-near activities after four weeks of treatment (PEDIG 2005). The results of the pilot study showed mean difference between groups was -0.17 LogMAR (95% CI -0.53 to 0.19). Results from a larger RCT (PEDIG 2008) are now available, showing that supplementing occlusion therapy with near activities may produce a better visual outcome after eight weeks of treatment; the mean difference between groups was -0.02 LogMAR (95% CI -0.10 to 0.06). One further article ia awaiting assessment as in its current format there is insufficient information to include (Alotaibi 2012). Occlusion, whilst wearing necessary refractive correction, appears to be more effective than refractive correction alone in the treatment of strabismic amblyopia. The benefit of combining near activities with occlusion is unproven. No RCTs were found that assessed the role of either partial occlusion or optical penalisation to refractive correction for strabismic amblyopia.
We included nine studies involving 210 participants. Out of these, four studies (involving 61 residents) assessed technical skills in the operating theatre (primary outcomes). Five studies (comprising 149 residents and medical students) assessed technical skills in controlled environments (secondary outcomes). The majority of the trials were at high risk of bias. We assessed the GRADE quality of evidence for most outcomes across studies as 'low'. Operating theatre environment (primary outcomes) In the operating theatre, there were no studies that examined two of three primary outcomes: real world patient outcomes and acquisition of non-technical skills. The third primary outcome (technical skills in the operating theatre) was evaluated in two studies comparing virtual reality endoscopic sinus surgery training with conventional training. In one study, psychomotor skill (which relates to operative technique or the physical co-ordination associated with instrument handling) was assessed on a 10-point scale. A second study evaluated the procedural outcome of time-on-task. The virtual reality group performance was significantly better, with a better psychomotor score (mean difference (MD) 3.20, 95% CI 2.05 to 4.34; 10-point scale) and a shorter time taken to complete the operation (MD -5.50 minutes, 95% CI -9.97 to -1.03). Controlled training environments (secondary outcomes) In a controlled environment five studies evaluated the technical skills of surgical trainees (one study) and medical students (three studies). One study was excluded from the analysis. Surgical trainees: One study (80 participants) evaluated the technical performance of surgical trainees during temporal bone surgery, where the outcome was the quality of the final dissection. There was no difference in the end-product scores between virtual reality and cadaveric temporal bone training. Medical students: Two other studies (40 participants) evaluated technical skills achieved by medical students in the temporal bone laboratory. Learners' knowledge of the flow of the operative procedure (procedural score) was better after virtual reality than conventional training (SMD 1.11, 95% CI 0.44 to 1.79). There was also a significant difference in end-product score between the virtual reality and conventional training groups (SMD 2.60, 95% CI 1.71 to 3.49). One study (17 participants) revealed that medical students acquired anatomical knowledge (on a scale of 0 to 10) better during virtual reality than during conventional training (MD 4.3, 95% CI 2.05 to 6.55). No studies in a controlled training environment assessed non-technical skills. There is limited evidence to support the inclusion of virtual reality surgical simulation into surgical training programmes, on the basis that it can allow trainees to develop technical skills that are at least as good as those achieved through conventional training. Further investigations are required to determine whether virtual reality training is associated with better real world outcomes for patients and the development of non-technical skills. Virtual reality simulation may be considered as an additional learning tool for medical students.
We included 13 small RCTs (479 participants) in this review (at least 274 participants were women, with 118 parturients after a lumbar puncture for regional anaesthesia). In the original version of this Cochrane review, only seven small RCTs (200 participants) were included. Pharmacological drugs assessed were oral and intravenous caffeine, subcutaneous sumatriptan, oral gabapentin, oral pregabalin, oral theophylline, intravenous hydrocortisone, intravenous cosyntropin and intramuscular adrenocorticotropic hormone (ACTH). Two RCTs reported data for PDPH persistence of any severity at follow-up (primary outcome). Caffeine reduced the number of participants with PDPH at one to two hours when compared to placebo. Treatment with caffeine also decreased the need for a conservative supplementary therapeutic option. Treatment with gabapentin resulted in better visual analogue scale (VAS) scores after one, two, three and four days when compared with placebo and also when compared with ergotamine plus caffeine at two, three and four days. Treatment with hydrocortisone plus conventional treatment showed better VAS scores at six, 24 and 48 hours when compared with conventional treatment alone and also when compared with placebo. Treatment with theophylline showed better VAS scores compared with acetaminophen at two, six and 12 hours and also compared with conservative treatment at eight, 16 and 24 hours. Theophylline also showed a lower mean "sum of pain" when compared with placebo. Sumatriptan and ACTH did not show any relevant effect for this outcome. Theophylline resulted in a higher proportion of participants reporting an improvement in pain scores when compared with conservative treatment. There were no clinically significant drug adverse events. The rest of the outcomes were not reported by the included RCTs or did not show any relevant effect. None of the new included studies have provided additional information to change the conclusions of the last published version of the original Cochrane review. Caffeine has shown effectiveness for treating PDPH, decreasing the proportion of participants with PDPH persistence and those requiring supplementary interventions, when compared with placebo. Gabapentin, hydrocortisone and theophylline have been shown to decrease pain severity scores. Theophylline has also been shown to increase the proportion of participants that report an improvement in pain scores when compared with conventional treatment. There is a lack of conclusive evidence for the other drugs assessed (sumatriptan, adrenocorticotropic hormone, pregabalin and cosyntropin). These conclusions should be interpreted with caution, due to the lack of information to allow correct appraisal of risk of bias, the small sample sizes of the studies and also their limited generalisability, as nearly half of the participants were postpartum women in their 30s.
Three trials, which included 140 infants, met the inclusion criteria. All three trials compared a nebulized dose of salbutamol with placebo; in one of the three trials newborns were assigned to two different doses of the intervention. We found differences in the duration of oxygen therapy (mean difference (MD) -43.10 hours, 95% confidence interval (CI) -81.60 to -4.60). There were no differences in the need for continuous positive airway pressure (risk ratio (RR) 0.73, 95% CI 0.38 to 1.39; risk difference (RD) -0.15, 95% CI -0.45 to 0.16; 1 study, 46 infants) or the need for mechanical ventilation (RR 1.50, 95% CI 0.06 to 34.79; RD 0.03, 95% CI -0.08 to 0.14; 1 study, 46 infants). Tests for heterogeneity were not applicable for any of the analyses as only one study was included. Among secondary outcomes, we found no differences in terms of duration of hospital stay and tachypnea. The quality of the evidence was very low due to the imprecision of the estimates. One trial is ongoing. At present there is insufficient evidence to determine the efficacy and safety of salbutamol in the management of transient tachypnea of the newborn. The quality of evidence was low due to paucity of included trials, small sample sizes and overall poor methodologic quality.
We included 70 RCTs with a total of 8461 participants randomised to either the intervention or control groups. The number of participants per trial ranged from 16 to 686. Fifty-five trials compared a behaviour-changing intervention with no treatment/usual care control and 15 evaluated the effectiveness of adding an additional component to a behaviour-changing intervention. Sixty-four trials were parallel RCTs, and four were cluster RCTs. Sixty-four trials were multicomponent, two were diet only and four were physical activity only interventions. Ten trials had more than two arms. The overall quality of the evidence was low or very low and 62 trials had a high risk of bias for at least one criterion. Total duration of trials ranged from six months to three years. The median age of participants was 10 years old and the median BMI z score was 2.2. Primary analyses demonstrated that behaviour-changing interventions compared to no treatment/usual care control at longest follow-up reduced BMI, BMI z score and weight. Mean difference (MD) in BMI was -0.53 kg/m2 (95% confidence interval (CI) -0.82 to -0.24); P < 0.00001; 24 trials; 2785 participants; low-quality evidence. MD in BMI z score was -0.06 units (95% CI -0.10 to -0.02); P = 0.001; 37 trials; 4019 participants; low-quality evidence and MD in weight was -1.45 kg (95% CI -1.88 to -1.02); P < 0.00001; 17 trials; 1774 participants; low-quality evidence. Thirty-one trials reported on serious adverse events, with 29 trials reporting zero occurrences RR 0.57 (95% CI 0.17 to 1.93); P = 0.37; 4/2105 participants in the behaviour-changing intervention groups compared with 7/1991 participants in the comparator groups). Few trials reported health-related quality of life or behaviour change outcomes, and none of the analyses demonstrated a substantial difference in these outcomes between intervention and control. In two trials reporting on minutes per day of TV viewing, a small reduction of 6.6 minutes per day (95% CI -12.88 to -0.31), P = 0.04; 2 trials; 55 participants) was found in favour of the intervention. No trials reported on all-cause mortality, morbidity or socioeconomic effects, and few trials reported on participant views; none of which could be meta-analysed. As the meta-analyses revealed substantial heterogeneity, we conducted subgroup analyses to examine the impact of type of comparator, type of intervention, risk of attrition bias, setting, duration of post-intervention follow-up period, parental involvement and baseline BMI z score. No subgroup effects were shown for any of the subgroups on any of the outcomes. Some data indicated that a reduction in BMI immediately post-intervention was no longer evident at follow-up at less than six months, which has to be investigated in further trials. Multi-component behaviour-changing interventions that incorporate diet, physical activity and behaviour change may be beneficial in achieving small, short-term reductions in BMI, BMI z score and weight in children aged 6 to 11 years. The evidence suggests a very low occurrence of adverse events. The quality of the evidence was low or very low. The heterogeneity observed across all outcomes was not explained by subgrouping. Further research is required of behaviour-changing interventions in lower income countries and in children from different ethnic groups; also on the impact of behaviour-changing interventions on health-related quality of life and comorbidities. The sustainability of reduction in BMI/BMI z score and weight is a key consideration and there is a need for longer-term follow-up and further research on the most appropriate forms of post-intervention maintenance in order to ensure intervention benefits are sustained over the longer term.
Twenty eight studies met our inclusion criteria. The majority of the studies were for the management of osteoporosis or low back pain, and most evaluated interventions aimed at health professionals. To improve the use of imaging in the management of osteoporosis, the effect of any type of intervention compared to no-intervention controls was modest (absolute improvement in bone mineral density test ordering +10%, IQR 0.0 to +27.7). Patient mediated, reminder, and organisational interventions appeared to have most potential for improving imaging use in osteoporosis. For low back pain studies, the most common intervention evaluated was distribution of educational materials and this showed varying effects. Other interventions in low back pain studies also showed variable effects. For other musculoskeletal conditions, distribution of educational materials, educational meetings and audit and feedback were not shown to be effective for changing imaging ordering behaviour. Across all conditions, increasing the number of intervention components did not increase effect. For improving the use of imaging in osteoporosis, most professional interventions demonstrated benefit, and patient mediated, reminder, and organisational interventions appeared to have most potential for benefit. For low back pain studies interventions showed varying effects. For other musculoskeletal conditions, no firm conclusions can be drawn.
In our original review we included 15 studies with 1020 participants and excluded two. In this updated review we included seven new studies and excluded six, bringing the total number of included studies to 22 and involving 1732 participants. The control group intervention was the axillary block in 14 studies, supraclavicular block in six studies, mid-humeral block in two studies, and parascalene block in one study. One study compared ICB to both axillary and supraclavicular blocks. Nine studies employed ultrasound-guided ICB. The risk of failed surgical anaesthesia 30 minutes after block completion was similar for ICB and all other BPBs (11.4% versus 12.9%, risk ratio (RR) 0.88, 95% CI 0.51 to 1.52, P = 0.64), but tourniquet pain was less likely with ICB (11.9% versus 18.0%; RR of experiencing tourniquet pain 0.66, 95% CI 0.47 to 0.92, P = 0.02). Subgroup analysis by method of nerve localization, and by control group intervention, did not show any statistically significant differences in the risk of failed surgical anaesthesia. However when compared to a single-injection axillary block, ICB was better at providing complete sensory block of the musculocutaneous nerve (RR for failure 0.46, 95% CI 0.27 to 0.60, P < 0.0001). ICB had a slightly longer sensory block onset time (mean difference (MD) 1.9 min, 95% CI 0.2 to 3.6, P = 0.03) but was faster to perform than multiple-injection axillary (MD -2.7 min, 95% CI -3.4 to -2.0, P < 0.00001) or mid-humeral (MD -4.8 min, 95% CI -6.0 to -3.6, P < 0.00001) blocks. ICB is as safe and effective as any other BPBs, regardless of whether ultrasound or neurostimulation guidance is used. The advantages of ICB include a lower likelihood of tourniquet pain during surgery, more reliable blockade of the musculocutaneous nerve when compared to a single-injection axillary block, and a significantly shorter block performance time compared to multi-injection axillary and mid-humeral blocks.
We identified six eligible studies in total. The six Included studies were generally of high quality, but the largest eligible study was excluded because of concerns about its validity. Study populations were statin naive, which led to a considerable loss of eligible participants. Five RCTs compared statin use with placebo or standard care. We pooled results from three studies, with a total of 178 participants, for mortality and non-fatal event outcomes. In the statin group, 7/105 (6.7%) participants died within 30 days of surgery, as did 10/73 (13.7%) participants in the control group. Only one death in each group was from cardiovascular causes, with an incidence of 0.95% in statin participants and 1.4% in control participants, respectively. All deaths occurred in a single study population, and so effect estimates were derived from one study only. The risk ratio (RR) of all-cause mortality in statin users showed a non-significant decrease in risk (RR 0.73, 95% CI 0.31 to 1.75). For cardiovascular death, the risk ratio was 1.05 (95% CI 0.07 to 16.20). Non-fatal MI within 30 days of surgery was reported in three studies and occurred in 4/105 (3.8%) participants in the statin group and 8/73 (11.0%) participants receiving placebo, for a non-significant decrease in risk (RR 0.47, 95% CI 0.15 to 1.52). Several studies reported muscle enzyme levels as safety measures, but only three (with a total of 188 participants) reported explicitly on clinical muscle syndromes, with seven events reported and no significant difference found between statin users and controls (RR 0.94, 95% CI 0.24 to 3.63). The only participant-reported outcome was nausea in one small study,with no significant difference in risk between groups. Two studies compared different doses of atorvastatin, with a total of 145 participants, but reported data were not sufficient to allow us to determine the effect of higher doses on any outcome. Evidence was insufficient to allow review authors to conclude that statin use resulted in either a reduction or an increase in any of the outcomes examined. The existing body of evidence leaves questions about the benefits of perioperative use of statins for vascular surgery unanswered. Widespread use of statins in the target population means that it may now be difficult for researchers to undertake the large RCTs needed to demonstrate any effect on the incidence of postoperative cardiovascular events. However, participant-reported outcomes have been neglected and warrant further study.
Ten trials involving 10,479 participants were included. There was inconclusive evidence of an effect on the proportion of participants with index case management (defined as individuals tested, diagnosed and treated for CT or NG, or both) in the group with home-based (45/778, 5.8%) compared with clinic-based (51/788, 6.5%) specimen collection (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.60 to 1.29; 3 trials, I² = 0%, 1566 participants, moderate quality). Harms of home-based specimen collection were not evaluated in any trial. All 10 trials compared the proportions of individuals tested. The results for the proportion of participants completing testing had high heterogeneity (I² = 100%) and were not pooled. We could not combine data from individual studies looking at the number of participants tested because the proportions varied widely across the studies, ranging from 30% to 96% in home group and 6% to 97% in clinic group (low-quality evidence). The number of participants with positive test was lower in the home-based specimen collection group (240/2074, 11.6%) compared with the clinic-based group (179/967, 18.5%) (RR 0.72, 95% CI 0.61 to 0.86; 9 trials, I² = 0%, 3041 participants, moderate quality). Home-based specimen collection could result in similar levels of index case management for CT or NG infection when compared with clinic-based specimen collection. Increases in the proportion of individuals tested as a result of home-based, compared with clinic-based, specimen collection are offset by a lower proportion of positive results. The harms of home-based specimen collection compared with clinic-based specimen collection have not been evaluated. Future RCTs to assess the effectiveness of home-based specimen collection should be designed to measure biological outcomes of STI case management, such as proportion of participants with negative tests for the relevant STI at follow-up.
Four studies in 170 participants compared antidepressant therapy (fluoxetine, sertraline, citalopram or escitalopram) versus placebo or psychological training for 8 to 12 weeks. In generally very low or ungradeable evidence, compared to placebo, antidepressant therapy had no evidence of benefit on quality of life, had uncertain effects on increasing the risk of hypotension (3 studies, 144 participants: RR 1.72, 95% CI 0.75 to 3.92), headache (2 studies 56 participants: RR 2.91, 95% CI 0.73 to 11.57), and sexual dysfunction (2 studies, 101 participants: RR 3.83, 95% CI 0.63 to 23.34), and increased nausea (3 studies, 114 participants: RR 2.67, 95% CI 1.26 to 5.68). There were few or no data for hospitalisation, suicide or all-cause mortality resulting in inconclusive evidence. Antidepressant therapy may reduce depression scores during treatment compared to placebo (1 study, 43 participants: MD -7.50, 95% CI -11.94 to -3.06). Antidepressant therapy was not statistically different from group psychological therapy for effects on depression scores or withdrawal from treatment and a range of other outcomes were not measured. Despite the high prevalence of depression in dialysis patients and the relative priority that patients place on effective treatments, evidence for antidepressant medication in the dialysis setting is sparse and data are generally inconclusive. The relative benefits and harms of antidepressant therapy in dialysis patients are poorly known and large randomised studies of antidepressants versus placebo are required.
We included 244 randomised clinical trials with 28,619 participants that met our inclusion criteria. We considered all trials to be at high risk of bias. Two trials accounted for one-third of all included participants. The included participants were heterogenous with regard to disease (20 different medical specialties). The experimental interventions were parenteral nutrition (86 trials); enteral nutrition (tube-feeding) (80 trials); oral nutrition support (55 trials); mixed experimental intervention (12 trials); general nutrition support (9 trials); and fortified food (2 trials). The control interventions were treatment as usual (122 trials); no intervention (107 trials); and placebo (15 trials). In 204/244 trials, the intervention lasted three days or more. We found no evidence of a difference between nutrition support and control for short-term mortality (end of intervention). The absolute risk was 8.3% across the control groups compared with 7.8% (7.1% to 8.5%) in the intervention groups, based on the risk ratio (RR) of 0.94 (95% confidence interval (CI) 0.86 to 1.03, P = 0.16, 21,758 participants, 114 trials, low quality of evidence). We found no evidence of a difference between nutrition support and control for long-term mortality (maximum follow-up). The absolute risk was 13.2% in the control group compared with 12.2% (11.6% to 13%) following nutritional interventions based on a RR of 0.93 (95% CI 0.88 to 0.99, P = 0.03, 23,170 participants, 127 trials, low quality of evidence). Trial Sequential Analysis showed we only had enough information to assess a risk ratio reduction of approximately 10% or more. A risk ratio reduction of 10% or more could be rejected. We found no evidence of a difference between nutrition support and control for short-term serious adverse events. The absolute risk was 9.9% in the control groups versus 9.2% (8.5% to 10%), with nutrition based on the RR of 0.93 (95% CI 0.86 to 1.01, P = 0.07, 22,087 participants, 123 trials, low quality of evidence). At long-term follow-up, the reduction in the risk of serious adverse events was 1.5%, from 15.2% in control groups to 13.8% (12.9% to 14.7%) following nutritional support (RR 0.91, 95% CI 0.85 to 0.97, P = 0.004, 23,413 participants, 137 trials, low quality of evidence). However, the Trial Sequential Analysis showed we only had enough information to assess a risk ratio reduction of approximately 10% or more. A risk ratio reduction of 10% or more could be rejected. Trial Sequential Analysis of enteral nutrition alone showed that enteral nutrition might reduce serious adverse events at maximum follow-up in people with different diseases. We could find no beneficial effect of oral nutrition support or parenteral nutrition support on all-cause mortality and serious adverse events in any subgroup. Only 16 trials assessed health-related quality of life. We performed a meta-analysis of two trials reporting EuroQoL utility score at long-term follow-up and found very low quality of evidence for effects of nutritional support on quality of life (mean difference (MD) -0.01, 95% CI -0.03 to 0.01; 3961 participants, two trials). Trial Sequential Analyses showed that we did not have enough information to confirm or reject clinically relevant intervention effects on quality of life. Nutrition support may increase weight at short-term follow-up (MD 1.32 kg, 95% CI 0.65 to 2.00, 5445 participants, 68 trials, very low quality of evidence). There is low-quality evidence for the effects of nutrition support on mortality and serious adverse events. Based on the results of our review, it does not appear to lead to a risk ratio reduction of approximately 10% or more in either all-cause mortality or serious adverse events at short-term and long-term follow-up. There is very low-quality evidence for an increase in weight with nutrition support at the end of treatment in hospitalised adults determined to be at nutritional risk. The effects of nutrition support on all remaining outcomes are unclear. Despite the clinically heterogenous population and the high risk of bias of all included trials, our analyses showed limited signs of statistical heterogeneity. Further trials may be warranted, assessing enteral nutrition (tube-feeding) for different patient groups. Future trials ought to be conducted with low risks of systematic errors and low risks of random errors, and they also ought to assess health-related quality of life.
Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78 to 1.01], 4 trials, N = 1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13 to 1.31], 5 trials, N = 1751) and complete remission (RR 1.94 [95% CI 1.65 to 2.28], 5 trials, N = 1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61 to 0.82], 4 trials, N = 1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30 to 2.58], 4 trials, N = 1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, N = 1620) and therapy-related mortality (RR 0.94 [95% CI 0.45 to 1.95]). Overall incidence of haemolytic anaemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27 to 8.91], 3 trials, N = 1258). Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and haemolytic anaemia.
Twenty two trials (3707 patients) were included. Hb ≥ 133 g/L was not associated with a reduction in the risk of all-cause mortality compared with 120 g/L in dialysis and pre-dialysis patients. In pre-dialysis patients, there was a significantly lower end of treatment creatinine clearance with Hb < 120 g/L compared to > 130 g/L (MD -4.17, 95% CI -6.33 to -2.02) but no significant difference in the risk of end-stage kidney disease (ESKD) (RR 1.05, 95% CI 0.50 to 2.22). Lower Hb targets resulted in an increased risk for seizures (RR 5.25, 95% CI 1.13 to 24.34) and a reduced risk of hypertensive episodes (RR 0.50, 95% CI 0.33 to 0.76). There were no significant differences in the risk of vascular access thrombosis. There was no significant difference in the risk of death for low (< 120 g/L) versus higher Hb targets (>133 g/L). Lower Hb targets were significantly associated with an increased risk for seizures but a reduced risk of hypertension. In general study quality was poor. There is a need for more adequately powered, well-designed and reported trials. Trials should be pragmatic, focusing on hard end-points (mortality, ESKD, major side effects) or outcomes which were previously not studied adequately (e.g. seizures, quality of life).
We included 41 articles reporting on 25 RCTs with 4404 participants. Risk of bias was low in 16 studies. Three studies involved workers with acute back pain, eight studies workers with subacute back pain, and 14 studies workers with chronic back pain. In 14 studies, physical conditioning as part of a return to work strategy was compared to usual care. The physical conditioning mostly consisted of graded activity with work-related exercises aimed at increasing back strength and flexibility, together with a set date for return to work. The programmes were divided into a light version with a maximum of five sessions, or an intense version with more than five sessions up to full time or as inpatient treatment. For acute back pain, there was low quality evidence that both light and intense physical conditioning programmes made little or no difference in sickness absence duration compared with care as usual at three to 12 months follow-up (3 studies with 340 workers). For subacute back pain, the evidence on the effectiveness of intense physical conditioning combined with care as usual compared to usual care alone was conflicting (four studies with 395 workers). However, subgroup analysis showed low quality evidence that if the intervention was executed at the workplace, or included a workplace visit, it may have reduced sickness absence duration at 12 months follow-up (3 studies with 283 workers; SMD -0.42, 95% CI -0.65 to -0.18). For chronic back pain, there was low quality evidence that physical conditioning as part of integrated care management in addition to usual care may have reduced sickness absence days compared to usual care at 12 months follow-up (1 study, 134 workers; SMD -4.42, 95% CI -5.06 to -3.79). What part of the integrated care management was most effective remained unclear. There was moderate quality evidence that intense physical conditioning probably reduced sickness absence duration only slightly compared with usual care at 12 months follow-up (5 studies, 1093 workers; SMD -0.23, 95% CI -0.42 to -0.03). Physical conditioning compared to exercise therapy showed conflicting results for workers with subacute and chronic back pain. Cognitive behavioural therapy was probably not superior to physical conditioning as an alternative or in addition to physical conditioning. The effectiveness of physical conditioning as part of a return to work strategy in reducing sick leave for workers with back pain, compared to usual care or exercise therapy, remains uncertain. For workers with acute back pain, physical conditioning may have no effect on sickness absence duration. There is conflicting evidence regarding the reduction of sickness absence duration with intense physical conditioning versus usual care for workers with subacute back pain. It may be that including workplace visits or execution of the intervention at the workplace is the component that renders a physical conditioning programme effective. For workers with chronic back pain physical conditioning has a small effect on reducing sick leave compared to care as usual after 12 months follow-up. To what extent physical conditioning as part of integrated care management may alter the effect on sick leave for workers with chronic back pain needs further research.
We included 23 studies with 1250 participants that compared one drug with one or more other drugs. Of these comparisons, 19 studies compared propofol with another drug. Seven of these compared propofol with etomidate (four of which combined the drugs with remifentanil or fentanyl), five midazolam, six thiopentone and two sevoflurane. Three studies compared etomidate with thiopentone, and three etomidate with midazolam. Two studies compared thiopentone with midazolam, one thiopentone with diazepam and one midazolam with diazepam. Drug doses and the time over which the drugs were given varied between studies. Although all studies were described as randomized, limited information was provided about the methods used for selection and group allocation. A high level of performance bias was observed across studies, as study authors had not attempted to blind the anaesthetist to group allocation. Similarly, study authors had rarely provided sufficient information on whether outcome assessors had been blinded. Included studies presented outcome data for hypotension, apnoea, participant recall, success of cardioversion, minor adverse events of nausea and vomiting, pain at injection site and myoclonus, additional analgesia and participant satisfaction. We did not pool the data from different studies in view of the multiple drug comparisons, differences in definitions and reporting of outcomes, variability of endpoints and high or unclear risk of bias across studies. Few studies reported statistically significant results for our relevant outcomes, and most study authors concluded that both, or all, agents compared in individual studies were adequate for cardioversion procedures. It is our opinion that at present, there is no evidence to suggest that current anaesthetic practice for cardioversion should change.
We included three RCTs involving a total of 2303 participants: 1150 participants were randomized to receive TDC and 1153 participants were randomized to receive medical therapy. Overall, the risk of bias was regarded as high. The mean follow-up period of all three included trials was less than five years. Baseline characteristics (age, sex, and vascular risk factors) were similar across trials. Intention-to-treat analyses did not show a statistically significant risk reduction in the composite endpoint of recurrent stroke or TIA in the TDC group when compared with medical therapy (RR 0.73, 95% CI 0.45 to 1.17). A time-to-event analysis combining the results of two RCTs also failed to show a significant risk reduction with TDC (HR 0.69, 95% CI 0.43 to 1.13). When assessing stroke prevention alone, TDC still did not show a statistically significant benefit (RR 0.61, 95% CI 0.29 to 1.27) (HR 0.55, 95% CI 0.26 to 1.18). In a sensitivity analysis including the two studies using the Amplatzer PFO occluder, TDC showed a possible protective effect on recurrent stroke compared with medical therapy (HR 0.38, 95% CI 0.14 to 1.02); however, it did not reach statistical significance. Safety analysis found that the overall risks for all-cause mortality and adverse events were similar in both the TDC and medical therapy groups. However, TDC increased the risk of new-onset atrial fibrillation (RR 3.50, 95% CI 1.47 to 8.35) and may be associated with the type of device used. The combined data from recent RCTs have shown no statistically significant differences between TDC and medical therapy in the prevention of recurrent ischemic stroke. TDC closure was associated with an increased risk of atrial fibrillation but not with serious adverse events.
We included 19 studies (1756 participants). We selected only randomized, placebo-controlled, double-blinded studies to minimize inclusion of poor quality studies. However, the risk of bias in the included studies was not formally assessed. Children receiving a single intraoperative dose of dexamethasone (dose range = 0.15 to 1.0 mg/kg) were half as likely to vomit in the first 24 hours compared to children receiving placebo (risk ratio (RR) 0.49; 95% confidence interval (CI) 0.41 to 0.58; P < 0.00001). Routine use in five children would be expected to result in one less patient experiencing post-tonsillectomy emesis (risk difference (RD) -0.24; 95% CI -0.32 to -0.15; P < 0.00001). Children receiving dexamethasone were also more likely to advance to a soft/solid diet on post-tonsillectomy day one (RR 1.45; 95% CI 1.15 to 1.83; P = 0.001) than those receiving placebo. Finally, postoperative pain was improved in children receiving dexamethasone as measured by a visual analog scale (VAS, 0 to 10) (MD -1.07; 95% CI -1.73 to -0.41; P = 0.001), which correlates clinically to a reduction in pain (on a VAS of 0 to 10) from 4.72 to 3.65. No adverse events were noted in the included studies. The evidence suggests that a single intravenous dose of dexamethasone is an effective, safe and inexpensive treatment for reducing morbidity from pediatric tonsillectomy.
Two studies with a total of 84 participants were included: a 12-month RCT of early rehabilitation in adults of mean age 72 years conducted in two centres in England (UK) and a six-month proof-of-concept RCT of an expert patient programme (EPP) in adults of mean age 60 years in a single regional respiratory centre in Northern Ireland (UK). The EPP was delivered in group format once a week for eight weeks using standardised EPP materials plus disease-specific education including airway clearance techniques, dealing with symptoms, exacerbations, health promotion and available support. We did not find any studies that included children. Data aggregation was not possible and findings are reported narratively in the review. For the primary outcomes, both studies reported health-related quality of life, as measured by the St George's Respiratory Questionnaire (SGRQ), but there was no clear evidence of benefit. In one study, the mean SGRQ total scores were not significantly different at 6 weeks', 3 months' and 12 months' follow-up (12 months mean difference (MD) -10.27, 95% confidence interval (CI) -45.15 to 24.61). In the second study there were no significant differences in SGRQ. Total scores were not significantly different between groups (six months, MD 3.20, 95% CI -6.64 to 13.04). We judged the evidence for this outcome as low or very low. Neither of the included studies reported data on exacerbations requiring antibiotics. For serious adverse events, one study reported more deaths in the intervention group compared to the control group, (intervention: 4 of 8, control: 2 of 12), though interpretation is limited by the low event rate and the small number of participants in each group. For our secondary outcomes, there was no evidence of benefit in terms of frequency of hospital admissions or FEV1 L, based on very low-quality evidence. One study reported self-efficacy using the Chronic Disease Self-Efficacy scale, which comprises 10 components. All scales showed significant benefit from the intervention but effects were only sustained to study endpoint on the Managing Depression scale. Further details are reported in the main review. Based on overall study quality, we judged this evidence as low quality. Neither study reported data on respiratory symptoms, economic costs or adverse events. There is insufficient evidence to determine whether self-management interventions benefit people with bronchiectasis. In the absence of high-quality evidence it is advisable that practitioners adhere to current international guidelines that advocate self-management for people with bronchiectasis. Future studies should aim to clearly define and justify the specific nature of self-management, measure clinically important outcomes and include children as well as adults.
We included 21 studies (6016 participants) in this review. Trimethoprim-sulfamethoxazole (TMP-SMX) was as effective as fluoroquinolones in achieving short-term (RR 1.00, 95% CI 0.97 to 1.03) and long-term (RR 0.99, 95% CI 0.94 to 1.05) symptomatic cure. Beta-lactam drugs were as effective as TMP-SMX for short-term (RR 0.95, 95% CI 0.81 to 1.12) and long-term (RR 1.06, 95% CI 0.93 to 1.21) symptomatic cure. Short-term cure for nitrofurantoin was similar to that of TMP-SMX (RR 0.99, 95% CI 0.95 to 1.04) as was long-term symptomatic cure (RR 1.01, 95% CI 0.94 to 1.09). Fluoroquinolones were more effective than beta-lactams (RR 1.22, 95% CI 1.13 to 1.31) for short-term bacteriological cure. Rashes were more frequent in patients treated with TMP-SMX than with nitrofurantoin or fluoroquinolones and in patients treated with beta-lactam drugs compared to fluoroquinolones. Minimal data were available on the emergence of resistant strains during or after antimicrobial treatment. No differences were observed between the classes of antimicrobials included in this review for the symptomatic cure of acute uncomplicated UTI. Fluoroquinolones proved more effective than beta-lactams for the short-term bacteriological outcome, probably with little clinical significance. Individualised treatment should take into consideration the predictable susceptibility of urinary pathogens in local areas, possible adverse events and resistance development, and patient preference.
We included a single-centre non-blinded randomised controlled trial that reported a total of 302 intubation attempts in 232 infants. The median gestational age of enrolled infants was 29 weeks. Paediatric residents and fellows performed the intubations. We judged the study to be at low risk of bias overall. Investigators compared success rates of first-attempt intubation with and without use of a stylet and reported success rates as similar between stylet and no-stylet groups (57% and 53%) (P = 0.47). Success rates did not differ between groups in subgroup analyses by provider level of training and infant weight. Results showed no differences in secondary review outcomes, including duration of intubation, number of attempts, participant instability during the procedure, and local airway trauma. Only 25% of all intubations took less than 30 seconds to perform. Study authors did not report neonatal morbidity nor mortality. We considered the quality of evidence as low on GRADE analysis, given that we identified only one unblinded study. Current available evidence suggests that use of a stylet during neonatal orotracheal intubation does not significantly improve the success rate among paediatric trainees. However, only one brand of stylet and one brand of endotracheal tube have been tested, and researchers performed all intubations on infants in a hospital setting. Therefore, our results cannot be generalised beyond these limitations.
For abdominal wall lift with pneumoperitoneum versus pneumoperitoneum, a total of 130 participants (all with low anaesthetic risk) scheduled for elective laparoscopic cholecystectomy were randomised in five trials to abdominal wall lift with pneumoperitoneum (n = 53) versus pneumoperitoneum only (n = 52). One trial which included 25 people did not state the number of participants in each group. All five trials had a high risk of bias. There was no mortality or conversion to open cholecystectomy in any of the participants in the trials that reported these outcomes. There was no significant difference in the rate of serious adverse events between the two groups (two trials; 2/29 events (0.069 events per person) versus 2/29 events (0.069 events per person); rate ratio 1.00; 95% CI 0.17 to 5.77). None of the trials reported quality of life, the proportion of people discharged as day-patient laparoscopic cholecystectomies, or pain between four and eight hours after the operation. There was no significant difference in the operating time between the two groups (four trials; 53 participants versus 54 participants; 13.39 minutes longer (95% CI 2.73 less to 29.51 minutes longer) in the abdominal wall lift with pneumoperitoneum group and 100 minutes in the pneumoperitoneum group). For abdominal wall lift versus pneumoperitoneum, a total of 774 participants (the majority with low anaesthetic risk) scheduled for elective laparoscopic cholecystectomy were randomised in 18 trials to abdominal wall lift without pneumoperitoneum (n = 332) versus pneumoperitoneum (n = 358). One trial which included 84 people did not state the number in each group. All the trials had a high risk of bias. There was no mortality in any of the trials that reported this outcome. There was no significant difference in the proportion of participants with serious adverse events (six trials; 5/172 (weighted proportion 2.4%) versus 2/171 (1.2%); RR 2.01; 95% CI 0.52 to 7.80). There was no significant difference in the rate of serious adverse events between the two groups (three trials; 5/99 events (weighted number of events per person = 0.346 events) versus 2/99 events (0.020 events per person); rate ratio 1.73; 95% CI 0.35 to 8.61). None of the trials reported quality of life or pain between four and eight hours after the operation. There was no significant difference in the proportion of people who underwent conversion to open cholecystectomy (11 trials; 5/225 (weighted proportion 2.3%) versus 7/235 (3.0%); RR 0.76; 95% CI 0.26 to 2.21). The operating time was significantly longer in the abdominal wall lift group than in the pneumoperitoneum group (16 trials; 6.87 minutes longer (95% CI 4.74 minutes to 9.00 minutes longer) in the abdominal wall lift group versus 75 minutes in the pneumoperitoneum group). There was no significant difference in the proportion of people discharged as laparoscopic cholecystectomy day-patients (two trials; 15/31 (weighted proportion 48.5%) versus 9/31 (29%); RR 1.67; 95% CI 0.85 to 3.26). Abdominal wall lift with or without pneumoperitoneum does not seem to offer an advantage over pneumoperitoneum in any of the patient-oriented outcomes for laparoscopic cholecystectomy in people with low anaesthetic risk. Hence it cannot be recommended routinely. The safety of abdominal wall lift is yet to be established. More research on the topic is needed because of the risk of bias in the included trials and because of the risk of type I and type II random errors due to the few participants included in the trials. Future trials should include people at higher anaesthetic risk. Furthermore, such trials should include blinded assessment of outcomes.
We included 13 studies, with a total 467 participants, testing a range of different interventions. Outcome measures included 36 measures of sensory impairment and 13 measures of upper limb function. All but two studies had unclear or high risk of bias. While there is insufficient evidence to reach conclusions about the effects of interventions included in this review, three studies provided preliminary evidence for the effects of some specific interventions, including mirror therapy for improving detection of light touch, pressure and temperature pain; a thermal stimulation intervention for improving rate of recovery of sensation; and intermittent pneumatic compression intervention for improving tactile and kinesthetic sensation. We could not perform meta-analysis due to a high degree of clinical heterogeneity in both interventions and outcomes. Multiple interventions for upper limb sensory impairment after stroke are described but there is insufficient evidence to support or refute their effectiveness in improving sensory impairment, upper limb function, or participants' functional status and participation. There is a need for more well-designed, better reported studies of sensory rehabilitation.
Nine trials involving 1822 patients with bleeding haemorrhoids were identified. The included trials were generally not of high quality and used one TCMH preparation compared with another TCMH preparation (Type I) (five trials) or western medicines (Type II) (four trials). We could not pool the data to perform a meta-analysis as only two of the included trials used the same intervention or comparison. In the nine trials, TCMHs showed a statistically significant difference for the improvement in the general curative effects or total grade of symptoms in six trials (P < 0.05; P < 0.01), of hematochezia in three trials (P < 0.05; P < 0.001), and of inflammation of perianal mucosa in one trial (P < 0.05). The adverse effects reported were not serious and were scarce. This review did not provide strong evidence concerning the effectiveness of TCMHs for stopping bleeding from haemorrhoids. Most of the included studies were of low quality and there was a scarcity of eligible trials and numbers of participants. Limited, weak evidence showed that some herbal formulae, when including Radix Sanguisorbae, Radix Rehmanniae, Fructus Sophorae, Radix Angelicae Sinensis, Radix Scutellariae, etc., may alleviate some symptoms caused by haemorrhoids. These include hematochezia, congestive haemorrhoidal cushions and inflammation of perianal mucosa in the short term. Well-designed clinical trials are required urgently before any confident conclusions can be drawn about the value of TCMHs for stopping bleeding from haemorrhoids. At present, the evidence is not enough that clinical practice should be changed immediately on the basis of these results.
We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer. The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer. Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty. The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy. Both studies reported that zoledronic acid in addition to androgen deprivation and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently. There was no available evidence regarding adverse effects. The evidence relating to interventions to prevent insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults is of very low certainty. This review highlights the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and avascular necrosis. Future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy. The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months. Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of avascular necrosis. Clinical assessments and patient reported outcomes would help to identify any associated adverse effects of treatment and quality of life outcomes.
The overall quality of the evidence was very low. In this update no new studies were identified for inclusion; one additional study was excluded. Of the two small included studies, one study showed a non-significant effect of calcitonin on the number of patients with complete pain relief (risk ratio (RR) 2.50; 95% confidence interval (CI) 0.55 to 11.41). The second study provided no evidence that calcitonin reduced analgesia consumption (RR 1.05; 95% CI 0.90 to 1.21) in patients with painful bone metastases. There was no evidence that calcitonin was effective in controlling complications due to bone metastases, for improving quality of life or for patients' survival. Although not statistically significant, a greater number of adverse effects were observed in the groups given calcitonin in the two included studies (RR 3.50; 95% CI 0.77 to 15.88). Current available research evidence is of very low quality and there is a lack of evidence to support the use of calcitonin for managing bone pain from bone metastases. Since the last version of this review, we did not identify any additional studies.
We included 30 trials, with a total of 1569 participants, in this review. We included trials of ventilator mode or type, earplugs or eye masks or both, massage, relaxation interventions, foot baths, music interventions, nursing interventions, valerian acupressure, aromatherapy, and sound masking. Outcomes included objective sleep outcomes, subjective sleep quality and quantity, risk of delirium, participant satisfaction, length of ICU stay, and adverse events. Clinical heterogeneity (e.g., participant population, outcomes measured) and research design limited quantitative synthesis, and only a small number of studies were available for most interventions. The quality of the evidence for an effect of non-pharmacological interventions on any of the outcomes examined was generally low or very low. Only three trials, all of earplugs or eye masks or both, provided data suitable for two separate meta-analyses. These meta-analyses, each of two studies, showed a lower incidence of delirium during ICU stay (risk ratio 0.55, 95% confidence interval (CI) 0.38 to 0.80, P value = 0.002, two studies, 177 participants) and a positive effect of earplugs or eye masks or both on total sleep time (mean difference 2.19 hours, 95% CI 0.41 to 3.96, P value = 0.02, two studies, 116 participants); we rated the quality of the evidence for both of these results as low. There was also some low quality evidence that music (350 participants; four studies) may improve subjective sleep quality and quantity, but we could not pool the data. Similarly, there was some evidence that relaxation techniques, foot massage, acupressure, nursing or social intervention, and sound masking can provide small improvements in various subjective measures of sleep quality and quantity, but the quality of the evidence was low. The effects of non-pharmacological interventions on objective sleep outcomes were inconsistent across 16 studies (we rated the quality of the evidence as very low): the majority of studies relating to the use of earplugs and eye masks found no benefit; results from six trials of ventilator modes suggested that certain ventilator settings might offer benefits over others, although the results of the individual trials did not always agree with each other. Only one study measured length of stay in the ICU and found no significant effect of earplugs plus eye masks. No studies examined the effect of any non-pharmacological intervention on mortality, risk of post-traumatic stress disorder, or cost-effectiveness; the included studies did not clearly report adverse effects, although there was very low quality evidence that ventilator mode influenced the incidence of central apnoeas and patient-ventilator asynchronies. The quality of existing evidence relating to the use of non-pharmacological interventions for promoting sleep in adults in the ICU was low or very low. We found some evidence that the use of earplugs or eye masks or both may have beneficial effects on sleep and the incidence of delirium in this population, although the quality of the evidence was low. Further high-quality research is needed to strengthen the evidence base.
Fifty-six trials met the inclusion criteria; 51 trials involving 4624 participants provided data for meta-analysis. Five trials were at low risk of bias, five at high and 46 at unclear risk of bias. There is moderate quality evidence that powered toothbrushes provide a statistically significant benefit compared with manual toothbrushes with regard to the reduction of plaque in both the short term (standardised mean difference (SMD) -0.50 (95% confidence interval (CI) -0.70 to -0.31); 40 trials, n = 2871) and long term (SMD -0.47 (95% CI -0.82 to -0.11; 14 trials, n = 978). These results correspond to an 11% reduction in plaque for the Quigley Hein index (Turesky) in the short term and 21% reduction long term. Both meta-analyses showed high levels of heterogeneity (I2 = 83% and 86% respectively) that was not explained by the different powered toothbrush type subgroups. With regard to gingivitis, there is moderate quality evidence that powered toothbrushes again provide a statistically significant benefit when compared with manual toothbrushes both in the short term (SMD -0.43 (95% CI -0.60 to -0.25); 44 trials, n = 3345) and long term (SMD -0.21 (95% CI -0.31 to -0.12); 16 trials, n = 1645). This corresponds to a 6% and 11% reduction in gingivitis for the Löe and Silness index respectively. Both meta-analyses showed high levels of heterogeneity (I2 = 82% and 51% respectively) that was not explained by the different powered toothbrush type subgroups. The number of trials for each type of powered toothbrush varied: side to side (10 trials), counter oscillation (five trials), rotation oscillation (27 trials), circular (two trials), ultrasonic (seven trials), ionic (four trials) and unknown (five trials). The greatest body of evidence was for rotation oscillation brushes which demonstrated a statistically significant reduction in plaque and gingivitis at both time points. Powered toothbrushes reduce plaque and gingivitis more than manual toothbrushing in the short and long term. The clinical importance of these findings remains unclear. Observation of methodological guidelines and greater standardisation of design would benefit both future trials and meta-analyses. Cost, reliability and side effects were inconsistently reported. Any reported side effects were localised and only temporary.
Seven studies mostly with small sample sizes, comparing 4 different interventions (prostaglandins alone, mifepristone alone, and mifepristone/misoprostol and methotrexate/misoprostol versus vacuum aspiration) were included. Results are sometimes based on one trial only.  Prostaglandins vs vacuum aspiration: the rate of abortions not completed with the intended method was statistically significant higher in the prostaglandin group (2.7, 95% CI 1.1 to 6.8) compared to surgery. There are no data on the most commonly medical (mifepristone/misoprostol) and surgical abortion available to be included in the review.  Duration of bleeding was longer in the medical abortion groups compared to vacuum aspiration. There was only one major complication (uterine perforation) in one trial in the surgical group. There was no difference between the groups for ongoing pregnancies at the time of follow-up or pelvic infections. No data on acceptability, side effects or women's satisfaction with the procedure were availbale for inclusion in the review. The results are derived from relatively small trials. Prostaglandins used alone seems to be less effective and more painful compared to surgical first-trimester abortion. However, there is inadequate evidence to comment on the acceptability and side effects of medical compared to surgical first-trimester abortions. There is a need for trials to address the efficacy of currently used methods and women's preferences more reliably.
Among 409 retrieved references, we identified 16 RCTs; six of them, published between 1987 and 2007, met the selection criteria and were included in this review. Five hundred and forty RR patients and 1049 PMS contributed to the analysis. In RR MS, a decrease in the mean EDSS score (-0.33 and -0.45), was found respectively at 2 years and 35 months without any significant effect on sustained disease progression. The reduction of mean number of relapse was evident at 1 year (-0.35 ) 2 years (-0.51 ) and 35 months (-0.64), but significant studies ' heterogeneity was found. The number of hospitalisations and steroid courses were significantly reduced. No benefit was shown in P MS patients. No major toxicity was found. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety. Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. Glatiramer acetate did show a partial efficacy in RR MS in term of relapse -related clinical outcomes, without any significant effect on clinical progression of disease measured as sustained disability. The drug is not effective in progressive MS patients.
The 2005 update includes a new trial (Kuriyama 2002) to bring the total of included studies to three (total n=33). One study, which used a cross-over design (Tolbert 1993) provided insufficient data to conduct an analysis. Another crossover study (Findling 1997) yielded no significant differences between treatment and placebo group performances following the B6 intervention on measures of social interaction, communication, compulsivity, impulsivity, or hyperactivity. The latest study (Kuriyama 2002) was motivated by evidence from epilepsy research and was focussed on a subgroup of children with pervasive developmental disorders (PDDs) who exhibited clinical features similar to those with pyroxidine-dependent epilepsy. This small study (n=8) only measured IQ and 'Social Quotient' and found a statistically significant benefit for IQ (5.2, 95% CI = [0.2 to 10.3]) when in the treated group, by using change scores. Due to the small number of studies, the methodological quality of studies, and small sample sizes, no recommendation can be advanced regarding the use of B6-Mg as a treatment for autism.
This review detected 36 eligible randomized controlled trials involving four major groups of developmental care interventions, 19 sub-groups and multiple clinical outcomes. In addition, the long-term outcomes of a previously included trial were added to the review. The results of the review indicate that developmental care interventions demonstrate limited benefit to preterm infants with respect to: decreased moderate-severe chronic lung disease, decreased incidence of necrotizing enterocolitis and improved family outcome. Conversely, an increase in mild lung disease and an increase in the length of stay were demonstrated in infants receiving developmental care compared to controls. There is also very limited evidence of the long-term positive effect of NIDCAP on behavior and movement at 5 years corrected age but no effect on cognition. Other individualized developmental care interventions have also demonstrated some effect in enhancing neurodevelopmental outcome. Although a limited number of other benefits were demonstrated, those results were from single studies with small sample sizes. The lack of blinding of the assessors was a significant methodological flaw in half of the studies. The cost of the interventions and personnel was not considered in any of the studies. Because of the inclusion of multiple interventions in most studies, the determination of the effect of any single intervention is difficult. Although there is evidence of limited benefit of developmental care interventions overall, and no major harmful effects reported, there were a large number of outcomes for which no or conflicting effects were demonstrated. The single trials that did show a significant effect of an intervention on a major clinical outcome were based on small sample sizes, and the findings were often not supported in other small trials. Before a clear direction for practice can be supported, evidence demonstrating more consistent effects of developmental care interventions on important short- and long-term clinical outcomes is needed. The economic impact of the implementation and maintenance of developmental care practices should be considered by individual institutions.
This review includes 19 studies with a total of 14,890 participants. We categorised the included studies according to the modes used to deliver the recruitment strategy: head to head comparison of individual recruitment strategies; comparison of the same delivery mode but with different content or intensity; and the addition of another mode to an existing recruitment method. We identified three studies that made head-to-head comparisons of different types of recruitment strategies. Of these, only one study detected a significant effect, finding that a personal phone call was more effective than a generic invitation letter (RR 40.73, 95% CI 2.53 to 654.74). Five studies compared interventions using the same delivery modes but different content. Results showed that tailored messages through an interactive voice response system resulted in a higher recruitment rate than assessment of smoking status alone using the same system (RR 8.64, 95% CI 4.41 to 16.93), and that text messages indicating scarcity of places available were more effective than generic text message reminders (RR 1.45, 95% CI 1.07 to 1.96). One study compared interventions using the same delivery mode but different intensity and found that allowing for more phone call attempts to reach potential participants can result in better recruitment (RR 1.87, 95% CI 1.61 to 2.18). Finally, 10 studies investigated the effect of adding a recruitment mode to existing recruitment strategies. Findings showed that: adding a text message reminder or real quotes from participants to a personal phone call improved recruitment of participants (RR 3.38, 95% CI 1.26 to 9.08 and RR 29.07, 95% CI 1.74 to 485.70, respectively); that adding a personal phone call to an existing newsletter can also increase recruitment rates (RR 65.12, 95% CI 4.06 to 1045.4]); that a reactive-proactive recruitment phase is more effective than a proactive phase alone (63.8% versus 47.5%, RR not available); and that active recruitment at schools is more effective than passive recruitment (p < 0.001, denominator not available for calculation of RR). Additionally, a number of studies in this category showed that providing incentives can effectively increase the number of participants recruited into smoking cessation programmes. Out of the 19 included studies, only four reported on the effect of recruitment strategy on smoking cessation at six months or longer. Three of these studies compared strategies that used the same delivery mode with different content. Their results were non-significant. The remaining three studies evaluated adding an additional mode to an existing recruitment intervention. Only one of them showed a significant difference in the levels of smoking cessation that favoured the enhanced recruitment strategy, but this may have reflected the offer of incentives once in the programme rather than the recruitment strategy itself (RR at 15 or 18 months 2.60, 95% CI 1.48 to 4.56). The substantial heterogeneity across the included studies restricts our ability to draw firm conclusions about the effectiveness of different recruitment strategies in relation to recruitment of participants into smoking cessation programmes or levels of smoking cessation. The limited evidence, however, suggests that the following elements may improve the recruitment of smokers into cessation programmes: personal, tailored interventions; recruitment methods that are proactive in nature; and more intensive recruitment strategies (i.e., those strategies that require increased contact with potential participants).
We included five studies with a total of 311 eyes (247 participants) of which 133 eyes (participants) were quasi-randomised. One hundred and sixty eyes which had trabeculectomy were compared to 151 eyes that had non-penetrating glaucoma surgery (of which 101 eyes had deep sclerectomy and 50 eyes had viscocanalostomy). The confidence interval (CI) for the odds ratio (OR) of success (defined as achieving target eye pressure without eye drops) does not exclude a beneficial effect of either deep sclerectomy or trabeculectomy (OR 0.98, 95% CI 0.51 to 1.88). The odds of success in viscocanalostomy participants was lower than in trabeculectomy participants (OR 0.33, 95% CI 0.13 to 0.81). We did not combine the different types of non-penetrating surgery because there was evidence of a subgroup difference when examining total success. The odds ratio for achieving target eye pressure with or without eye drops was imprecise and was compatible with a beneficial effect of either trabeculectomy or non-penetrating filtration surgery (NPFS) (OR 0.79, 95% CI 0.35 to 1.79). Operative adjuvants were used in both treatment groups; more commonly in the NPFS group compared to the trabeculectomy group but no clear effect of their use could be determined. Although the studies were too small to provide definitive evidence regarding the relative safety of the surgical procedures we noted that there were relatively fewer complications with non-filtering surgery compared to trabeculectomy (17% and 65% respectively). Cataract was more commonly reported in the trabeculectomy studies. None of the five trials used quality of life measure questionnaires. The methodological quality of the studies was not good. Most studies were at high risk of bias in at least one domain and for many, there was lack of certainty due to incomplete reporting. Adequate sequence generation was noted only in one study. Similarly, only two studies avoided detection bias. We detected incomplete outcome data in three of the included studies. This review provides some limited evidence that control of IOP is better with trabeculectomy than viscocanalostomy. For deep sclerectomy, we cannot draw any useful conclusions. This may reflect surgical difficulties in performing non-penetrating procedures and the need for surgical experience. This review has highlighted the lack of use of quality of life outcomes and the need for higher methodological quality RCTs to address these issues. Since it is unlikely that better IOP control will be offered by NPFS, but that these techniques offer potential gains for patients in terms of quality of life, we feel that such a trial is likely to be of a non-inferiority design with quality of life measures.
A total of 171 studies were included in the analysis (24,868 participants). The included studies were undertaken between 1984 and 2012. Studies had homogenous characteristics in terms of design, intervention and outcome measures. The assessment of quality with the risk of bias tool revealed that the great majority of them failed to report methodological details, like the method of random sequence generation, the allocation concealment and blinding. Moreover, most of the included studies were sponsored by drug companies, so the potential for overestimation of treatment effect due to sponsorship bias should be considered in interpreting the results. Fluoxetine was as effective as the TCAs when considered as a group both on a dichotomous outcome (reduction of at least 50% on the Hamilton Depression Scale) (OR 0.97, 95% CI 0.77 to 1.22, 24 RCTs, 2124 participants) and a continuous outcome (mean scores at the end of the trial or change score on depression measures) (SMD 0.03, 95% CI -0.07 to 0.14, 50 RCTs, 3393 participants). On a dichotomous outcome, fluoxetine was less effective than dothiepin or dosulepin (OR 2.13, 95% CI 1.08 to 4.20; number needed to treat (NNT) = 6, 95% CI 3 to 50, 2 RCTs, 144 participants), sertraline (OR 1.37, 95% CI 1.08 to 1.74; NNT = 13, 95% CI 7 to 58, 6 RCTs, 1188 participants), mirtazapine (OR 1.46, 95% CI 1.04 to 2.04; NNT = 12, 95% CI 6 to 134, 4 RCTs, 600 participants) and venlafaxine (OR 1.29, 95% CI 1.10 to 1.51; NNT = 11, 95% CI 8 to 16, 12 RCTs, 3387 participants). On a continuous outcome, fluoxetine was more effective than ABT-200 (SMD -1.85, 95% CI -2.25 to -1.45, 1 RCT, 141 participants) and milnacipran (SMD -0.36, 95% CI -0.63 to -0.08, 2 RCTs, 213 participants); conversely, it was less effective than venlafaxine (SMD 0.10, 95% CI 0 to 0.19, 13 RCTs, 3097 participants). Fluoxetine was better tolerated than TCAs considered as a group (total dropout OR 0.79, 95% CI 0.65 to 0.96; NNT = 20, 95% CI 13 to 48, 49 RCTs, 4194 participants) and was better tolerated in comparison with individual ADs, in particular amitriptyline (total dropout OR 0.62, 95% CI 0.46 to 0.85; NNT = 13, 95% CI 8 to 39, 18 RCTs, 1089 participants), and among the newer ADs ABT-200 (total dropout OR 0.18, 95% CI 0.08 to 0.39; NNT = 3, 95% CI 2 to 5, 1 RCT, 144 participants), pramipexole (total dropout OR 0.12, 95% CI 0.03 to 0.42, NNT = 3, 95% CI 2 to 5, 1 RCT, 105 participants), and reboxetine (total dropout OR 0.60, 95% CI 0.44 to 0.82, NNT = 9, 95% CI 6 to 24, 4 RCTs, 764 participants). The present study detected differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain. Moreover, the assessment of quality with the risk of bias tool showed that the great majority of included studies failed to report details on methodological procedures. Of consequence, no definitive implications can be drawn from the studies' results. The better efficacy profile of sertraline and venlafaxine (and possibly other ADs) over fluoxetine may be clinically meaningful, as already suggested by other systematic reviews. In addition to efficacy data, treatment decisions should also be based on considerations of drug toxicity, patient acceptability and cost.
We included a total of 15 eligible studies randomising 3760 participants in this review. The age of participants across the studies ranged from 3 to 101 years, with a mean of 25.42 years. 48% of participants were male. All included studies were published between 2002 and 2016. Two of the 15 studies declared that the financial support was from companies that manufacture restorative material. Five studies were individually randomised parallel-group studies; six were cluster-randomised parallel-group studies; and four were randomised studies that used a split-mouth design. Eleven studies evaluated the effects of ART on primary teeth only, and four on permanent teeth. The follow-up period of the included studies ranged from 6 months to 36 months. We judged all studies to be at high risk of bias. For the main comparison of ART compared to conventional treatment using the same material: all but two studies used high-viscosity glass ionomer (H-GIC) as the restorative material; one study used a composite material; and one study used resin-modified glass ionomer cement (RM-GIC)). Compared to conventional treatment using H-GIC, ART may increase the risk of restoration failure in the primary dentition, over a follow-up period from 12 to 24 months (OR 1.60, 95% CI 1.13 to 2.27, five studies; 643 participants analysed; low-quality evidence). Our confidence in this effect estimate is limited due to serious concerns over risk of performance and attrition bias. For this comparison, ART may reduce pain during procedure compared with conventional treatment (MD -0.65, 95% CI -1.38 to 0.07; 40 participants analysed; low-quality evidence) Comparisons of ART to conventional treatment using composite or RM-GIC were downgraded to very low quality due to indirectness, imprecision and high risk of performance and attrition bias. Given the very low quality of the evidence from single studies, we are uncertain about the restoration failure of ART compared with conventional treatment using composite over a 24-month follow-up period (OR 1.11, 95% CI 0.54 to 2.29; one study; 57 participants) and ART using RM-GIC in the permanent teeth of older adults with root caries lesions over a six-month follow-up period (OR 2.71, 95% CI 0.94 to 7.81; one study; 64 participants). No studies reported on adverse events or costs. Low-quality evidence suggests that ART using H-GIC may have a higher risk of restoration failure than conventional treatment for caries lesions in primary teeth. The effects of ART using composite and RM-GIC are uncertain due to the very low quality of the evidence and we cannot rely on the findings. Most studies evaluated the effects of ART on the primary dentition. Well-designed RCTs are required that report on restoration failure at clinically meaningful time points, as well as participant-reported outcomes such as pain and discomfort. Due to the potential confounding effects from the use of different dental materials, a robust body of evidence on the effects of ART compared with conventional treatment using the same restoration material is necessary. We identified four ongoing trials that could provide further insights into this area.
We included 25 RCTs that evaluated the BP lowering effects of seven nonselective beta-blockers in 1264 people with hypertension. Among the 25 RCTs, four were parallel studies and 21 were cross-over studies. Overall, nonselective beta-blockers lowered systolic BP and diastolic BP compared with placebo. Nonselective beta-blockers, in the recommended dose range, did not showed a convincing dose-response relationship by direct comparison. The once (1x) and twice (2x) starting dose subgroups contained the largest sample size. The estimate of BP lowering efficacy for nonselective beta-blockers by combining the 1x and 2x starting dose subgroup was -10 mmHg (95% CI -11 to -8) for systolic BP and -7 mmHg (95% CI -8 to -6) for diastolic BP (low-quality evidence). Nonselective beta-blockers starting at the 1x recommended starting doses lowered heart rate by 12 beats per minute (95% CI 10 to 13) (low-quality evidence). The dose-response relationship in heart rate was evident by both direct and indirect comparison. Due to imprecision, there was no clear evidence of an effect of nonselective beta-blockers on pulse pressure in any dose subgroups except for a small reduction with the 2x starting dose (-2.2 mmHg, 95% CI -3.7 to -0.7) (very low quality evidence). The point estimates in the 1x, four times (4x) and eight times (8x) starting dose subgroups were similar to the 2x starting dose subgroup. Therefore, it would appear that if nonselective beta-blockers do lower pulse pressure, the magnitude is likely to be about 2 mmHg. There were very limited data (two studies) on withdrawals due to adverse effects (risk ratio (RR) 0.84; 95% CI 0.38 to 1.82). In people with mild-to-moderate hypertension, nonselective beta-blockers lowered peak BP by a mean of -10/-7 mmHg (systolic/diastolic) and reduced heart rate by 12 beats per minute. Propranolol and penbutolol were the two drugs that contributed to most of the data for nonselective beta-blockers. This estimate is likely exaggerated due to the presence of extreme outliers and other sources of bias. If we removed the extreme outliers from the analysis, the estimate for non-selective beta-blockers was lower (-8/-5 mmHg (systolic/diastolic)). Nonselective beta-blockers did not show a convincing graded dose-response in the recommended dose range for systolic BP and diastolic BP, while higher dose nonselective beta-blockers provided greater reduction of heart rate. Using higher dose nonselective beta-blockers might cause more side effects, such as bradycardia, without producing an additional BP lowering effect. The effect of nonselective beta-blockers on pulse pressure was likely small, at about 2 mmHg.
We identified seven trials, with 895 evaluable participants for this review. All provided data suitable for the primary outcome meta-analysis. One of the trials was new since the last version of this Cochrane systematic review. Risk of bias in the older, smaller studies included some unclear- or high-risk assessments, whereas we deemed the larger studies at low risk of bias. Overall, 79/452 (17%) participants allocated to corticosteroids had incomplete recovery of facial motor function six months or more after randomisation; significantly fewer than the 125/447 (28%) in the control group (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.50 to 0.80, seven trials, n = 895). The number of people who need to be treated with corticosteroids to avoid one incomplete recovery was 10 (95% CI 6 to 20). The reduction in the proportion of participants with cosmetically disabling sequelae six months after randomisation was very similar in the corticosteroid and placebo groups (RR 0.96, 95% CI 0.40 to 2.29, two trials, n = 75, low-quality evidence). However, there was a significant reduction in motor synkinesis during follow-up in participants receiving corticosteroids (RR 0.64, 95% CI 0.45 to 0.91, three trials, n = 485, moderate-quality evidence). Three studies explicitly recorded the absence of adverse effects attributable to corticosteroids. One trial reported that three participants receiving prednisolone had temporary sleep disturbances and two trials gave a detailed account of adverse effects occurring in 93 participants, all non-serious; the combined analysis of data from these three trials found no significant difference in adverse effect rates between people receiving corticosteroids and people receiving placebo (RR 1.04, 95% CI 0.71 to 1.51, n = 715). The available moderate- to high-quality evidence from randomised controlled trials showed significant benefit from treating Bell's palsy with corticosteroids.
Twelve trials met our eligibility criteria, included the three added in this update. The studies included a total of 4145 women. Eight trials were conducted in the USA; the others were from Australia, Nepal, Pakistan, and Syria. Four studies provided one session before hospital discharge; three had structured counseling of varying intensity and one involved informal counseling. Of eight interventions with than one contact, five focused on adolescents. Three of the five involved home visiting, one provided multiple clinic services, and one had in-person contact and phone follow-up. Of the remaining three for women of varying ages, two involved home visits and one provided phone follow-up. Our sensitivity analysis included six trials with evidence of moderate or high quality. In a study with adolescents, the group with home-based mentoring had fewer second births within two years compared to the control group (OR 0.41, 95% CI 0.17 to 1.00). The other five interventions had no effect. Of trials with lower quality evidence, two showed some effectiveness. In Nepal, women with an educational session immediately postpartum were more likely to use contraception at six months than those with a later or no session (OR 1.62, 95% CI 1.06 to 2.50). In an Australian study, teenagers in a structured home-visiting program were more likely to have effective contraception use at six months than those with standard home visits (OR 3.24; 95% CI 1.35 to 7.79). We focused our results summary on trials with moderate or high quality evidence. Overall, the overall quality of evidence in this review was moderate to low and the evidence of effectiveness was mostly low quality. The interventions could be improved by strengthening the program design and implementation. Some studies did not report program training for providers, adherence to the intervention protocol, or measurement of participants' knowledge and skills. Many trials did not have an objective outcome measure, i.e., pregnancy test or structured questionnaire for contraceptive use. Valid and reliable outcome measures are needed to obtain meaningful results. Still, given the associated costs and logistics, some programs would not be feasible in many settings.
We include 15 randomised controlled trials (RCTs) (17 comparisons, ˜59,000 participants), which used a variety of interventions from providing all food to advice on how to reduce saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.72 to 0.96, 13 comparisons, 53,300 participants of whom 8% had a cardiovascular event, I² 65%, GRADE moderate quality of evidence), but effects on all-cause mortality (RR 0.97; 95% CI 0.90 to 1.05; 12 trials, 55,858 participants) and cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 12 trials, 53,421 participants) were less clear (both GRADE moderate quality of evidence). There was some evidence that reducing saturated fats reduced the risk of myocardial infarction (fatal and non-fatal, RR 0.90; 95% CI 0.80 to 1.01; 11 trials, 53,167 participants), but evidence for non-fatal myocardial infarction (RR 0.95; 95% CI 0.80 to 1.13; 9 trials, 52,834 participants) was unclear and there were no clear effects on stroke (any stroke, RR 1.00; 95% CI 0.89 to 1.12; 8 trials, 50,952 participants). These relationships did not alter with sensitivity analysis. Subgrouping suggested that the reduction in cardiovascular events was seen in studies that primarily replaced saturated fat calories with polyunsaturated fat, and no effects were seen in studies replacing saturated fat with carbohydrate or protein, but effects in studies replacing with monounsaturated fats were unclear (as we located only one small trial). Subgrouping and meta-regression suggested that the degree of reduction in cardiovascular events was related to the degree of reduction of serum total cholesterol, and there were suggestions of greater protection with greater saturated fat reduction or greater increase in polyunsaturated and monounsaturated fats. There was no evidence of harmful effects of reducing saturated fat intakes on cancer mortality, cancer diagnoses or blood pressure, while there was some evidence of improvements in weight and BMI. The findings of this updated review are suggestive of a small but potentially important reduction in cardiovascular risk on reduction of saturated fat intake. Replacing the energy from saturated fat with polyunsaturated fat appears to be a useful strategy, and replacement with carbohydrate appears less useful, but effects of replacement with monounsaturated fat were unclear due to inclusion of only one small trial. This effect did not appear to alter by study duration, sex or baseline level of cardiovascular risk. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturated fats. The ideal type of unsaturated fat is unclear.
Eight studies with 343 participants were included. The review found evidence for lower post-treatment OCD severity and reduced risk of continuing with OCD for the BT/CBT group compared to pill placebo or wait-list comparisons. There was no evidence found that the efficacy of BT/CBT alone and medication alone differ in terms of post treatment symptom severity or in the risk of having OCD. There was some evidence of a benefit for combined BT/CBT and medication compared to medication alone but not relative to BT/CBT alone. The low rates of drop out suggested BT/CBT is an acceptable treatment to child and adolescent patients and their families. Although only based on a small number of studies which vary in quality, behavioural or cognitive-behaviour therapy alone appears to be an effective treatment for OCD in children and adolescents. It is as effective as medication alone and may lead to better outcomes when combined with medication compared to medication alone. Additional higher quality trials are needed to confirm these findings.
We identified only one randomised controlled trial, which compared open surgery and radiotherapy in 234 patients with early glottic laryngeal cancer. The overall risk of bias in this study was high. For T1 tumours, the five-year survival was 91.7% following radiotherapy and 100% following surgery and for T2 tumours, 88.8% following radiotherapy and 97.4% following surgery. There were no significant differences in survival between the two groups. For T1 tumours, the five-year disease-free survival rate was 71.1% following radiotherapy and 100.0% following surgery, and for the T2 tumours, 60.1% following radiotherapy and 78.7% following surgery. Only the latter comparison was statistically significant (P value = 0.036), but statistical significance would not have been achieved with a two-sided test. Data were not available on side effects, quality of life, voice outcomes or cost. We identified no randomised controlled trials that included endolaryngeal surgery. A number of trials comparing endolaryngeal resection and radiotherapy have terminated early because of difficulty recruiting participants. One randomised controlled trial is still ongoing. There is only one randomised controlled trial comparing open surgery and radiotherapy but its interpretation is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis.
Ten studies were found including 366 patients in total. We included eight studies in the as-published data analysis, comprising 337 patients . The methodological quality of the studies was overall satisfactory, however there was potential for introduction of significant bias in several specific areas relating to performance of the index test and to the timing of index versus reference tests. Results demonstrated a sensitivity estimate of 0.84 (95% confidence interval (CI) 0.69 to 0.93). The 95% approximate prediction interval was very wide (0.34 to 0.98). Data in three studies were available as a four-vessel interpretation model and the data could be re-analysed to a four-vessel interpretation model in a further five studies, comprising 314 patient events. Results demonstrated a similar sensitivity estimate of 0.85 (95% CI 0.77 to 0.91) but with an improved 95% approximate prediction interval (0.56 to 0.96). The available evidence cannot support the use of CT angiography as a mandatory test, or as a complete replacement for neurological testing, in the management pathway of patients who are suspected to be clinically brain dead. CT angiography may be useful as a confirmatory or add-on test following a clinical diagnosis of death, assuming that clinicians are aware of the relatively low overall sensitivity. Consensus on a standard radiological interpretation protocol for future published studies would facilitate further meta-analysis.
We identified no new studies for this update. We included five trials with a total of 1292 participants; agents used for thrombolysis were recombinant tissue plasminogen activator and urokinase. Trials were generally of moderate methodological quality. The quality of evidence according to GRADE was generally low owing to risk of bias (lack of blinding), imprecision in estimates, and heterogeneity. Trial results showed no clear differences in limb salvage, amputation, or death at 30 days (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.41 to 2.55, 4 studies, 636 participants; OR 0.97, 95% CI 0.51 to 1.85, 3 studies, 616 participants; OR 0.59, 95% CI 0.31 to 1.14, 4 studies, 636 participants, respectively), and we rated the evidence as low, low, and moderate quality, respectively. Trial results show no clear differences for any of the three outcomes at six months or one year between initial surgery and initial thrombolysis. A single study evaluated vessel patency, so no overall association could be determined (OR 0.46, 95% CI 0.08 to 2.76, 20 participants; very low-quality evidence). Evidence of increased risk of major haemorrhage (OR 3.22, 95% CI 1.79 to 5.78, 4 studies, 1070 participants; low-quality evidence) and distal embolisation (OR 31.68, 95% CI 6.23 to 161.07, 3 studies, 678 participants; very low-quality evidence) was associated with thrombolysis treatment at 30 days, and there was no clear difference in stroke (OR 5.33, 95% CI 0.95 to 30.11, 5 studies, 1180 participants; low-quality evidence). Participants treated by initial thrombolysis had a greater reduction in the level of intervention required, compared with a pre-intervention prediction, at 30 days (OR 9.06, 95% CI 4.95 to 16.56, 2 studies, 502 participants). None of the included studies evaluated time to thrombolysis as an outcome. There is currently no evidence in favour of either initial thrombolysis or initial surgery as the preferred option in terms of limb salvage, amputation, or death at 30 days, six months, or one year. Low-quality evidence suggests that thrombolysis may be associated with higher risk of haemorrhagic complications and ongoing limb ischaemia (distal embolisation). The higher risk of complications must be balanced against risks of surgery in each individual case. Trial results show no statistical difference in stroke, but the confidence interval is very wide, making it difficult to interpret whether this finding is clinically important. We used GRADE criteria to assess the quality of the evidence as generally low. We downgraded quality owing to risk of bias, imprecision, and heterogeneity between included studies.
Five trials (619 participants) met the inclusion criteria; two addressed inpatient rehabilitation (261 participants) and three (358 participants) home-based settings. There were no trials addressing outpatient centre-based programmes. Pooling of data was not possible due to differences in study design and outcomes used. Methodological assessment showed all trials were of low quality. For inpatient settings early commencement of rehabilitation and clinical pathways led to more rapid attainment of functional milestones (disability) (Functional Independence Measure (FIM) transfer WMD 0.5, 95% CI 0.15, 0.85, number needed to treat to benefit (NNTB) = 6, FIM ambulation WMD 1.55 (95%CI 0.96, 2.14), NNTB = 3), shorter hospital stay, fewer post-operative complications and reduced costs in the first three to four months. Home-based multidisciplinary care improved functional gain (Oxford Hip Score (OHS) WMD at 6 months -7.00 (95%CI -10.36, -3.64), NNT = 2 and quality of life (QoL) and reduced hospital stay in the medium term (six months). No trials addressed longer-term outcomes following hip replacement only. Based on the heterogeneity and the low quality of the included trials that precluded pooled meta-analysis, there is silver level evidence that following hip or knee joint replacement, early multidisciplinary rehabilitation can improve outcomes at the level of activity and participation. The optimal intensity, frequency and effects of rehabilitation over a longer period and associated social costs need further study. Future research should focus on improving methodological and scientific rigour of clinical trials, and use of standardised outcome measures, so that results can be pooled for statistical analysis.
We included 32 RCTs involving 2762 participants in this review. We considered 16 trials, representing 57% of all participants, to have a low risk of bias based on the Cochrane Back Review Group's 'Risk of bias' tool. For people with mixed symptom patterns (acute, subacute and chronic LBP with and without sciatica), there was low- to moderate-quality evidence that traction may make little or no difference in pain intensity, functional status, global improvement or return to work when compared to placebo, sham traction or no treatment. Similarly, when comparing the combination of physiotherapy plus traction with physiotherapy alone or when comparing traction with other treatments, there was very-low- to moderate-quality evidence that traction may make little or no difference in pain intensity, functional status or global improvement. For people with LBP with sciatica and acute, subacute or chronic pain, there was low- to moderate-quality evidence that traction probably has no impact on pain intensity, functional status or global improvement. This was true when traction was compared with controls and other treatments, as well as when the combination of traction plus physiotherapy was compared with physiotherapy alone. No studies reported the effect of traction on return to work. For chronic LBP without sciatica, there was moderate-quality evidence that traction probably makes little or no difference in pain intensity when compared with sham treatment. No studies reported on the effect of traction on functional status, global improvement or return to work. Adverse effects were reported in seven of the 32 studies. These included increased pain, aggravation of neurological signs and subsequent surgery. Four studies reported that there were no adverse effects. The remaining studies did not mention adverse effects. These findings indicate that traction, either alone or in combination with other treatments, has little or no impact on pain intensity, functional status, global improvement and return to work among people with LBP. There is only limited-quality evidence from studies with small sample sizes and moderate to high risk of bias. The effects shown by these studies are small and are not clinically relevant. Implications for practice  To date, the use of traction as treatment for non-specific LBP cannot be motivated by the best available evidence. These conclusions are applicable to both manual and mechanical traction. Implications for research Only new, large, high-quality studies may change the point estimate and its accuracy, but it should be noted that such change may not necessarily favour traction. Therefore, little priority should be given to new studies on the effect of traction treatment alone or as part of a package.
Seven studies met the inclusion criteria. No studies had investigated selective inclusion of results in systematic reviews, or discrepancies in outcomes and analyses between systematic review registry entries and published systematic reviews. Based on a meta-analysis of four studies (including 485 Cochrane Reviews), 38% (95% confidence interval (CI) 23% to 54%) of systematic reviews added, omitted, upgraded or downgraded at least one outcome between the protocol and published systematic review. The association between statistical significance and discrepant outcome reporting between protocol and published systematic review was uncertain. The meta-analytic estimate suggested an increased risk of adding or upgrading (i.e. changing a secondary outcome to primary) when the outcome was statistically significant, although the 95% CI included no association and a decreased risk as plausible estimates (RR 1.43, 95% CI 0.71 to 2.85; two studies, n = 552 meta-analyses). Also, the meta-analytic estimate suggested an increased risk of downgrading (i.e. changing a primary outcome to secondary) when the outcome was statistically significant, although the 95% CI included no association and a decreased risk as plausible estimates (RR 1.26, 95% CI 0.60 to 2.62; two studies, n = 484 meta-analyses). None of the included studies had investigated whether the association between statistical significance and adding, upgrading or downgrading of outcomes was modified by the type of comparison, direction of effect or type of outcome; or whether there is an association between direction of the effect estimate and discrepant outcome reporting. Several secondary outcomes were reported in the included studies. Two studies found that reasons for discrepant outcome reporting were infrequently reported in published systematic reviews (6% in one study and 22% in the other). One study (including 62 Cochrane Reviews) found that 32% (95% CI 21% to 45%) of systematic reviews did not report all primary outcomes in the abstract. Another study (including 64 Cochrane and 118 non-Cochrane reviews) found that statistically significant primary outcomes were more likely to be completely reported in the systematic review abstract than non-significant primary outcomes (RR 2.66, 95% CI 1.81 to 3.90). None of the studies included systematic reviews published after 2009 when reporting standards for systematic reviews (Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement, and Methodological Expectations of Cochrane Intervention Reviews (MECIR)) were disseminated, so the results might not be generalisable to more recent systematic reviews. Discrepant outcome reporting between the protocol and published systematic review is fairly common, although the association between statistical significance and discrepant outcome reporting is uncertain. Complete reporting of outcomes in systematic review abstracts is associated with statistical significance of the results for those outcomes. Systematic review outcomes and analysis plans should be specified prior to seeing the results of included studies to minimise post-hoc decisions that may be based on the observed results. Modifications that occur once the review has commenced, along with their justification, should be clearly reported. Effect estimates and CIs should be reported for all systematic review outcomes regardless of the results. The lack of research on selective inclusion of results in systematic reviews needs to be addressed and studies that avoid the methodological weaknesses of existing research are also needed.
The search identified 2178 citations, 28 of which were considered potentially relevant. After independent review of the full text of these studies, no eligible studies were identified for inclusion in this review due to the absence of studies with a randomised controlled study design. There was no evidence available to support conclusions about the effectiveness of nursing handover styles for ensuring continuity of information in hospitalised patients because we found no studies that fulfilled the methodological criteria for this review. As a consequence, uncertainty about the most effective practice remains. Research efforts should focus on strengthening the evidence abut the effectiveness of nursing handover styles using well designed, rigorous studies. According to current knowledge, the following guiding principles can be applied when redesigning the nursing handover process: face-to-face communication, structured documentation, patient involvement and use of IT technology to support the process.
We included 31 studies that explored the views and experiences of different types of SBAs, including doctors, midwives, nurses, auxiliary nurses and their managers. The included studies took place in Africa, Asia, and Latin America. Our synthesis pointed to a number of factors affecting SBAs’ provision of quality care. The following factors were based on evidence assessed as of moderate to high confidence. Skilled birth attendants reported that they were not always given sufficient training during their education or after they had begun clinical work. Also, inadequate staffing of facilities could increase the workloads of skilled birth attendants, make it difficult to provide supervision and result in mothers being offered poorer care. In addition, SBAs did not always believe that their salaries and benefits reflected their tasks and responsibilities and the personal risks they undertook. Together with poor living and working conditions, these issues were seen to increase stress and to negatively affect family life. Some SBAs also felt that managers lacked capacity and skills, and felt unsupported when their workplace concerns were not addressed. Possible causes of staff shortages in facilities included problems with hiring and assigning health workers to facilities where they were needed; lack of funding; poor management and bureaucratic systems; and low salaries. Skilled birth attendants and their managers suggested factors that could help recruit, keep, and motivate health workers, and improve the quality of care; these included good-quality housing, allowances for extra work, paid vacations, continuing education, appropriate assessments of their work, and rewards. Skilled birth attendants’ ability to provide quality care was also limited by a lack of equipment, supplies, and drugs; blood and the infrastructure to manage blood transfusions; electricity and water supplies; and adequate space and amenities on maternity wards. These factors were seen to reduce SBAs’ morale, increase their workload and infection risk, and make them less efficient in their work. A lack of transport sometimes made it difficult for SBAs to refer women on to higher levels of care. In addition, women’s negative perceptions of the health system could make them reluctant to accept referral. We identified some other factors that also may have affected the quality of care, which were based on findings assessed as of low or very low confidence. Poor teamwork and lack of trust and collaboration between health workers appeared to negatively influence care. In contrast, good collaboration and teamwork appeared to increase skilled birth attendants’ motivation, their decision-making abilities, and the quality of care. Skilled birth attendants’ workloads and staff shortages influenced their interactions with mothers. In addition, poor communication undermined trust between skilled birth attendants and mothers. Many factors influence the care that SBAs are able to provide to mothers during childbirth. These include access to training and supervision; staff numbers and workloads; salaries and living conditions; and access to well-equipped, well-organised healthcare facilities with water, electricity, and transport. Other factors that may play a role include the existence of teamwork and of trust, collaboration, and communication between health workers and with mothers. Skilled birth attendants reported many problems tied to all of these factors.
We included 5 randomised trials with 662 participants out of 93 publications identified through the literature searches. The number of deaths was 47 in the wait-and-see group (334 patients) compared to 26 in the prophylactic cholecystectomy group (328 patients) for a 78% increased risk of mortality (RR 1.78, 95% CI 1.15 to 2.75, P = 0.010). The survival benefit of prophylactic cholecystectomy was independent of trial design, inclusion of high risk patients or inclusion of any one of the five trials. Patients in the wait-and-see group had higher rates of recurrent biliary pain (RR 14.56, 95% CI 4.95 to 42.78, P < 00001), jaundice or cholangitis (RR 2.53, 95% CI 1.09 to 5.87, P = 0.03), and of repeat ERCP or other forms of cholangiography (RR 2.36, 95% CI 1.29 to 4.32, P = 0.005). Cholecystectomy was eventually performed in 35% (115 patients) of the wait-and-see group. Prophylactic cholecystectomy should be offered to patients whose gallbladders remain in-situ after endoscopic sphincterotomy and common bile duct clearance.
Two studies (involving 286 women) from amniocentesis (but none from CVS) compared the impact of communicating results of rapid testing with waiting for definitive karyotype. Unfortunately, it was not possible to perform pooled analysis because one study reported only median (interquartile range) data, presumably because the data were not normally distributed. One study reported a statistically significant reduction in the average anxiety during the waiting period for women who had had a rapid test compared with those who had not (mean difference (MD) -2.30, 95% confidence intervals (CI) -3.08 to - 1.52). The other study compared median (interquartile range) for the trait- and state-anxiety scores and found no difference between the two groups. We found no conclusive evidence that, while waiting for the full karyotype following amniocentesis, issuing results from a rapid analysis reduces maternal anxiety. The limited evidence from the two trials included in this review does not help resolve the dilemma about whether full karyotyping should be abandoned in favour of limited rapid testing for women undergoing Down's syndrome screening. This choice will rest on clinical arguments and cost-effectiveness rather than impact on anxiety. There is also no evidence to support the view that issuing amniocentesis results as soon as they are available is more user friendly than using a pre-defined fixed date. Studies evaluating the effect of different strategies for disclosing results on women anxiety for CVS are needed.
We include 10 RCTs (n = 1850); almost all participants had moderate or severe ARDS. For the primary analysis, the risk of bias was low in three studies and unclear in five studies; the overall quality of evidence was very low due to imprecision, inconsistency, indirectness and methodologic limitations. In participants randomized to HFO, there was no significant difference in hospital or 30-day mortality (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.72 to 1.16; P = 0.46, I² = 66%; 8 trials, 1779 participants, 807 deaths) compared with conventional ventilation. One large multicentre RCT was terminated early because of increased mortality in participants randomized to HFO compared to mechanical ventilation with low tidal volume and high positive end expiratory pressure, with HFO reserved only as a rescue therapy. We found substantial between-trial statistical heterogeneity (I² = 0% to 66%) for clinical outcomes, including mortality. The findings of this systematic review suggest that HFO does not reduce hospital and 30-day mortality due to ARDS; the quality of evidence was very low. Our findings do not support the use of HFO as a first-line strategy in people undergoing mechanical ventilation for ARDS.
We included six RCTs (692 participants). The overall risk of bias in the studies was low. Two studies assessed oral administration of tranexamic acid, given regularly over several days, and compared it to placebo. In the other four studies, a single application of topical tranexamic acid was compared with placebo (one study) and a combination of epinephrine and lidocaine or phenylephrine (three studies). All participants were adults. Tranexamic acid versus placebo For our primary outcome, control of epistaxis: re-bleeding (proportion re-bleeding within 10 days), we were able to pool data from three studies. The pooled result demonstrated a benefit of tranexamic acid compared to placebo, the risk of re-bleeding reducing from 67% to 47% (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.56 to 0.90; three studies; 225 participants; moderate-quality evidence). When we compared the effects of oral and topical tranexamic acid separately the risk of re-bleeding with oral tranexamic acid reduced from 69% to 49%, RR 0.73 (95% CI 0.55 to 0.96; two studies, 157 participants; moderate-quality evidence) and with topical tranexamic acid it reduced from 66% to 43%, RR 0.66 (95% CI 0.41 to 1.05; single study, 68 participants). We rated the quality of evidence provided by the single study as low, therefore it is uncertain whether topical tranexamic acid is effective in stopping bleeding in the 10-day period after a single application. No study specifically sought to identify and report our primary outcome: significant adverse effects (i.e. seizures, thromboembolic events). The secondary outcome time to stop initial bleeding (proportion with bleeding controlled within 30 minutes) was measured in one study using topical tranexamic acid and there was no evidence of a difference at 30 minutes (RR 0.79, 95% CI 0.56 to 1.11; 68 participants; low-quality evidence). No studies reported the proportion of patients requiring any further intervention (e.g. repacking, surgery, embolisation). One study of oral tranexamic acid reported the proportion of patients requiring blood transfusion and found no difference between groups: 5/45 (11%) versus 6/44 (14%) (RR 0.81, 95% CI 0.27 to 2.48; 89 participants; low-quality evidence). Two studies reported hospital length of stay. One study reported a significantly shorter stay in the oral tranexamic acid group (mean difference (MD) -1.60 days, 95% CI -2.49 to -0.71; 68 participants). The other study found no evidence of a difference between the groups. Tranexamic acid versus other haemostatic agents When we pooled the data from three studies the proportion of patients whose bleeding stopped within 10 minutes was significantly higher in the topical tranexamic acid group compared to the group receiving another haemostatic agent (70% versus 30%: RR 2.35, 95% CI 1.90 to 2.92; 460 participants) (moderate-quality evidence). Adverse effects across all studies Five studies recorded 'adverse effects' in a general way. None found any difference between the groups in the occurrence of minor adverse effects (e.g. mild nausea and diarrhoea, 'bad taste' of gel). In one study a patient developed a superficial thrombophlebitis of both legs following discharge, however it is not reported in which group this occurred. No "other serious adverse effect" was reported in any study. We found moderate-quality evidence that there is probably a reduction in the risk of re-bleeding with the use of either oral or topical tranexamic acid in addition to usual care in adult patients with epistaxis, compared to placebo with usual care. However, the quality of evidence relating solely to topical tranexamic acid was low (one study only), so we are uncertain whether or not topical tranexamic acid is effective in stopping bleeding in the 10-day period after a single application. We found moderate-quality evidence that topical tranexamic acid is probably better than other topical agents in stopping bleeding in the first 10 minutes. There have been only three RCTs on this subject since 1995. Since then there have been significant changes in nasal cauterisation and packing techniques (for example, techniques including nasal endoscopy and more invasive approaches such as endoscopic sphenopalatine artery ligation). New trials would inform us about the effectiveness of tranexamic acid in light of these developments.
One double blind randomised crossover trial met the inclusion criteria and compared 5% albumin to normal saline in patients with a previous history of IDH. Results from 45 assessable participants did not lead to rejection of the null hypothesis of no difference between 5% albumin and normal saline in the primary outcome measure of percentage target ultrafiltration achieved, nor in 11/12 secondary outcomes. Additional (unblinded) saline was given less often when 5% albumin was used compared with saline (16% versus 36%, P = 0.04). However, the volume of additional fluid administered was similar in both groups. There were no significant differences in the nursing time required to treat IDH and the time to restore BP. No randomised or controlled trial was identified comparing albumin to crystalloids (other than normal saline) or non-protein colloids, or a combination of both, in the treatment of symptomatic hypotension during dialysis. One double blind crossover RCT in 45 assessable patients showed that 5% albumin is not superior to normal saline for the treatment of symptomatic hypotension in maintenance haemodialysis patients with a previous history of IDH. Given the cost and relative rarity of albumin use compared to saline, saline should be first line of therapy for treatment of IDH in stable dialysis patients.
We included three studies with a total of 122 children (62/60 in intervention/control arms) aged up to 12 months that investigated nasal CPAP compared with supportive (or "standard") therapy. We included one new trial (72 children) that contributed data to the assessment of respiratory rate and need for mechanical ventilation for this update. The included studies were single-centre trials conducted in France, the UK, and India. Two studies were parallel-group RCTs and one was a cross-over RCT. The evidence provided by the included studies was low quality; we assessed high risk of bias for blinding, incomplete outcome data, and selective reporting, and confidence intervals were wide. The effect of CPAP on the need for mechanical ventilation in children with acute bronchiolitis was uncertain due to imprecision around the effect estimate (3 RCTs, 122 children; risk ratio (RR) 0.69, 95% confidence interval (CI) 0.14 to 3.36; low-quality evidence). None of the trials measured time to recovery. Limited, low-quality evidence indicated that CPAP decreased respiratory rate (2 RCTs, 91 children; mean difference (MD) -3.81, 95% CI -5.78 to -1.84). Only one trial measured change in arterial oxygen saturation, and the results were imprecise (19 children; MD -1.70%, 95% CI -3.76 to 0.36). The effect of CPAP on change in arterial partial carbon dioxide pressure (pCO₂) was imprecise (2 RCTs, 50 children; MD -2.62 mmHg, 95% CI -5.29 to 0.05; low-quality evidence). Duration of hospital stay was similar in both CPAP and supportive care groups (2 RCTs, 50 children; MD 0.07 days, 95% CI -0.36 to 0.50; low-quality evidence). Two studies did not report about pneumothorax, but pneumothorax did not occur in one study. No studies reported occurrences of deaths. Several outcomes (change in partial oxygen pressure, hospital admission rate (from emergency department to hospital), duration of emergency department stay, and need for intensive care unit admission) were not reported in the included studies. Limited, low-quality evidence suggests that breathing improved (a decreased respiratory rate) in children with bronchiolitis who received CPAP; this finding is unchanged from the 2015 review. Further evidence for this outcome was provided by the inclusion of a low-quality study for the 2018 update. Due to the limited available evidence, the effect of CPAP in children with acute bronchiolitis is uncertain for other outcomes. Larger, adequately powered trials are needed to evaluate the effect of CPAP for children with acute bronchiolitis.
Twenty eight short-term (average of seven weeks) randomised controlled trials (740 participants) were included in the review, 20 of which investigated augmentation of medication for treatment-resistant obsessive compulsive disorder (OCD). Summary statistics for responder status from nine trials demonstrate overall superiority of a variety of medication agents to placebo (relative risk of non-response (RR) 3.16, 95% CI 1.08 to 9.23). Similarly, symptom severity was significantly reduced in the medication groups, relative to placebo (number of trials (N) = 14, standardised mean difference (SMD) -0.87, 95% CI -1.37 to -0.36). There is no evidence of a difference between medication and placebo in total dropout rate, or in the number of dropouts due to adverse events. Medication augmentation can be an effective and well-tolerated short-term treatment strategy for non-responders to first-line pharmacotherapy of anxiety disorders. However, any conclusions must be tentative in view of methodological and clinical heterogeneity, and the fact that much of the relevant database is based on antipsychotic augmentation trials in OCD patients resistant to serotonin reuptake inhibitors (SRIs). Additional data are needed to address several areas, including the efficacy of augmentation over the longer-term, and the value of medication augmentation in comparison to other strategies (eg switching medication, adding psychotherapy).
We included four RCTs with a total of 463 participants (aged 42 years to 93 years); one report was only available as a published abstract. Meta-analysis of three RCTs suggests an increase in the proportion of ulcers completely healed with sulodexide as an adjuvant to local treatment (including wound care and compression therapy) compared with local treatment alone (rate of complete healing with sulodexide 49.4% compared with 29.8% with local treatment alone; RR 1.66; 95% CI 1.30 to 2.12). This evidence for sulodexide increasing the rate of complete healing is low quality due to risk of bias. It is unclear whether sulodexide is associated with any increase in adverse events (4.4% with sulodexide versus 3.1% with no sulodexide; RR 1.44; 95% CI 0.48 to 4.34). The evidence for adverse events is very low quality, downgraded twice for risk of bias and once for imprecision. Sulodexide may increase the healing of venous ulcers, when used alongside local wound care, however the evidence is only low quality and the conclusion is likely to be affected by new research. It is not clear whether sulodexide is associated with adverse effects. The standard dosage, route and frequency of sulodexide reported in the trials was unclear. Further rigorous, adequately powered RCTs examining the effects of sulodexide on healing, ulcer recurrence, quality of life and costs are necessary.
We included seven studies (662 participants) in this review. All except one study was assessed as being at high risk of bias. Three studies assessed atorvastatin, three assessed simvastatin and one investigated rosuvastatin. All studies collected data during the immediate perioperative period only; data collection to hospital discharge and postoperative biochemical data collection ranged from 24 hours to 7 days. Overall, pre-operative statin treatment was not associated with a reduction in postoperative AKI, need for RRT, or mortality. Only two studies (195 participants) reported postoperative SCr level. In those studies, patients allocated to receive statins had lower postoperative SCr concentrations compared with those allocated to no drug treatment/placebo (MD 21.2 µmol/L, 95% CI -31.1 to -11.1). Adverse effects were adequately reported in only one study; no difference was found between the statin group compared to placebo. Analysis of currently available data did not suggest that preoperative statin use is associated with decreased incidence of AKI in adults after surgery who required cardiac bypass. Although a significant reduction in SCr was seen postoperatively in people treated with statins, this result was driven by results from a single study, where SCr was considered as a secondary outcome. The results of the meta-analysis should be interpreted with caution; few studies were included in subgroup analyses, and significant differences in methodology exist among the included studies. Large high quality RCTs are required to establish the safety and efficacy of statins to prevent AKI after cardiac surgery.
Nineteen trials involving 10,667 women were included. Risk of bias in trials was difficult to assess accurately due to incomplete reporting. None of the evidence relating to our main outcomes was graded as high quality. The quality of evidence was downgraded due to missing information on trial methods, imprecision in risk estimates and heterogeneity. Eighteen of these studies compared the use of Doppler ultrasound of the umbilical artery of the unborn baby with no Doppler or with cardiotocography (CTG). One more recent trial compared Doppler examination of other fetal blood vessels (ductus venosus) with computerised CTG. The use of Doppler ultrasound of the umbilical artery in high-risk pregnancy was associated with fewer perinatal deaths (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.52 to 0.98, 16 studies, 10,225 babies, 1.2% versus 1.7 %, number needed to treat (NNT) = 203; 95% CI 103 to 4352, evidence graded moderate). The results for stillbirths were consistent with the overall rate of perinatal deaths, although there was no clear difference between groups for this outcome (RR 0.65, 95% CI 0.41 to 1.04; 15 studies, 9560 babies, evidence graded low). Where Doppler ultrasound was used, there were fewer inductions of labour (average RR 0.89, 95% CI 0.80 to 0.99, 10 studies, 5633 women, random-effects, evidence graded moderate) and fewer caesarean sections (RR 0.90, 95% CI 0.84 to 0.97, 14 studies, 7918 women, evidence graded moderate). There was no comparative long-term follow-up of babies exposed to Doppler ultrasound in pregnancy in women at increased risk of complications. No difference was found in operative vaginal births (RR 0.95, 95% CI 0.80 to 1.14, four studies, 2813 women), nor in Apgar scores less than seven at five minutes (RR 0.92, 95% CI 0.69 to 1.24, seven studies, 6321 babies, evidence graded low). Data for serious neonatal morbidity were not pooled due to high heterogeneity between the three studies that reported it (1098 babies) (evidence graded very low). The use of Doppler to evaluate early and late changes in ductus venosus in early fetal growth restriction was not associated with significant differences in any perinatal death after randomisation. However, there was an improvement in long-term neurological outcome in the cohort of babies in whom the trigger for delivery was either late changes in ductus venosus or abnormalities seen on computerised CTG. Current evidence suggests that the use of Doppler ultrasound on the umbilical artery in high-risk pregnancies reduces the risk of perinatal deaths and may result in fewer obstetric interventions. The results should be interpreted with caution, as the evidence is not of high quality. Serial monitoring of Doppler changes in ductus venosus may be beneficial, but more studies of high quality with follow-up including neurological development are needed for evidence to be conclusive.
We identified nine RCTs (587 participants) for inclusion in the review, of which three studies were found at this update. The sequence generation was inadequate in one study and not described in three studies. We performed two meta-analyses to evaluate the clinical (3 trials, 261 participants) and neurophysiological (2 trials, 101 participants) outcomes of simple decompression versus decompression with submuscular or subcutaneous transposition; four trials in total examined this comparison. We found no difference between simple decompression and transposition of the ulnar nerve for both clinical improvement (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08; moderate-quality evidence) and neurophysiological improvement (mean difference (in m/s) 1.47, 95% CI -0.94 to 3.87). The number of participants to clinically improve was 91 out of 131 in the simple decompression group and 97 out of 130 in the transposition group. Transposition showed a higher number of wound infections (RR 0.32, 95% CI 0.12 to 0.85; moderate-quality evidence). In one trial (47 participants), the authors compared medial epicondylectomy with anterior transposition and found no difference in clinical and neurophysiological outcomes. In one trial (48 participants), the investigators compared subcutaneous transposition with submuscular transposition and found no difference in clinical outcomes. In one trial (54 participants for 56 nerves treated), the authors found no difference between endoscopic and open decompression in improving clinical function. One trial (51 participants) assessed conservative treatment in clinically mild or moderate UNE. Based on low-quality evidence, the trial authors found that information on avoiding prolonged movements or positions was effective in improving subjective discomfort. Night splinting and nerve gliding exercises in addition to information provision did not result in further improvement. One trial (55 participants) assessed the effectiveness of corticosteroid injection and found no difference versus placebo in improving symptoms at three months' follow-up. We found only two studies of treatment of ulnar neuropathy using conservative treatment as the comparator. The available comparative treatment evidence is not sufficient to support a multiple treatment meta-analysis to identify the best treatment for idiopathic UNE on the basis of clinical, neurophysiological, and imaging characteristics. We do not know when to treat a person with this condition conservatively or surgically. Moderate-quality evidence indicates that simple decompression and decompression with transposition are equally effective in idiopathic UNE, including when the nerve impairment is severe. Decompression with transposition is associated with more deep and superficial wound infections than simple decompression, also based on moderate-quality evidence. People undergoing endoscopic surgery were more likely to have a haematoma. Evidence from one small RCT of conservative treatment showed that in mild cases, information on movements or positions to avoid may reduce subjective discomfort.
We included 10 trials with a total of 3417 women randomised. Seven of these trials, recruiting 2629 women, contributed data to the review. However, results for all outcomes were based on single studies. There was limited evidence for the primary outcomes of reduction of episodes of violence (physical, sexual, and/or psychological) and prevention of violence during and up to one year after pregnancy (as defined by the authors of trials). In one study, women who received the intervention reported fewer episodes of partner violence during pregnancy and in the postpartum period (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.43 to 0.88, 306 women, moderate quality). Groups did not differ for Conflict Tactics Score - the mean partner abuse scores in the first three months postpartum (mean difference (MD) 4.20 higher, 95% CI -10.74 to 19.14, one study, 46 women, very low quality). The Current Abuse Score for partner abuse in the first three months was also similar between groups (MD -0.12 lower, 95% CI -0.31 lower to 0.07 higher, one study, 191 women, very low quality). Evidence for the outcomes episodes of partner abuse during pregnancy or episodes during the first three months postpartum was not significant (respectively, RR 0.50, 95% CI 0.25 to 1.02, one study with 220 women, very low quality; and RR 0.60, 95% CI 0.35 to 1.04, one study, 271 women, very low quality). Finally, the risk for low birthweight (< 2500 g) did not differ between groups (RR 0.74, 95 % CI 0.41 to 1.32, 306 infants, low quality). There were few statistically significant differences between intervention and control groups for depression during pregnancy and the postnatal period. Only one study reported findings for neonatal outcomes such as preterm delivery and birthweight, and there were no clinically significant differences between groups. None of the studies reported results for other secondary outcomes: Apgar score less than seven at one minute and five minutes, stillbirth, neonatal death, miscarriage, maternal mortality, antepartum haemorrhage, and placental abruption. There is insufficient evidence to assess the effectiveness of interventions for domestic violence on pregnancy outcomes. There is a need for high-quality, RCTs with adequate statistical power to determine whether intervention programs prevent or reduce domestic violence episodes during pregnancy, or have any effect on maternal and neonatal mortality and morbidity outcomes.
Twelve trials were included (2514 patients, average follow-up six years), 11 using selegiline. The methodological quality was reasonable although concealment of allocation was definitely adequate in only five trials. MAO-B inhibitors were not associated with a significant increase in deaths (odds ratio (OR) 1.12; 95% confidence interval (CI) 0.90 to 1.41). They provided small benefits over control in impairment (weighted mean difference (WMD) for change in motor UPDRS score 3.79 points less with MAO-B inhibitors; 95% CI 2.27 to 5.30) and disability (WMD for change in UPDRS ADL score 1.49 less; 95% CI 0.49 to 2.49) at one year which may not be clinically significant. There was a levodopa-sparing effect with MAO-B inhibitors, which was associated with a significant reduction in motor fluctuations (OR 0.73; 95% CI 0.58 to 0.91) but not dyskinesia (OR 0.96; 95% CI 0.76 to 1.22). The reduction in motor fluctuations was, however, not robust in sensitivity analyses. There was a trend to more withdrawals due to adverse events with MAO-B inhibitors (OR 1.72; 95% CI 0.98 to 3.01). MAO-B inhibitors (more specifically selegiline which contributes most of the data) do not appear to delay disease progression in terms of improved survival but may reduce later motor fluctuations. At present, we do not feel these drugs can be recommended for routine use in the treatment of early Parkinson's disease.
We included 14 RCTs that evaluated a range of interventions across different settings. The study methods were generally poorly described, and consequently all included trials were judged to be at high or unclear risk of selection and reporting bias. Only seven trials reported clinical outcome data which limits our ability to make broad generalizations to different epidemiological settings and cultures. Cutaneous leishmaniasis One four-arm RCT from Afghanistan compared indoor residual spraying (IRS), insecticide-treated bednets (ITNs), and insecticide-treated bedsheets, with no intervention. Over 15 months follow-up, all three insecticide-based interventions had a lower incidence of CL than the control area (IRS: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.38 to 0.97, 2892 participants, moderate quality evidence; ITNs: RR 0.32, 95% CI 0.18 to 0.56, 2954 participants, low quality evidence; ITS: RR 0.34, 95% CI 0.20 to 0.57, 2784 participants, low quality evidence). No difference was detected between the three interventions (low quality evidence). One additional trial of ITNs from Iran was underpowered to show a difference. Insecticide treated curtains were compared with no intervention in one RCT from Venezuela, where there were no CL episodes in the intervention areas over 12 months follow-up compared to 142 in control areas (RR 0.00, 95% CI 0.00 to 0.49, one trial, 2938 participants, low quality evidence). Personal protection using insecticide treated clothing was evaluated by two RCTs in soldiers, but the trials were underpowered to reliably detect effects on the incidence of CL (RR 0.40, 95% CI 0.13 to 1.20, two trials, 558 participants, low quality evidence). Visceral leishmaniasis In a single RCT of ITNs versus no intervention from India and Nepal, the incidence of VL was low in both groups and no difference was detected (RR 0.99, 95% CI 0.46 to 2.15, one trial, 19,810 participants, moderate quality evidence). Two trials from Brazil evaluated the effects of culling infected dogs compared to no intervention or IRS. Although they report a reduction in seroconversion over 18 months follow-up, they did not measure or report effects on clinical disease. Using insecticides to reduce phlebotomine sandfly numbers may be effective at reducing the incidence of CL, but there is insufficient evidence from trials to know whether it is better to spray the internal walls of houses or to treat bednets, curtains, bedsheets or clothing.
The search resulted in 524 potentially relevant articles. Five eligible randomized controlled trials (RCTs) were identified (305 women). Trials using oral tablets, transdermal patches and implants were identified. No trial used gels. One small cross-over trial (11 women, effective sample size 22 women considering cross-over trials) compared oral luteal-phase oestrogen versus placebo. Data were very low quality and unsuitable for analysis, but study authors reported that the intervention was ineffective and might aggravate the symptoms of PMS. They also reported that there were no adverse events. Three studies compared continuous oestrogen with progestogen versus placebo (with or without progestogen). These trials were of reasonable quality, although with a high risk of attrition bias and an unclear risk of bias due to potential carry-over effects in two cross-over trials. Continuous oestrogen had a small to moderate positive effect on global symptom scores (SMD −0.34, 95% CI −0.59 to −0.10, P = 0.005, 3 RCTs, 158 women, effective sample size 267 women, I² = 63%, very low quality evidence). The evidence was too imprecise to determine if the groups differed in withdrawal rates due to adverse effects (RR 0.64, 95% CI 0.26 to 1.58, P = 0.33, 3 RCTs, 196 women, effective sample size 284 women, I² = 0%, very low quality evidence). Similarly, the evidence was very imprecise in measures of specific adverse events, with large uncertainties around the true value of the relative risk. None of the studies reported on long-term risks such as endometrial cancer or breast cancer. One study compared patch dosage (100 vs 200 µg oestrogen, with progestogen in both arms) and had a high risk of performance bias, detection bias and attrition bias. The study did not find evidence that dosage affects global symptoms but there was much uncertainty around the effect estimate (SMD −1.55, 95% CI −8.88 to 5.78, P = 0.68, 1 RCT, 98 women, very low quality evidence). The evidence on rates of withdrawal for adverse events was too imprecise to draw any conclusions (RR 0.70, 95% CI 0.34 to 1.46, P = 0.34, 1 RCT, 107 women, low-quality evidence). However, it appeared that the 100 µg dose might be associated with a lower overall risk of adverse events attributed to oestrogen (RR 0.51, 95% Cl 0.26 to 0.99, P = 0.05, 1 RCT, 107 women, very low quality evidence) with a large uncertainty around the effect estimate. The overall quality of the evidence for all comparisons was very low, mainly due to risk of bias (specifically attrition), imprecision, and statistical and clinical heterogeneity. We found very low quality evidence to support the effectiveness of continuous oestrogen (transdermal patches or subcutaneous implants) plus progestogen, with a small to moderate effect size. We found very low quality evidence from a study based on 11 women to suggest that luteal-phase oral unopposed oestrogen is probably ineffective and possibly detrimental for controlling the symptoms of PMS. A comparison between 200 µg and 100 µg doses of continuous oestrogen was inconclusive with regard to effectiveness, but suggested that the lower dose was less likely to cause side effects. Uncertainty remains regarding safety, as the identified studies were too small to provide definite answers. Moreover, no included trial addressed adverse effects that might occur beyond the typical trial duration of 2-8 months. This suggests the choice of oestrogen dose and mode of administration could be based on an individual woman’s preference and modified according to the effectiveness and tolerability of the chosen regimen.
We included six small trials involving 244 adults with olecranon fractures. Of these, four were RCTs and two were quasi-RCTs; both of were at high risk of selection bias. All six trials were at high risk of performance bias, reflecting lack of blinding, and four trials were at high risk of detection bias. The quality of the evidence for most outcomes was generally very low because of limitations in study design and implementation, and either imprecision of the results or inadequate outcome measures. Thus, we are very uncertain about the estimates of effect. One trial (41 participants) comparing plate fixation with standard tension band wiring provided very low quality evidence at 16 to 86 weeks' follow-up of a better clinical outcome after plate fixation (good outcome (little pain or loss of elbow motion): 19/22 versus 9/19, risk ratio (RR) 1.82 favouring plate fixation, 95% confidence interval (CI) 1.10 to 3.01). There was very low quality evidence of less symptomatic prominent metalwork after plate fixation (1/22 versus 8/19; RR 0.11, 95% CI 0.01 to 0.79). The results for other adverse effects (infection and delayed or non-union) were inconclusive. Evidence is pending from a newly (September 2014) completed trial (67 participants) making the same comparison. Four trials compared four different modified techniques of tension band wiring (i.e. additional intramedullary screw fixation, biodegradable pins, Netz pins and cable pin system) versus standard tension band wiring. There was very low quality evidence of little difference at six to 14 months in function assessed by a non-validated scoring tool from the addition of an intramedullary screw. However, there were fewer cases of metalwork prominence in the intramedullary screw group (1/15 versus 8/15; RR 2.00, 95% CI 1.15 to 3.49; one trial; 30 participants). There was very low quality evidence from one trial (25 participants) of little difference in subjectively or objectively assessed good outcome at a mean of 20 months between tension band wiring with biodegradable implants versus metal implants. There were no adverse events, either non-union or sinus or fluid accumulation, reported. All 10 participants in the metalwork group had an extra operation to remove their metalwork at one year. One trial, which did not report on function or pain, provided very low quality evidence of lower rates of metalwork for any reason or for symptoms after Netz pin tension band wiring compared with standard tension band wiring (11/21 with Netz pin versus 17/25 with standard tension band wiring; RR 0.77, 95% CI 0.47 to 1.26; 46 participants); this evidence also supports the possibility of higher rates of metalwork removal for Netz pins. Two intra-operative complications occurred in the Netz pin group. The fourth trial, which compared the cable pin system with standard procedure, found low quality evidence that cable pin improved functional outcome at a mean of 21 months (Mayo Elbow Performance Score (MEPS), range 0 to 100: best outcome: mean difference (MD) 7.89 favouring cable pin, 95% CI 3.14 to 12.64; one trial; 62 participants). It also found low quality evidence of fewer postoperative complications in the cable pin group (1/30 with cable pin system versus 7/32 standard tension band wiring; RR 0.15, 95% CI 0.02 to 1.17), although the evidence did not rule out the converse. One trial provided very low quality evidence of similar patient-reported function using the Disabilities of the Arm, Shoulder and Hand questionnaire (0 to 100: worst function) at two or more years after fixation using a novel olecranon memory connector (OMC) compared with locking plate fixation (MD -0.70 favouring OMC, 95% CI -4.20 to 2.80; 40 participants). The only adverse event was a superficial infection in the locking plate group. There is insufficient evidence to draw robust conclusions on the relative effects of the surgical interventions evaluated by the included trials. Further evidence, including patient-reported data, on the relative effects of plate versus tension band wiring is already pending from one recently completed RCT. Further RCTs, using good quality methods and reporting validated patient-reported measures of function, pain and activities of daily living at set follow-ups, are needed, including checking positive findings such as those relating to the use of an intramedullary screw and the cable pin system. Such trials should also include the systematic assessment of complications, further treatment including routine removal of metalwork and use of resources.
Thirty-four trials (3230 participants) were included. Meta-analysis showed that the mean change in urinary sodium (reduced salt vs usual salt) was -75 mmol/24-h (equivalent to a reduction of 4.4 g/d salt), the mean change in BP was -4.18 mmHg (95% CI: -5.18 to -3.18, I2=75%) for systolic and -2.06 mmHg (95% CI: -2.67 to -1.45, I2=68%) for diastolic BP. Meta-regression showed that age, ethnic group, BP status (hypertensive or normotensive) and the change in 24-h urinary sodium were all significantly associated with the fall in systolic BP, explaining 68% of the variance between studies. A 100 mmol reduction in 24 hour urinary sodium (6 g/day salt) was associated with a fall in systolic BP of 5.8 mmHg (95%CI: 2.5 to 9.2, P=0.001) after adjusting for age, ethnic group and BP status. For diastolic BP, age, ethnic group, BP status and the change in 24-h urinary sodium explained 41% of the variance between studies. Meta-analysis by subgroup showed that, in hypertensives, the mean effect was -5.39 mmHg (95% CI: -6.62 to -4.15, I2=61%) for systolic and -2.82 mmHg (95% CI: -3.54 to -2.11, I2=52%) for diastolic BP. In normotensives, the mean effect was -2.42 mmHg (95% CI: -3.56 to -1.29, I2=66%) for systolic and -1.00 mmHg (95% CI: -1.85 to -0.15, I2=66%) for diastolic BP. Further subgroup analysis showed that the decrease in systolic BP was significant in both whites and blacks, men and women. Meta-analysis of hormone and lipid data showed that the mean effect was 0.26 ng/ml/hr (95% CI: 0.17 to 0.36, I2=70%) for plasma renin activity, 73.20 pmol/l (95% CI: 44.92 to 101.48, I2=62%) for aldosterone, 31.67 pg/ml (95% CI: 6.57 to 56.77, I2=5%) for noradrenaline, 6.70 pg/ml (95% CI: -0.25 to 13.64, I2=12%) for adrenaline, 0.05 mmol/l (95% CI: -0.02 to 0.11, I2=0%) for cholesterol, 0.05 mmol/l (95% CI: -0.01 to 0.12, I2=0%) for LDL, -0.02 mmol/l (95% CI: -0.06 to 0.01, I2=16%) for HDL, and 0.04 mmol/l (95% CI: -0.02 to 0.09, I2=0%) for triglycerides. A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. With salt reduction, there is a small physiological increase in plasma renin activity, aldosterone and noradrenaline. There is no significant change in lipid levels. These results provide further strong support for a reduction in population salt intake. This will likely lower population BP and, thereby, reduce cardiovascular disease. Additionally, our analysis demonstrates a significant association between the reduction in 24-h urinary sodium and the fall in systolic BP, indicating the greater the reduction in salt intake, the greater the fall in systolic BP. The current recommendations to reduce salt intake from 9-12 to 5-6 g/d will have a major effect on BP, but are not ideal. A further reduction to 3 g/d will have a greater effect and should become the long term target for population salt intake.
Investigators included 6201 participants in the 51 included trials. Twenty studies included only children, two included only preschool children and ten only adolescents; all others included both children and adolescents. Participants were exposed to sexual abuse in 12 trials, to war or community violence in ten, to physical trauma and natural disaster in six each and to interpersonal violence in three; participants had suffered a life-threatening illness and had been physically abused or maltreated in one trial each. Participants in remaining trials were exposed to a range of traumas. Most trials compared a psychological therapy with a control such as treatment as usual, wait list or no treatment. Seventeen trials used cognitive-behavioural therapy (CBT); four used family therapy; three required debriefing; two trials each used eye movement desensitisation and reprocessing (EMDR), narrative therapy, psychoeducation and supportive therapy; and one trial each provided exposure and CBT plus narrative therapy. Eight trials compared CBT with supportive therapy, two compared CBT with EMDR and one trial each compared CBT with psychodynamic therapy, exposure plus supportive therapy with supportive therapy alone and narrative therapy plus CBT versus CBT alone. Four trials compared individual delivery of psychological therapy to a group model of the same therapy, and one compared CBT for children versus CBT for both mothers and children. The likelihood of being diagnosed with PTSD in children and adolescents who received a psychological therapy was significantly reduced compared to those who received no treatment, treatment as usual or were on a waiting list for up to a month following treatment (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.34 to 0.77; number needed to treat for an additional beneficial outcome (NNTB) 6.25, 95% CI 3.70 to 16.67; five studies; 874 participants). However the overall quality of evidence for the diagnosis of PTSD was rated as very low. PTSD symptoms were also significantly reduced for a month after therapy (standardised mean difference (SMD) -0.42, 95% CI -0.61 to -0.24; 15 studies; 2051 participants) and the quality of evidence was rated as low. These effects of psychological therapies were not apparent over the longer term. CBT was found to be no more or less effective than EMDR and supportive therapy in reducing diagnosis of PTSD in the short term (OR 0.74, 95% CI 0.29 to 1.91; 2 studies; 160 participants), however this was considered very low quality evidence. For reduction of PTSD symptoms in the short term, there was a small effect favouring CBT over EMDR, play therapy and supportive therapies (SMD -0.24, 95% CI -0.42 to -0.05; 7 studies; 466 participants). The quality of evidence for this outcome was rated as moderate. We did not identify any studies that compared pharmacological therapies with psychological therapies. The meta-analyses in this review provide some evidence for the effectiveness of psychological therapies in prevention of PTSD and reduction of symptoms in children and adolescents exposed to trauma for up to a month. However, our confidence in these findings is limited by the quality of the included studies and by substantial heterogeneity between studies. Much more evidence is needed to demonstrate the relative effectiveness of different psychological therapies for children exposed to trauma, particularly over the longer term. High-quality studies should be conducted to compare these therapies.
In the initial review, we included one ITS study that evaluated a targeted educational intervention aimed at reducing the incidence of wrong-site tooth extractions. The intervention included examination of previous cases of wrong-site tooth extractions, educational intervention including a presentation of cases of erroneous extractions, explanation of relevant clinical guidelines and feedback by an instructor. Data were reported from all patients on the surveillance system of a University Medical centre in Taiwan with a total of 24,406 tooth extractions before the intervention and 28,084 tooth extractions after the intervention. We re-analysed the data using the Prais-Winsten time series and the change in level for annual number of mishaps was statistically significant at -4.52 (95% confidence interval (CI) -6.83 to -2.217) (standard error (SE) 0.5380). The change in slope was statistically significant at -1.16 (95% CI -2.22 to -0.10) (SE 0.2472; P < 0.05). This update includes an additional study reporting on the incidence of neurological WSS at a university hospital both before and after the Universal Protocol’s implementation. A total of 22,743 patients undergoing neurosurgical procedures at the University of Illionois College of Medicine at Peoria, Illinois, United States of America were reported. Of these, 7286 patients were reported before the intervention and 15,456 patients were reported after the intervention. The authors found a significant difference (P < 0.001) in the incidence of WSS between the before period, 1999 to 2004, and the after period, 2005 to 2011.  Similarly, data were re-analysed using Prais-Winsten regression to correct for autocorrelation. As the incidences were reported by year only and the intervention occurred in July 2004, the intervention year 2004 was excluded from the analysis. The change in level at the point the intervention was introduced was not statistically significant at -0.078 percentage points (pp) (95% CI -0.176 pp to 0.02 pp; SE 0.042; P = 0.103). The change in slope was statistically significant at 0.031 (95% CI 0.004 to 0.058; SE 0.012; P < 0.05). The findings of this update added one additional ITS study to the previous review which contained one ITS study. The original review suggested that the use of a specific educational intervention in the context of a dental outpatient setting, which targets junior dental staff using a training session that included cases of wrong-site surgery, presentation of clinical guidelines and feedback by an instructor, was associated with a reduction in the incidence of wrong-site tooth extractions. The additional study in this update evaluated the annual incidence rates of wrong-site surgery in a neurosurgical population before and after the implementation of the Universal Protocol. The data suggested a strong downward trend in the incidence of wrong-site surgery prior to the intervention with the incidence rate approaching zero. The effect of the intervention in these studies however remains unclear, as data reflect only two small low-quality studies in very specific population groups.
Five studies (182 children) met the inclusion criteria, and four contributed data to at least one meta-analysis. The included studies were overall at low risk of bias, but our confidence in the evidence was generally low, mainly due to the small sample sizes. Treatment with IV MgSO4 reduced the odds of admission to hospital by 68% (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14 to 0.74; children = 115; studies = 3; I2 = 63%). This result was based on data from just three studies including 115 children. Meta-analysis for the secondary outcomes was extremely limited by paucity of data. We performed meta-analysis for the outcome 'return to the emergency department within 48 hours', which showed a very imprecise effect estimate that was not statistically significant (OR 0.40, 95% CI 0.02 to 10.30; children = 85; studies = 2; I2 = 0%). Side effects and adverse events were not consistently reported and meta-analysis was not possible, however few side effects or adverse events were reported. IV MgSO4 may reduce the need for hospital admission in children presenting to the ED with moderate to severe exacerbations of asthma, but the evidence is extremely limited by the number and size of studies. Few side effects of the treatment were reported, but the data were extremely limited.
We included 12 trials (576 participants); 11 had two arms and one had three arms. All assessed topical agents, none looked at systemic antibiotics. The included trials assessed the following antimicrobial agents: povidone iodine, cadexomer iodine, gentian violet, lysozyme, silver dressings, honey, pine resin, polyhexanide, silver sulfadiazine, and nitrofurazone with ethoxy-diaminoacridine. Comparators included a range of other dressings and ointments without antimicrobial properties and alternative antimicrobials. Each comparison had only one trial, participant numbers were low and follow-up times short. The evidence varied from moderate to very low quality. Six trials reported the primary outcome of wound healing. All except one compared an antiseptic with a non-antimicrobial comparator. There was some moderate and low quality evidence that fewer ulcers may heal in the short term when treated with povidone iodine compared with non-antimicrobial alternatives (protease-modulating dressings (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.98) and hydrogel (RR 0.64, 95% CI 0.43 to 0.97)); and no clear difference between povidone iodine and a third non-antimicrobial treatment (hydrocolloid) (low quality evidence). Pine resin salve may heal more pressure ulcers than hydrocolloid (RR 2.83, 95% CI 1.14 to 7.05) (low quality evidence). There is no clear difference between cadexomer iodine and standard care, and between honey and a combined antiseptic and antibiotic treatment (very low quality evidence). Six trials reported adverse events (primary safety outcome). Four reported no adverse events; there was very low quality evidence from one showing no clear evidence of a difference between cadexomer iodine and standard care; in one trial it was not clear whether data were appropriately reported. There was limited reporting of secondary outcomes. The five trials that reported change in wound size as a continuous outcome did not report any clear evidence favouring any particular antiseptic/anti-microbial treatments. For bacterial resistance, one trial found some evidence of more MRSA eradication in participants with ulcer treated with a polyhexanide dressing compared with a polyhexanide swab (RR 1.48, 95% CI 1.02 to 2.13); patients in the dressing group also reported less pain (MD −2.03, 95% CI −2.66 to −1.40). There was no clear evidence of a difference between interventions in infection resolution in three other comparisons. Evidence for secondary outcomes varied from moderate to very low quality; where no GRADE assessment was possible we identified substantial limitations which an assessment would have taken into account. The relative effects of systemic and topical antimicrobial treatments on pressure ulcers are not clear. Where differences in wound healing were found, these sometimes favoured the comparator treatment without antimicrobial properties. The trials are small, clinically heterogenous, generally of short duration, and at high or unclear risk of bias. The quality of the evidence ranges from moderate to very low; evidence on all comparisons was subject to some limitations.
Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence but all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome. No significant effect of any of the treatments was seen compared to placebo. Immediate side effects were not found to be significantly different from placebo in the two trials where this information was reported. We considered the quality of evidence to be low to very low as all of the trials were at risk of bias and all had low participant numbers. There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.
Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed. Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha2-adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine. Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient without indicating the level of care provided. The included studies were heterogeneous in terms of the type of opioid antagonist treatment regimen, the comparator, the outcome measures assessed, and the means of assessing outcomes. As a result, the validity of any estimates of overall effect is doubtful, therefore we did not calculate pooled results for any of the analyses. The quality of the evidence for treatment with an opioid antagonist-adrenergic agonist combination versus an alpha2-adrenergic agonist is very low. Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity over the period of withdrawal. Peak withdrawal induced by opioid antagonists in combination with an adrenergic agonist appears to be more severe than withdrawal managed with clonidine or lofexidine alone, but the average severity over the withdrawal period is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of treatment completion compared to withdrawal managed with adrenergic agonists. However, this result was not consistent across studies, and the extent of any benefit is highly uncertain. We could not extract any data on the occurrence of adverse events, but two studies reported delirium or confusion following the first dose of naltrexone. Delirium may be more likely with higher initial doses and with naltrexone rather than naloxone (which has a shorter half-life), but we could not confirm this from the available evidence. Insufficient data were available to make any conclusions on the best duration of treatment. Using opioid antagonists plus alpha2-adrenergic agonists is a feasible approach for managing opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist. A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium. Using opioid antagonists to induce and accelerate opioid withdrawal is not currently an active area of research or clinical practice, and the research community should give greater priority to investigating approaches, such as those based on buprenorphine, that facilitate the transition to sustained-release preparations of naltrexone.